bluuebunny/crossref_metadata_2025 huggingface dataset:
Tofacitinib Suppresses Several JAK-STAT Pathways in Rheumatoid Arthritis In Vivo and Baseline Signaling Profile Associates With Treatment Response
Authors: Palmroth Maaria , Kuuliala Krista , Peltomaa Ritva , Virtanen Anniina , Kuuliala Antti , Kurttila Antti , Kinnunen Anna , Leirisalo-Repo Marjatta , Silvennoinen Olli , Isomäki Pia
Published: September 2021

Objective

Current knowledge on the actions of tofacitinib on cytokine signaling pathways in rheumatoid arthritis (RA) is based on in vitro studies. Our study is the first to examine the effects of tofacitinib treatment on Janus kinase (JAK) - signal transducer and activator of transcription (STAT) pathways in vivo in patients with RA.

Methods

Sixteen patients with active RA, despite treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), received tofacitinib 5 mg twice daily for three months. Levels of constitutive and cytokine-induced phosphorylated STATs in peripheral blood monocytes, T cells and B cells were measured by flow cytometry at baseline and three-month visits. mRNA expression of JAKs, STATs and suppressors of cytokine signaling (SOCS) were measured from peripheral blood mononuclear cells (PBMCs) by quantitative PCR. Association of baseline signaling profile with treatment response was also investigated.

Results

Tofacitinib, in csDMARDs background, decreased median disease activity score (DAS28) from 4.4 to 2.6 (p < 0.001). Tofacitinib treatment significantly decreased cytokine-induced phosphorylation of all JAK-STAT pathways studied. However, the magnitude of the inhibitory effect depended on the cytokine and cell type studied, varying from 10% to 73% inhibition following 3-month treatment with tofacitinib. In general, strongest inhibition by tofacitinib was observed with STAT phosphorylations induced by cytokines signaling through the common-γ-chain cytokine receptor in T cells, while lowest inhibition was demonstrated for IL-10 -induced STAT3 phosphorylation in monocytes. Constitutive STAT1, STAT3, STAT4 and STAT5 phosphorylation in monocytes and/or T cells was also downregulated by tofacitinib. Tofacitinib treatment downregulated the expression of several JAK-STAT pathway components in PBMCs, SOCSs showing the strongest downregulation. Baseline STAT phosphorylation levels in T cells and monocytes and SOCS3 expression in PBMCs correlated with treatment response.

Conclusions

Tofacitinib suppresses multiple JAK-STAT pathways in cytokine and cell population specific manner in RA patients in vivo. Besides directly inhibiting JAK activation, tofacitinib downregulates the expression of JAK-STAT pathway components. This may modulate the effects of tofacitinib on JAK-STAT pathway activation in vivo and explain some of the differential findings between the current study and previous in vitro studies. Finally, baseline immunological markers associate with the treatment response to tofacitinib.
Antigen Presenting Cells Contribute to Persistent Immune Activation Despite Antiretroviral Therapy Initiation During Hyperacute HIV-1 Infection
Authors: Naidoo Kewreshini K. , Ndumnego Okechukwu C. , Ismail Nasreen , Dong Krista L. , Ndung’u Thumbi
Published: September 2021

Human immunodeficiency virus (HIV)-induced changes in immune cells during the acute phase of infection can cause irreversible immunological damage and predict the rate of disease progression. Antiretroviral therapy (ART) remains the most effective strategy for successful immune restoration in immunocompromised people living with HIV and the earlier ART is initiated after infection, the better the long-term clinical outcomes. Here we explored the effect of ART on peripheral antigen presenting cell (APC) phenotype and function in women with HIV-1 subtype C infection who initiated ART in the hyperacute phase (before peak viremia) or during chronic infection. Peripheral blood mononuclear cells obtained longitudinally from study participants were used for immunophenotyping and functional analysis of monocytes and dendritic cells (DCs) using multiparametric flow cytometry and matched plasma was used for measurement of inflammatory markers IL-6 and soluble CD14 (sCD14) by enzyme-linked immunosorbent assay. HIV infection was associated with expansion of monocyte and plasmacytoid DC (pDC) frequencies and perturbation of monocyte subsets compared to uninfected persons despite antiretroviral treatment during hyperacute infection. Expression of activation marker CD69 on monocytes and pDCs in early treated HIV was similar to uninfected individuals. However, despite early ART, HIV infection was associated with elevation of plasma IL-6 and sCD14 levels which correlated with monocyte activation. Furthermore, HIV infection with or without early ART was associated with downmodulation of the co-stimulatory molecule CD86. Notably, early ART was associated with preserved toll-like receptor (TLR)-induced IFN-α responses of pDCs. Overall, this data provides evidence of the beneficial impact of ART initiated in hyperacute infection in preservation of APC functional cytokine production activity; but also highlights persistent inflammation facilitated by monocyte activation even after prolonged viral suppression and suggests the need for therapeutic interventions that target residual immune activation.
Venetoclax or Ruxolitinib in Pre-Transplant Conditioning Lowers the Engraftment Barrier by Different Mechanisms in Allogeneic Stem Cell Transplant Recipients
Authors: Davis Joanne E. , Du Kelei , Ludford-Menting Mandy J. , Prabahran Ashvind , Wong Eric , Huntington Nicholas D. , Koldej Rachel M. , Ritchie David S.
Published: September 2021

