Foxtail millet supplementation improves glucose metabolism and gut microbiota in rats with high-fat diet/streptozotocin-induced diabetes

Foxtail millet(FM)whole grain has received special attention in recent years.To confirm the hypoglycemic effects of FM,we investigated the effects of FM supplementation on glucose metabolism and gut microbiota in rats with high-fat diet/streptozotocin(HFD/STZ)-induced diabetes.Specifically,we fully assessed the blood biochemical profiles,pancreatic histopathology,insulin-glucagon immunofluorescence,short-chain fatty acids,and gut microbiota composition of rats with HFD/STZ-induced diabetes before and after FM supplementation.Results showed that both 30% and 48% FM supplementation significantly decreased concentrations of fasting blood glucose,60-min blood glucose,and blood triglycerides(P<0.05);additionally,48% FM supplementation significantly improved blood glucose tolerance and insulin resistance(P<0.05).However,FM supplementation could not effectively repair damage to β-cells over a short period of time.In addition,4 weeks of 48% FM supplementation siginificantly increased the relative abundance of Bifidobacterium and concentration of butyrate,suggesting that the hypoglycemic effects of FM supplementation might be partially mediated by gut microbiota.Collectively,we found a dose-dependent relationship between FM supplementation and improvement of blood glucose metabolism,but did not find a synergistic effect between FM supplementation and metformin(Met)treatment.Our findings provide further support that consuming more whole-grain FM might be beneficial to individuals suffering from type 2 diabetes.

Role of the periotic mesenchyme in the development of sensory cells in early mouse cochlea

Objective:To investigate the role of the periotic mesenchyme(POM)in the development of sensory cells of developing auditory epithelium.Methods:Developing auditory epithelium with or without periotic mesenchyme was isolated from mice at embryonic days 11.5(E11.5),E12.5 and E13.5,respectively,and cultured in vitro to an equivalent of E18.5’s epithelium in vivo.Then,the explants were co-stained with antibodies targeting myosin VIIA,Sox2 and BrdU.Results:More hair cells in E11.5 t 7 DIV,E12.5 t 6 DIV and E13.5 t 5 DIV auditory epithelia were found upon culture with POM(225.90±62.44,476.94±100.81,and 1386.60±202.38,respectively)compared with the non-POM group(68.17±23.74,205.00±44.23,and 1266.80±38.84,respectively).Moreover,regardless of developmental stage,the mesenchymal tissue increased the amount of cochlear sensory cells as well as the ratio of differentiated hair cells to total sensory cells.Conclusions:The periotic mesenchyme promotes the development of cochlear sensory cells,and its effect depends on the developmental stage of the auditory epithelium.

Stability of computed tomography densitometry in patients with otosclerosis:a two-year follow-up

Objectives:To quantify the progression of otosclerosis in the unoperated ear between two stapedotomy procedures for patients with bilateral otosclerosis which can help to determine whether a HRCT scan should be re-performed before the second surgery for patients who already received HRCT imaging before the initial surgery.Methods:35 patients who underwent bilateral stapedotomy were included.Two rounds of HRCT examination and audiometry were performed at the time of the first surgery and second surgery on the ear that was not operated on during the initial surgery.The relationship between the changes in HRCT densitometry and audiometry over time was analyzed.Results:The second round of HRCT did not add significant information about the changes to the otosclerosis lesions in either the imaging diagnosis or the HRCT density values except for small changes in the HRCT densitometry readings at the area anterior to the inner auditory(P=0.01).While the changes in HRCT manifestation are small,changes near the fissula ante fenestram(FAF)were still positively correlated with the air bone gap(ABG)of patients(p=0.031,r=0.388).Conclusions:The progression of lesions in otosclerosis is slow resulting in small and insignificant changes to the HRCT features.Therefore,a repeat HRCT evaluations prior to surgery is not necessary for patients who have had a previous HRCT evaluation within 2 years of the operation.The small changes in HRCT manifestation near the FAF were still correlated with negative effects on the ABG which could cause worsened hearing thresholds over this timeframe。

Inhibition of histone methyltransferase PRMT5 attenuates cisplatininduced hearing loss through the PI3K/Akt-mediated mitochondrial apoptotic pathway

