bluuebunny/crossref_metadata_2025 huggingface dataset:
Compressive femoral neuropathy caused by anticoagulant therapy induced retroperitoneal hematoma
Authors: Kim Tae-Hoon , Lee Da-Jung , Kim Wanil , Do Hwan-Kwon
Published: April 2022

Rationale:

Spontaneous retroperitoneal hematomas due to anticoagulant therapy rarely occur. Retroperitoneal hematomas can cause severe pain in the groin, quadriceps femoris muscle weakness, hemodynamic instability, and abdominal distension. They rarely cause compressive neuropathy of the femoral nerve transversing the iliacus muscle. Differential diagnosis is not easy because they have similar clinical features to retroperitoneal hematomas.

Patient concerns:

A 72-year-old female patient whose right arm was stuck in a bookshelf for 5 days developed right cephalic vein thrombosis. After 5 days of intravenous heparin therapy for venous thrombosis, she presented with sudden right groin pain, right leg paresis, hemodynamic instability, and abdominal distension.

Diagnosis:

Emergency abdominal and pelvic CT showed a large number of hematomas in the bilateral retroperitoneal space with active bleeding of the right lumbar artery. An electrodiagnostic study was performed 2 weeks later to check for neuromuscular damage in the right lower extremity, and right compressive femoral neuropathy was confirmed.

Interventions:

Heparin therapy was discontinued; emergency embolization of the lumbar artery was performed. After 2 weeks, the patient started receiving physical, occupational, and transcutaneous electrical stimulation therapies.

Outcomes:

She became hemodynamically stable after arterial embolization; a significant decrease in hematoma and patency of the femoral nerve was confirmed on follow-up pelvic MRI. After 2 months of comprehensive rehabilitation, the muscle strength of the right leg significantly improved, and the pain disappeared.

Lessons:

Although rare, spontaneous retroperitoneal hematomas may occur in patients receiving anticoagulant medications. They may even occur in patients receiving emergency anticoagulant therapy. Compressive femoral neuropathy due to retroperitoneal hematomas should be considered if muscle weakness and groin pain are observed. Early diagnosis and appropriate treatment plan of compressive femoral neuropathy due to retroperitoneal hematoma are helpful for a good prognosis.
Academic burnout among undergraduate history students
Authors: Oloidi Frances Jumoke , Sewagegn Abatihun Alehegn , Amanambu Ogechukwu Vivian , Umeano Blessing Chisom , Ilechukwu Leonard Chidi
Published: April 2022

Background:

This study aimed to examine the effect of an online psychological intervention on academic burnout of undergraduate history students in Nigeria.

Method:

The sample for the study consists of burned-out undergraduate history students selected randomly from public universities. A total of 18 undergraduate history students with moderate to high burnout symptoms were randomly allocated to the online intervention group, while 17 were randomly assigned to the waitlist control group.

Results:

The use of online rational emotive behavior therapy (online REBT) effectively reduced academic burnout and sustained this significant reduction among Nigerian undergraduate history students compared with a waitlist control condition.

Conclusion:

Online rational emotive behavior therapy intervention delivered to undergraduate history students brought about a significant decrease in academic burnout. Further studies should expand the benefits of online psychological intervention for burnout treatment among Nigerian undergraduate history students.
Risk factors for acute renal injury caused by contrast media after percutaneous coronary intervention and coronary angiography
Authors: Hou Junhuan , Cao Guanghua , Liu Junling , Cai Li , Zhao Li , Li Xue
Published: April 2022

Background:

Contrast-induced acute kidney injury (CI-AKI) caused by contrast medium is one of the common complications of percutaneous coronary intervention (PCI)/coronary angiography (CAG). Early identification of the risk factors of CI-AKI in patients with PCI/CAG and help clinical staff to prevent and intervene as soon as possible is very important to improve the clinical outcome of patients. Although domestic and foreign scholars have studied and summarized the risk factors of CI-AKI in PCI/CAG, the conclusions are not the same. Therefore, in this study, meta-analysis was used to summarize the risk factors of CI-AKI in patients with PCI/CAG, and to explore the characteristics of high-risk groups of CI-AKI, to provide reference for early identification and prevention of clinical doctors and nurses.

Methods:

We will search related literature of PubMed, Embase, Cochrane Library, Web of Science, China Biology Medicine Database, China National Knowledge Infrastructure, China Science and Technology Journal Database, and Wanfang Database. Eligible studies will be screened based on inclusion criteria, and data extraction, risk of bias assessment, publication bias assessment, subgroup analysis, and quality assessment will be performed. Review Manager version 5.3 software will be used for data analysis. Each process is independently conducted by 2 researchers, and if there is any objection, it will be submitted to the third researcher for resolution.

Results:

We will disseminate the findings of this systematic review and meta-analysis via publications in peer-reviewed journals.

Conclusions:

The results of this analysis can be used to generate a risk prediction model and provide an intervention strategy for the occurrence of CI-AKI in PCI/CAG.
Comprehensive comparison between geriatric and nongeriatric patients with trauma
Authors: Lin Pei-Chen , Wu Nan-Chun , Su Hsiu-Chen , Hsu Chien-Chin , Chen Kuo-Tai
Published: April 2022

The incidence of geriatric trauma is increasing due to the growing elderly population. Healthcare providers require a global perspective to differentiate critical factors that might alter patients’ prognosis.

