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Mendelian susceptibility to mycobacterial disease (MSMD) is a rare monogenetic disease, which is characterized by susceptibility to some weakly virulent mycobacteria. Here, we explored the pathogenic genes and molecular mechanisms of MSMD patients. We recruited three patients diagnosed with MSMD from two families. Two novel mutations (c.1228A > G, p.K410E and c.2071A > G, p.M691V) in STAT1 gene were identified from two families. The translocation of K410E mutant STAT1 protein into nucleus was not affected. The binding ability between gamma-activating sequence (GAS) and K410E mutant STAT1 protein was significantly reduced, which will reduce the interaction between STAT1 protein with the promoters of target genes. The M691V mutant STAT1 protein cannot translocate into the nucleus after IFN-γ stimulation, which will affect the STAT1 protein form gamma-activating factors (GAF) and bind the GAS in the promoter region of downstream target genes. Taken together, our results showed that the mutation of K410E led to impaired binding of STAT1 to target DNA, and the mutation of M691V prevented the transport of STAT1 into the nucleus, which led to MSMD. Together, we identified two novel mutations (c.1228A > G, p.K410E and c.2071A > G, p.M691V) in STAT1 gene in MSMD patients, and deciphered the molecular mechanism of MSMD caused by STAT1 mutations.

Hemorrhagic transformation (HT) is a common complication after thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) in ischemic stroke. In this article, recent research progress of HT in vivo and in vitro studies was reviewed. We have discussed new potential mechanisms and possible experimental models of HT development, as well as possible biomarkers and treatment methods. Meanwhile, we compared and analyzed rodent models, large animal models and in vitro BBB models of HT, and the limitations of these models were discussed. The molecular mechanism of HT was investigated in terms of BBB disruption, rt-PA neurotoxicity and the effect of neuroinflammation, matrix metalloproteinases, reactive oxygen species. The clinical features to predict HT were represented including blood biomarkers and clinical factors. Recent progress in neuroprotective strategies to improve HT after stroke treated with rt-PA is outlined. Further efforts need to be made to reduce the risk of HT after rt-PA therapy and improve the clinical prognosis of patients with ischemic stroke.

Background Male infertility is a major issue in human reproduction health, yet known genetic factors are only responsible for a small fraction of cases. TSGA10 is a testis-specific protein that is highly conserved among different species. A previous study has reported a homozygous mutation in TSGA10 in a male infertile patient; however, function analysis of Tsga10 genes in knockout mice has not yet been undertaken. Objectives The aim of the present work was to analyse the function of TSGA10 protein in the spermatogenesis of Tsga10+/- mice. Materials and methods Tsga10+/- mice were generated by CRISPR/Cas9 technology, in vitro fertilization (IVF), western blot, co-immunoprecipitation and other methods were used to the function analysis. Results Heterozygous Tsga10 male mice created by CRISPR/Cas9 were infertile and presented significantly reduced sperm motility because of disordered mitochondrial sheath formation. Furthermore, TSGA10 can interact with GRP78 and NSUN2, which are associated with peri-implantation lethality and the gonadotropin-releasing hormone (GnRH) network. Discussion and conclusion We demonstrate that deficiency of Tsga10 gene can lead to male infertility in mice. TSGA10 is involved in the correct arrangement of mitochondrial sheath in spermatozoa. Future studies on TSGA10 include an in-depth exploration of the underlying mechanisms of TSGA10 in spermatogenesis, early embryonic development and GnRH network.

In this review paper, the most recent research on intracerebral hemorrhage (ICH) is summarized and novel perspectives are offered on the pathomechanisms of ICH. These underlying pathomechanisms of ICH provide clues for development of novel drugs or drug target screening. Specifically, recent research has provided evidence that iron chelators, lipid peroxidation/ferroptosis inhibitors, agonists or antagonists of prostaglandin E2 receptors (EP1/3 or EP2), and nonsteroidal anti-inflammatory drugs protect against ICH-induced brain edema, secondary brain tissue damage as well as inhibition of the toxicity in related tissue damage products. This review will provide a theoretical basis for testing new compounds that may have potential for future clinical trials.

In this review, we compare behavioral protocols (e.g., equipment specification, test duration), evaluation indexes, application characteristics, and advantages and disadvantages of six tests used to assess post-stroke depression and anxiety in rodent models. We also discuss experimental models of intracerebral hemorrhage, the neuroanatomic and pathophysiologic basis of behavioral tests, their applications in drug screening, and their limitations. This review will facilitate the performance of behavioral tests in basic research and ultimately provide references for the clinical diagnosis and treatment of post-stroke depression.

Immunologic changes in the hematoma of patients with intracerebral hemorrhage (ICH) and the contribution of these changes to prognosis are unknown. We collected the blood samples and hematoma fluid from 35 patients with acute ICH (

Background and objectives Widespread applications of supercontinuum (SC) source lead to the possibility of ocular damages. However, the corneal damage effects induced by SC have not been explored before. The objectives of this study are to determine the rabbit corneal injury threshold for SC radiation and to examine whether the existing safety guidelines and standards are suitable for the hazard evaluation of this new kind of light source. Study design/materials and methods A series of experiments was conducted in the New Zealand white rabbit model to determine the corneal damage thresholds induced by a 770-2,500 nm SC source, with a corneal 1/e beam diameter of 0.37 mm. Through slit-lamp biomicroscope, optical coherence tomography (OCT), and histopathology the corneal damage characteristics at the threshold level were revealed. By employing the action spectra determined through the analysis of safety guidelines and standards, the damage thresholds for SC source could be compared with the corresponding exposure limits. Results The determined damage thresholds given in terms of the peak radiant exposure for exposure durations of 2.0 and 10.0 seconds were 2.1 × 103 and 7.4 × 103 J/cm2 , respectively. At threshold level, corneal damages involved the epithelium and the shallower stroma, and no obvious changes could be found in the deep stroma, Descemet's membrane, and endothelium. Conclusions The exposure limits for the anterior parts of the eye in the wavelength range of 700-1,200 nm are overly conservative. The obtained results contribute to the knowledge base for the hazard evaluation of SC source. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