Allogeneic stem cell transplantation (alloSCT) is utilised to cure haematological malignancies through a combination of conditioning regimen intensity and immunological disease controlviathe graft versus tumour (GVT) effect. Currently, conventional myeloablative chemotherapeutic or chemoradiation conditioning regimens are associated with significant side effects including graft versus host disease (GVHD), infection, and organ toxicity. Conversely, more tolerable reduced intensity conditioning (RIC) regimens are associated with unacceptably higher rates of disease relapse, partly through an excess incidence of mixed chimerism. Improvement in post-alloSCT outcomes therefore depends on promotion of the GVT effect whilst simultaneously reducing conditioning-related toxicity. We have previously shown that this could be achieved through BCL-2 inhibition, and in this study, we explored the modulation of JAK1/2 as a strategy to lower the barrier to donor engraftment in the setting of RIC. We investigated the impact of short-term treatment of BCL2 (venetoclax) or JAK1/2 (ruxolitinib) inhibition on recipient natural killer and T cell immunity and the subsequent effect on donor engraftment. We identified striking differences in mechanism of action of these two drugs on immune cell subsets in the bone marrow of recipients, and in the regulation of MHC class-II and interferon-inducible gene expression, leading to different rates of GVHD. This study demonstrates that the repurposed use of ruxolitinib or venetoclax can be utilised as pre-transplant immune-modulators to promote the efficacy of alloSCT, whilst reducing its toxicity.
Lynch Syndrome and MSI-H Cancers: From Mechanisms to “Off-The-Shelf” Cancer Vaccines
Authors: Roudko Vladimir , Cimen Bozkus Cansu , Greenbaum Benjamin , Lucas Aimee , Samstein Robert , Bhardwaj Nina
Published: September 2021

Defective DNA mismatch repair (dMMR) is associated with many cancer types including colon, gastric, endometrial, ovarian, hepatobiliary tract, urinary tract, brain and skin cancers. Lynch syndrome – a hereditary cause of dMMR – confers increased lifetime risk of malignancy in different organs and tissues. These Lynch syndrome pathogenic alleles are widely present in humans at a 1:320 population frequency of a single allele and associated with an up to 80% risk of developing microsatellite unstable cancer (microsatellite instability – high, or MSI-H). Advanced MSI-H tumors can be effectively treated with checkpoint inhibitors (CPI), however, that has led to response rates of only 30-60% despite their high tumor mutational burden and favorable immune gene signatures in the tumor microenvironment (TME). We and others have characterized a subset of MSI-H associated highly recurrent frameshift mutations that yield shared immunogenic neoantigens. These frameshifts might serve as targets for off-the-shelf cancer vaccine designs. In this review we discuss the current state of research around MSI-H cancer vaccine development, its application to MSI-H and Lynch syndrome cancer patients and the utility of MSI-H as a biomarker for CPI therapy. We also summarize the tumor intrinsic mechanisms underlying the high occurrence rates of certain frameshifts in MSI-H. Finally, we provide an overview of pivotal clinical trials investigating MSI-H as a biomarker for CPI therapy and MSI-H vaccines. Overall, this review aims to inform the development of novel research paradigms and therapeutics.
Rhizostomins: A Novel Pigment Family From Rhizostome Jellyfish (Cnidaria, Scyphozoa)
Authors: Lawley Jonathan W. , Carroll Anthony R. , McDougall Carmel
Published: September 2021

Many pigments, such as melanins, are widely distributed throughout the animal kingdom. Others have arisen as novelties in particular lineages, for example, the Green Fluorescent Protein (GFP) found in cnidarians. While GFPs, widely used as fluorescent tags in biomedical research, are the most famous cnidarian example, other novel proteins have also been identified within this phylum. A blue protein that contains a Kringle (KR) domain inserted within a Frizzled cysteine-rich domain (Fz-CRD) was previously described from the jellyfish Rhizostoma pulmo (named rpulFKz1), however little is known about this pigment’s evolution or distribution among cnidarians. We performed a systematic search for homologs of this protein in published genomes and transcriptomes of 93 cnidarians. Phylogenetic analyses revealed eight predicted proteins that possess both domains in the same arrangement and that fall within the same clade as rpulFKz1. The sequence of one of these proteins contains motifs that match sequenced peptides of Cassio Blue, the blue pigment from Cassiopea xamachana. Another one of these proteins belongs to Stomolophus meleagris, and chemical studies on blue pigments that may occur in this genus have shown similarities to rpulFKz1 and Cassio Blue. Therefore, we hypothesize that the eight rpulFKz1 homologs identified are also pigment precursors. All precursors identified were exclusive to jellyfish in the order Rhizostomeae, so we herein name this new pigment family “rhizostomins.” Not all rhizostomes analyzed are blue, however, so these rhizostomin proteins may also be responsible for other colors, or perform other biochemical and biophysical roles. Previous studies have hypothesized that cnidarian pigments are photoprotective, and this study serves as basis for future investigations not only on the function of rhizostomins, but also on potential biotechnological applications for these proteins.
Malnutrition Is an Independent Risk Factor for Low Health-Related Quality of Life Among Centenarians
Authors: Yang Shanshan , Wang Shengshu , Liu Wei , Han Ke , Jia Wangping , Liu Miao , He Yao
Published: September 2021

Background: To explore the association and understand gender disparities between nutritional status and quality of life among centenarians.

Methods: It was a full-sample survey of centenarians conducted in Hainan that included a total of 1,002 eligible centenarians whose age had been verified. The Mini Nutritional Assessment – Short Form (MNA-SF) questionnaire and the EuroQol five dimensions visual analog scale (EQ-5D-VAS) were used to measure participants' nutritional status and quality of life, respectively.

