Slow inward currents are known as neuronal excitatory currents mediated by glutamate release and activation of neuronal extra synaptic N-met hyl-D-aspartate receptors with the contribution of astrocytes.These events a...Slow inward currents are known as neuronal excitatory currents mediated by glutamate release and activation of neuronal extra synaptic N-met hyl-D-aspartate receptors with the contribution of astrocytes.These events are significantly slower than the excitatory postsynaptic currents.Parameters of slow inward currents are determined by seve ral factors including the mechanisms of astrocytic activation and glutamate release,as well as the diffusion pathways from the release site towards the extra synaptic recepto rs.Astrocytes are stimulated by neuronal network activity,which in turn excite neurons,forming an astrocyte-neuron feedback loop.Mostly as a consequence of brain edema,astrocytic swelling can also induce slow inward currents under pathological conditions.There is a growing body of evidence on the roles of slow inward currents on a single neuron or local network level.These events often occur in synchro ny on neurons located in the same astrocytic domain.Besides synchronization of neuronal excitability,slow inward currents also set synaptic strength via eliciting timing-dependent synaptic plasticity.In addition,slow inward currents are also subject to non-synaptic plasticity triggered by long-la sting stimulation of the excitatory inputs.Of note,there might be important regionspecific differences in the roles and actions triggering slow inward currents.In greater networks,the pathophysiological roles of slow inward currents can be better understood than physiological ones.Slow inward currents are identified in the pathophysiological background of autism,as slow inward currents drive early hypersynchrony of the neural networks.Slow inward currents are significant contributors to paroxysmal depolarizational shifts/interictal spikes.These events are related to epilepsy,but also found in Alzheimer's disease,Parkinson's disease,and stroke,leading to the decline of cognitive functions.Events with features overlapping with slow inward currents(excitatory,N-methyl-Daspartate-receptor mediated currents with astrocytic contribution) as ischemic currents and spreading depolarization also have a well-known pathophysiological role in worsening consequences of stroke,traumatic brain injury,or epilepsy.One might assume that slow inward currents occurring with low frequency under physiological conditions might contribute to synaptic plasticity and memory formation.However,to state this,more experimental evidence from greater neuronal networks or the level of the individual is needed.In this review,I aimed to summarize findings on slow inward currents and to speculate on the potential functions of it.展开更多
Drought is one of the abiotic stresses limiting the production of soybean(Glycine max).Elucidation of the genetic and molecular basis of the slow-wilting(SW)trait of this crop offers the prospect of its genetic improv...Drought is one of the abiotic stresses limiting the production of soybean(Glycine max).Elucidation of the genetic and molecular basis of the slow-wilting(SW)trait of this crop offers the prospect of its genetic improvement.A panel of 188 accessions and a set of recombinant inbred lines produced from a cross between cultivars Liaodou 14 and Liaodou 21 were used to identify quantitative-trait loci(QTL)associated with SW.Plants were genotyped by Specific-locus amplified fragment sequencing and seedling leaf wilting was assessed under three water-stress treatments.A genome-wide association study identified 26 SW-associated single-nucleotide polymorphisms(SNPs),including three located in a 248-kb linkage-disequilibrium(LD)block on chromosome 2.Linkage mapping revealed a major-effect QTL,qSW2,associated with all three treatments and adjacent to the LD block.Fine mapping in a BC_(2)F_(3) population derived from a backcross between Liaodou 21 and R26 confined qSW2 to a 60-kb interval.Gene expression and sequence variation analysis identified the gene Glyma.02 g218100,encoding an auxin transcription factor,as a candidate gene for qSW2.Our results will contribute significantly to improving drought-resistant soybean cultivars by providing genetic information and resources.展开更多
In the coal-to-ethylene glycol(CTEG)process,precisely estimating quality variables is crucial for process monitoring,optimization,and control.A significant challenge in this regard is relying on offline laboratory ana...In the coal-to-ethylene glycol(CTEG)process,precisely estimating quality variables is crucial for process monitoring,optimization,and control.A significant challenge in this regard is relying on offline laboratory analysis to obtain these variables,which often incurs substantial monetary costs and significant time delays.The resulting few-shot learning scenarios present a hurdle to the efficient development of predictive models.To address this issue,our study introduces the transferable adversarial slow feature extraction network(TASF-Net),an innovative approach designed specifically for few-shot quality prediction in the CTEG process.TASF-Net uniquely integrates the slowness principle with a deep Bayesian framework,effectively capturing the nonlinear and inertial characteristics of the CTEG process.Additionally,the model employs a variable attention mechanism to identify quality-related input variables adaptively at each time step.A key strength of TASF-Net lies in its ability to navigate the complex measurement noise,outliers,and system interference typical in CTEG data.Adversarial learning strategy using a min-max game is adopted to improve its robustness and ability to model irregular industrial data accurately and significantly.Furthermore,an incremental refining transfer learning framework is designed to further improve few-shot prediction performance achieved by transferring knowledge from the pretrained model on the source domain to the target domain.The effectiveness and superiority of TASF-Net have been empirically validated using a real-world CTEG dataset.Compared with some state-of-the-art methods,TASF-Net demonstrates exceptional capability in addressing the intricate challenges for few-shot quality prediction in the CTEG process.展开更多
Rock fracture warning is one of the significant challenges in rock mechanics.Many true triaxial and synchronous acoustic emission(AE)tests were conducted on granite samples.The investigation focused on the characteris...Rock fracture warning is one of the significant challenges in rock mechanics.Many true triaxial and synchronous acoustic emission(AE)tests were conducted on granite samples.The investigation focused on the characteristics of AE signals preceding granite fracture,based on the critical slowing down(CSD)theory.The granite undergoes a transition from the stable phase to the fracture phase and exhibits a clear CSD phenomenon,characterized by a pronounced increase in variance and autocorrelation coefficient.The variance mutation points were found to be more identifiable and suitable as the primary criterion for predicting precursor information related to granite fracture,compared to the autocorrelation coefficient.It is noteworthy to emphasize that the CSD factor holds greater potential in elucidating the underlying mechanisms responsible for the critical transition of granite fracture,in comparison to the AE timing parameters.Furthermore,a novel multi-parameter collaborative prediction method for rock fracture was developed by comprehensively analyzing predictive information,including abnormal variation modes and the CSD factor of AE characteristic parameters.This method enhances the understanding and prediction of rock fracture-related geohazards.展开更多