PURPOSE: To identify the disease-causing gene in a family with female infertility and fertilization failure. METHODS: Whole-exome sequencing and Sanger sequencing were used to identify the disease-causing gene in a female with infertility and fertilization failure. Subcellular localization and western blot analysis were used to check the effect of mutations. RESULTS: We identified novel compound heterozygous mutations c.598C>T (p.Arg200Ter) and c.1319G>C (p.Trp440Ser) in WEE2 gene in a female with infertility and fertilization failure. The p.Arg200Ter mutant WEE2 gene produce truncated protein and mainly located in the nucleus, the same as the wild protein, while the p.Trp440Ser mutant WEE2 proteins are located in the nucleus and cytoplasm and the expression level of p.Trp440Ser mutant WEE2 protein is reduced significantly compared with that of wild-type WEE2. CONCLUSIONS: We discovered novel compound heterozygous mutations c.598C>T (p.Arg200Ter) and c.1319G>C (p.Trp440Ser) in WEE2 gene in a female whose oocytes could not form pronucleus after intracytoplasmic sperm injection (ICSI). Moreover, mutations in WEE2 gene affect the normal function of WEE2 proteins and cause fertilization failure.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third human coronavirus within 20 years that gave rise to a life-threatening disease and the first to reach pandemic spread. To make therapeutic headway against current and future coronaviruses, the biology of coronavirus RNA during infection must be precisely understood. Here, we present a robust and generalizable framework combining high-throughput confocal and super-resolution microscopy imaging to study coronavirus infection at the nanoscale. Employing the model human coronavirus HCoV-229E, we specifically labeled coronavirus genomic RNA (gRNA) and double-stranded RNA (dsRNA) via multicolor RNA-immunoFISH and visualized their localization patterns within the cell. The 20nm resolution achieved by of our approach uncovers a striking spatial organization of gRNA and dsRNA into three distinct structures and enables quantitative characterization of the status of the infection after antiviral drug treatment. Our approach provides a comprehensive imaging framework that will enable future investigations of coronavirus fundamental biology and therapeutic effects., Graphical Abstract

Intracerebral hemorrhage (ICH) is the second most common type of stroke and has one of the highest fatality rates of any disease. There are many clinical signs and symptoms after ICH due to brain cell injury and network disruption resulted from the rupture of a tiny artery and activation of inflammatory cells, such as motor dysfunction, sensory impairment, cognitive impairment, and emotional disturbance, etc. Thus, researchers have established many tests to evaluate behavioral changes in rodent ICH models, in order to achieve a better understanding and thus improvements in the prognosis for the clinical treatment of stroke. This review summarizes existing protocols that have been applied to assess neurologic function outcomes in the rodent ICH models such as pain, motor, cognition, and emotion tests. Pain tests include mechanical, hot, and cold pain tests; motor tests include the following 12 types: neurologic deficit scale test, staircase test, rotarod test, cylinder test, grid walk test, forelimb placing test, wire hanging test, modified neurologic severity score, beam walking test, horizontal ladder test, and adhesive removal test; learning and memory tests include Morris water maze, Y-maze, and novel object recognition test; emotion tests include elevated plus maze, sucrose preference test, tail suspension test, open field test, and forced swim test. This review discusses these assessments by examining their rationale, setup, duration, baseline, procedures as well as comparing their pros and cons, thus guiding researchers to select the most appropriate behavioral tests for preclinical ICH research.

The non-ionizing and non-invasive nature of THz radiation, combined with its high sensitivity to water, has made THz imaging and spectroscopy highly attractive for in vivo biomedical applications for many years. Among them, the skin is primarily investigated due to the short penetration depth of THz waves caused by the high attenuation by water in biological samples. However, a complete model of skin describing the THz–skin interaction is still needed. This is also fundamental to reveal the optical properties of the skin from the measured THz spectrum. It is crucial that the correct model is used, not just to ensure compatibility between different works, but more importantly to ensure the reliability of the data and conclusions. Therefore, in this review, we summarize the models applied to skin used in the THz regime, and we compare their adaptability, accuracy, and limitations. We show that most of the models attempt to extract the hydration profile inside the skin while there is also the anisotropic model that displays skin structural changes in the stratum corneum.

Tubulin beta 8 class VIII (TUBB8) is a special β-tubulin isotype that mainly expressed in primate oocytes and early embryos and identified as the disease-causing gene of human oocyte maturation arrest. To identify the disease-causing genes in 2 patients with female infertility due to large polar body oocyte or fertilization failure, whole-exome sequencing was performed on the patients and available family members. We identified a novel heterozygous missense mutation c.817C>G (p.L273V) and a recently reported heterozygous missense mutation c.608A>G (p.D203G) in TUBB8 from two patients, respectively. We found oocyte with a large polar body in the patient who carried the p.D203G mutation in TUBB8. Bioinformatics analysis showed that these two mutations are harmful. The results of western blot and RT-PCR experiments showed that the D203G mutation caused a significant decrease in the expression of TUBB8, and immunostaining showed that the TUBB8 mutation caused abnormal microtubule morphology. These findings suggest that TUBB8 mutations resulted in oocyte with a large polar body and fertilization failure in patients.

