Human lineage mutations regulate RNA-protein binding of conserved genes NTRK2 and ITPR1 involved in human evolution

Background The role of human lineage mutations(HLMs)in human evolution through post-transcriptional modification is unclear.Aims To investigate the contribution of HLMs to human evolution through post-transcriptional modification.Methods We applied a deep learning model Seqweaver to predict how HLMs impact RNA-binding protein affinity.Results We found that only 0.27%of HLMs had significant impacts on RNA-binding proteins at the threshold of the top 1%of human common variations.These HLMs enriched in a set of conserved genes highly expressed in adult excitatory neurons and prenatal Purkinje neurons,and were involved in synapse organisation and the GTPase pathway.These genes also carried excess damaging coding mutations that caused neurodevelopmental disorders,ataxia and schizophrenia.Among these genes,NTRK2 and ITPR1 had the most aggregated evidence of functional importance,suggesting their essential roles in cognition and bipedalism.Conclusions Our findings suggest that a small subset of human-specific mutations have contributed to human speciation through impacts on post-transcriptional modification of critical brain-related genes.

Diagnostic performance of intravascular ultrasound-based fractional flow reserve in evaluating of intermediate left main stenosis

BACKGROUND The recently introduced ultrasonic flow ratio(UFR),is a novel fast computational method to derive fractional flow reserve(FFR)from intravascular ultrasound(IVUS)images.In the present study,we evaluate the diagnostic performance of UFR in patients with intermediate left main(LM)stenosis.METHODS This is a prospective,single center study enrolling consecutive patients with presence of intermediated LM lesions(diameter stenosis of 30%-80%by visual estimation)underwent IVUS and FFR measurement.An independent core laboratory assessed offline UFR and IVUS-derived minimal lumen area(MLA)in a blinded fashion.RESULTS Both UFR and FFR were successfully achieved in 41 LM patients(mean age,62.0±9.9 years,46.3%diabetes).An acceptable correlation between UFR and FFR was identified(r=0.688,P<0.0001),with an absolute numerical difference of 0.03(standard difference:0.01).The area under the curve(AUC)in diagnosis of physiologically significant coronary stenosis for UFR was 0.94(95%CI:0.87-1.01),which was significantly higher than angiographic identified stenosis>50%(AUC=0.66,P<0.001)and numerically higher than IVUS-derived MLA(AUC=0.82;P=0.09).Patient level diagnostic accuracy,sensitivity and specificity for UFR to identify FFR≤0.80 was 82.9%(95%CI:70.2-95.7),93.1%(95%CI:82.2-100.0),58.3%(95%CI:26.3-90.4),respectively.CONCLUSION In patients with intermediate LM diseases,UFR was proved to be associated with acceptable correlation and high accuracy with pressure wire-based FFR as standard reference.The present study supports the use of UFR for functional evaluation of intermediate LM stenosis.

Detecting HI Galaxies with Deep Neural Networks in the Presence of Radio Frequency Interference

In the neutral hydrogen(H I)galaxy survey,a significant challenge is to identify and extract the H I galaxy signal from the observational data contaminated by radio frequency interference(RFI).For a drift-scan survey,or more generally a survey of a spatially continuous region,in the time-ordered spectral data,the H I galaxies and RFI all appear as regions that extend an area in the time-frequency waterfall plot,so the extraction of the H I galaxies and RFI from such data can be regarded as an image segmentation problem,and machine-learning methods can be applied to solve such problems.In this study,we develop a method to effectively detect and extract signals of H I galaxies based on a Mask R-CNN network combined with the PointRend method.By simulating FAST-observed galaxy signals and potential RFI impact,we created a realistic data set for the training and testing of our neural network.We compared five different architectures and selected the best-performing one.This architecture successfully performs instance segmentation of H I galaxy signals in the RFI-contaminated time-ordered data,achieving a precision of 98.64%and a recall of 93.59%.

Research Center of 3D Bioprinting in Shanghai Ninth People’s Hospital

The center was first established in 2013 and affiliated to the Shanghai Ninth People’s Hospital,Shanghai Jiao Tong University School of Medicine.In 2015,the center was entitled as 3D Bioprinting Clinical Transformation Collaborative Innovation Center.In 2016,the center was renamed as Medical 3D Printing Innovation Research Center of Shanghai Jiao Tong University School of Medicine.Although the center was established in 2013,the clinical application of 3D printing in Shanghai Ninth People’s Hospital can be traced back to the 1990s.As early as 30 years ago,Prof.Kerong Dai had tried to rebuild patients pelvic by manually cutting the foam boards and layering them together based on the theory of 3D printing for preoperative planning model of abnormal skeleton structures and development of personalized prosthesis.That was the first application of 3D printing in the area of medicine in China.Now,The Research Center of 3D Bioprinting in Shanghai Ninth People’s Hospital comprised of subcenters including the outpatient department of 3D printing,medical 3D printing innovation research center and Shanghai key laboratory of orthopedic implant.