Findings: In the 1002 centenarians (822 women and 180 men), 797 (79.5%) (79.5%) reported multimorbidity. The adjusted standardized β estimate association between the MNA-SF and EQ-5D scores was 0.508 in the complete sample. With reference to the normal nutrition group, the standardized β estimate of the association between EQ-5D score and nutritional status were −0.179 and −0.583 for the at risk of malnutrition and malnutrition groups, respectively (both P <0.001). Nutritional status significantly affected the five dimensions of quality of life, particularly mobility and self-care. Compared with the normal nutrition group, the malnutrition group had greater odds of low mobility [Odds ratio (OR)=23.15; 95% CI: 9.81–54.64] and low self-care (OR=24.58; 95% CI: 12.62–47.89). Among males, nutritional status was significantly associated with the usual activities and anxiety/depression dimensions after adjustment. Female participants had results similar to the general population.

Interpretation: Malnutrition and being at risk of malnutrition is prevalent among centenarians. Maintaining normal nutritional status is an important protective factor and should receive more attention to improve centenarians' quality of life.
Complete Genome Sequence of the Newly Developed Lactobacillus acidophilus Strain With Improved Thermal Adaptability
Authors: Jeon Soomin , Kim Hyaekang , Choi Youngseok , Cho Seoae , Seo Minseok , Kim Heebal
Published: September 2021

Lactobacillus acidophilus (L. acidophilus) is a representative probiotic and is widely used in many industrial products for its beneficial effects on human and animal health. This bacterium is exposed to harsh environments such as high temperatures for manufacturing industrial products, but cell yield under high temperatures is relatively low. To resolve this issue, we developed a new L. acidophilus strain with improved heat resistance while retaining the existing beneficial properties through the adaptive laboratory evolution (ALE) method. The newly developed strain, L. acidophilus EG008, has improved the existing limit of thermal resistance from 65°C to 75°C. Furthermore, we performed whole-genome sequencing and comparative genome analysis of wild-type and EG008 strains to unravel the molecular mechanism of improved heat resistance. Interestingly, only two single-nucleotide polymorphisms (SNPs) were different compared to the L. acidophilus wild-type. We identified that one of these SNPs is a non-synonymous SNP capable of altering the structure of MurD protein through the 435th amino acid change from serine to threonine. We believe that these results will directly contribute to any industrial field where L. acidophilus is applied. In addition, these results make a step forward in understanding the molecular mechanisms of lactic acid bacteria evolution under extreme conditions.
Prevalence, Antimicrobial Susceptibility, and Molecular Characterization of Escherichia coli Isolated From Raw Milk in Dairy Herds in Northern China
Authors: Liu Huimin , Meng Lu , Dong Lei , Zhang Yangdong , Wang Jiaqi , Zheng Nan
Published: September 2021

Escherichia coli is a common bacterium in the intestines of animals, and it is also the major important cause of toxic mastitis, which is an acute or peracute disease that causes a higher incidence of death and culling of cattle. The purpose of this study was to investigate E. coli strains isolated from the raw milk of dairy cattle in Northern China, and the antibacterial susceptibility of these strains and essential virulence genes. From May to September 2015, 195 raw milk samples were collected from 195 dairy farms located in Northern China. Among the samples, 67 (34.4%) samples were positive for E. coli. About 67 E. coli strains were isolated from these 67 samples. The prevalence of Shiga toxin-producing E. coli (STEC), enterotoxigenic E. coli (ETEC), enteropathogenic E. coli (EPEC), and enteroinvasive E. coli (EIEC) were 9, 6, 4.5, and 1.5%, respectively. Among the virulence genes detected, stx1 was the most prevalent (6/67, 9%) gene, followed by eae (3/67, 4.5%), and estB (2/67, 3%). Moreover, the strains exhibited different resistance levels to ampicillin (46.3%), amoxicillin-clavulanic acid (16.4%), trimethoprim-sulfamethoxazole (13.4%), tetracycline (13.4%), cefoxitin (11.9%), chloramphenicol (7.5%), kanamycin (7.5%), streptomycin (6.0%), tobramycin (4.5%), azithromycin (4.5%), and ciprofloxacin (1.5%). All of the E. coli isolates were susceptible to gentamicin. The prevalence of β-lactamase-encoding genes was 34.3% in 67 E. coli isolates and 45% in 40 β-lactam-resistance E. coli isolates. The overall prevalence of blaSHV, blaTEM, blaCMY, and blaCTX-M genes were 1.5, 20.9, 10.4, and 1.5%, respectively. Nine non-pathogenic E. coli isolates also carried β-lactamase resistance genes, which may transfer to other pathogenic E. coli and pose a threat to the farm’s mastitis management projects. Our results showed that most of E. coli were multidrug resistant and possessed multiple virulence genes, which may have a huge potential hazard with public health, and antibiotic resistance of E. coli was prevalent in dairy herds in Northern China, and ampicillin should be used cautiously for mastitis caused by E. coli in Northern China.
Dihydroartemisinin-Loaded Chitosan Nanoparticles Inhibit the Rifampicin-Resistant Mycobacterium tuberculosis by Disrupting the Cell Wall
Authors: Gu Xiujuan , Cheng Qi , He Ping , Zhang Yan , Jiang Zhengfang , Zeng Yali
Published: September 2021