Objective. The objective of this study is to assess the effectiveness of erythropoietin (EPO) on mortality, neurological outcomes, and adverse event in the treatment of traumatic brain injury (TBI). Methods. We searched databases including PubMed, OVID, and the Cochrane Library from inception until October 18, 2019 for randomized controlled trials (RCTs) to compare EPO treatment group and placebo in patients with TBI. Two authors independently processed the data and evaluated the quality of inclusion studies. Statistical analysis was performed with heterogeneity test with I 2 and chi-square tests. We summarized the mortality, prognosis of neurological function, and deep vein thrombosis (DVT) outcomes and presented as risk ratio (RR) or risk difference (RD) with a 95% CI. Results. Seven RCTs accounting for 1180 patients were included after meeting the inclusion criteria. Compared with placebo, the overall mortality of EPO-treated patients was significantly reduced (RR 0.68 [95% CI 0.50-0.93]; p = 0.02 ). EPO therapy did not improve neurological prognosis (RR 1.21 [95% CI 0.93-1.15]; p = 0.16 ) or increase the occurrence of DVT (RR 0.83 [95% CI 0.61–1.13]; p = 0.242 ), which showed no significant difference. Conclusions. The results showed that the administration of EPO may reduce the risk of mortality without enhancing the occurrence of DVT in TBI patients. However, the effect of EPO on neurological outcome remains indistinct. Through subgroup analysis, we demonstrated that the dose of EPO may be a potential factor affecting the heterogeneity in neurological function and that the follow-up duration may influence the stability of the result.

This paper describes the design and development of CUCHILD, a large-scale Cantonese corpus of child speech. The corpus contains spoken words collected from 1,986 child speakers aged from 3 to 6 years old. The speech materials include 130 words of 1 to 4 syllables in length. The speakers cover both typically developing (TD) children and children with speech disorder. The intended use of the corpus is to support scientific and clinical research, as well as technology development related to child speech assessment. The design of the corpus, including selection of words, participants recruitment, data acquisition process, and data pre-processing are described in detail. The results of acoustical analysis are presented to illustrate the properties of child speech. Potential applications of the corpus in automatic speech recognition, phonological error detection and speaker diarization are also discussed., Accepted to INTERSPEECH 2020, Shanghai, China

Introduction The origin of contactin-associated protein-like 2 (Caspr2) antibodies in patients with Morvan syndrome is currently unknown. This case report investigated a possible association between the production of Caspr2 antibodies and aberrant proliferation of B lymphocytes. Case report We admitted a critically ill 65-year-old female patient with a suspected infection of the central nervous system (CNS). In addition to acquired neuromyotonia and CNS involvement, Caspr2 antibodies detected in her serum led to the presumptive diagnosis of Morvan syndrome. However, steroid and immunoglobulin treatment did not result in a satisfactory therapeutic outcome. On the basis of findings from immunohistochemistry, flow cytometric analysis, and immunoglobulin/T-cell receptor gene rearrangement detection of cerebrospinal fluid cells, we also made a concurrent diagnosis of diffuse large B-cell lymphoma in the CNS of this patient. The patient then received 4 cycles of rituximab and methylprednisolone therapy with an interval of 2 weeks, which temporarily led to a near-complete remission of her symptoms. Upon follow-up, her symptoms relapsed at 3 months after the last treatment with rituximab and methylprednisolone. Conclusions This is a first reported case of a patient who was concurrently diagnosed with Morvan syndrome and diffuse large B-cell lymphoma in the CNS. Additional studies are needed to determine whether aberrantly proliferating B lymphocytes are responsible for the production of Caspr2 antibodies.

Background X-linked intellectual disability type Nascimento, also known as UBE2A deficiency syndrome, is an intellectual disability syndrome characterized by moderate to severe intellectual disability, dysmorphic facial features, speech impairment, genital anomalies and skin abnormalities. The syndrome is caused by mutations of the UBE2A gene, or larger deletions of Xq24 encompassing UBE2A. Methods We report the case of a 19-year-old male with UBE2A deficiency syndrome, who showed severe intellectual disability and seizures. Whole exome sequencing and Sanger sequencing were used to identify the disease-causing mutations in this patient. Results A novel hemizygous missense UBE2A mutation (c.TAT245TGT, p.Tyr82Cys) was identified in our patient. The heterozygous missense UBE2A mutation was identified in his mother, although not in his father or sister. Conclusions The present study identified a novel UBE2A mutation in a patient with severe intellectual disability and seizures. Our findings expand the mutational spectrum of the UBE2A gene.

Importance: Since December 2019, a novel coronavirus (SARS-CoV-2) causing COVID-19 has spread across the world in a global pandemic. Tens of thousands of people were infected, several thousand patients died. However, key risk factors for predicting mortality remain unclear.Objective: To identify the key risk factors for COVID-19 mortality.Design, Setting, Participants: Retrospective, randomly selected eight family clusters consisting of 21 individual cases who had been confirmed positive for SARS-CoV-2 and admitted to the Wuhan Union Hospital, Wuhan, China, from February 6 to March 3 2020. This study aims to analyze the differences in mortal risk factors between fatal and non-fatal cases within each family.