Laparoscopic colectomy with ileorectal anastomosis may be beneficial for patients with slow transit constipation who do not respond to conservative treatment,particularly if the superior rectal artery(SRA)is preserved...Laparoscopic colectomy with ileorectal anastomosis may be beneficial for patients with slow transit constipation who do not respond to conservative treatment,particularly if the superior rectal artery(SRA)is preserved.Several important concerns have been addressed in this commentary.It is important to first go over the definition of surgical procedure as it is used in this text.Second,the current study lacked a control group that had SRA preservation.Thirdly,it would be best to use a prospective,randomized controlled study.Lastly,a description of the mesenteric defect’s state following a laparoscopic colectomy is necessary.展开更多
The continuous change of communica-tion frequency brings difficulties to the reconnaissance and prediction of non-cooperative communication net-works.Since the frequency-hopping(FH)sequence is usually generated by a c...The continuous change of communica-tion frequency brings difficulties to the reconnaissance and prediction of non-cooperative communication net-works.Since the frequency-hopping(FH)sequence is usually generated by a certain model with certain regularity,the FH frequency is thus predictable.In this paper,we investigate the FH frequency reconnais-sance and prediction of a non-cooperative communi-cation network by effective FH signal detection,time-frequency(TF)analysis,wavelet detection and fre-quency estimation.With the intercepted massive FH signal data,long short-term memory(LSTM)neural network model is constructed for FH frequency pre-diction.Simulation results show that our parameter es-timation methods could estimate frequency accurately in the presence of certain noise.Moreover,the LSTM-based scheme can effectively predict FH frequency and frequency interval.展开更多
High resolution range imaging with correlation processing suffers from high sidelobe pedestal in random frequency-hopping wideband radar. After the factors which affect the sidelobe pedestal being analyzed, a compress...High resolution range imaging with correlation processing suffers from high sidelobe pedestal in random frequency-hopping wideband radar. After the factors which affect the sidelobe pedestal being analyzed, a compressed sensing based algorithm for high resolution range imaging and a new minimized ll-norm criterion for motion compensation are proposed. The random hopping of the transmitted carrier frequency is converted to restricted isometry property of the observing matrix. Then practical problems of imaging model solution and signal parameter design are resolved. Due to the particularity of the proposed algorithm, two new indicators of range profile, i.e., average signal to sidelobe ratio and local similarity, are defined. The chamber measured data are adopted to testify the validity of the proposed algorithm, and simulations are performed to analyze the precision of velocity measurement as well as the performance of motion compensation. The simulation results show that the proposed algorithm has such advantages as high precision velocity measurement, low sidelobe and short period imaging, which ensure robust imaging for moving targets when signal-to-noise ratio is above 10 dB.展开更多
A new Frequency-Hopping(FH) signal detection method is proposed.Different from pre-vious methods which need to monitor the total band,it can monitor part of the band and decrease the range of the bandwidth.According t...A new Frequency-Hopping(FH) signal detection method is proposed.Different from pre-vious methods which need to monitor the total band,it can monitor part of the band and decrease the range of the bandwidth.According to this method,a new detection model is set and the computation formulas of the detection probability and false-alarm probability are given.The parameters of a VHF radio are used to prove the validity of the method.Simulation results show that this method can de-crease the range of the bandwidth and detect the FH signal with some penalty on the SNR and signal loss.展开更多
We theoretically explore the tunability of magnomechanically induced transparency(MMIT) phenomenon and fastslow light effect in a hybrid cavity magnomechanical system in which a high-quality yttrium iron garnet(YIG) s...We theoretically explore the tunability of magnomechanically induced transparency(MMIT) phenomenon and fastslow light effect in a hybrid cavity magnomechanical system in which a high-quality yttrium iron garnet(YIG) sphere and an atomic ensemble are placed inside a microwave cavity. In the probe output spectrum, we can observe magnoninduced transparency(MIT) and MMIT due to the photon-magnon and phonon-magnon couplings. We further investigate the effect of atomic ensemble on the absorption spectrum. The results show that better transparency can be obtained by choosing appropriate atomic ensemble parameters. We give an explicit explanation for the mechanism of the Fano resonance phenomenon. Moreover, we discuss phenomena of slow-light propagation. The maximum group delay increases significantly with the increasing atom–cavity coupling strength, and the conversion between slow light and fast light can also be achieved by adjusting the atom–cavity coupling strength. These results may have potential applications for quantum information processing and high precision measurements.展开更多
BACKGROUND Impaired interstitial cells of Cajal(ICCs)are central to the pathophysiology of acute cholecystitis(AC).Common bile duct ligation is a common model of AC,producing acute inflammatory changes and decrease in...BACKGROUND Impaired interstitial cells of Cajal(ICCs)are central to the pathophysiology of acute cholecystitis(AC).Common bile duct ligation is a common model of AC,producing acute inflammatory changes and decrease in gallbladder contractility.AIM To investigate the origin of slow wave(SW)in the gallbladder and the effect of ICCs on gallbladder contractions during the process of AC.METHODS Methylene blue(MB)with light was used to establish selective impaired ICCs gallbladder tissue.Gallbladder motility was assessed using the frequency of SW and gallbladder muscle contractility in vitro in normal control(NC),AC12h,AC24h,and AC48h groups of guinea pigs.Hematoxylin and eosin and Massonstained gallbladder tissues were scored for inflammatory changes.ICCs pathological changes alterations were estimated using immunohistochemistry and transmission electron microscopy.The alterations of c-Kit,α-SMA,cholecystokinin A receptor(CCKAR),and connexin 43(CX43)were assessed using Western blot.RESULTS Impaired ICCs muscle strips resulted in the decrease in gallbladder SW frequency and contractility.The frequency of SW and gallbladder contractility were significantly lower in the AC12h group.Compared with the NC group,the density and ultrastructure of ICCs were remarkably impaired in the AC groups,especially in the AC12h group.The protein expression levels of c-Kit were significantly decreased in the AC12h group,while CCKAR and CX43 protein expression levels were significantly decreased in the AC48h group.CONCLUSION Loss ICCs could lead to a decrease in gallbladder SW frequency and contractility.The density and ultrastructure of ICCs were clearly impaired in the early stage of AC,while CCKAR and CX43 were significantly reduced at end stage.展开更多