Tuberculosis (TB) caused by Mycobacterium tuberculosis (MTB) is a deadly infection, and increasing resistance worsens an already bad scenario. In this work, a new nanomedicine antibacterial agent, based on dihydroartemisinin (DHA) and chitosan (CS), has been successfully developed to overcome MTB’s drug-resistant. To enhance DHA’s solubility, we have prepared nanoparticles of DHA loaded CS by an ionic crosslinking method with sodium tripolyphosphate (STPP) as the crosslinking agent. The DHA-CS nanoparticles (DHA-CS NPs) have been fully characterized by scanning electron microscopy, Fourier transforms infrared spectroscopy, dynamic light scattering, and ultraviolet spectrophotometry. DHA-CS NPs show an excellent antibacterial effect on the rifampicin (RFP)-resistant strain (ATCC 35838) and, at a concentration of 8.0 μg/ml, the antibacterial impact reaches up to 61.0 ± 2.13% (n = 3). The results of Gram staining, acid-fast staining, auramine “O” staining and electron microscopy show that the cell wall of RFP-resistant strains is destroyed by DHA-CS NPs (n = 3), and it is further verified by gas chromatography-mass spectrometry. Since all the metabolites identified in DHA-CS NPs treated RFP-resistant strains indicate an increase in fatty acid synthesis and cell wall repair, it can be concluded that DHA-CS NPs act by disrupting the cell wall. In addition, the resistance of 12 strains is effectively reduced by 8.0 μg/ml DHA-CS NPs combined with RFP, with an effective rate of 66.0%. The obtained results indicate that DHA-CS NPs combined with RFP may have potential use for TB treatment.
Structural and Mechanistic Insights Into Dimethylsulfoxide Formation Through Dimethylsulfide Oxidation
Authors: Wang Xiu-Juan , Zhang Nan , Teng Zhao-Jie , Wang Peng , Zhang Wei-Peng , Chen Xiu-Lan , Zhang Yu-Zhong , Chen Yin , Fu Hui-Hui , Li Chun-Yang
Published: September 2021

Dimethylsulfide (DMS) and dimethylsulfoxide (DMSO) are widespread in marine environment, and are important participants in the global sulfur cycle. Microbiol oxidation of DMS to DMSO represents a major sink of DMS in marine surface waters. The SAR11 clade and the marine Roseobacter clade (MRC) are the most abundant heterotrophic bacteria in the ocean surface seawater. It has been reported that trimethylamine monooxygenase (Tmm, EC 1.14.13.148) from both MRC and SAR11 bacteria likely oxidizes DMS to generate DMSO. However, the structural basis of DMS oxidation has not been explained. Here, we characterized a Tmm homolog from the SAR11 bacterium Pelagibacter sp. HTCC7211 (Tmm7211). Tmm7211 exhibits DMS oxidation activity in vitro. We further solved the crystal structures of Tmm7211 and Tmm7211 soaked with DMS, and proposed the catalytic mechanism of Tmm7211, which comprises a reductive half-reaction and an oxidative half-reaction. FAD and NADPH molecules are essential for the catalysis of Tmm7211. In the reductive half-reaction, FAD is reduced by NADPH. In the oxidative half-reaction, the reduced FAD reacts with O2 to form the C4a-(hydro)peroxyflavin. The binding of DMS may repel the nicotinamide ring of NADP+, and make NADP+ generate a conformational change, shutting off the substrate entrance and exposing the active C4a-(hydro)peroxyflavin to DMS to complete the oxidation of DMS. The proposed catalytic mechanism of Tmm7211 may be widely adopted by MRC and SAR11 bacteria. This study provides important insight into the conversion of DMS into DMSO in marine bacteria, leading to a better understanding of the global sulfur cycle.
Fecal Bacterial Community of Allopatric Przewalski’s Gazelles and Their Sympatric Relatives
Authors: Liu Ruoshuang , Shi Jianbin , Shultz Susanne , Guo Dongsheng , Liu Dingzhen
Published: September 2021

Mammal gastrointestinal tracts harbor diverse bacterial communities that play important roles in digestion, development, behavior, and immune function. Although, there is an increasing understanding of the factors that affect microbial community composition in laboratory populations, the impact of environment and host community composition on microbiomes in wild populations is less understood. Given that the composition of bacterial communities can be shaped by ecological factors, particularly exposure to the microbiome of other individuals, inter-specific interactions should impact on microbiome community composition. Here, we evaluated inter-population and inter-specific similarity in the fecal microbiota of Przewalski’s gazelle (Procapra przewalskii), an endangered endemic ruminant around Qinghai Lake in China. We compared the fecal bacterial communities of three Przewalski’s gazelle populations, with those of two sympatric ruminants, Tibetan gazelle (Procapra picticaudata) and Tibetan sheep (Ovis aries). The fecal bacterial community richness (Chao1, ACE) did not vary across the three Przewalski’s gazelle populations, nor did the composition vary between species. In contrast, the managed Przewalski’s gazelle population had higher bacterial diversity (Shannon and Simpson) and was more similar to its sympatric Tibetan sheep in beta diversity than the wild Przewalski’s gazelle populations. These results suggest that ecological factors like host community composition or diet affect Przewalski’s gazelle’s gastrointestinal bacterial community. The role of bacterial community composition in maintaining gastrointestinal health should be assessed to improve conservation management of endangered Przewalski’s gazelle. More broadly, captive breeding and reintroduction efforts may be impeded, where captive management results in dysbiosis and introduction of pathogenic bacteria. In free ranging populations, where wildlife and livestock co-occur, infection by domestic pathogens and diseases may be an underappreciated threat to wild animals.
Simultaneous PET/fMRI Detects Distinctive Alterations in Functional Connectivity and Glucose Metabolism of Precuneus Subregions in Alzheimer’s Disease
Authors: Zhang Miao , Sun Wanqing , Guan Ziyun , Hu Jialin , Li Binyin , Ye Guanyu , Meng Hongping , Huang Xinyun , Lin Xiaozhu , Wang Jin , Liu Jun , Li Biao , Zhang Yaoyu , Li Yao
Published: September 2021