We retrospectively reviewed all adult patients admitted to a trauma center during a 4-year period. We identified 655 adult trauma patients aged from 18 to 64 (nongeriatric group) and 273 trauma patients ≥65 years (geriatric group). Clinical data were collected and compared between the 2 groups.

The geriatric group had a higher incidence of trauma and higher Injury Severity Scores than did the nongeriatric group. Fewer geriatric patients underwent surgical treatment (all patients: geriatric vs nongeriatric: 65.9% vs 70.7%; patients with severe trauma: geriatric vs nongeriatric: 27.6% vs 44.5%). Regarding prognosis, the geriatric group exhibited higher mortality rate and less need for long-term care (geriatric vs nongeriatric: mortality: 5.5% vs 1.8%; long-term care: 2.2% vs 5.0%).

We observed that geriatric patients had higher trauma incidence and higher trauma mortality rate. Aging is a definite predictor of poor outcomes for trauma patients. Limited physiological reserves and preference for less aggressive treatment might be the main reasons for poor outcomes in elderly individuals.
Compound Danshen dripping pills in treating with coronary heart disease
Authors: Sun Ling , Zhang Yan-Na
Published: April 2022

Background:

Coronary heart disease (CHD) patients are categorized by occlusion or vascular stenosis leading to myocardial ischemia, hypoxia, and necrosis. In clinical cardiovascular, CHD remains as a leading disease that is primarily prevalent among older people and mid-aged groups. CHD has a drastic impact on their life standard, and is known to have debilitating effects on both mental and physical wellbeing. As a Chinese patent medicine, compound Danshen dripping pills (CDDPs) are commonly administered to treat CHD in China. Despite the common intake of CDDPs, there is a lack of evidence-based clinical practice to inform its efficacy and safety through related systematic reviews. Therefore, the present protocol proposes to conduct a meta-analysis aiming to evaluate the effectivity and safeness of using CDDP for treating CHD patients.

Methods:

Randomized controlled trials that have evaluated the efficacy and safety of CDDP for treating CHD patients will be searched in MEDLINE, Cochrane Library, EMBASE, China National Knowledge Infrastructure, and WanFang databases. The search will include all related articles published till January 3, 2022. The extracted data will include information on study design, characteristics of the participants, details on intervention, and outcomes. Cochrane risk of bias tool will be employed to assess the quality of the trials. We will use either a random-effects model or fixed-effects model to pool the data. We will present the results as a risk ratio for dichotomous data and weighted mean difference for continuous data. We will visualize publication bias using funnel plots. Disagreements shall be resolved through discussion.

Ethics and dissemination:

Not required.

OSF registration number:

10.17605/OSF.IO/HJTP8
Role of 18F-FDG PET/CT in the assessment of therapy response and clinical outcome in metastatic renal cell carcinoma treated with tyrosine kinase inhibitors or immunotherapy
Authors: Tatar Gamze , Alçin Göksel , Şengül Samanci Nilay , Erol Fenercioglu Özge , Beyhan Ediz , Fikret Çermik Tevfik
Published: April 2022

Objective

This study aimed to determine the role and prognostic significance of 18F-FDG PET/CT on treatment response and survival outcomes in metastatic renal cell carcinoma patients treated with immunotherapy or tyrosine kinase inhibitors (TKIs).

Patients and methods

Forty patients scheduled for a standard treatment protocol with TKIs (n = 17; group-1) or PD-1 inhibitors (nivolumab, n = 23; group-2) were evaluated by 18F-FDG PET/CT. Peak standardized uptake value corrected for lean body mass (SULpeak) and maximum standardized uptake value (SUVmax) were calculated, and their relationship to treatment response was evaluated.

Results

Complete response (CR) in three patients, partial response (PR) in two patients and stable disease (SD) in eight patients were observed in group-1, and the results were as follows for group-2: PR in seven and SD in five patients. At a mean of 17.5-month observation period (range, 7–47), 35.2% of patients progressed, and 23.5% achieved a CR, and no recurrence was observed on PET/CT scans during follow-up. Among all patients enrolled in the study, the 5-year OS in patients with progressive disease (PD) was significantly shorter than patients with clinical benefit (CB = CR and PR and SD) (P = 0.016). Significant differences in both ΔSULpeak and ΔSUVmax were found between PD versus CB (P = 0.001 and P < 0.001, respectively).