This study aimed to evaluate the therapeutic potential of inhibiting protein arginine methyltransferase 5(PRMT5)in cisplatin-induced hearing loss.The effects of PRMT5 inhibition on cisplatin-induced auditory injury were determined using immunohistochemistry,apoptosis assays,and auditory brainstem response.The mechanism of PRMT5 inhibition on hair cell survival was assessed using RNA-seq and Cleavage Under Targets and Tagment-quantitative polymerase chain reaction(CUT&Tag-qPCR)analyses in the HEI-OC1 cell line.Pharmacological inhibition of PRMT5 significantly alleviated cisplatin-induced damage to hair cells and spiral ganglion neurons in the cochlea and decreased apoptosis by protecting mitochondrial function and preventing the accumulation of reactive oxygen species.CUT&Tag-qPCR analysis demonstrated that inhibition of PRMT5 in HEI-OC1 cells reduced the accumulation of H4R3me2s/H3R8me2s marks at the promoter region of the Pik3ca gene,thus activating the expression of Pik3ca.These findings suggest that PRMT5 inhibitors have strong potential as agents against cisplatininduced ototoxicity and can lay the foundation for further research on treatment strategies of hearing loss.

Evaluation on Effectiveness of a New System as well as Analysis on Optimal Horizontal Eye Position for Vertical Video Head Impulse Test

Objective To compare the performances among three different systems for video head impulse test(vHIT),and to identify an optimal target angle for precisely evaluating the function of vertical semicircular canals in vHIT.Methods A two-center prospective study was done.Participants were sit 1.2 m away from the wall in a noise-proved room that dedicated for vHIT experiments.During the comparison experiments,similar settings were ensured in both hospitals,with the same distance to wall and angle of staring.For each equipment,the procedures followed the developers’recommendations.The same examiner performed the comparison between two systems in one location.For the eye-position projects,targets were placed on the wall sequentially at the pre-marked lines for different angles.For the comparison projects,9 and 13 participants were recruited,respectively.Any participant with otologic or vestibular disorders was excluded.A total of 26 healthy participants were recruited in the eye-position experiments,16 of which were further involved in inter-examiner tests.Results Our evaluations of three different systems showed that a new vHIT system,VertiGoggles®ZT-VNG-I(VG)performed as good as the long-tested Otometrics®ICS impulse(Oto)and EyeSeeCam®(ESC).During the comparison,we validated 25-degree,instead of right ahead at 0 degree,is a better place to set the targets when torsion was applied at vertical semicircular canal planes.Conclusion The new VG system is good for clinical practices.Furthermore,we proposed a new protocol to set the targets 25 degrees from right ahead after tilting head 45 degrees to evaluate vertical canals during vHIT.

Preface:Value and dynamics of salt lakes in a changing world

The statement that the world’s ecosystems are rapidly deteriorating due to human intervention and global warming is nowadays commonplace.Some of the ecosystems most heavily impacted are inland salt lakes.The salt lakes are among the most valuable and fascinating ecosystems on Earth,and their study has both basic scientifi c interest as well as applied aspects.

Novel heterozygous USH1C mutation impacts hair cell mechanotransduction and causes progressive hearing loss

Hearing loss is one of the most common sensory disorders worldwide,affecting approximately 466 million people,including 34 million children[1].Genetic mutations accounts for approximately 60%of inherited hearing loss cases[2,3].These genetic changes result in a wide variety of clinical manifestations,ranging from nonsyndromic hearing loss(NSHL)to over 400 syndromes involving hearing loss and from mild adult-onset hearing loss to profound congenital deafness,covering the entire spectrum of Mendelian inheritance.

Inhibiting DNA methylation alleviates cisplatininduced hearing loss by decreasing oxidative stress-induced mitochondria-dependent apoptosis via the LRP1-PI3K/AKT pathway