As a central hub in the interconnected brain network, the precuneus has been reported showing disrupted functional connectivity and hypometabolism in Alzheimer’s disease (AD). However, as a highly heterogeneous cortical structure, little is known whether individual subregion of the precuneus is uniformly or differentially involved in the progression of AD. To this end, using a hybrid PET/fMRI technique, we compared resting-state functional connectivity strength (FCS) and glucose metabolism in dorsal anterior (DA_pcu), dorsal posterior (DP_pcu) and ventral (V_pcu) subregions of the precuneus among 20 AD patients, 23 mild cognitive impairment (MCI) patients, and 27 matched cognitively normal (CN) subjects. The sub-parcellation of precuneus was performed using a K-means clustering algorithm based on its intra-regional functional connectivity. For the whole precuneus, decreased FCS (p = 0.047) and glucose hypometabolism (p = 0.006) were observed in AD patients compared to CN subjects. For the subregions of the precuneus, decreased FCS was found in DP_pcu of AD patients compared to MCI patients (p = 0.011) and in V_pcu for both MCI (p = 0.006) and AD (p = 0.008) patients compared to CN subjects. Reduced glucose metabolism was found in DP_pcu of AD patients compared to CN subjects (p = 0.038) and in V_pcu of AD patients compared to both MCI patients (p = 0.045) and CN subjects (p < 0.001). For both FCS and glucose metabolism, DA_pcu remained relatively unaffected by AD. Moreover, only in V_pcu, disruptions in FCS (r = 0.498, p = 0.042) and hypometabolism (r = 0.566, p = 0.018) were significantly correlated with the cognitive decline of AD patients. Our results demonstrated a distinctively disrupted functional and metabolic pattern from ventral to dorsal precuneus affected by AD, with V_pcu and DA_pcu being the most vulnerable and conservative subregion, respectively. Findings of this study extend our knowledge on the differential roles of precuneus subregions in AD.
Measuring Behavior in the Home Cage: Study Design, Applications, Challenges, and Perspectives
Authors: Grieco Fabrizio , Bernstein Briana J. , Biemans Barbara , Bikovski Lior , Burnett C. Joseph , Cushman Jesse D. , van Dam Elsbeth A. , Fry Sydney A. , Richmond-Hacham Bar , Homberg Judith R. , Kas Martien J. H. , Kessels Helmut W. , Koopmans Bastijn , Krashes Michael J. , Krishnan Vaishnav , Logan Sreemathi , Loos Maarten , McCann Katharine E. , Parduzi Qendresa , Pick Chaim G. , Prevot Thomas D. , Riedel Gernot , Robinson Lianne , Sadighi Mina , Smit August B. , Sonntag William , Roelofs Reinko F. , Tegelenbosch Ruud A.J. , Noldus Lucas P.J.J.
Published: September 2021

The reproducibility crisis (or replication crisis) in biomedical research is a particularly existential and under-addressed issue in the field of behavioral neuroscience, where, in spite of efforts to standardize testing and assay protocols, several known and unknown sources of confounding environmental factors add to variance. Human interference is a major contributor to variability both within and across laboratories, as well as novelty-induced anxiety. Attempts to reduce human interference and to measure more "natural" behaviors in subjects has led to the development of automated home-cage monitoring systems. These systems enable prolonged and longitudinal recordings, and provide large continuous measures of spontaneous behavior that can be analyzed across multiple time scales. In this review, a diverse team of neuroscientists and product developers share their experiences using such an automated monitoring system that combines Noldus PhenoTyper® home-cages and the video-based tracking software, EthoVision® XT, to extract digital biomarkers of motor, emotional, social and cognitive behavior. After presenting our working definition of a “home-cage”, we compare home-cage testing with more conventional out-of-cage tests (e.g., the open field) and outline the various advantages of the former, including opportunities for within-subject analyses and assessments of circadian and ultradian activity. Next, we address technical issues pertaining to the acquisition of behavioral data, such as the fine-tuning of the tracking software and the potential for integration with biotelemetry and optogenetics. Finally, we provide guidance on which behavioral measures to emphasize, how to filter, segment, and analyze behavior, and how to use analysis scripts. We summarize how the PhenoTyper has applications to study neuropharmacology as well as animal models of neurodegenerative and neuropsychiatric illness. Looking forward, we examine current challenges and the impact of new developments. Examples include the automated recognition of specific behaviors, unambiguous tracking of individuals in a social context, the development of more animal-centered measures of behavior and ways of dealing with large datasets. Together, we advocate that by embracing standardized home-cage monitoring platforms like the PhenoTyper, we are poised to directly assess issues pertaining to reproducibility, and more importantly, measure features of rodent behavior under more ethologically relevant scenarios.
Computational Modeling: Human Dynamic Model
Authors: Liu Lijia , Cooper Joseph L. , Ballard Dana H.
Published: September 2021