Background Hematoma expansion (HE) and peri-hematomal edema (PHE) are associated with adverse outcomes of patients with acute spontaneous intracerebral hemorrhage (sICH). Due to a lack of proven treatments, it is critical to explore novel treatments for HE and PHE to improve functional recovery after sICH. Methods This is a prospective, multicenter, placebo-controlled, double-blind, and randomized clinical study of approximately 2400 patients with sICH. Patients within 4.5 h of sICH onset that fulfilling the clinical criteria for diagnosis (e.g. age more than 18 years old, the Glasgow Coma Scal>7, and no planned surgery) will randomly receive either intravenous tranexamic acid (TXA) 1 g 10-min bolus followed by 1 g eight-hour infusion or placebo (sodium chloride 0.9%). Clinical data including the ICH score and the Glasgow Coma Scale score will be collected on admission. After assessment of HE and PHE expansion, follow-up will be conducted with enrolled patients for 90 days. Results Primary outcome metrics are HE (defined as either >33% or >6 ml increase from baseline) and PHE expansion rate at 24 ± 3 h and 72 ± 3 h post-sICH. Secondary outcome metrics include mortality and the modified Rankin Scale on day 90 after sICH. Appropriate statistic methods will be used to evaluate the efficacy of TXA on patients with sICH within 4.5 h of symptom onset. Conclusions HE usually occurs within the first few hours after onset of symptoms. It is essential to evaluate the efficacy of TXA on HE within a narrow window of time. This will be the first trial to evaluate the efficacy of TXA on HE and PHE expansion in sICH patients within 4.5 h after symptom onset. This trial is registered as ChiCTR1900027065 at http://www.chictr.org.cn .

PURPOSE: To identify the disease gene in 40 patients with female infertility due to oocyte maturation arrest. METHODS: Genomic DNA was extracted from peripheral blood of 40 patients and their family members. Whole-exome sequencing was performed on the patients, and the PATL2 mutations were identified and confirmed by Sanger sequencing. Harmfulness of the mutations was analyzed by SIFT, Polyphen-2, Mutation Taster, and M-CAP software, and we used western immunoblotting analysis to check the effect of mutations on PATL2 protein expression in vitro. RESULTS: Two novel missense mutations c.1528C>A (p.Pro510Thr) and c.1376C>A (p.Ser459Tyr) in PATL2 were identified in three patients (7.5%) from two consanguineous families in our cohort. We found that mutations in PATL2 resulted in variable oocyte phenotypes, including GV arrest, MI arrest, and morphologic abnormalities. Western immunoblotting analysis showed that the expression levels of the two novel mutant PATL2 proteins decreased significantly. CONCLUSIONS: We identified two novel PATL2 mutations that caused oocyte maturation arrest and abnormal morphology, and variable phenotypes in patients.

Transdermal drug delivery (TDD) is widely used for painless dosing due to its minimally invasive nature compared to hypodermic needle injection and its avoidance of the gastrointestinal tract. However, the stratum corneum obstructs the permeation of drugs into skin. Microneedle and nanoneedle patches are ways to enhance this permeation. In this work, terahertz (THz) imaging is utilized to compare the efficacy of different TDD methods including topical application and via a needle patch. Our work shows the feasibility and potential of using THz imaging to quantify and evaluate different transdermal application methods.

Background. Group A streptococcus (GAS) infections and poststreptococcal sequelae remain a health problem worldwide, which necessitates searching for an effective vaccine, while no licensed GAS vaccine is available. We have developed a divalent peptide vaccine composed of 84 amino acids to cover the main GAS serotypes (M1 and M12 streptococci) in China, and herein, we aimed to evaluate immunogenicity and safety of this vaccine.Methods. Mice were immunized with the vaccine. ELISA, indirect bactericidal test, and immunofluorescent assay were used to study immunogenicity. GAS challenge assay was used to test the protective effect. Safety was tested by histopathological analysis.Results. Immunized group mice (n=16) developed higher titer antibody after immunization than nonimmunized group mice (n=16) did. This antibody can deposit on the surface of GAS and promote killing of GAS, resulting in 93.1% decrease of M1 GAS and 89.5% of M12 GAS. When challenged with M1 and M12 streptococci, immunized group mice had a higher survival rate (87.5% and 75%) than nonimmunized group mice (37.5% and 25%). No autoimmune reactions were detected on organs of mice.Conclusion. The results suggest that this vaccine shows fair immunogenicity and safety, which will lead our research on GAS vaccine into clinical trial.

Secretory carrier membrane proteins (SCAMPs) play an important role in exocytosis in animals, but the precise function of SCAMPs in human disease is unknown. In this study, we identified a homozygous mutation, SCAMP5 R91W, in a Chinese consanguineous family with pediatric epilepsy and juvenile Parkinson's disease. Scamp5 R91W mutant knock-in mice showed typical early-onset epilepsy similar to that in humans. Single-neuron electrophysiological recordings showed that the R91W mutation significantly increased the frequency of miniature excitatory postsynaptic currents (mEPSCs) at a resting state and also increased the amplitude of evoked EPSCs. The R91W mutation affected the interaction between SCAMP5 and synaptotagmin 1 and may affect the function of the SNARE complex, the machinery required for vesicular trafficking and neurotransmitter release. Our work shows that dysfunction of SCAMP5 shifted the excitation/inhibition balance of the neuronal network in the brain, and the deficiency of SCAMP5 leads to pediatric epilepsy.