Cisplatin-related ototoxicity is a critical side effect of chemotherapy and can lead to irreversible hearing loss.This study aimed to assess the potential effect of the DNA methyltransferase(DNMT)inhibitor RG108 on cisplatin-induced ototoxicity.Immunohistochemistry,apoptosis assay,and auditory brainstem response(ABR)were employed to determine the impacts of RG108 on cisplatin-induced injury in murine hair cells(HCs)and spiral ganglion neurons(SGNs).Rhodamine 123 and TMRM were utilized for mitochondrial membrane potential(MMP)assessment.Reactive oxygen species(ROS)amounts were evaluated by Cellrox green and Mitosox-red probes.Mitochondrial respiratory function evaluation was performed by determining oxygen consumption rates(OCRs).The results showed that RG108 can markedly reduce cisplatin induced damage in HCs and SGNs,and alleviate apoptotic rate by protecting mitochondrial function through preventing ROS accumulation.Furthermore,RG108 upregulated BCL-2 and downregulated APAF1,BAX,and BAD in HEI-OC1 cells,and triggered the PI3K/AKT pathway.Decreased expression of low-density lipoprotein receptor-related protein 1(LRP1)and high methylation of the LRP1 promoter were observed after cisplatin treatment.RG108 treatment can increase LRP1expression and decrease LRP1 promoter methylation.In conclusion,RG108 might represent a new potential agent for preventing hearing loss induced by cisplatin via activating the LRP1-PI3K/AKT pathway.

Unidirectional and stage-dependent roles of Notch1 in Wnt-responsive Lgr5+ cells during mouse inner ear development

Wnt and Notch signaling play crucial roles in the determination of the prosensory domain and in the differentiation of hair cells(HCs)and supporting cells during mouse inner ear development;however,the relationship between the two signaling pathways in the mouse cochlea remains largely unknown.Here,we investigated the interactions between Notch and Wnt signaling on the basis of the bidirectional regulation of Notch1 specifically in Wnt-responsive Lgr5+progenitors during different cochlear development stages.We found that the downregulation of Notch1 in Lgr5+cells from embryonic day(E)14.5 to E18.5 can drive the quiescent Lgr5+cells to re-enter the cell cycle and differentiate into extra HCs,whereas the upregulation of Notch1 expression did not affect the proliferation or differentiation of otic progenitor cells.No effect was observed on the upregulation or downregulation of Notch1 in Lgr5+cells from E10.5 to E14.5.We concluded that the roles of Notch1 in Wnt-responsive Lgr5+cells are unidirectional and stage dependent and Notch1 serves as a negative regulator for Lgr5+progenitor activation during cochlear differentiation.Our findings improved the understanding of the interactions between Notch and Wnt signaling in cochlear development.

Bioinspired structural color particles with multi-layer graphene oxide encapsulated nanoparticle components

Because of the unique features of spherical symmetry,angle-independency,good monodispersity,controllable components and morphologies,structural color particles(SCPs)have found great significances in various fields such as sensing,monitoring,biological assays,etc.Here,inspired by the melanosome-derived bright structural colors and the self-adhesivity of mussels,we present a kind of bioinspired SCPs assembled from polydopamine(PDA)-adhered multi-layer graphene oxide(GO)encapsulated silica nanoparticles(SNs).It is demonstrated that compared with traditional SCPs,the designed particles possess brighter and more vibrant structural colors,and no complicated modification is required during the functionalization process due to the abundant inherent functional groups of GO.The resultant SCPs are verified to be capable for direct hybridization chain reaction and multiplexed nucleic acid assays.These properties indicate the promising prospects of our designed SCPs.

Preventing autosomal-dominant hearing loss in Bth mice with CRISPR/CasRx-based RNA editing

CRISPR/RfxCas13d(CasRx)editing system can specifically and precisely cleave single-strand RNAs,which is a promising treatment for various disorders by downregulation of related gene expression.Here,we tested this RNA-editing approach on Beethoven(Bth)mice,an animal model for human DFNA36 due to a point mutation in Tmc1.We first screened 30 sgRNAs in cell cultures and found that CasRx with sgRNA3 reduced the Tmc1^(Bth)transcript by 90.8%,and the Tmc1 wild type transcript(Tmc1^(+))by 44.3%.We then injected a newly developed AAV vector(AAV-PHP.eB)based CasRx into the inner ears of neonatal Bth mice,and we found that Tmc1^(Bth)was reduced by 70.2%in 2 weeks with few off-target effects in the whole transcriptome.Consistently,we found improved hair cell survival,rescued hair bundle degeneration,and reduced mechanoelectrical transduction current.Importantly,the hearing performance,measured in both ABR and DPOAE thresholds,was improved significantly in all ages over 8 weeks.We,therefore,have validated the CRISPR/CasRx-based RNA editing strategy in treating autosomal-dominant hearing loss,paving way for its further application in many other hereditary diseases in hearing and beyond.