BACKGROUND Slow transit constipation(STC)is a disorder with delayed colonic transit.Cinnamic acid(CA)is an organic acid in natural plants,such as Radix Scrophulariae(Xuan Shen),with low toxicity and biological activit...BACKGROUND Slow transit constipation(STC)is a disorder with delayed colonic transit.Cinnamic acid(CA)is an organic acid in natural plants,such as Radix Scrophulariae(Xuan Shen),with low toxicity and biological activities to modulate the intestinal microbiome.AIM To explore the potential effects of CA on the intestinal microbiome and the primary endogenous metabolites-short-chain fatty acids(SCFAs)and evaluate the therapeutic effects of CA in STC.METHODS Loperamide was applied to induce STC in mice.The treatment effects of CA on STC mice were assessed from the 24 h defecations,fecal moisture and intestinal transit rate.The enteric neurotransmitters:5-hydroxytryptamine(5-HT)and vasoactive intestinal peptide(VIP)were determined by the enzyme-linked immunosorbent assay.Hematoxylin-eosin and Alcian blue and Periodic acid Schiff staining were used to evaluate intestinal mucosa's histopathological performance and secretory function.16S rDNA was employed to analyze the composition and abundance of the intestinal microbiome.The SCFAs in stool samples were quantitatively detected by gas chromatography-mass spectrometry.RESULTS CA ameliorated the symptoms of STC and treated STC effectively.CA ameliorated the infiltration of neutrophils and lymphocytes,increased the number of goblet cells and acidic mucus secretion of the mucosa.In addition,CA significantly increased the concentration of 5-HT and reduced VIP.CA significantly improved the diversity and abundance of the beneficial microbiome.Furthermore,the production of SCFAs[including acetic acid(AA),butyric acid(BA),propionic acid(PA)and valeric acid(VA)]was significantly promoted by CA.The changed abundance of Firmicutes,Akkermansia,Lachnoclostridium,Monoglobus,UCG.005,Paenalcaligenes,Psychrobacter and Acinetobacter were involved in the production of AA,BA,PA and VA.CONCLUSION CA could treat STC effectively by ameliorating the composition and abundance of the intestinal microbiome to regulate the production of SCFAs.展开更多
Previous studies have shown that the bulk topology of single-particle systems can be captured by the band inversion surface or by the spin inversion surface emerging on the time-averaged spin polarization.Most of the ...Previous studies have shown that the bulk topology of single-particle systems can be captured by the band inversion surface or by the spin inversion surface emerging on the time-averaged spin polarization.Most of the studies,however,are based on the single-particle picture even though the systems are fermionic and multi-bands.Here,we study the slow quench dynamics of topological systems with all the valence bands fully occupied,and show that the concepts of band inversion surface and spin inversion surface are still valid.More importantly,the many-particle nonadiabatic quench dynamics is shown to be reduced to a new and nontrivial three-level Landau-Zener model.This nontrivial three-level Landau-Zener problem is then solved analytically by applying the integrability condition and symmetry considerations,and thus adds a new member to the few models that are exactly solvable.Based on the analytical results,the topological spin texture revealed by the time-averaged spin polarization can be applied to characterize the bulk topology and thus provides a direct comparison for future experiments.展开更多
The slow traffic system is an important component of urban transportation,and the prerequisite and necessary condition for Beijing to continue promoting“green priority”are establishing a good urban slow traffic syst...The slow traffic system is an important component of urban transportation,and the prerequisite and necessary condition for Beijing to continue promoting“green priority”are establishing a good urban slow traffic system.Shijingshan District of Beijing City is taken as a research object.By analyzing and processing population distribution data,POI data,and shared bicycle data,the shortcomings and deficiencies of the current slow traffic system in Shijingshan District are explored,and corresponding solutions are proposed,in order to provide new ideas and methods for future urban planning from the perspective of data.展开更多
[Objectives] This study was carried out to explore the combined effects of Fu Zi(Radix Aconiti Lateralis Praeparata, the secondary root of perennial herbaceous plant Acontium carmichaeli Dehx. of family Ranunculaceae)...[Objectives] This study was carried out to explore the combined effects of Fu Zi(Radix Aconiti Lateralis Praeparata, the secondary root of perennial herbaceous plant Acontium carmichaeli Dehx. of family Ranunculaceae) and Rou Gui(Cortex Cinnamomi, the bark of Cinnamamunz cassia Presl of family Lauraceae) on intestinal neurotransmitters and microflora in rats with slow transit constipation(STC). [Methods] Experimental rats were given loperamide hydrochloride by gavage to induce STC, and then treated with Fu Zi alone, Rou Gui alone, a combination of Fu Zi and Rou Gui(2:1 w/w), and prucalopride, respectively, for 14 days. Meanwhile, the general condition, the time to first black stool and the rate of intestinal propulsion of rats in each group were observed after STC was induced and after drug treatment, and the pathological changes in rat colon were observed via hematoxylin-eosin(HE) staining, and the levels of colonic 5-hydroxytryptamine(HT), vasoactive intestinal peptide(VIP) and substance P(SP) were detected by ELISA, and the changes in intestinal flora were detected by 16S rRNA Real-time PCR. [Results] Compared with healthy rats, the time to first black stool and the rate of intestinal propulsion, colonic 5-HT and SP levels significantly decreased(p<0.01), while their colonic VIP level significantly increased(p<0.01). Compared with STC rats, the time to first black stool, the rate of intestinal propulsion, colonic 5-HT and SP levels in Fu Zi-Rou Gui(2:1) treated rats and prucalopride treated rats significantly increased(p<0.01), while their colonic VIP level significantly decreased(p<0.01). There was no significant difference in alpha diversity between healthy rats and STC rats. However, analysis on beta diversity revealed that there were differences in microflora structure and composition between them. Compared with healthy rats, the relative abundance of Firmicutes and Proteobacteria in STC rats significantly increased, while that of Bacteroidetes decreased. Compared with STC rats, the relative abundance of Proteobacteria decreased and that of Bacteroidetes and Firmicutes increased in Fu Zi-Rou Gui(2:1) treated rats;the relative abundance of Bacteroidetes and Proteobacteria decreased while that of Firmicutes increased in Fu Zi treated rats;the relative abundance of Proteobacteria decreased while that of Bacteroidetes increased in Rou Gui treated rats;the relative abundance of Firmicutes and Proteobacteria decreased while that of Bacteroidetes increased in prucalopride treated rats. The intestinal flora in rats of all groups was dominated by Lactobacillus spp. and other genera of anaerobic bacteria. Compared with healthy rats, the relative abundance of Lactobacillus spp. and Clostridium spp. in STC rats decreased, while those of Blautia spp. and Ruminococcus spp. and Allobaculum spp. increased. Compared with STC rats, the relative abundance of Lactobacillus spp. in all rats treated with drugs increased. [Conclusions] The combination of Fu Zi and Rou Gui(2:1) can effectively improve intestinal motility in STC rats by regulating intestinal microbial community and the levels of colonic neurotransmitters.展开更多