The cell cycle-regulated methylation state of Caulobacter DNA mediates the temporal control of transcriptional activation of several key regulatory proteins. Temporally controlled synthesis of the CcrM DNA methyltransferase and Lon-mediated proteolysis restrict CcrM to a specific time in the cell cycle, thereby allowing the maintenance of the hemimethylated state of the chromosome during the progression of DNA replication. We determined that a chromosomal DNA-based platform stimulates CcrM degradation by Lon and that the CcrM C terminus both binds to its DNA substrate and is recognized by the Lon protease. Upon asymmetric cell division, swarmer and stalked progeny cells employ distinct mechanisms to control active CcrM. In progeny swarmer cells, CcrM is completely degraded by Lon before its differentiation into a replication-competent stalked cell later in the cell cycle. In progeny stalked cells, however, accumulated CcrM that has not been degraded before the immediate initiation of DNA replication is sequestered to the cell pole. Single-molecule imaging demonstrated physical anticorrelation between sequestered CcrM and chromosomal DNA, thus preventing DNA remethylation. The distinct control of available CcrM in progeny swarmer and stalked cells serves to protect the hemimethylated state of DNA during chromosome replication, enabling robustness of cell cycle progression.

With the rapid developments and widespread applications of supercontinuum (SC) sources, ocular damage induced by this new light source becomes possible and receives our concern. To explore the ocular damage effect of an SC source, a series of experiments were conducted in a chinchilla grey rabbit model to determine the in-vivo retinal damage thresholds induced by a 420-750 nm SC source and a 532 nm laser. For the SC source, the beam divergence and the corneal 1/e(2) beam diameter were 3.8 mrad and 2.45 mm, respectively. The determined ED(50) values given in terms of total intraocular energy (TIE) for exposure durations of 0.1, 1.0, and 10.0 s were 1.57, 12.1, and 86.0 mJ, respectively. For the 532 nm laser, the beam divergence and the corneal 1/e(2) beam diameter were 0.9 mrad and 2.25 mm, respectively. The determined ED(50) value for an exposure duration of 0.1 s was 1.39 mJ. By employing the retinal thermal action spectrum in the ICNIRP guidelines, the damage thresholds for SC sources could be compared with the exposure limits for incoherent and laser radiation. Between the 420-750 nm SC source and the 532 nm laser, no significant difference could be found for the damage effects including damage threshold, retinal lesion size, and histological damage characteristics.

Mendelian Susceptibility to Mycobacterial Diseases (MSMD) is a primary immunodeficiency disease (PID) characterized by variable susceptibility to weakly virulent mycobacteria (Bacille Calmette-Guerin, BCG) and various intramacrophagic bacteria, fungi, parasites. Mycobacterial disease generally begins in childhood, more rarely during adolescence and adulthood. The pathogenesis of MSMD is the inherited impaired production of interferon gamma (IFN-γ) or inadequate response to it. Autosomal recessive IL12RB1 deficiency is the most common genetic etiology of MSMD. Here we identified three novel compound heterozygous mutations in IL12RB1 gene (c.635G>A, c.765delG; c.632G>C, c.847C>T; c.64G>A, c.1673insGAGCTTCCTGAG) in three Chinese families with MSMD.

BACKGROUND We analyzed the effect of limitation of movement of the first metatarsophalangeal joint (FMJ) on the biomechanics of the lower limbs during walking. MATERIAL AND METHODS Eight healthy college students completed walking under barefoot (BF) and FMJ constraint (FMJC) conditions. We synchronously collected kinematics and dynamics data, and calculated the torque, power, and work of hip, knee, and ankle joints. RESULTS Compared with normal conditions, when the FMJ is restricted from walking, the maximum ankle dorsiflexion angle is significantly increased (P

SUMMARY Cognition depends on rapid and robust communication between neural circuits spanning different brain areas. We investigated the mesoscopic network of cortico-cortical interactions in the human brain in an extensive dataset consisting of 6,024 h of intracranial field potential recordings from 4,142 electrodes in 48 subjects. We evaluated communication between brain areas at the network level across different frequency bands. The interaction networks were validated against known anatomical measurements and neurophysiological interactions in humans and monkeys. The resulting human brain interactome is characterized by a broad and spatially specific, dynamic, and extensive network. The physiological interactome reveals small-world properties, which we conjecture might facilitate efficient and reliable information transmission. The interaction dynamics correlate with the brain sleep/awake state. These results constitute initial steps toward understanding how the interactome orchestrates cortical communication and provide a reference for future efforts assessing how dysfunctional interactions may lead to mental disorders., Graphical Abstract, In brief Cognition relies on rapid and robust communication between brain areas. Wang et al. leverage multi-day intracranial field potential recordings to characterize the human mesoscopic functional interactome. They validated the methods using monkey anatomical and physiological data. The human interactome reveals small-world properties and is modulated by sleep versus awake state.