Robust photo-assisted removal of NO at room temperature:Experimental and density functional theory calculation with optical carrier

Photo-assisted SCR(PSCR) offers a potential solution for removal of NO at room temperature. MnTiO_(x)as PSCR catalyst exhibits superior performance with NO removal of 100% at the room temperature. Electron paramagnetic resonance(EPR) analysis revealed the presence of numerous oxygen vacancies on MnTiO_(x). Optical carrier density functional theory(DFT) calculations showed that the threedimensional orbital hybridization of Mn and Ti is significantly enhanced under light irradiation. The MnTiO_(x)catalyst exhibited excellent electron–hole separation ability, which can adsorbe NH_(3)and dissociate to form NH_(2)fragments and H atoms. In-situ diffuse reflectance infrared fourier-transform spectroscopy(DRIFTS) indicated that the optical carrier enhanced NH_(3)adsorption on MnTiO_(x), which makes it possess excellent PSCR activity. This work provided an additional strategy to NO removal with PSCR catalysts and showed potential for use in photocatalysis.

Optical penetration of surface-enhanced micro-scale spatial offset Raman spectroscopy in turbid gel and biological tissue

The limited penetration of photons in biological tissue restricts the deep-tissue detection and imaging application.The micro-scale spatially offset Raman spectroscopy(micro-SORS)with an optical fiber probe,colleting photons from deeper regions by offsetting the position of laser excitation from the collection optics in a range of hundreds of microns,shows great potential to be integrated with endoscopy for inside-body noninvasive detection by circumventing this restric-tion,particularly with the combination of surface-enhanced Raman spectroscopy(SERS).However,a detailed tissue penetration study of micro-SORS in combination with SERS is still lacking.Herein,we compared the signal decay of enhanced Raman nanotags through the tissue phantom of agarose gel and the biological tissue of porcine muscle in the near-infrared(NIR)region using a portable Raman spectrometer with a micro-SORS probe(2.1 mm in diameter)and a conventional hand-held probe(9.7mm in diameter).Two kinds of Raman nanotags were prepared from gold nanorods decorated with the nonresonant(4-nitrobenzenethiol)or resonant Raman reporter molecules(IR-780 iodide).The SERS measurements show that the penetration depths of two Raman nanotags are both over 2 cm in agarose gel and 3 mm in porcine muscle.The depth could be improved to over 4 cm in agarose gel and 5 mm in porcine tissue when using the micro-SORS system.This demonstrates the superiority of optical-fiber micro-SORS system over the conventional Raman detection for the detection of nanotags in deeper layers in the turbid medium and biological tissue,offering the possibility of combining the micro-SORS technique with SERS for noninvasive in vivo endoscopy-integrated clinical application.

Systems Neuroengineering: Understanding and Interacting with the Brain

In this paper, we review the current state- of-the-art techniques used for understanding the inner workings of the brain at a systems level. The neural activity that governs our everyday lives involves an intricate coordination of many processes that can be attributed to a variety of brain regions. On the surface, many of these functions can appear to be controlled by specific anatomical structures; however, in reality, numerous dynamic networks within the brain contribute to its function through an interconnected web of neuronal and synaptic pathways. The brain, in its healthy or pathological state, can therefore be best understood by taking a systems-level approach. While numerous neuroengineering technologies exist, we focus here on three major thrusts in the field of systems neuroengineering： neuroimaging, neural interfacing, and neuromodulation. Neuroimaging enables us to delineate the structural and functional organization of the brain, which is key in understanding how the neural system functions in both normal and disease states. Based on such knowledge, devices can be used either to communicate with the neural system, as in neural interface systems, or to modulate brain activity, as in neuromodulation systems. The consideration of these three fields is key to the development and application of neuro-devices. Feedback-based neuro-devices require the ability to sense neural activity （via a neuroimaging modality） through a neural interface （invasive or noninvasive） and ultimately to select a set of stimulation parameters in order to alter neural function via a neuromodulation modality. Systems neuroengineering refers to the use of engineering tools and technologies to image, decode, and modulate the brain in order to comprehend its functions and to repair its dysfunction. Interactions between these fields will help to shape the future of systems neuroengineering--to develop neurotechniques for enhancing the understanding of whole- brain function and dysfunction, and the management of neurological and mental disorders.