To build an“ecological and livable city”,it is important to figure out the relationship between human activity and urban park space and create a high-quality urban park through the integration of“people”and“park...To build an“ecological and livable city”,it is important to figure out the relationship between human activity and urban park space and create a high-quality urban park through the integration of“people”and“park”.Taking Longhu Park in Huainan Province as an example,the study quantitatively analyzed and evaluated the characteristics and service quality of slow traffic space using importance-performance analysis(IPA)and space syntax,clarified the key indexes and areas to be optimized,and put forward corresponding design countermeasures and suggestions in combination with human activity demand.The results suggest that:①The mean performance of park recreation service quality is 3.63,less than the mean importance(3.95).Tourists pay special attention to the safety and convenience of slow traffic space,and the diversity and identiability of site functions is the focus“to be improved”.②The accessibility of Longhu Park shows a strong irregular shape in the southwest.The dead-end roads in the far lake area and the flora and fauna area on the northwest side have weak spatial perception,and the composite function carrying potential of slow traffic space is better reflected in a small range.Therefore,an optimization strategy for slow traffic space is proposed to enhance the continuity of road network,site identifiability,and functional diversification.The results will provide new thoughts of governance based on spatial humanism for the high-quality renewal of urban parks in the new era.展开更多
BACKGROUND Cognitive dysfunction in epileptic patients is a high-incidence complication.Its mechanism is related to nervous system damage during seizures,but there is no effective diagnostic biomarker.Neuronal pentrax...BACKGROUND Cognitive dysfunction in epileptic patients is a high-incidence complication.Its mechanism is related to nervous system damage during seizures,but there is no effective diagnostic biomarker.Neuronal pentraxin 2(NPTX2)is thought to play a vital role in neurotransmission and the maintenance of synaptic plasticity.This study explored how serum NPTX2 and electroencephalogram(EEG)slow wave/fast wave frequency ratio relate to cognitive dysfunction in patients with epilepsy.AIM To determine if serum NPTX2 could serve as a potential biomarker for diagnosing cognitive impairment in epilepsy patients.METHODS The participants of this study,conducted from January 2020 to December 2021,comprised 74 epilepsy patients with normal cognitive function(normal group),37 epilepsy patients with cognitive dysfunction[epilepsy patients with cognitive dysfunction(ECD)group]and 30 healthy people(control group).The minimental state examination(MMSE)scale was used to evaluate cognitive function.We determined serum NPTX2 levels using an enzyme-linked immunosorbent kit and calculated the signal value of EEG regions according to the EEG recording.Pearson correlation coefficient was used to analyze the correlation between serum NPTX2 and the MMSE score.RESULTS The serum NPTX2 level in the control group,normal group and ECD group were 240.00±35.06 pg/mL,235.80±38.01 pg/mL and 193.80±42.72 pg/mL,respectively.The MMSE score was lowest in the ECD group among the three,while no significant difference was observed between the control and normal groups.In epilepsy patients with cognitive dysfunction,NPTX2 level had a positive correlation with the MMSE score(r=0.367,P=0.0253)and a negative correlation with epilepsy duration(r=−0.443,P=0.0061)and the EEG slow wave/fast wave frequency ratio value in the temporal region(r=−0.339,P=0.039).CONCLUSION Serum NPTX2 was found to be related to cognitive dysfunction and the EEG slow wave/fast wave frequency ratio in patients with epilepsy.It is thus a potential biomarker for the diagnosis of cognitive impairment in patients with epilepsy.展开更多
Objective:To review the current literature on the practice of intramuscular injections(IMIs),focusing on immunizations.Methods:The present study comprises 2 reviews,characterized by high-quality evidence,per taining t...Objective:To review the current literature on the practice of intramuscular injections(IMIs),focusing on immunizations.Methods:The present study comprises 2 reviews,characterized by high-quality evidence,per taining to the deployment of the slow injection technique without aspiration(referred to in this paper as the without-aspiration slow injection technique[WASi T])and combined with the Zeta-track technique(ZTT).The literature review is oriented toward the analysis of 2 features associated with IMIs techniques:safety and pain,integrating new evidence on vaccinee positioning for each muscle site and general relaxation techniques in the multi-parametric analysis.Results:The rigorous and in-depth reviews in the current study reveal the usefulness of including,among the international guidelines for via intramuscular immunizations,the adoption of WASi T only for compliant vaccinees,and in combination with all validated techniques for IMIs,and the use of ZTT limitedly if specific well-developed muscles are indicated.All the technique's limitations are exposed.Conclusions:Future research directions are presented by including the author's study designs to provide indirect evidence for the validity of the rationale of the slow injection technique using scientific methods,and for the conduction of future randomized controlled trials(RCTs)focused on revisiting the adoption of ZTT in a dynamic and integrated immunizations protocol in anterolateral thigh(ALT),ventrogluteal(VG),and also in the deltoid muscle,in the specific cases analyzed.展开更多
Slow transit constipation(STC),one of the most common chronic constipation in the clinic,is characterized by prolonged colonic transit time.Pathogenesis is unclear,and abnormalities can be found in enteric nervous sys...Slow transit constipation(STC),one of the most common chronic constipation in the clinic,is characterized by prolonged colonic transit time.Pathogenesis is unclear,and abnormalities can be found in enteric nervous system,intestinal neurotransmitters,intestinal smooth muscle,and Cajal stromal cell.Various methods have been used to improve the quality of life of patients with STC,including dietary fiber supplements,various cathartics,prokinetic drugs,and surgical intervention.However,there are still a large number of patients showing poor response to conservative treatment and intolerance to surgical treatment.Patients with STC suffer from severe constipation for long periods of time,faced with heavy economic burden and mental torture.Exploration the pathogenesis of STC to provide a clearer direction for future drug development is needed.展开更多
基金funded by the National Research Developm ent and Innovation Office (NKFIH-K1468 73) (to BP)。