When milling a thin-walled workpiece, knowledge of machining error due to the workpiece deformation induced by cutting force is crucial to ensuring the quality of the final machined part. In the current research of deformation prediction, the finite element method (FEM) is the dominant tool for calculating the deformation induced by the cutting force. However, FEM needs tremendous manual effort to generate a mesh of the in-process workpiece (IPW) and cannot be directly applied to discrete structured models such as the voxel or dexel models that are widely used for its advantage on parallel computation. In addition, a very fine mesh is needed for FEM to preserve the geometry of IPW, but it will lead to a huge global stiffness matrix. Therefore, it calls for a new method of fast deformation prediction in the milling of thin-walled workpieces. In this paper, aiming at the fast prediction of the deformation error of five-axis milling directly and efficiently on the voxel model, we present a prediction algorithm based on a combination of the finite cell method (FCM) and the voxel model. Specifically, in this study, a pipeline of FCM combined with the voxel model is specially designed for the efficient analysis of IPW deformation along a continuous tool path in the five-axis milling of thin-walled workpieces. By introducing a technique of partially updating the global stiffness matrix and the cells’ stiffness matrices, the proposed algorithm can tremendously reduce the FCM calculation time per sample point on the tool path, by as much as 19 times in our test examples. Both computer simulation and physical cutting experiments performed by us have convincingly verified the accuracy of the proposed deformation prediction algorithm. To our best knowledge, this is the first work of introducing FCM on the voxel model to the prediction of deformation induced by cutting force in milling problems, which enables customized tool path design and optimization in the five-axis milling of free-form surfaces.

Speech sound disorder (SSD) in children refers to persistent errors in producing certain speech sounds after the expected age of acquisition. This demonstration system performs automated assessment of SSD for Cantonese-speaking pre-school children. The system comprises a mobile application software, a back-end automatic speech recognition (ASR) system for child speech, and a clinically informed assessment scheme. It can be used to detect and identify suspected SSD symptoms at an early stage.

Diabetes may affect myocardial fibrosis through oxidative stress. Trimetazidine (TMZ) is an anti-anginal agent. The present study aimed to determine the modulatory effect of TMZ on reactive oxygen species (ROS) and connective tissue growth factor (CTGF) expression and to evaluate the potential of TMZ to improve diastolic function in streptozotocin (STZ)-induced diabetic rats. After treating STZ-induced diabetic rats with TMZ for 16 weeks, a decrease in malondialdehyde levels, cardiac collagen volume fraction, left ventricular (LV) end-diastolic pressure and protein expression of collagen-I (Col I), Col III and CTGF compared with those in diabetic control rats was observed. In vitro, TMZ inhibited Col I, Col III and CTGF protein expression in cardiac fibroblasts treated with high glucose and decreased intracellular ROS generation and hydroxyproline content in the cell culture medium of cardiac fibroblasts. TMZ markedly improved cardiac fibrosis and diastolic function in diabetic rats. This effect was associated with a reduction in ROS production and CTGF expression in cardiac fibroblasts. The present study suggests that TMZ may be beneficial for protecting the hearts of diabetic patients.

Background Working memory, as a complex system, consists of two independent components: manipulation and maintenance process, which are defined as executive control and storage process. Previous studies mainly focused on the overall effect of transcranial direct current stimulation (tDCS) on working memory. However, little has been known about the segregative effects of tDCS on the sub-processes within working memory. Method Transcranial direct current stimulation, as one of the non-invasive brain stimulation techniques, is being widely used to modulate the cortical activation of local brain areas. This study modified a spatial n-back experiment with anodal and cathodal tDCS exertion on the right dorsolateral prefrontal cortex (DLPFC), aiming to investigate the effects of tDCS on the two sub-processes of working memory: manipulation (updating) and maintenance. Meanwhile, considering the separability of tDCS effects, we further reconfirmed the causal relationship between the right DLPFC and the sub-processes of working memory with different tDCS conditions. Results The present study showed that cathodal tDCS on the right DLPFC selectively improved the performance of the modified 2-back task in the difficult condition, whereas anodal tDCS significantly reduced the performance of subjects and showed an speeding-up tendency of response time. More precisely, the results of discriminability index and criterion showed that only cathodal tDCS enhanced the performance of maintenance in the difficult condition. Neither of the two tDCS conditions affected the performance of manipulation (updating). Conclusion These findings provide evidence that cathodal tDCS of the right DLPFC selectively affects maintenance capacity. Besides, cathodal tDCS also serves as an interference suppressor to reduce the irrelevant interference, thereby indirectly improving the working memory capacity. Moreover, the right DLPFC is not the unique brain regions for working memory manipulation (updating).

There is an increasing use of near-infrared lasers in biomedical applications operating in the spectrum between 1300 and 1400 nm. To corroborate and expand the existing safety data for skin exposure to lasers in this wavelength region, the in-vivo ED50 damage thresholds were determined in Guizhou miniature pigs for 1319-nm laser radiation. Exposure durations of 0.4, 1.0, and 3.0 s and 1 / e 2 beam diameters of 0.98 and 1.96 cm were employed. Damage lesion determinations were performed at 1- and 24 h post exposure. The Bliss probit analysis was employed to establish the ED50 damage thresholds. Histopathological studies of skin damage were performed at 48 h after irradiation to reveal the damage characteristics. The skin damage thresholds at 1 h post exposure, given in peak radiant exposure, were 35.5, 36.1, and 37.1 J / cm2 at exposure durations of 0.4, 1.0, and 3.0 s with the spot diameter of 0.98 cm, and 28.6 J / cm2 at exposure duration of 3.0 s with the spot diameter of 1.96 cm. At 24 h post exposure, the ED50s increased slightly. Histologically, the thermal damage characteristics at the near-threshold level included gathering of the nuclear chromatin and cell vacuolation in the epidermis and deposition of blood cells in the capillary vessels. However, at the apparently above-threshold level, the damage characteristics included obvious stretching of the nuclear chromatin in the epidermis, closing of the capillary lumen, structural change of collagen fibers, and coagulative necrosis of the hair follicle cells. The damage induced by this laser could go deep into the fatty tissue. The obtained results may contribute to the knowledge base for the damage mechanisms and expand the database for the refinement of laser safety standards in the wavelength range of 1300 to 1400 nm.