Conclusion

18F-FDG-PET/CT can accurately assess therapy response and predict patient outcome in metastatic RCC. 18F-FDG PET/CT may facilitate patient management by evaluating the biological and immunological responses to treatment in patients treated with TKIs or ICIs.
Psychosomatic Medicine: Looking Forward
Authors: Segerstrom Suzanne C.
Published: April 2022

The new Editor-in-Chief of Psychosomatic Medicine thanks the outgoing editorial team, reflects on the longevity and impact of the journal, and looks forward to challenges and opportunities. Science—and scientific publications—must address and embrace reproducibility and replication, inclusivity and diversity, statistical advances, and more.
Achieving Antiretroviral Therapy Uptake and Viral Suppression Among Children and Adolescents Living With HIV in the UNAIDS 90-90-90 Era Across Six Countries in Eastern and Southern Africa—Lessons From the BIPAI Network
Authors: Bacha Jason M. , Dlamini Sandile , Anabwani Florence , Gwimile Judith , Kanywa Jacqueline Balungi , Farirai John , Bvumbwe Menard , Steffy Teresa , Nguyen Diane , Wanless Richard S. , Haq Heather
Published: April 2022

Background:

Although achievements have been made globally since the UNAIDS 90-90-90 targets were announced, paediatric data remain sparse. We describe achievements toward antiretroviral therapy (ART) uptake and viral load (VL) suppression, existing gaps, and potential best practices among children and adolescents living with HIV (CALHIV) across 6 Eastern and Southern African countries.

Setting:

Baylor College of Medicine International Paediatric AIDS Initiative Network sites in Botswana, Eswatini, Lesotho, Malawi, Tanzania, and Uganda.

Methods:

We performed retrospective data analysis among CALHIV ages 0–19 years between 2014 and 2019.

Results:

A total of 25,370 CALHIV received care, 85.8% (21,773/25,370) received ART, 84.4% (18,376/21,773) had documented VL results, and 74.6% (13,715/18,376) had VL < 1000 cps/mL. By 2019, the pooled proportion of CALHIV receiving ART and having viral suppression increased to 99.8% [95% confidence interval (CI): 98.1 to 100.0] and 89.8% (95 CI: 88.2 to 91.5) respectively. Lower rates of viral suppression and higher lost to follow-up (LTFU) were seen in the 0–4-year and 15–19-year cohorts. CALHIV on ART not achieving viral suppression were younger, received care in Malawi or Mbeya, had a history of tuberculosis, lower rates of integrase-strand inhibitor-based ART, and were on ART for shorter durations. Best practices reported included adopting universal ART, ART optimization with protease inhibitor-based and/or dolutegravir-based regimens, peer-supported activities, child/adolescent friendly services, community-supported activities, and technology-driven quality improvement activities and digital solutions.

Conclusions:

High rates of CALHIV receiving ART and having viral suppression can be achieved in settings in Eastern and Southern Africa through using pediatric best practices. Increased efforts must be made to address LTFU and to support under-fives and adolescents.
Attitudes and Experiences Surrounding Female Genital Mutilation/Cutting in the United States: A Scoping Review
Authors: Besera Ghenet , Goldberg Howard , Okoroh Ekwutosi M , Snead Margaret Christine , Johnson-Agbakwu Crista E , Goodwin Mary M
Published: April 2022

In recent decades, growing migration to the United States from countries where female genital mutilation/cutting (FGM/C) is widely practiced has caused a rise in the number of women and girls in the United States who could have potentially experienced FGM/C. A scoping review was conducted to identify research and gaps in literature about FGM/C–related attitudes and experiences among individuals from FGM/C–practicing countries living in the United States. This scoping review identified 40 articles meeting inclusion criteria. The findings of this review suggest that both women and men from FGM/C-practicing countries living in the United States generally oppose FGM/C, and that women with FGM/C have significant physical and mental health needs and have found US healthcare providers to lack understanding of FGM/C. Future research can improve measurement of FGM/C by applying a health equity lens and taking into account the sociocultural influences on FGM/C–related attitudes and experiences.
Speech disturbances in schizophrenia: assessing cross-linguistic generalizability of NLP automated measures of coherence
Authors: Parola Alberto , Lin Jessica Mary , Simonsen Arndis , Bliksted Vibeke , Zhou Yuan , Wang Huiling , Inoue Lana , Koelkebeck Katja , Fusaroli Riccardo
Published: April 2022

Introduction

Language disorders – disorganized and incoherent speech in particular - are distinctive features of schizophrenia. Natural language processing (NLP) offers automated measures of incoherent speech as promising markers for schizophrenia. However, the scientific and clinical impact of NLP markers depends on their generalizability across contexts, samples, and languages, which we systematically assessed in the present study relying on a large, novel, cross-linguistic corpus.

Methods

We collected a Danish (DK), German (GE), and Chinese (CH) cross-linguistic dataset involving transcripts from 187 participants with schizophrenia (111DK, 25GE, 51CH) and 200 matched controls (129DK, 29GE, 42CH) performing the Animated Triangle task. Fourteen previously published NLP coherence measures were calculated, and between-groups differences and association with symptoms were tested for cross-linguistic generalizability.

Results

One coherence measure robustly generalized across samples and languages. We found several language-specific effects, some of which partially replicated previous findings (lower coherence in German and Chinese patients), while others did not (higher coherence in Danish patients). We found several associations between symptoms and measures of coherence, but the effects were generally inconsistent across languages and rating scales.