The kinase p38αfunctions in dendritic cells to regulate Th2-cell differentiation and allergic inflammation

Dendritic cells(DCs)play a critical role in controlling T helper 2(Th2)cell-dependent diseases,but the signaling mechanism that triggers this function is not fully understood.We showed that p38αactivity in DCs was decreased upon HDM stimulation and dynamically regulated by both extrinsic signals and Th2-instructive cytokines.p38α-specific deletion in cDC1s but not in cDC2s or macrophages promoted Th2 responses under HDM stimulation.Further study showed that p38αin cDC1s regulated Th2-cell differentiation by modulating the MK2−c-FOS−IL-12 axis.Importantly,crosstalk between p38α-dependent DCs and Th2 cells occurred during the sensitization phase,not the effector phase,and was conserved between mice and humans.Our results identify p38αsignaling as a central pathway in DCs that integrates allergic and parasitic instructive signals with Th2-instructive cytokines from the microenvironment to regulate Th2-cell differentiation and function,and this finding may offer a novel strategy for the treatment of allergic diseases and parasitic infection.

Effect of Sodium Salicylate on Calcium Currents and Exocytosis in Cochlear Inner Hair Cells:Implications for Tinnitus Generation

Sodium salicylate is an anti-inflammatory medication with a side-effect of tinnitus.Here,we used mouse cochlear cultures to explore the effects of salicylate treatment on cochlear inner hair cells(IHCs).We found that IHCs showed significant damage after exposure to a high concentration of salicylate.Whole-cell patch clamp recordings showed that 1–5 mmol/L salicylate did not affect the exocytosis of IHCs,indicating that IHCs are not involved in tinnitus generation by enhancing their neuronal input.Instead,salicylate induced a larger peak amplitude,a more negative half-activation voltage,and a steeper slope factor of Ca^(2+)current.Using noise analysis of Ca^(2+)tail currents and qRT-PCR,we further found that salicylate increased the number of Ca^(2+)channels along with CaV1.3 expression.All these changes could act synergistically to enhance the Ca^(2+)influx into IHCs.Inhibition of intracellular Ca^(2+)overload significantly attenuated IHC death after 10 mmol/L salicylate treatment.These results implicate a cellular mechanism for tinnitus generation in the peripheral auditory system.

Development of a Robotic Cochlear Implantation System

Traditional cochlear implantation surgery has problems such as high surgical accuracy requirement and large trauma,which cause the difficulty of the operation and the high requirements for doctors,so that only a few doctors can complete the operation independently.However,there is no research on robotic cochlear implantation in China.In response to this problem,a robotic cochlear implantation system is proposed.The robot is controlled by robot operating system(ROS).A simulation environment for the overall surgery is established on the ROS based on the real surgery environment.Through the analysis of the kinematics and the motion planning algorithm of the manipulator,an appropriate motion mode is designed to control the motion of the manipulator,and perform the surgery under the simulation environment.A simple and feasible method of navigation is proposed,and through the model experiment,the feasibility of robotic cochlear implantation surgery is verified.

Structural insights into Cas9 mismatch:promising for development of high-fidelity Cas9 variants

The recent research published in Nature by Bravo and colleagues has deeply carifed the mechanisms of Cas9 recognizing the base-pair mismatches by kinetics-guided Cryo-EM analysis,which provides a perspective for the development of next-generation Cas9 variants with high fidelity.

Atypical manifestations of acute coronary syndrome—throat discomfort:a multi-center observational study

To present the clinical characteristics and the misdiagnosis rate of acute coronary syndrome manifested primarily as throat discomfort,we conducted a multicentric and retrospective study in the cardiology and otorhinolaryngology departments.Records of patients with primary complaint of throat discomfort,absence of chest pain at onset,and an ultimate diagnosis of acute coronary syndrome,as well as patients with pharyngitis(as controls)were collected from May 2015 to April 2016.The patients’main manifestations were compared.Logistic regression results showed that chest tightness,dyspnea,perspiring,and exertional throat symptoms were significantly associated with acute coronary syndrome,with odds ratios of 8.3(95%CI 2.2–31.5),10.9(95%CI 1.8–66.9),25.4(95%CI 3.6–179.9),and 81.2(95%CI 13.0–506.7).A total of 25(56.82%)out of 44 acute coronary syndrome patients,who were first admitted to the otorhinolaryngology department,were misdiagnosed,with a 12%(3/25)mortality rate.Throat discomfort can be the principal manifestation of acute coronary syndrome.Such patients exhibit high misdiagnosis and mortality rates.Exertional throat symptoms,chest tightness,perspiring,and dyspnea were important indicators of acute coronary syndrome in patients whose main complaint was throat discomfort.The awareness of this condition will result in prompt diagnosis and reduce morbidity and mortality.