文摘Slow inward currents are known as neuronal excitatory currents mediated by glutamate release and activation of neuronal extra synaptic N-met hyl-D-aspartate receptors with the contribution of astrocytes.These events are significantly slower than the excitatory postsynaptic currents.Parameters of slow inward currents are determined by seve ral factors including the mechanisms of astrocytic activation and glutamate release,as well as the diffusion pathways from the release site towards the extra synaptic recepto rs.Astrocytes are stimulated by neuronal network activity,which in turn excite neurons,forming an astrocyte-neuron feedback loop.Mostly as a consequence of brain edema,astrocytic swelling can also induce slow inward currents under pathological conditions.There is a growing body of evidence on the roles of slow inward currents on a single neuron or local network level.These events often occur in synchro ny on neurons located in the same astrocytic domain.Besides synchronization of neuronal excitability,slow inward currents also set synaptic strength via eliciting timing-dependent synaptic plasticity.In addition,slow inward currents are also subject to non-synaptic plasticity triggered by long-la sting stimulation of the excitatory inputs.Of note,there might be important regionspecific differences in the roles and actions triggering slow inward currents.In greater networks,the pathophysiological roles of slow inward currents can be better understood than physiological ones.Slow inward currents are identified in the pathophysiological background of autism,as slow inward currents drive early hypersynchrony of the neural networks.Slow inward currents are significant contributors to paroxysmal depolarizational shifts/interictal spikes.These events are related to epilepsy,but also found in Alzheimer's disease,Parkinson's disease,and stroke,leading to the decline of cognitive functions.Events with features overlapping with slow inward currents(excitatory,N-methyl-Daspartate-receptor mediated currents with astrocytic contribution) as ischemic currents and spreading depolarization also have a well-known pathophysiological role in worsening consequences of stroke,traumatic brain injury,or epilepsy.One might assume that slow inward currents occurring with low frequency under physiological conditions might contribute to synaptic plasticity and memory formation.However,to state this,more experimental evidence from greater neuronal networks or the level of the individual is needed.In this review,I aimed to summarize findings on slow inward currents and to speculate on the potential functions of it.
基金The study was supported by the National Natural Science Foundation of China(32101795,32301782)National Key Research and Development Program of China(2016YFD0100201-01)+2 种基金Liaoning Provincial Major Special Project of Agricultural Science and Technology(2022JH1/10200002,2021JH1/10400038)Key Research and Development Plan of Liaoning Science and Technology Department(2021JH2/1020027)Shenyang Seed Industry Innovation Project(22-318-2-12).
文摘Drought is one of the abiotic stresses limiting the production of soybean(Glycine max).Elucidation of the genetic and molecular basis of the slow-wilting(SW)trait of this crop offers the prospect of its genetic improvement.A panel of 188 accessions and a set of recombinant inbred lines produced from a cross between cultivars Liaodou 14 and Liaodou 21 were used to identify quantitative-trait loci(QTL)associated with SW.Plants were genotyped by Specific-locus amplified fragment sequencing and seedling leaf wilting was assessed under three water-stress treatments.A genome-wide association study identified 26 SW-associated single-nucleotide polymorphisms(SNPs),including three located in a 248-kb linkage-disequilibrium(LD)block on chromosome 2.Linkage mapping revealed a major-effect QTL,qSW2,associated with all three treatments and adjacent to the LD block.Fine mapping in a BC_(2)F_(3) population derived from a backcross between Liaodou 21 and R26 confined qSW2 to a 60-kb interval.Gene expression and sequence variation analysis identified the gene Glyma.02 g218100,encoding an auxin transcription factor,as a candidate gene for qSW2.Our results will contribute significantly to improving drought-resistant soybean cultivars by providing genetic information and resources.
基金supported by the National Natural Science Foundation of China(62333010,61673205).
文摘In the coal-to-ethylene glycol(CTEG)process,precisely estimating quality variables is crucial for process monitoring,optimization,and control.A significant challenge in this regard is relying on offline laboratory analysis to obtain these variables,which often incurs substantial monetary costs and significant time delays.The resulting few-shot learning scenarios present a hurdle to the efficient development of predictive models.To address this issue,our study introduces the transferable adversarial slow feature extraction network(TASF-Net),an innovative approach designed specifically for few-shot quality prediction in the CTEG process.TASF-Net uniquely integrates the slowness principle with a deep Bayesian framework,effectively capturing the nonlinear and inertial characteristics of the CTEG process.Additionally,the model employs a variable attention mechanism to identify quality-related input variables adaptively at each time step.A key strength of TASF-Net lies in its ability to navigate the complex measurement noise,outliers,and system interference typical in CTEG data.Adversarial learning strategy using a min-max game is adopted to improve its robustness and ability to model irregular industrial data accurately and significantly.Furthermore,an incremental refining transfer learning framework is designed to further improve few-shot prediction performance achieved by transferring knowledge from the pretrained model on the source domain to the target domain.The effectiveness and superiority of TASF-Net have been empirically validated using a real-world CTEG dataset.Compared with some state-of-the-art methods,TASF-Net demonstrates exceptional capability in addressing the intricate challenges for few-shot quality prediction in the CTEG process.
基金Project(52074294)supported by the National Natural Science Foundation of ChinaProject(2022YJSNY16)supported by the Fundamental Research Funds for the Central Universities,China。
文摘Rock fracture warning is one of the significant challenges in rock mechanics.Many true triaxial and synchronous acoustic emission(AE)tests were conducted on granite samples.The investigation focused on the characteristics of AE signals preceding granite fracture,based on the critical slowing down(CSD)theory.The granite undergoes a transition from the stable phase to the fracture phase and exhibits a clear CSD phenomenon,characterized by a pronounced increase in variance and autocorrelation coefficient.The variance mutation points were found to be more identifiable and suitable as the primary criterion for predicting precursor information related to granite fracture,compared to the autocorrelation coefficient.It is noteworthy to emphasize that the CSD factor holds greater potential in elucidating the underlying mechanisms responsible for the critical transition of granite fracture,in comparison to the AE timing parameters.Furthermore,a novel multi-parameter collaborative prediction method for rock fracture was developed by comprehensively analyzing predictive information,including abnormal variation modes and the CSD factor of AE characteristic parameters.This method enhances the understanding and prediction of rock fracture-related geohazards.