Conclusions

Using a cumulative approach, we have shown that NLP findings of reduced semantic coherence in schizophrenia have limited generalizability across different languages, samples, and measures. We argue that several factors such as sociodemographic and clinical heterogeneity, cross-linguistic variation, and the different NLP measures reflecting different clinical aspects may be responsible for this variability. Future studies should take this variability into account in order to develop effective clinical applications targeting different patient populations.
Resolution of glycogen and glycogen-degrading activities reveals correlates of Lactobacillus crispatus dominance in a cohort of young African women
Authors: Lithgow Karen V. , Cochinamogulos Athena , Muirhead Kevin , Konschuh Shaelen , Oluoch Lynda , Mugo Nelly R. , Roxby Alison C. , Sycuro Laura K.
Published: April 2022

Background

A healthy vaginal microbiome is dominated by Lactobacillus species that produce lactic acid, lowering vaginal pH and limiting colonization by pathogens. Lactobacillus dominance (LD) is established during puberty, but many women, especially those of Black race, lose LD during their reproductive years. Glycogen is thought to be a key host nutrient that supports vaginal lactobacilli and their fermentative lactic acid production, but mechanisms of glycogen utilization by Lactobacillus species are incompletely understood. By partitioning glycogen and glycogen-derived maltodextrin, as well as the activity of glycogen-degrading pullulanase enzymes, this work refines understanding of vaginal glycogen catabolism and identifies correlates of LD.

Results

Vaginal swab samples were collected from a cohort of young women with limited sexual experience in Thika, Kenya (N=17, ages 17–20). Metagenomic profiling of the vaginal microbiome revealed that most samples exhibited LD, particularly dominant Lactobacillus crispatus. Amylopullulanase activity, cleavage of glycogen α-1,4 and α-1,6 linkages by individual/multifunctional enzymes, showed a significant positive correlation with glycogen-derived maltodextrin, but no relationship with L. crispatus dominance. Pullulanase activity, which specifically targets glycogen α-1,6 linkages, was 3-fold higher in L. crispatus-dominated samples and significantly correlated with D-lactic acid levels. Metagenomics and targeted PCR revealed that 36% of L. crispatus-dominated metagenomes from our African cohort lacked a functional L. crispatus pullulanase (pulA) gene, a 3-fold higher frequency of gene loss than that seen in metagenomes from European and North American women. Our findings suggest pulA gene loss or inactivation may correspond with reductions in L. crispatus abundance, pullulanase activity and lactic acid levels compared to samples dominated by pulA-competent L. crispatus.

Conclusions

Our results indicate that although amylase activity drives the accumulation of glycogen catabolites in vaginal fluid, pullulanase appears to specifically contribute to maximal D-lactic acid production by L. crispatus. However, this is only possible when a functional pulA gene is present, which was not the case in a substantial proportion of young African women with dominant L. crispatus. Scaling this analysis to a larger cohort will address whether genomic and enzymatic indicators of L. crispatus pullulanase activity are predictive of sustained LD and vaginal health.
Felidae call type and species identification based on acoustic features
Authors: Bandara Danushka , Exantus Karen , Navarro-Martinez Cristian , Patterson Murray , Byun Ashley
Published: April 2022

The cat family Felidae is one of the most successful carnivore lineages today. However, the study of the evolution of acoustic communication between felids remains a challenge due to the lack of fossils, the limited availability of audio recordings because of their largely solitary and secretive behavior, and the underdevelopment of computational models and methods needed to address acoustic evolutionary questions. This study is a first attempt at developing a machine learning-based approach to the classification of felid calls as well as the identification of acoustic features that distinguish felid call types and species from one another. A felid call dataset was developed by extracting audio clips from diverse sources. The audio clips were manually annotated for call type and species. Due to the limited availability of samples, this study focused on the Pantherinae subfamily. Time-frequency features were then extracted from the Pantherinae dataset. Finally, several classification algorithms were applied to the resulting data. We achieved 91% accuracy for this Pantherinae call type classification. For the species classification, we obtained 86% accuracy. We also obtained the most predictive features for each of the classifications performed. These features can inform future research into the evolutionary acoustic analysis of the felid group.
Prioritization of driver genes in cancer-associated copy number alterations identifies B4GALT5 as a glycooncogene
Authors: Parashuraman Seetharaman , Sahu Pranoy , Russo Francesco , Agliarulo Ilenia , Rizzo Riccardo , Lo Monte Matteo , Normanno Nicola , Soddu Silvia , Carlomagno Francesca , Luini Alberto
Published: April 2022