Improvements in quantitative measurements of human physical activity are proving extraordinarily useful for studying the underlying musculoskeletal system. Dynamic models of human movement support clinical efforts to analyze, rehabilitate injuries. They are also used in biomechanics to understand and diagnose motor pathologies, find new motor strategies that decrease the risk of injury, and predict potential problems from a particular procedure. In addition, they provide valuable constraints for understanding neural circuits. This paper describes a physics-based movement analysis method for analyzing and simulating bipedal humanoid movements. The model includes the major body segments and joints to report human movements' energetic components. Its 48 degrees of freedom strike a balance between very detailed models that include muscle models and straightforward two-dimensional models. It has sufficient accuracy to analyze and synthesize movements captured in real-time interactive applications, such as psychophysics experiments using virtual reality or human-in-the-loop teleoperation of a simulated robotic system. The dynamic model is fast and robust while still providing results sufficiently accurate to be used to animate a humanoid character. It can also estimate internal joint forces used during a movement to create effort-contingent stimuli and support controlled experiments to measure the dynamics generating human behaviors systematically. The paper describes the innovative features that allow the model to integrate its dynamic equations accurately and illustrates its performance and accuracy with demonstrations. The model has a two-foot stance ability, capable of generating results comparable with an experiment done with subjects, and illustrates the uncontrolled manifold concept. Additionally, the model's facility to capture large energetic databases opens new possibilities for theorizing as to human movement function. The model is freely available.
The Role of Hub Neurons in Modulating Cortical Dynamics
Authors: Gal Eyal , Amsalem Oren , Schindel Alon , London Michael , Schürmann Felix , Markram Henry , Segev Idan
Published: September 2021

Many neurodegenerative diseases are associated with the death of specific neuron types in particular brain regions. What makes the death of specific neuron types particularly harmful for the integrity and dynamics of the respective network is not well understood. To start addressing this question we used the most up-to-date biologically realistic dense neocortical microcircuit (NMC) of the rodent, which has reconstructed a volume of 0.3 mm3 and containing 31,000 neurons, ∼37 million synapses, and 55 morphological cell types arranged in six cortical layers. Using modern network science tools, we identified hub neurons in the NMC, that are connected synaptically to a large number of their neighbors and systematically examined the impact of abolishing these cells. In general, the structural integrity of the network is robust to cells’ attack; yet, attacking hub neurons strongly impacted the small-world topology of the network, whereas similar attacks on random neurons have a negligible effect. Such hub-specific attacks are also impactful on the network dynamics, both when the network is at its spontaneous synchronous state and when it was presented with synchronized thalamo-cortical visual-like input. We found that attacking layer 5 hub neurons is most harmful to the structural and functional integrity of the NMC. The significance of our results for understanding the role of specific neuron types and cortical layers for disease manifestation is discussed.
Mechanisms Underlying Target Selectivity for Cell Types and Subcellular Domains in Developing Neocortical Circuits
Authors: Gutman-Wei Alan Y. , Brown Solange P.
Published: September 2021

The cerebral cortex contains numerous neuronal cell types, distinguished by their molecular identity as well as their electrophysiological and morphological properties. Cortical function is reliant on stereotyped patterns of synaptic connectivity and synaptic function among these neuron types, but how these patterns are established during development remains poorly understood. Selective targeting not only of different cell types but also of distinct postsynaptic neuronal domains occurs in many brain circuits and is directed by multiple mechanisms. These mechanisms include the regulation of axonal and dendritic guidance and fine-scale morphogenesis of pre- and postsynaptic processes, lineage relationships, activity dependent mechanisms and intercellular molecular determinants such as transmembrane and secreted molecules, many of which have also been implicated in neurodevelopmental disorders. However, many studies of synaptic targeting have focused on circuits in which neuronal processes target different lamina, such that cell-type-biased connectivity may be confounded with mechanisms of laminar specificity. In the cerebral cortex, each cortical layer contains cell bodies and processes from intermingled neuronal cell types, an arrangement that presents a challenge for the development of target-selective synapse formation. Here, we address progress and future directions in the study of cell-type-biased synaptic targeting in the cerebral cortex. We highlight challenges to identifying developmental mechanisms generating stereotyped patterns of intracortical connectivity, recent developments in uncovering the determinants of synaptic target selection during cortical synapse formation, and current gaps in the understanding of cortical synapse specificity.
Endoscopic Endonasal Resection of Symptomatic Rathke Cleft Cysts: Total Resection or Partial Resection
Authors: Zhang Xiejun , Yang Jihu , Huang Yan , Liu Yufei , Chen Lei , Chen Fanfan , Huang Guodong
Published: September 2021

Objective: Rathke cleft cysts (RCC) are benign sellar lesions, and endoscopic endonasal surgery (EES) for symptomatic RCC is becoming increasingly popular, but total resection or partial resection (TR or PR) of the cyst wall is still inconclusive. The aim of this study was to review the complications and clinical prognoses associated with total and partial resection of the cyst wall by EES.

Methods: We retrospectively analyzed a series of 72 patients with symptomatic RCC treated by EES from -January 2011 to June 2019 at Shenzhen University First Affiliated Hospital. For these 72 cases, 30 were treated with TR and 42 were treated with PR. Intra- and post-operative complications and clinical prognosis were investigated.

Results: All 72 patients underwent a pure EES. In the TR group, 10 patients (33.3%) had intraoperative cerebrospinal fluid leakage (CSF leak), three patients (10%) had postoperative CSF leak, eight patients (26.7%) had postoperative diabetes insipidus (DI), eight patients (26.7%) had postoperative electrolyte disturbance, and 12 patients (40%) had temporary hypopituitarism postoperatively. While in the PR group, three patients (7.1%) had intraoperative CSF leak, two patients (4.8%) had postoperative DI, three patients (7.1%) had postoperative electrolyte disturbance, four patients (9.5%) had temporary hypopituitarism postoperatively, and no cases experienced postoperative CSF leak. The intra- and post-operative complications were significantly higher in TR group then PR group (P IntraoperativeCSFleak = 0.004, P Post−operativeCSFleak =0.036, P TransientDI = 0.008, P Temporaryhypopituitarism = 0.002, P Permanenthypopituitarism = 0.036, P Electrolytedisturbance = 0.023). No significant differences in post-operative improvement and recurrence.