Background and Objectives The purpose of this study was to explore the retinal injury thresholds in rabbits and evaluate the influence of retinal pigmentation on threshold irradiance at laser wavelengths of 532, 578, and 630 nm which might be involved in hypocrellin B (HB) and hematoporphyrin monomethyl ether (HMME) photodynamic therapy (PDT) for choroidal neovascularization (CNV). Materials and Methods The eyes of pigmented and non-pigmented rabbits were exposed to 532, 578, and 630 nm lasers coupled to a slit lamp biological microscope. The exposure duration was 100 seconds and the retinal spot size was 2 mm throughout the experiment. The minimum visible lesions were detected by funduscopy at 1 and 24 hours post exposure. Bliss probit analysis was performed to determine the ED50 thresholds, fiducial limits and probit slope. Results In pigmented rabbits, the 24-hour retinal threshold irradiances at 532, 578, and 630 nm were 1,003, 1,475, and 1,720 mW/cm2, respectively. In non-pigmented rabbits, the 24-hour threshold irradiances were 1,657, 1,865, and 15,360 mW/cm2, respectively. The ED50 for 24-hour observation differed very little from the ED50 for 1-hour observation. The non-pigmented rabbits required a ninefold increase in threshold irradiance at 630 nm comparing to the pigmented rabbits. Conclusion This study will contribute to the knowledge base for the limits of laser irradiance in application of HB or HMME PDT for CNV. Lasers Surg. Med. 46:54–60, 2014. © 2013 Wiley Periodicals, Inc.

Background and Objectives: High energy loss of 1,319 nm laser due to pre-retinal water absorption makes the ocular axial length more critical, while the relative low absorbance of melanin makes retinal pigmented epi- thelium less contributing, to retinal damage threshold. However, both have never been illustrated experimen- tally. Here we determined and compared the retinal dam- age thresholds at this wavelength in three species with different axial lengths and retinal pigmentations. The cor- neal damage threshold was also determined for further comparative analysis. Materials and Methods: The retinal damage thresholds of albino rat, non-pigmented and pigmented rabbit, and the corneal damage threshold of non-pigmented rabbit were determined for 0.2 and/or 0.4-second exposure durations. The incident beam diameter on cornea was 5 mm for rabbit retinal and 2 mm for rat retinal and rabbit corneal lesion. Minimum visible lesions were examined 1- and 24-hour post-exposure. Probit analysis was used to establish the estimated damage threshold for 50% of exposures (ED50). The direct transmittance of pre-retinal eye media was used for further comparative

Water diffusion and the concentration profile within the skin significantly affect the surrounding chemical absorption and molecular synthesis. Occluding the skin causes water to accumulate in the top layer of the skin (the stratum corneum) and also affects the water diffusivity. Scar treatments such as silicone gel and silicone sheets make use of occlusion to increase skin hydration. However with existing techniques, it is not possible to quantitatively measure the diffusivity of the water during occlusion: current methods determine water diffusivity by measuring the water evaporated through the skin and thus require the skin to breathe. In this work we use the high sensitivity of terahertz light to water to study how the water content in the stratum corneum changes upon occlusion. From our measurements, we can solve the diffusion equations in the stratum corneum to deduce the water concentration profile in occluded skin and subsequently to determine the diffusivity. To our knowledge this is the first work showing how the diffusivity of human skin can be measured during occlusion and we envisage this paper as being used as a guide for non‐invasively determining the diffusivity of occluded human skin in vivo.

The corneal damage effects induced by 1319-nm transitional near-infrared laser have been inves- tigated for years. However, the damage threshold dependence on exposure duration has not been revealed. The in vivo corneal damage thresholds (ED50s) were determined in New Zealand rabbits for 1319-nm laser radiation for exposure durations from 75 ms to 10 s. An additional corneal ED50 was determined at 1338 nm for a 5-ms exposure. The incident corneal irradiance diameter was fixed at 2 mm for all exposure conditions to avoid the influence of spot size on threshold. The ED50s given in terms of the corneal radiant exposure for exposure dura- tions of 5 ms, 75 ms, 0.35 s, 2 s, and 10 s were 39.4, 51.5, 87.2, 156.3, and 311.1 J∕cm 2 , respectively. The 39.4 J∕cm 2 was derived from the ED50 for 1338 nm (27.0 J∕cm 2 ). The ED50s for exposure durations of 75 ms to 10 s were correlated by a power law equation, ED50 ¼ 128.9t 0.36 in J∕cm 2 , where t was the input in the unit of second, with correlation coefficient (R) of 0.997. Enough safe margins existed between the ED50s and the maxi- mum permitted exposures from current laser safety standard. © 2016 Society of Photo-Optical Instrumentation Engineers (SPIE)

The ocular damage effects induced by transitional near-infrared (NIR) lasers have been investigated for years. However, no retinal damage thresholds are determined in a wide interval between 0.65 ms and 80 ms, and a definite relationship between corneal damage threshold and spot size cannot be drawn from existing data points. In this paper, the in-vivo corneal damage thresholds (ED50s) were determined in New Zealand white rabbits for a single 5 ms pulse at the wavelength of 1338 nm for spot sizes from 0.28 mm to 3.55 mm. Meanwhile, the retinal damage threshold for this laser was determined in chinchilla grey rabbits under the condition that the beam was collimated, and the incident corneal spot diameter was 5.0 mm. The corneal ED50s given in terms of the corneal radiant exposure for spot diameters of 0.28, 0.94, 1.91, and 3.55 mm were 70.3, 35.6, 29.6 and 30.3 J/cm2, respectively. The retinal ED50 given in terms of total intraocular energy (TIE) was 0.904 J. The most sensitive ocular tissue to this laser changed from the cornea to retina with the increase of spot size.