Neural computational modeling reveals a major role of corticospinal gating of central oscillations in the generation of essential tremor

Essential tremor, also referred to as familial tremor, is an autosomal dominant genetic disease and the most common movement disorder. It typically involves a postural and motor tremor of the hands, head or other part of the body. Essential tremor is driven by a central oscillation signal in the brain. However, the corticospinal mechanisms involved in the generation of essential tremor are unclear. Therefore, in this study, we used a neural computational model that includes both monosynaptic and multisynaptic corticospinal pathways interacting with a propriospinal neuronal network. A virtual arm model is driven by the central oscillation signal to simulate tremor activity behavior. Cortical descending commands are classified as alpha or gamma through monosynaptic or multisynaptic corticospinal pathways, which converge respectively on alpha or gamma motoneurons in the spinal cord. Several scenarios are evaluated based on the central oscillation signal passing down to the spinal motoneurons via each descending pathway. The simulated behaviors are compared with clinical essential tremor characteristics to identify the corticospinal pathways responsible for transmitting the central oscillation signal. A propriospinal neuron with strong cortical inhibition performs a gating function in the generation of essential tremor. Our results indicate that the propriospinal neuronal network is essential for relaying the central oscillation signal and the production of essential tremor.

Human natural killer cells for targeting delivery of gold nanostars and bimodal imaging directed photothermal/photodynamic therapy and immunotherapy

Objective:To construct a novel nanoplatform GNS@CaCO3/Ce6-NK by loading the CaCO3-coated gold nanostars(GNSs)with Chlorin e6 molecules(Ce6)into human peripheral blood mononuclear cells(PBMCs)-derived NK cells for tumor targeted therapy.Methods:GNS@CaCO3/Ce6 nanoparticles were prepared and characterized by TEM and UV-vis.The cell surface markers and cytokines secretion of NK cells before and after loading the GNS@CaCO3/Ce6 nanoparticles were detected by Flow Cytometry(FCM)and ELISA.Effects of the GNS@CaCO3/Ce6-NK cells on A549 cancer cells was determined by FCM and CCK-8.Intracellular fluorescent signals of GNS@CaCO3/Ce6-NK cells were detected via Confocal laser scanning microscopic(CLSM)and FCM at different time points.Intracellular ROS generation of GNS@CaCO3/Ce6-NK cells under laser irradiation were examined by FCM.The distribution of GNS@CaCO3/Ce6-NK in A549 tumor-bearing mice were observed by fluorescence imaging and PA imaging.The combination therapy of GNS@CaCO3/Ce6-NK under laser irradiation were investigated on tumor-bearing mice.Results:The coated CaC03 shell on the surface of GNSs exhibited prominent delivery and protection effect of Ce6 during the cellular uptake process.The as-prepared multifunctional GNS@CaCO3/Ce6-NK cells possessed bimodal functions of fluorescence imaging and photoacoustic imaging.The as-prepared multifunctional GNS@CaCO3/Ce6-NK cells could actively target tumor tissues with the enhanced photothermal/photodynamic therapy and immunotherapy.Conclusions:The GNS@CaCO3/Ce6-NK shows effective tumor-targeting ability and prominent therapeutic efficacy toward lung cancer A549 tumor-bearing mice.Through fully utilizing the features of GNSs and NK cells,this new nanoplatform provides a new synergistic strategy for enhanced photothermal/photodynamic therapy and immunotherapy in the field of anticancer development in the near future.

Near infra-red light treatment of Alzheimer's disease

Alzheimers disease(AD)is a chronic neurodegenerative disease.The symptoms include memoryand spatial learning dificulties,language disorders,and loss of motivation,which get worse overtime,eventually ending in death.No ffective treatments are available for AD,currently.Currenttreatments only attenuate symptoms temporarily and are associated with severe side ffects.Nearinfra-red(NIR)light has been studied for a long time.We investigated the effect of NIR on ADusing a transgenic mouse model,which was obtained by co-injecting two vectors carrying ADmutations in amyloid precursor protein(APP)and presenilin-i(PSEN1)into C57BL/6J mice.The irradiation equipment consisted of an accommodating box and an LED array.The wave-length of NIR light emitted from LED was between 1040 nm and 1090 nm.The power densitydelivered at the level of the mice was approximately 15 mW/cm^(2),Firstly,we treated the micewith NIR for 40 days,Then,the irradiation was suspended for 28 days.Finally,another 15 daystreatment was brought to mice.We conducted Morris water maze and immunofluorescenceanalysis to evaluate the effects of treatment.Immunofuorescence analysis was based on mea-suring the quantity of plaques in mouse brain slices,Our results show that NIR light improvesmemory and spatial learning ability and reduces plaques moderately.NIR light represents apotential treatment for AD.