Conclusions: EES is a safe and effective approach for the treatment of symptomatic RCC. Complete sucking out the cyst contents and partial resection of the cyst wall may be sufficient for treatment, and total resection of the cyst wall is associated with a higher incidence of complications.
Stability of MDS-UPDRS Motor Subtypes Over Three Years in Early Parkinson's Disease
Authors: Kohat Abhijeet K. , Ng Samuel Y. E. , Wong Aidan S. Y. , Chia Nicole S. Y. , Choi Xinyi , Heng Dede L. , Li Wei , Ng Hwee-Lan , Chua Shu-Ting , Neo Shermyn X. M. , Xu Zheyu , Tay Kay-Yaw , Au Wing-Lok , Tan Eng-King , Tan Louis C. S.
Published: September 2021

Background: Various classifications have been proposed to subtype Parkinson's disease (PD) based on their motor phenotypes. However, the stability of these subtypes has not been properly evaluated.

Objective: The goal of this study was to understand the distribution of PD motor subtypes, their stability over time, and baseline factors that predicted subtype stability.

Methods: Participants (n = 170) from two prospective cohorts were included: the Early PD Longitudinal Singapore (PALS) study and the National Neuroscience Institute Movement Disorders Database. Early PD patients were classified into tremor-dominant (TD), postural instability and gait difficulty (PIGD), and indeterminate subtypes according to the Movement Disorder Society's Unified PD Rating Scale (MDS-UPDRS) criteria and clinically evaluated for three consecutive years.

Results: At baseline, 60.6% patients were TD, 12.4% patients were indeterminate, and 27.1% patients were PIGD subtypes (p < 0.05). After 3 years, only 62% of patients in TD and 50% of patients in PIGD subtypes remained stable. The mean levodopa equivalent daily dose (LEDD) was higher in the PIGD subtype (276.92 ± 232.91 mg; p = 0.01). Lower LEDD [p < 0.05, odds ratio (OR) 0.99, 95% confidence interval (CI): 0.98–0.99] and higher TD/PIGD ratios (p < 0.05, OR 1.77, 95% CI: 1.29–2.43) were independent predictors of stability of TD subtype with an area under the curve (AUC) of 0.787 (95%CI: 0.669–0.876), sensitivity = 57.8%, and specificity = 89.7%.

Conclusion: Only 50–62% of PD motor subtypes as defined by MDS-UPDRS remained stable over 3 years. TD/PIGD ratio and baseline LEDD were independent predictors for TD subtype stability over 3 years.
The Function of Tranexamic Acid to Prevent Hematoma Expansion After Intracerebral Hemorrhage: A Systematic Review and Meta-Analysis From Randomized Controlled Trials
Authors: Yan Zeya , Chen Shujun , Xue Tao , Wu Xin , Song Zhaoming , Wang Zongqi , Chen Zhouqing , Wang Zhong
Published: September 2021

Objectives: The clinical results caused by spontaneous intracerebral hemorrhage (ICH) are disastrous to most patient. As tranexamic acid (TXA) has been proved to decrease the influence of ICH, we conducted this research to explore the function of TXA for the prognosis of ICH compared with placebo.

Methods: We searched MEDLINE, Embase, Cochrane Library, and Clinicaltrials.gov for randomized controlled trials (RCTs) that were performed to evaluate TXA vs. placebo for ICH up to February 2021. The data were assessed by Review Manager 5.3 software. The risk ratio (RR) and mean difference were analyzed using dichotomous outcomes and continuous outcomes, respectively, with a fixed effect model.

Results: We collected 2,479 patients from four RCTs. Then, we took the change of hematoma volume, modified Rankin Scale (mRS), and adverse events as evaluation standard of the treatment for ICH. Through statistical analysis, we found that there is no obvious hematoma expansion effect after the application of TXA (RR = 1.05), and we proceeded the quantitative analysis of percentage change in hematoma volume from baseline, indicating that TXA could inhibit the expansion of hematoma volume (RR = −2.02) compared with placebo. However, according to the outcomes of mRS (0–1, RR = 1.04; 0–2, RR = 0.96), TXA cannot improve neurological functional prognosis. As for the security outcomes—mortality (RR = 1.02), thromboembolic events (RR = 0.99), neurological deterioration (RR = 0.92), infection (RR = 0.86), and craniotomy (RR = 0.41), there seems exist no statistical difference between TXA and placebo.

Conclusions: TXA has an advantage in the aspect of preventing hematoma expansion compared with placebo for ICH, but cannot illustrate the efficacy of TXA in improving neurological functional prognosis, which still needs more researches with large sample sizes. Moreover, for safety, we did not find obvious statistical difference between TXA and placebo.
Pathology and Protein Changes of the Spinal Dural Arteriovenous Fistula Arterial Draining Vein Under Sustained High Vascular Pressure
Authors: Liu Peixi , Shi Yuan , Li Sichen , Liu Yingjun , Zhou Yingjie , Song Yaying , Zhu Wei , An Qingzhu
Published: September 2021

Object: Spinal dural arteriovenous fistula (SDAVF) is the most common spinal vascular shunt lesion. Although pathological changes in the SDAVF draining vein (SDAVF-DV) have been elucidated, protein changes remain enigmatic. We investigated the pathology and protein changes in the SDAVF-DV under sustained high vascular pressure.