文摘Laparoscopic colectomy with ileorectal anastomosis may be beneficial for patients with slow transit constipation who do not respond to conservative treatment,particularly if the superior rectal artery(SRA)is preserved.Several important concerns have been addressed in this commentary.It is important to first go over the definition of surgical procedure as it is used in this text.Second,the current study lacked a control group that had SRA preservation.Thirdly,it would be best to use a prospective,randomized controlled study.Lastly,a description of the mesenteric defect’s state following a laparoscopic colectomy is necessary.
文摘The continuous change of communica-tion frequency brings difficulties to the reconnaissance and prediction of non-cooperative communication net-works.Since the frequency-hopping(FH)sequence is usually generated by a certain model with certain regularity,the FH frequency is thus predictable.In this paper,we investigate the FH frequency reconnais-sance and prediction of a non-cooperative communi-cation network by effective FH signal detection,time-frequency(TF)analysis,wavelet detection and fre-quency estimation.With the intercepted massive FH signal data,long short-term memory(LSTM)neural network model is constructed for FH frequency pre-diction.Simulation results show that our parameter es-timation methods could estimate frequency accurately in the presence of certain noise.Moreover,the LSTM-based scheme can effectively predict FH frequency and frequency interval.
基金Project(61171133) supported by the National Natural Science Foundation of ChinaProject(CX2011B019) supported by Hunan Provincial Innovation Foundation for Postgraduate,ChinaProject(B110404) supported by Innovation Foundation for Outstanding Postgraduates of National University of Defense Technology,China
文摘High resolution range imaging with correlation processing suffers from high sidelobe pedestal in random frequency-hopping wideband radar. After the factors which affect the sidelobe pedestal being analyzed, a compressed sensing based algorithm for high resolution range imaging and a new minimized ll-norm criterion for motion compensation are proposed. The random hopping of the transmitted carrier frequency is converted to restricted isometry property of the observing matrix. Then practical problems of imaging model solution and signal parameter design are resolved. Due to the particularity of the proposed algorithm, two new indicators of range profile, i.e., average signal to sidelobe ratio and local similarity, are defined. The chamber measured data are adopted to testify the validity of the proposed algorithm, and simulations are performed to analyze the precision of velocity measurement as well as the performance of motion compensation. The simulation results show that the proposed algorithm has such advantages as high precision velocity measurement, low sidelobe and short period imaging, which ensure robust imaging for moving targets when signal-to-noise ratio is above 10 dB.
文摘A new Frequency-Hopping(FH) signal detection method is proposed.Different from pre-vious methods which need to monitor the total band,it can monitor part of the band and decrease the range of the bandwidth.According to this method,a new detection model is set and the computation formulas of the detection probability and false-alarm probability are given.The parameters of a VHF radio are used to prove the validity of the method.Simulation results show that this method can de-crease the range of the bandwidth and detect the FH signal with some penalty on the SNR and signal loss.
基金the National Natural Science Foundation of China (Grant No. 62061028)the Opening Project of Shanghai Key Laboratory of Special Artificial Microstructure Materials and Technology (Grant No. ammt2021A4)+4 种基金the Foundation for Distinguished Young Scientists of Jiangxi Province (Grant No. 20162BCB23009)the Open Research Fund Program of the State Key Laboratory of LowDimensional Quantum Physics (Grant No. KF202010)the Interdisciplinary Innovation Fund of Nanchang University (Grant No. 9166-27060003-YB12)the Open Research Fund Program of Key Laboratory of Opto-Electronic Information Acquisition and Manipulation of Ministry of Education (Grant No. OEIAM202004)the Graduate Innovation Special Fund of Jiangxi Province (Grant No. YC2021-S054)。
文摘We theoretically explore the tunability of magnomechanically induced transparency(MMIT) phenomenon and fastslow light effect in a hybrid cavity magnomechanical system in which a high-quality yttrium iron garnet(YIG) sphere and an atomic ensemble are placed inside a microwave cavity. In the probe output spectrum, we can observe magnoninduced transparency(MIT) and MMIT due to the photon-magnon and phonon-magnon couplings. We further investigate the effect of atomic ensemble on the absorption spectrum. The results show that better transparency can be obtained by choosing appropriate atomic ensemble parameters. We give an explicit explanation for the mechanism of the Fano resonance phenomenon. Moreover, we discuss phenomena of slow-light propagation. The maximum group delay increases significantly with the increasing atom–cavity coupling strength, and the conversion between slow light and fast light can also be achieved by adjusting the atom–cavity coupling strength. These results may have potential applications for quantum information processing and high precision measurements.
基金Supported by the Pudong New Area Clinical Traditional Chinese Medicine of Top Discipline Project,No.PDZY-2018-0603 and the Featured Clinical Discipline Project of Shanghai Pudong,No.PWYts2021-06.
文摘BACKGROUND Impaired interstitial cells of Cajal(ICCs)are central to the pathophysiology of acute cholecystitis(AC).Common bile duct ligation is a common model of AC,producing acute inflammatory changes and decrease in gallbladder contractility.AIM To investigate the origin of slow wave(SW)in the gallbladder and the effect of ICCs on gallbladder contractions during the process of AC.METHODS Methylene blue(MB)with light was used to establish selective impaired ICCs gallbladder tissue.Gallbladder motility was assessed using the frequency of SW and gallbladder muscle contractility in vitro in normal control(NC),AC12h,AC24h,and AC48h groups of guinea pigs.Hematoxylin and eosin and Massonstained gallbladder tissues were scored for inflammatory changes.ICCs pathological changes alterations were estimated using immunohistochemistry and transmission electron microscopy.The alterations of c-Kit,α-SMA,cholecystokinin A receptor(CCKAR),and connexin 43(CX43)were assessed using Western blot.RESULTS Impaired ICCs muscle strips resulted in the decrease in gallbladder SW frequency and contractility.The frequency of SW and gallbladder contractility were significantly lower in the AC12h group.Compared with the NC group,the density and ultrastructure of ICCs were remarkably impaired in the AC groups,especially in the AC12h group.The protein expression levels of c-Kit were significantly decreased in the AC12h group,while CCKAR and CX43 protein expression levels were significantly decreased in the AC48h group.CONCLUSION Loss ICCs could lead to a decrease in gallbladder SW frequency and contractility.The density and ultrastructure of ICCs were clearly impaired in the early stage of AC,while CCKAR and CX43 were significantly reduced at end stage.