Cancer is a disease resulting from aberrant communication between cells of a multicellular organism. The glycan coat that surrounds the cells is an important player in cellular communication. While altered cell surface glycans are known biomarkers for cancer, glycan biosynthesis itself has not been considered a potential oncogenic pathway. So, to understand the oncogenic potential of the glycan biosynthetic pathways we have analyzed the copy number alterations (CNA) of genes encoding for glycosylation regulators (glycogenes) in cancer genome datasets and identify novel glyco-oncogenes and glyco-tumor suppressor genes (TSGs). CNA of oncogenes and TSGs is an important cancer-associated genetic alteration that associates with worst prognosis. Nevertheless, identity of the driver genes in the copy number altered segments of the genome remains obscure in most cases. We developed a prioritization pipeline based on bioinformatic and experimental criteria to identify putative driver genes. In addition to correctly identifying several well-established oncogenes/TSGs, this pipeline discerns several novel oncogenes and TSGs, some of which are glycogenes. Further, among glyco-oncogenes there is an enrichment for glycosphingolipid biosynthetic pathway and trans-Golgi associated lysosomal sorting machinery and among glyco-TSGs there is an enrichment for early N-glycan biosynthetic enzymes. As a proof-of-principle we show that one of the identified glycooncogene B4GALT5, encoding a key enzyme in the glycosphingolipid pathway exhibits oncogenic property of promoting increased growth of hepatocellular carcinoma cells. Thus, this study identifies glycosylation pathways with oncoregulatory properties and opens up a new group of enzymes as potential therapeutic targets for cancer.
Fear extinction is regulated by long noncoding RNA activity at the synapse
Authors: Liau Wei-Siang , Zhao Qiongyi , Bademosi Adekunle , Gormal Rachel , Gong Hao , Marshall Paul R. , Periyakaruppiah Ambika , Madugalle Sachithrani U. , Zajackowski Esmi L. , Leighton Laura J. , Ren Haobin , Musgrove Mason , Davies Joshua , Rauch Simone , He Chuan , Dickinson Bryan C. , Li Xiang , Wei Wei , Meunier Frédéric A. , Fernandez Moya Sandra M. , Kiebler Michael A. , Srinivasan Bharath , Banerjee Sourav , Clark Michael , Spitale Robert C. , Bredy Timothy W.
Published: April 2022

Long noncoding RNAs (lncRNAs) represent a multidimensional class of regulatory molecules involved in many aspects of brain function. Emerging evidence indicates that lncRNAs are expressed at the synapse; however, a direct role for their activity in this subcellular compartment in memory formation has yet to be demonstrated. Using lncRNA capture-seq on synaptosomes, we identified a significant number of lncRNAs that accumulate at synapses within the infralimbic prefrontal cortex of adult male C57/Bl6 mice. Among these is a splice variant related to the stress-associated lncRNA, Gas5. RNA immunoprecipitation followed by mass spectrometry and single molecule imaging revealed that this Gas5 isoform, in association with the RNA binding proteins G3bp2 and Caprin1, regulates the activity-dependent trafficking and clustering of RNA granules in dendrites. In addition, we found that cell-type-specific, state-dependent, and synapse-specific knockdown of the Gas5 variant led to impaired fear extinction memory. These findings identify a new mechanism of fear extinction that involves the dynamic interaction between local lncRNA activity and the coordination of RNA condensates in the synaptic compartment.
Atypical Child-Parent Neural Synchrony Links to Children’s Psychopathological Symptoms
Authors: Su Haowen , Young Christina B. , Han Zhuo Rachel , Xu Jianjie , Xiong Bingsen , Wang Jingyi , Hao Lei , Yang Zhi , Chen Gang , Qin Shaozheng
Published: April 2022

Family emotional climate is fundamental to child’s emotional wellbeing and mental health. Negative family emotional climate may lead to heightened psychopathological symptoms via dysfunctional child-parent interactions. Single-brain paradigms have uncovered changes in brain systems and networks related to negative family environments, but how neurobiological reciprocity between child and parent brains is associated with children’s psychopathological symptoms remains unknown. In study1, we investigated the relationship between family emotional climate and children’s psychopathological symptoms in 395 child-parent dyads. In study2, using a naturalistic movie-watching functional magnetic imaging technique in a subsample of 100 children and parents, we investigate the neurobiological underpinnings of how family emotional climate is associated with children’s psychopathological symptoms through child-parent neural synchrony. Children from negative family emotional climate experienced more severe psychopathological symptoms. We revealed significantly higher inter-subject correlations in the dorsal and ventral portions of the medial prefrontal cortex (mPFC), and greater concordance of activity with widespread brain regions critical for socioemotional skills in child-parent than child-stranger dyads. Critically, negative family emotional climate was associated with decreased inter-subject functional correlation between the ventral mPFC and the hippocampus in child-parent dyads, which further accounted for higher children’s internalizing symptoms especially for anxious and depressed aspects. Family emotional climate might transmit into the brain of parent-child dyads, which may associate with child development outcomes. The present study identified that child-parent vmPFC-hippocampal circuitry is linked to children’s psychopathological symptoms. Our findings suggest a neurobiological mechanism of how negative family emotional climate affects children’s psychopathological symptoms through altered child-parent neural synchrony.
Identification of C270 as a novel site for allosteric modulators of SARS-CoV-2 papain-like protease
Authors: Hu Hangchen , Wang Qian , Su Haixia , Shao Qiang , Zhao Wenfeng , Chen Guofeng , Li Minjun , Xu Yechun
Published: April 2022