STUDYING THE ROLE OF MACROPHAGES IN CIRCULATING PROSTATE CANCER CELLS BY IN VIVO FLOW CYTOMETRY

Metastasis is a very complicated multi-step process and accounts for the low survival rate of the cancerous patients.To metastasize,t he malignant cells must detach from the primary tumor and migrate to secondary sites in the body through either blood or lymph circulation.Macrophages appear to be directly involved in tumor progression and metastasis.However,the role of macrophages in affecting cancer metast asis has not been fully elucidated.Here,we have utilized an emerging technique,namely in vivo flow cytometry(IVFC)to study the depletion kinetics of circulating prostate cancer cells in mice and determine how depletion of macrophages by the liposome encapsulated clodronate affects the depletion kinetics.Our results show diferent depletion kinetics of PC-3 cells between the macrophagedeficient group and the control group.The number of circulating tumor cells(CTCs)in the macrophage-deficient group decreases in a slower manner compared to the control mice group.The differences in depletion kinetics indicate that the absence of macrophages facilitates the stay of prostate cancer cells in circulation.In addition,our imaging data suggest that macrophages might be able to arrest,phagocytose and digest PC-3 cells.Therefore,phagocy tosis may mainly contribute to the de-pletion kinetic diferences.The developed methods elaborated here would be useful to study the relationship between macr ophages and tumor metastasis in small animal cancer models.

Novel Graphene Biosensor Based on the Functionalization of Multifunctional Nano-bovine Serum Albumin for the Highly Sensitive Detection of Cancer Biomarkers

A simple,convenient,and highly sensitive bio-interface for graphene field-effect transistors(GFETs) based on multifunctional nano-denatured bovine serum albumin(nano-dBSA) functionalization was developed to target cancer bio-markers.The novel graphene–protein bioelectronic interface was constructed by heating to denature native BSA on the graphene substrate surface.The formed nano-d BSA film served as the cross-linker to immobilize monoclonal antibody against car-cinoembryonic antigen(anti-CEA mAb) on the graphene channel activated by EDC and Sulfo-NHS.The nano-dBSA film worked as a self-protecting layer of graphene to prevent surface contamination by lithographic processing.The improved GFETbiosensor exhibited good specificity and high sensitivity toward the target at an ultralow concentration of 337.58 fg mL-1.The electrical detection of the binding of CEA followed the Hill model for ligand–receptor interaction,indicating the negative binding cooperativity between CEA and anti-CEA mAb with a dissociation constant of 6.82×10-10M.The multifunctional nano-dBSA functionalization can confer a new function to graphene-like 2D nanomaterials and provide a promising bio-functionalization method for clinical application in biosensing,nanomedicine,and drug delivery.

Determination of Polynomial Degree in the Regression of Drug Combinations

Studies on drug combinations are becoming more and more popular in the past few decades, with the development of computer and algorithms. One of the most common methods in optimizing drug combinations is regression of a polynomial model based on certain number of experimental observations. In this paper, we study how to determine the degree of polynomials in different circumstances of drug combination optimization. Using cross-validation, we have found that in most cases, a high degree results in failures of accurate prediction, named overfitting. An anti-noise test has also revealed that polynomial model with high degree tends to be less resistant to random errors in the observations. © 2014 Chinese Association of Automation.

The Chemical Mechanism of Pestilences or Coronavirus Disease 2019 (COVID-19)

In this paper, the chemical mechanism of the coronavirus disease 2019 (COVID-19) has been explored and clearly revealed.

The Topological Entropy Mechanism of Coronavirus Disease 2019 (COVID-19)

The biological principal or its detailed mechanism for the pandemic coronavirus disease 2019 (COVID-19) has been investigated and analyzed from the topological entropy approach. The findings thus obtained have provided very useful clues and information for developing both powerful and safe vaccines against the pandemic COVID-19.

Effects of Spike Frequency Adaptation on Synchronization Transitions in Electrically Coupled Neuronal Networks with Scale-Free Connectivity

Effects of spike frequency adaptation （SFA ） on the synchronous behavior of population neurons are investigated in electrically coupled networks with a scale-free property. By a computational approach, we corroborate that pairwise correlations between neurons would decrease if neurons exhibit the feature of SFA, which is similar to previous experimental observations. However, unlike the case of pairwise correlations, population activities of neurons show a rather complex variation mode： compared with those of non-adapted neurons, neurons in the networks having weak-degrees of SFA will impair population synchronizations; while neurons exhibiting strong- degrees of SFA will enhance population synchronizations. Moreover, a variation of coupling strength between neurons will not alter this phenomenon significantly, unless the coupling strength is too weak. Our results suggest that synchronous activity of electrically coupled population neurons is adaptation-dependent, and this adaptive feature may imply some coding strategies of neuronal populations.