基金Supported by the "333 Scientific Project" of Jiangsu Province in 2020, No. BRA2020237the Science and Technology Project of Suqian, Jiangsu Province in 2020, No. Z2020057
文摘BACKGROUND Slow transit constipation(STC)is a disorder with delayed colonic transit.Cinnamic acid(CA)is an organic acid in natural plants,such as Radix Scrophulariae(Xuan Shen),with low toxicity and biological activities to modulate the intestinal microbiome.AIM To explore the potential effects of CA on the intestinal microbiome and the primary endogenous metabolites-short-chain fatty acids(SCFAs)and evaluate the therapeutic effects of CA in STC.METHODS Loperamide was applied to induce STC in mice.The treatment effects of CA on STC mice were assessed from the 24 h defecations,fecal moisture and intestinal transit rate.The enteric neurotransmitters:5-hydroxytryptamine(5-HT)and vasoactive intestinal peptide(VIP)were determined by the enzyme-linked immunosorbent assay.Hematoxylin-eosin and Alcian blue and Periodic acid Schiff staining were used to evaluate intestinal mucosa's histopathological performance and secretory function.16S rDNA was employed to analyze the composition and abundance of the intestinal microbiome.The SCFAs in stool samples were quantitatively detected by gas chromatography-mass spectrometry.RESULTS CA ameliorated the symptoms of STC and treated STC effectively.CA ameliorated the infiltration of neutrophils and lymphocytes,increased the number of goblet cells and acidic mucus secretion of the mucosa.In addition,CA significantly increased the concentration of 5-HT and reduced VIP.CA significantly improved the diversity and abundance of the beneficial microbiome.Furthermore,the production of SCFAs[including acetic acid(AA),butyric acid(BA),propionic acid(PA)and valeric acid(VA)]was significantly promoted by CA.The changed abundance of Firmicutes,Akkermansia,Lachnoclostridium,Monoglobus,UCG.005,Paenalcaligenes,Psychrobacter and Acinetobacter were involved in the production of AA,BA,PA and VA.CONCLUSION CA could treat STC effectively by ameliorating the composition and abundance of the intestinal microbiome to regulate the production of SCFAs.
基金Project supported by the National Key Research and Development Program of China(Grant No.2021YFA1200700)the National Natural Science Foundation of China(Grant Nos.11905054,12275075 and 12105094)the Fundamental Research Funds for the Central Universities of China。
文摘Previous studies have shown that the bulk topology of single-particle systems can be captured by the band inversion surface or by the spin inversion surface emerging on the time-averaged spin polarization.Most of the studies,however,are based on the single-particle picture even though the systems are fermionic and multi-bands.Here,we study the slow quench dynamics of topological systems with all the valence bands fully occupied,and show that the concepts of band inversion surface and spin inversion surface are still valid.More importantly,the many-particle nonadiabatic quench dynamics is shown to be reduced to a new and nontrivial three-level Landau-Zener model.This nontrivial three-level Landau-Zener problem is then solved analytically by applying the integrability condition and symmetry considerations,and thus adds a new member to the few models that are exactly solvable.Based on the analytical results,the topological spin texture revealed by the time-averaged spin polarization can be applied to characterize the bulk topology and thus provides a direct comparison for future experiments.
基金Sponsored by Beijing Natural Science Foundation General Project(8212009)Construction of Philosophy and Social Sciences Base in Beijing-Research on Beijing Urban Renewal and Comprehensive Management of Old Community En-vironment2023 Education Reform Project of North China University of Technology(108051360023XN264-25).
文摘The slow traffic system is an important component of urban transportation,and the prerequisite and necessary condition for Beijing to continue promoting“green priority”are establishing a good urban slow traffic system.Shijingshan District of Beijing City is taken as a research object.By analyzing and processing population distribution data,POI data,and shared bicycle data,the shortcomings and deficiencies of the current slow traffic system in Shijingshan District are explored,and corresponding solutions are proposed,in order to provide new ideas and methods for future urban planning from the perspective of data.
基金Supported by The Natural Science Foundation of Guizhou Province (Qiankehe Jichu[2020]1Y362)Special Project for Scientific and Technological Research on Traditional Chinese Medicine and Ethnic Medicine of Guizhou Province(QZYY-2021-016)+1 种基金The Natural Science Foundation of Guizhou Province(Qiankehe Jichu-ZK[2022]Yiban 510)Young Science and Technology Talents Growth Project of Guizhou Provincial Department of Education (Qian Jiao He KY Zi[2022]No. 261)。
文摘[Objectives] This study was carried out to explore the combined effects of Fu Zi(Radix Aconiti Lateralis Praeparata, the secondary root of perennial herbaceous plant Acontium carmichaeli Dehx. of family Ranunculaceae) and Rou Gui(Cortex Cinnamomi, the bark of Cinnamamunz cassia Presl of family Lauraceae) on intestinal neurotransmitters and microflora in rats with slow transit constipation(STC). [Methods] Experimental rats were given loperamide hydrochloride by gavage to induce STC, and then treated with Fu Zi alone, Rou Gui alone, a combination of Fu Zi and Rou Gui(2:1 w/w), and prucalopride, respectively, for 14 days. Meanwhile, the general condition, the time to first black stool and the rate of intestinal propulsion of rats in each group were observed after STC was induced and after drug treatment, and the pathological changes in rat colon were observed via hematoxylin-eosin(HE) staining, and the levels of colonic 5-hydroxytryptamine(HT), vasoactive intestinal peptide(VIP) and substance P(SP) were detected by ELISA, and the changes in intestinal flora were detected by 16S rRNA Real-time PCR. [Results] Compared with healthy rats, the time to first black stool and the rate of intestinal propulsion, colonic 5-HT and SP levels significantly decreased(p<0.01), while their colonic VIP level significantly increased(p<0.01). Compared with STC rats, the time to first black stool, the rate of intestinal propulsion, colonic 5-HT and SP levels in Fu Zi-Rou Gui(2:1) treated rats and prucalopride treated rats significantly increased(p<0.01), while their colonic VIP level significantly decreased(p<0.01). There was no significant difference in alpha diversity between healthy rats and STC rats. However, analysis on beta diversity revealed that there were differences in microflora structure and composition between them. Compared with healthy rats, the relative abundance of Firmicutes and Proteobacteria in STC rats significantly increased, while that of Bacteroidetes decreased. Compared with STC rats, the relative abundance of Proteobacteria decreased and that of Bacteroidetes and Firmicutes increased in Fu Zi-Rou Gui(2:1) treated rats;the relative abundance of Bacteroidetes and Proteobacteria decreased while that of Firmicutes increased in Fu Zi treated rats;the relative abundance of Proteobacteria decreased while that of Bacteroidetes increased in Rou Gui treated rats;the relative abundance of Firmicutes and Proteobacteria decreased while that of Bacteroidetes increased in prucalopride treated rats. The intestinal flora in rats of all groups was dominated by Lactobacillus spp. and other genera of anaerobic bacteria. Compared with healthy rats, the relative abundance of Lactobacillus spp. and Clostridium spp. in STC rats decreased, while those of Blautia spp. and Ruminococcus spp. and Allobaculum spp. increased. Compared with STC rats, the relative abundance of Lactobacillus spp. in all rats treated with drugs increased. [Conclusions] The combination of Fu Zi and Rou Gui(2:1) can effectively improve intestinal motility in STC rats by regulating intestinal microbial community and the levels of colonic neurotransmitters.