Methods: Three SDAVF-DV samples were compared with superficial temporal artery (STA) and superficial temporal vein (STV) samples as controls. Vascular structure was revealed by hematoxylin and eosin (H&E) and Masson staining; and cell distribution, extracellular matrix, and inflammation infiltration were observed by immunohistochemistry. Label-free quantitative proteomics was performed, and the peptide mixture was fractionated and analyzed by liquid chromatography–tandem mass spectrometry (LC-MS/MS) to identify differentially expressed proteins. Bioinformatics analysis of the differentially expressed proteins was performed using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein–protein interaction (PPI) networks.

Results: H&E and Masson staining showed an artery-like structure of the SDAVF-DV. Immunostaining showed that vWF+ cells were not continuous in the SDAVF-DV. Although α-SMA+ and AT1+ cells were more abundant in the STV than in the SDAVF-DV, piezo-1 expression was lower in the SDAVF-DV. The SDAVF-DV showed different distributions of elastin, COL I, and COL III. COL IV and COL VI were decreased in the SDAVF-DV, while CD45+ cells and COX-1 were increased compared with those in the controls. No differences in CD68 expression and COX-2 staining were observed between the SDAVF-DV and controls. Compared with the STA, 95 proteins were upregulated and 303 proteins were downregulated in the SDAVF-DV. The most differential GO terms in each category were the adenylate cyclase-modulating G protein-coupled receptor signaling pathway, U6 snRNP, and SH3 domain binding. The most differentially expressed KEGG protein pathway was focal adhesion. Compared with the STV, the SDAVF-DV had 158 upregulated proteins and 362 downregulated proteins. The most differential GO terms in each category were lamellipodium assembly, U6 snRNP, and SH3 domain binding; and the most differentially expressed KEGG protein pathway was dilated cardiomyopathy. PPI analysis revealed PPIs among the top 300 proteins.

Conclusions: The SDAVF-DV exhibits specific pathology and protein expression changes under sustained high vascular pressure. The results of the present study provide insights into the pathogenesis of SDAVF formation at the protein level as well as a scientific foundation for further exploration of the pathophysiological mechanism of the SDAVF.
A Study Protocol for an Open-Label Feasibility Treatment Trial of Visual Snow Syndrome With Transcranial Magnetic Stimulation
Authors: Grande Marissa , Lattanzio Lucas , Buard Isabelle , McKendrick Allison M. , Chan Yu Man , Pelak Victoria S.
Published: September 2021

Background: Visual Snow (VS) syndrome is believed to be due to aberrant central visual processing. Positron Emission Tomography (PET) brain imaging and visual evoked potential studies provide evidence for excessive neuronal activity in the medial temporal lobe, specifically the lingual gyrus, and suggest the VS syndrome is a hyperexcitability syndrome. These data provide the basis for consideration of repetitive transcranial magnetic stimulation (rTMS) as a potential treatment for the VS syndrome.

Objective: To publish the study protocol for a pilot study underway at the University of Colorado School of Medicine to investigate the use of rTMS intervention to improve symptoms and visual dysfunction associated with VS. The study aims to determine the adverse events and drop-out rate, evaluate performance of outcome measures, including a novel VS symptom scale, and describe changes in outcomes associated with treatment.

Methods and Design: Up to 10 participants meeting criteria for VS syndrome, age 19–65 years, will undergo an open-label intervention consisting of 10 rTMS sessions, occurring 5 days a week over a 2-week period. Participants will complete pre-treatment and post-treatment assessments that include: the Colorado Visual Snow Scale (CVSS), the National Eye Institute Visual Functional Questionnaire—25 (VFQ-25), the General Anxiety Disorder—7 scale (GAD-7), and three psychophysical visual processing tasks.

Discussion: Knowledge gained from this pilot study will inform future study planning and provide valuable lessons for future investigation of rTMS for the VS syndrome. An overview of study proceedings thus far demonstrates recruitment challenges associated with the COVID-19 pandemic, and additional challenges that are unique to the VS syndrome and to treatment schedules associated with TMS.

Registration: This study has been approved by the Colorado Multiple Institutional Review Board. ClinicalTrials.gov Identifier: NCT04925232.
Cerebral Venous Sinus Thrombosis, Pulmonary Embolism, and Thrombocytopenia After COVID-19 Vaccination in a Taiwanese Man: A Case Report and Literature Review
Authors: Lin Wei , Ko Chien-An , Sung Yueh-Feng , Chen Yeu-Chin , Lee Jiunn-Tay , Lin Yun-Qian , Lin Yu-Kai
Published: September 2021

Objective: Coronavirus disease (COVID-19) vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare but fatal complication observed within 2 weeks of adenovirus-vectored vaccination.

Case Report: A 52-year-old male patient, with a family history of autoimmune diseases, presented with a new onset of worsening headache with nausea and vomiting post-vaccination. The patient was diagnosed with VITT based on laboratory findings demonstrating thrombocytopenia, elevated D-dimer, and dural sinus thrombosis identified on neuroimaging. The patient was successfully treated with high-dose immunoglobulin, steroids, and non-heparin anticoagulants, without any neurologic sequelae. Finally, a confirmatory test with anti-platelet factor 4 antibody was strongly positive.

Conclusion: Physicians should be vigilant when treating patients presenting with new-onset thunderclap headache, progressive worsening headache, and awakening headache accompanied by nausea or vomiting after vaccination, even if no definite clinical neurological deficits are identified. Emergency laboratory test results for demonstrating elevated D-dimer levels, decreased platelet count, and neuroimaging correlation are integral for diagnosis and must be the standard protocol. Treatment with non-heparin anticoagulants, high-dose intravenous immunoglobulin, and steroids that halt or slow the immune-mediated prothrombotic process should be initiated immediately. Considering the high mortality rate of VITT, treatment should be initiated prior to confirmatory test results.