We use data from 52 countries on child stunting, poverty, determinants of food security, environmental health, and quality of maternal and child care to carry out a cluster analysis of country typologies. The purpose is to identify where agriculture-led interventions might address binding constraints to progress in improving nutrition outcomes and to identify how existing research on the links between agriculture and nutrition in particular country contexts may or may not be representative. We find that countries with average to poor nutrition outcomes within this sample set fall into groups where one supporting area tends to lag, such as environmental health or food security. Although integrated programs to address all aspects that support nutrition are needed in most of these 52 countries, we identify a group of 11 countries where interventions to improve diet diversity may be most relevant toward progress in alleviating child malnutrition. Agriculture for Nutrition and Health intervention research is underway in 6 of these 11 countries.

Novel quantitative proteomic approaches were used to study the effects of inhibition of glycogen phosphorylase on proteome and signaling pathways in MIA PaCa-2 pancreatic cancer cells.We performed quantitative proteomic analysis in MIA PaCa-2 cancer cells treated with a stratified dose of CP-320626 (5-chloro-1H-indole-2-carboxylic acid [1-(4-fuorobenzyl)-2-(4-hydroxypiperidin-1-yl)-2 oxoethyl] amide) (25, 50, and 100 μM). The effect of metabolic inhibition on cellular protein turnover dynamics was also studied using the modified SILAC (stable isotope labeling with amino acids in cell culture) method.A total of 22 protein spots and 4 phosphoprotein spots were quantitatively analyzed. We found that dynamic expression of total proteins and phosphoproteins was significantly changed in MIA PaCa-2 cells treated with an incremental dose of CP-320626. Functional analyses suggested that most of the proteins differentially expressed were in the pathways of mitogen-activated protein kinase/extracellular signal-regulated kinase and tumor necrosis factor α/nuclear factor κB.Signaling pathways and metabolic pathways share many common cofactors and substrates forming an extended metabolic network. The restriction of substrate through 1 pathway such as inhibition of glycogen phosphorylation induces pervasive metabolomic and proteomic changes manifested in protein synthesis, breakdown, and posttranslational modification of signaling molecules. Our results suggest that quantitative proteomic is an important approach to understand the interaction between metabolism and signaling pathways.

This study aimed to determine the relationship between the endogenous levels of P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), lung resistance-related protein (LRP), glutathione-s-transferase-π (GST‑π) and topoisomerase IIα (TopoIIα) and intrinsic drug resistance in four human lung cancer cell lines, SK-MES-1, SPCA-1, NCI-H-460 and NCI-H-446, of different histological types. The expression of P-gp, MRP, LRP, GST-π and TopoIIα was measured by immunofluorescence, Western blotting and RT-PCR. Drug resistance to cisplatin, doxorubicin and VP-16 was determined using MTT assays. The correlation between expression of the resistance-related proteins and their roles in the resistance to drugs in these cancer cell lines was analyzed. We found that the endogenous levels of P-gp, MRP, LRP, GST-π and TopoIIα in the four cell lines varied. The level of GST-π in the SK-MES-1 cells was the highest, whereas the level of P-gp in the SPCA-1 cells was the lowest. The chemoresistance to cisplatin, doxorubicin and VP-16 in the four cell lines was different. The SPCA-1 cell line was most resistance to cisplatin; SK-MES-1 was most resistance to VP-16; whereas SK-MES-1 was most sensitive to doxorubicin. There was a positive correlation between GST-π expression and resistance to cisplatin, between TopoIIα expression and resistance to VP-16; and a negative correlation was noted between TopoIIα expression and resistance to doxorubicin. In summary, the endogenous expression of P-gp, MRP, LRP, GST-π and TopoIIα was different in the four human lung cancer cell lines of different histological types, and this variance may be associated with the variation in chemosensitivity to cisplatin, doxorubicin and VP-16. Among the related proteins, GST-π may be useful for the prediction of the intrinsic resistance to cisplatin, whereas TopoIIα may be useful to predict resistance to doxorubicin and VP-16 in human lung cancer cell lines.

The laser-tissue interaction has not been well defined at the 1319 nm wavelength for brain exposure. The goal of this research effort was to identify the behavioral and histological changes of brain lesion induced by 1319 nm laser. The experiment was performed on China Kunming mice. Unilateral brain lesions were created with a continuous-wave Nd:YAG laser (1319nm). The brain lesions were identified through behavioral observation and histological haematoxylin and eosin (H&E) staining method. The behavior change was observed for a radiant exposure range of 97~773 J/cm 2 . The histology of the recovery process was identified for radiant exposure of 580 J/cm 2 . Subjects were sacrificed 1 hour, 1 week, 2 weeks, 3 months, 7 months and 13 months after laser irradiation. Results showed that after laser exposure, behavioral deficits, including kyphosis, tail entasia, or whole body paralysis could be noted right after the animals recovered from anesthesia while gradually disappeared within several days and never recurred again. Histologically, the laser lesion showed a typical architecture dependent on the interval following laser treatment. The central zone of coagulation necrosis is not apparent right after exposure but becomes obvious within several days. The nerotic tissue though may persist for a long time, will finally be completely resorbed. No carbonization granules formed under our exposure condition.