Separation of cortical arteries and veins in optical neurovascular imaging

Separation of arteries and veins in the cerebral cortex is of significant importance in the studies of cortical hemodynamics,such as the changes of cerebral blood flow,perfusion or oxygen con-centration in arteries and veins under different pathological and physiological conditions.Yet the cerebral vessel segmentation and vessel-type separation are challenging due to the complexity of cortical vessel characteristics and low spatial signal-to-noise ratio.In this work,we presented an effective full-field method to differentiate arteries and veins in cerebral cortex using dual-modal optical imaging technology including laser speckle imaging(LSI)and optical intrinsic signals(OIS)imaging.The raw contrast images were acquired by LSI and processed with enhanced laser speckle contrast analysis(eLASCA),algorithm.The vascular pattern was extracted and seg-mented using region growing algorithm from the eLASCA-based LSI.Meanwhile,OIS imageswere acquired altermatively with 630 and 870 nm to obtain an oxy hemoglobin concentration mapover cerebral cortex.Then the separation of arteries and veins was accomplished by Otsuthreshold segmentation algorithm based on the OIS information and segmentation of LSI.Finally,the segmentation and separation performances were assessed using area overlap measure(AOM).The segmentation and separation of cerebral vessels in cortical optical imaging have great potential applications in full-field cerebral hemodynamics monitoring and pathological study of cerebral vascular diseases,as well as in clinical intraoperative monitoring.

Enhancement of the Neuronal Dynamic Range by Proper Intensities of Channel Noise

The capability of a biological neuron to discriminate the intensity of external stimulus is measured in its dynamic range.In previous studies,a few factors have been reported to be able to enhance the dynamic range,e.g.,electrical coupling and active dendrites.Here we numerically show that intrinsic channel noise within neurons has a subtle effect in neuronal dynamic range modulation.Our simulation results indicate that for relatively weak noise intensity,the dynamic range of the neuron is enhanced significantly.However,as the noise intensity becomes stronger,the dynamic range of the neuron is weakened.Further investigation suggests that sodium channel noise and potassium channel noise play opposite roles in modulating the dynamic range.Consequently,the model results suggest a new function of channel noise,that is,a proper value of noise intensity could optimize the dynamic range of neurons.

ICAM-1 depletion in the center of immunological synapses is important for calcium releasing in T-cells

T-cell activation requires the formation of the immunological sy napse(IS)bet ween a T-cll and anantigen-presenting cell(AP C)to control the development of the adaptive immune response.How-ever,calcium release,an initial signal of T-cell activation,has been found to occur before IS for-mation.The mechanism for triggering the calcium signaling and relationship bet ween calciumrelease and IS format ion remains unclear.Herein,using live-cell imaging,we found that int ercellularadhesion molecule 1(ICAM-1),an essential mdlecule for IS formation,accumulated and then wasdepleted at the center of the synapse before complete IS formation.During the proces of ICAM1depletion,calcium was released.if ICAM-1 failed to be depleted from the center of the synapse,thesustained calcium signaling could not be induced.Moreover,depletion of ICAM-1 in ISs preferen-tially ccurred with the contact of antigen-specific T-cels and dendritic clls(DCs).Blocking thebinding ofICA M-1 and lymphocy te finction-associated antigen 1(LFA-1),ICAM-1 failed to depleteat the center of the synapse,and calcium release in T-clls decreased.In studying the mechanism ofhow the depletion ofiCA M1 could influence calcium release in T-clls,we found that the movementof ICAM-1 was associat ed with the localization of LFA-1 in the IS,which afected the localization ofcalcium microdomains,ORAIl and mitochondria in IS.Therefore,the depletion of ICAM-1 in the center of the synapse is an important factor for an initial sust ained calcium release in T-cells.

Theoretical Calculation of a Focused Acoustic Field from a Linear Phased Array on a Concave Cylindrical Transducer

A new linear phased array on a concave cylindrical transducer is designed for meeting the specific requirements of applications for interstitial thermal ablation.Using the array,a focal line can be generated rapidly and the focal position can be adjusted in the proper range without the use of complex mechanical structures.The focused acoustic field distributions in the axial,radial and azimuthal directions of the transducer are investigated theoretically by numerical simulation.Effects of the focal distance,steering angle,element arc-width,arc-space between adjacent elements and number of elements on the acoustic field are also thoroughly studied.Many important results are obtained.