Hidden hearing loss:current perspectives and potential therapies

Hidden hearing loss(HHL),an auditory dysfunction that has gained much recent attention,has the hallmarks of speech discrimination and intelligibility deficits with normal or near-normal hearing thresholds.The pathological mechanisms of HHL are complicated and are not yet fully understood.HHL can be resulted from disorders of the central nervous system such as auditory cortex,and/or pathological changes of inner ear.Thus far,2 pathological phenomena,synaptopathy and auditory nerve demyelination,have been reported as underlying causes of otogenic HHL.Here,we review the clinical and physiological characteristics of HHL as well as the molecular pathological mechanisms of otogenic HHL and aim to allude to potential therapy targets for clinical applications in the future.

Artificial Water Channel that Couples with Cell Protrusion Formation

In natural systems,water transport across the cellular plasma membranes is mainly mediated by naturally occurring channel protein aquaporins(AQPs),which lead to a series of important physiological functions including cell migration.The construction of artificial analogs of the natural AQPs would generate a new strategy for treating AQP-related diseases.In this report,an artificial water channel has been developed from a unimolecular tubular molecule,which featured structural encapsulation of a single-file water wire composed of oppositely orientated dipolar water molecules.This AQP-like structure endowed the artificial channel in living cells with AQP-like water permeability and selectivity.Interestingly,the artificial channel coupled with cell protrusion formation by mediating water transmembrane transport,leading to cell shape change and migration acceleration.The artificial channel-facilitated cell migration showed application in enhancing in vivo healing of traumatic injury.

Artificial Water Channel Promoting Depolymerization of Actin Filaments to Trigger Cancer Cell Apoptosis

Actin filaments play important physiological functions,which have become potential targets of antitumor drugs.Using chemicals to intervene their polymerization-depolymerization dynamics would generate new strategies for designing antitumor drugs.In this report,an artificial water channel appending acetazolamide moiety,a ligand that can selectively bind to carbonic anhydrase IX,has been prepared.

Vascularized lymph node flaps can survive on venous blood without an arterial inflow:an experimental model describing the dynamics of venous flow using indocyanine green angiography(With video)

Background:Several surgeons have described studies of free-tissue transfers using veins instead of arteries.These innovative microsurgical techniques can offer several advantages,such as an easier dissection during flap harvesting,and represent an alternative during an accidental surgical mistake or development of new surgical procedures.The purpose of this study was to describe and explore different constructs of vascularized lymph node transfer(VLNT)only based on venous blood flow in a mouse model,evaluate their blood flow microcirculation through indocyanine green(ICG)angiography and investigate the lymphatic drainage function and the lymph nodes’structures.Methods:Five types of venous lymph node flaps(LNF)were created and investigated:Types IA,IB,IC,IIA and IIB were developed by ICG intraoperatively(with videos in the article).Seven weeks later,by applying methylene blue,the recanalization of the lymphatic vessels between the LNF and the recipient site was detected.Lymph nodes were collected at the same time and their structures were analyzed by hematoxylin and eosin staining analysis.Results:All of the venous LNFs developed except Type IC.Seven weeks later,methylene blue flowed into Types IA,IB,IIA and IIB from recipient sites.When comparing with arteriovenous lymph node,the medullary sinus was diffusely distributed in venous lymph nodes.The proportion of cells was significantly reduced(p<0.05).The artery diameters were significantly smaller(p<0.05).The veins diameters and lymphatic vessels output in Types IA,IB,IIA and IIB were more dilated(p<0.05).Conclusions:This research demonstrated that Type IA,IB,IIA and IIB venous LNFs can retrogradely receive venous blood supply;they can survive,produce a lymphatic recanalization and integrate with the surrounding tissue,despite lymph node structural changes.Our results will improve the understanding of the survival mechanism of venous LNFs and will help researchers to design new studies or lymphatic models and eventually find an alternative procedure for the surgical treatment of lymphedema.