基金Sponsored by National Key Research and Development Project(2018YFD1100203)Research Topics of Huainan Municipal People’s Government Development Research Center,Innovation Topics of Huainan Urban Renewal Strategy Research(K2110098).
文摘To build an“ecological and livable city”,it is important to figure out the relationship between human activity and urban park space and create a high-quality urban park through the integration of“people”and“park”.Taking Longhu Park in Huainan Province as an example,the study quantitatively analyzed and evaluated the characteristics and service quality of slow traffic space using importance-performance analysis(IPA)and space syntax,clarified the key indexes and areas to be optimized,and put forward corresponding design countermeasures and suggestions in combination with human activity demand.The results suggest that:①The mean performance of park recreation service quality is 3.63,less than the mean importance(3.95).Tourists pay special attention to the safety and convenience of slow traffic space,and the diversity and identiability of site functions is the focus“to be improved”.②The accessibility of Longhu Park shows a strong irregular shape in the southwest.The dead-end roads in the far lake area and the flora and fauna area on the northwest side have weak spatial perception,and the composite function carrying potential of slow traffic space is better reflected in a small range.Therefore,an optimization strategy for slow traffic space is proposed to enhance the continuity of road network,site identifiability,and functional diversification.The results will provide new thoughts of governance based on spatial humanism for the high-quality renewal of urban parks in the new era.
基金Supported by 2022 Educational Research Program for Young and Middle-aged Teachers in Fujian Province(Science and Technology),No.JAT220107.
文摘BACKGROUND Cognitive dysfunction in epileptic patients is a high-incidence complication.Its mechanism is related to nervous system damage during seizures,but there is no effective diagnostic biomarker.Neuronal pentraxin 2(NPTX2)is thought to play a vital role in neurotransmission and the maintenance of synaptic plasticity.This study explored how serum NPTX2 and electroencephalogram(EEG)slow wave/fast wave frequency ratio relate to cognitive dysfunction in patients with epilepsy.AIM To determine if serum NPTX2 could serve as a potential biomarker for diagnosing cognitive impairment in epilepsy patients.METHODS The participants of this study,conducted from January 2020 to December 2021,comprised 74 epilepsy patients with normal cognitive function(normal group),37 epilepsy patients with cognitive dysfunction[epilepsy patients with cognitive dysfunction(ECD)group]and 30 healthy people(control group).The minimental state examination(MMSE)scale was used to evaluate cognitive function.We determined serum NPTX2 levels using an enzyme-linked immunosorbent kit and calculated the signal value of EEG regions according to the EEG recording.Pearson correlation coefficient was used to analyze the correlation between serum NPTX2 and the MMSE score.RESULTS The serum NPTX2 level in the control group,normal group and ECD group were 240.00±35.06 pg/mL,235.80±38.01 pg/mL and 193.80±42.72 pg/mL,respectively.The MMSE score was lowest in the ECD group among the three,while no significant difference was observed between the control and normal groups.In epilepsy patients with cognitive dysfunction,NPTX2 level had a positive correlation with the MMSE score(r=0.367,P=0.0253)and a negative correlation with epilepsy duration(r=−0.443,P=0.0061)and the EEG slow wave/fast wave frequency ratio value in the temporal region(r=−0.339,P=0.039).CONCLUSION Serum NPTX2 was found to be related to cognitive dysfunction and the EEG slow wave/fast wave frequency ratio in patients with epilepsy.It is thus a potential biomarker for the diagnosis of cognitive impairment in patients with epilepsy.
文摘Objective:To review the current literature on the practice of intramuscular injections(IMIs),focusing on immunizations.Methods:The present study comprises 2 reviews,characterized by high-quality evidence,per taining to the deployment of the slow injection technique without aspiration(referred to in this paper as the without-aspiration slow injection technique[WASi T])and combined with the Zeta-track technique(ZTT).The literature review is oriented toward the analysis of 2 features associated with IMIs techniques:safety and pain,integrating new evidence on vaccinee positioning for each muscle site and general relaxation techniques in the multi-parametric analysis.Results:The rigorous and in-depth reviews in the current study reveal the usefulness of including,among the international guidelines for via intramuscular immunizations,the adoption of WASi T only for compliant vaccinees,and in combination with all validated techniques for IMIs,and the use of ZTT limitedly if specific well-developed muscles are indicated.All the technique's limitations are exposed.Conclusions:Future research directions are presented by including the author's study designs to provide indirect evidence for the validity of the rationale of the slow injection technique using scientific methods,and for the conduction of future randomized controlled trials(RCTs)focused on revisiting the adoption of ZTT in a dynamic and integrated immunizations protocol in anterolateral thigh(ALT),ventrogluteal(VG),and also in the deltoid muscle,in the specific cases analyzed.
文摘Slow transit constipation(STC),one of the most common chronic constipation in the clinic,is characterized by prolonged colonic transit time.Pathogenesis is unclear,and abnormalities can be found in enteric nervous system,intestinal neurotransmitters,intestinal smooth muscle,and Cajal stromal cell.Various methods have been used to improve the quality of life of patients with STC,including dietary fiber supplements,various cathartics,prokinetic drugs,and surgical intervention.However,there are still a large number of patients showing poor response to conservative treatment and intolerance to surgical treatment.Patients with STC suffer from severe constipation for long periods of time,faced with heavy economic burden and mental torture.Exploration the pathogenesis of STC to provide a clearer direction for future drug development is needed.