The papain-like protease (PLpro) in coronavirus is one of key cysteine proteases responsible for the proteolytic processing of viral polyproteins, and plays an important role in dysregulation of host immune response. PLprois a promising therapeutic target with a major challenge in inhibitor design due to the restricted S1/S2 sites for two consecutive glycine of substrates. Here we reported the discovery of two activators of the SARS-CoV-2 PLprofrom a biochemical screening, and the identification of the unique residue, C270, as an allosteric and covalent regulation site for the activators. This site was also specifically modified by glutathione oxidized, resulting in the S-glutathionylation and activation of the protease. Furthermore, one compound was found to allosterically inhibit the protease by covalent binding to this crucial site. Together, these results elucidated an unrevealed molecular mechanism for allosteric modulation of the protease’s activity, and provided a new strategy for discovery of allosteric inhibitors of the SARS-CoV-2 PLpro.
Identification and characterization of the T cell receptor (TCR) repertoire of the Cynomolgus macaque (Macaca Fascicularis)
Authors: Jaiswal Swati , Boyce Shayla , Nyquist Sarah K. , Jivanjee Tasneem , Ibrahim Samira , Bromley Joshua D. , Gatter G. James , Gideon Hannah P. , Patel Kush V. , Ganchua Sharie Keanne C. , Berger Bonnie , Fortune Sarah M. , Flynn JoAnne L. , Shalek Alex K. , Behar Samuel M.
Published: April 2022

Background

Non-human primates (NHP) are desirable as animal models of human disease because they share behavioral, physiological, and genomic traits with people. Hence, NHP recapitulate manifestations of disease not observed in other animal species. The Macaca fascicularis (i.e., Cynomolgus macaque) is an NHP species extensively used for biomedical research, but the TCR repertoire hasn’t been characterized yet.

Result

We used the genomic sequences to design primers to identify the expressed TCR repertoire by single cell RNAseq. The data analysis from 22 unique samples were used to assign a functional status to each TCR genes. We identified and analyzed the TRA/D, TRB and TRG loci of the Cynomolgus macaque.

Conclusion

The genomic organization of the Cynomolgus macaque has great similarity with Macaca mulatta (i.e., Rhesus macaque) and they shared >90% sequence similarity with the human TCR repertoire. These data will facilitate the analysis of T cell immunity in Cynomolgus macaques.
High-contrast en-bloc staining of mouse whole-brain samples for EM-based connectomics
Authors: Song Kun , Feng Zhihui , Helmstaedter Moritz
Published: April 2022

Connectomes of human cortical gray matter require high-contrast homogeneously stained samples sized at least 2-3 mm on a side, and a whole-mouse brain connectome requires samples sized at least 5-10 mm on a side. Here we report en-bloc staining and embedding protocols for these and other applications, removing a key obstacle for connectomic analyses at mammalian whole-brain level.
The Role of Replication-induced Chromosomal Copy Numbers in Spatio-temporal Gene Regulation and Evolutionary Chromosome Plasticity
Authors: Teufel Marc , Henkel Werner , Sobetzko Patrick
Published: April 2022

For a coherent response to environmental changes, bacterial evolution has formed a complex transcriptional regulatory system comprising classical DNA binding proteins sigma factors and modulation of DNA topology. In this study, we investigate replication-induced gene copy numbers - a regulatory concept that is unlike the others not based on modulation of promoter activity but replication dynamics. We show that a large fraction of genes are predominantly affected by transient copy numbers and identify cellular functions and central pathways governed by this mechanism in Escherichia coli. Furthermore, we show quantitatively that the previously observed spatio-temporal expression pattern between different growth phases mainly emerges from transient chromosomal copy numbers. We extend the analysis to the plant pathogen Dickeya dadantii and the biotechnologically relevant organism Vibrio natriegens. The analysis reveals a connection between growth phase dependent gene expression and evolutionary gene migration in these species. Further extension to the bacterial kingdom shows that chromosome evolution is governed by growth rate related transient copy numbers.
Deep learning to decompose macromolecules into independent Markovian domains
Authors: Mardt Andreas , Hempel Tim , Clementi Cecilia , Noé Frank
Published: April 2022

The increasing interest in modeling the dynamics of ever larger proteins has revealed a fundamental problem with models that describe the molecular system as being in a global configuration state. This notion limits our ability to gather sufficient statistics of state probabilities or state-to-state transitions because for large molecular systems the number of metastable states grows exponentially with size. In this manuscript, we approach this challenge by introducing a method that combines our recent progress on independent Markov decomposition (IMD) with VAMPnets, a deep learning approach to Markov modeling. We establish a training objective that quantifies how well a given decomposition of the molecular system into independent subdomains with Markovian dynamics approximates the overall dynamics. By constructing an end-to-end learning framework, the decomposition into such subdomains and their individual Markov state models are simultaneously learned, providing a data-efficient and easily interpretable summary of the complex system dynamics. While learning the dynamical coupling between Markovian subdomains is still an open issue, the present results are a significant step towards learning “Ising models” of large molecular complexes from simulation data.
Excitatory and inhibitory effects of HCN channel modulation on excitability of layer V pyramidal cells
Authors: Mäki-Marttunen Tuomo , Mäki-Marttunen Verónica
Published: April 2022

Dendrites of cortical pyramidal cells are densely populated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, a.k.a. Ih channels. Ih channels are targeted by multiple neuromodulatory pathways, and thus are one of the key ion-channel populations regulating the pyramidal cell activity. Previous observations and theories attribute opposing effects of the Ih channels on neuronal excitability due to their mildly hyperpolarized reversal potential. These effects are difficult to measure experimentally due to the fine spatiotemporal landscape of the Ih activity in the dendrites, but computational models provide an efficient tool for studying this question in a reduced but generalizable setting. In this work, we build upon existing biophysically detailed models of thick-tufted layer V pyramidal cells and model the effects of over- and under-expression of Ih channels as well as their neuromodulation by dopamine (gain of Ih function) and acetylcholine (loss of Ih function). We show that Ih channels facilitate the action potentials of layer V pyramidal cells in response to proximal dendritic stimulus while they hinder the action potentials in response to distal dendritic stimulus at the apical dendrite. We also show that the inhibitory action of the Ih channels in layer V pyramidal cells is due to the interactions between Ih channels and a hot zone of low voltage-activated Ca2+ channels at the apical dendrite. Our simulations suggest that a combination of Ih-enhancing neuromodulation at the proximal apical dendrite and Ih-inhibiting modulation at the distal apical dendrite can increase the layer V pyramidal excitability more than any of the two neuromodulators alone. Our analyses uncover the effects of Ih-channel neuromodulation of layer V pyramidal cells at a single-cell level and shed light on how these neurons integrate information and enable higher-order functions of the brain.
Incertohypothalamic A13 dopaminergic neurons are involved in fine forelimb movements but not reward
Authors: Garau C , Hayes J , Chiacchierini G , McCutcheon JE , Apergis-Shoute J
Published: April 2022

Tyrosine hydroxylase (TH)-containing neurons of the dopamine (DA) cell group A13 are well-positioned to impact known dopamine-related functions since their descending projections innervate target regions that regulate vigilance, sensorimotor integration and execution. Despite this known connectivity little is known regarding the functionality of A13-DA circuits. Using TH-specific loss-of-function methodology and techniques to monitor population activity in transgenic rats in vivo we investigated the contribution of A13-DA neurons in reward and movement-related actions. Our work demonstrates a role for A13-DA neurons in grasping and handling of objects that is independent from reward. A13-DA neurons respond strongly when animals grab and manipulate food items while their inactivation or degeneration prevents animals from successfully doing so - a deficit partially attributed to a reduction in grip strength. In contrast, there was no relation between A13-DA activity and food-seeking behavior when animals were tested on a reward-based task that did not include a reaching/grasping response. Moreover, motivation for food was unaffected as goal-directed behavior for food items was in general intact following A13 neuronal inactivation/degeneration. These results demonstrate a functional role for A13-DA neurons in prehensile actions that are uncoupled from reward and as such position A13-DA neurons into the functional framework regarding centrally-located DA populations and their ability to coordinate movement.
A divide-and-conquer approach for genomic prediction in rubber tree using machine learning
Authors: Aono Alexandre Hild , Francisco Felipe Roberto , Souza Livia Moura , Gonçalves Paulo de Souza , Scaloppi Erivaldo J. , Guen Vincent Le , Fritsche-Neto Roberto , Gorjanc Gregor , Quiles Marcos Gonçalves , de Souza Anete Pereira
Published: April 2022

Rubber tree (Hevea brasiliensis) is the main feedstock for commercial rubber; however, its long vegetative cycle has hindered the development of more productive varieties via breeding programs. With the availability ofH. brasiliensisgenomic data, several linkage maps with associated quantitative trait loci (QTLs) have been constructed and suggested as a tool for marker-assisted selection (MAS). Nonetheless, novel genomic strategies are still needed, and genomic selection (GS) may facilitate rubber tree breeding programs aimed at reducing the required cycles for performance assessment. Even though such a methodology has already been shown to be a promising tool for rubber tree breeding, increased model predictive capabilities and practical application are still needed. Here, we developed a novel machine learning-based approach for predicting rubber tree stem circumference based on molecular markers. Through a divide-and-conquer strategy, we propose a neural network prediction system with two stages: (1) subpopulation prediction and (2) phenotype estimation. This approach yielded higher accuracies than traditional statistical models in a single-environment scenario. By delivering large accuracy improvements, our methodology represents a powerful tool for use inHeveaGS strategies. Therefore, the incorporation of machine learning techniques into rubber tree GS represents an opportunity to build more robust models and optimizeHeveabreeding programs.
Introduced crops supplement rather than replace indigenous crops in an African center of agrobiodiversity
Authors: Rampersad Chris , Geto Tesfu , Samuel Tarekegn , Abebe Meseret , Gomez Marybel Soto , Pironon Samuel , Büchi Lucie , Haggar Jeremy , Stocks Jonathan , Ryan Philippa , Buggs Richard , Demissew Sebsebe , Wilkin Paul , Abebe Wendawek M. , Borrell James S.
Published: April 2022

Crop diversity plays a major role in underpinning food security. It is especially important to smallholder and subsistence farmers, who often rely on crop diversity for stable and resilient production. Despite this, global expansion of a small pool of major crops and the associated homogenisation of global agricultural systems may decrease on-farm crop diversity.

We surveyed 1,369 subsistence farms stratified across climate gradients in the Ethiopian Highlands, to characterise the richness and cultivated area of the 83 edible crops they contained. We further categorise these crops by their period of introduction to Ethiopia. We apply non-metric multidimensional scaling and mixed effects modelling to characterise agrisystem composition and test the impact of crop introductions.

We find a significant positive relationship between introduced and indigenous crop richness, suggesting that crop introductions have tended to supplement rather than replace or reduce indigenous crop diversity. Geographically matched farms with higher proportions of introduced crops, had significantly higher overall crop richness. Analysis of socio-economic drivers indicates that both poverty and low accessibility are associated with reduced cultivation of modern introductions.

We conclude that global patterns of major crop expansion do not necessarily result in agrobiodiversity loss for subsistence farmers, in our Ethiopian case study. Importantly, socioeconomic factors may strongly influence the farmers propensity to adopt novel species, suggesting targets for agricultural extension policies. Given the rapid climatic, economic and demographic changes impacting global food systems and the threats to food security these entail, robust indigenous agricultural systems supplemented with diverse introduced crops may enhance resilience.
Computational analysis of memory consolidation following inhibitory avoidance (IA) training in adult and infant rats: critical roles of CaMKIIα and MeCP2
Authors: Zhang Yili , Smolen Paul , Alberini Cristina M. , Baxter Douglas A. , Byrne John H.
Published: April 2022

Key features of long-term memory (LTM), such as its stability and persistence, are acquired during processes collectively referred to as consolidation. The dynamics of biological changes during consolidation are complex. In adult rodents, consolidation exhibits distinct periods during which the engram is more or less resistant to disruption. Moreover, the ability to consolidate memories differs during developmental periods. Although the molecular mechanisms underlying consolidation are poorly understood, the initial stages rely on interacting signaling pathways that regulate gene expression, including brain-derived neurotrophic factor (BDNF) and Ca2+/calmodulin-dependent protein kinase II α (CaMKIIα) dependent feedback loops. We investigated the ways in which these pathways may contribute to developmental and dynamical features of consolidation. A computational model of molecular processes underlying consolidation following inhibitory avoidance (IA) training in rats was developed. Differential equations described the actions of CaMKIIα, multiple feedback loops regulating BDNF expression, and several transcription factors including methyl-CpG binding protein 2 (MeCP2), histone deacetylase 2 (HDAC2), and SIN3 transcription regulator family member A (Sin3a). This model provides novel explanations for the (apparent) rapid forgetting of infantile memory and the temporal progression of memory consolidation in adults. Simulations predict that dual effects of MeCP2 on the expression of bdnf, and interaction between MeCP2 and CaMKIIα, play critical roles in the rapid forgetting of infantile memory and the progress of memory resistance to disruptions. These insights suggest new potential targets of therapy for memory impairment.

Author Summary

Long-term memories (LTMs) are enduring and resistant to disruption These features are acquired via processes collectively referred to as consolidation. In adults, the initial stages of consolidation follow complex dynamics that are believed to emerge from interacting biochemical signaling pathways [1], including BDNF and CaMKIIα dependent feedback loops. Similarly, the acquisition of ability to consolidate memory in infantile animals is believed to emerge from the functional maturation of these molecular pathways [2]. Here, the ways in which these pathways contribute to consolidation were investigated using a computational model. This model provides novel explanations for the apparent rapid forgetting of infantile memory and for development of resistance to disruption during memory consolidation.
Prostaglandin D2 pathway in a transgenic rat model of Alzheimer’s disease: therapeutic potential of timapiprant a DP2 antagonist
Authors: Wallace Charles H. , Oliveros Giovanni , Serrano Peter A , Rockwell Patricia , Xie Lei , Figueiredo-Pereira Maria
Published: April 2022

The cyclooxygenase pathway, a key mediator of inflammation, is implicated in Alzheimer’s disease (AD). A deeper investigation is required into the contributions of this pathway to the neuropathology of AD. Cyclooxygenases produce prostaglandins, which have multiple receptors and functions including inflammation, nociception, sleep, cardiovascular maintenance and reproduction. In the brain, prostaglandin D2 (PGD2) is the most abundant prostaglandin, increases the most under pathological conditions, and plays roles in sleep, stroke and inflammation. PGD2 signals through its DP1 and DP2 receptors and their activation can be protective or detrimental. We address the relationship between the PGD2 pathway and AD neuropathology with F344-AD transgenic (Tg-AD) rats that exhibit age-dependent and progressive pathology similar to AD patients. We analyzed the PGD2 pathway in the hippocampus of wild type (WT) rats and their Tg-AD littermates, at the age of 11 months, when Tg-AD rats exhibit plaques and perform significantly worse in hippocampal-dependent cognitive tasks than WT rats. Using mass spectrometry, we determined that PGD2 levels were at least 14.5-fold higher than PGE2, independently of genotype. Immunohistochemistry established that microglial DP1 receptors were more abundant and neuronal DP2 receptors were fewer in Tg-AD than in WT rats. RNA sequencing profiling of 33 genes involved in the PGD2 and PGE2 pathways revealed that mRNA levels were the highest for L-PGDS, the major PGD2 synthase in the brain. To evaluate the pathophysiological significance of our findings on the PGD2 pathway, we treated a subset of rats (WT and Tg-AD males) with timapiprant, a potent and highly selective oral DP2 antagonist being developed as a once-daily oral treatment in patients with allergic inflammation. We conclusively show that timapiprant significantly mitigated some of the AD pathology exhibited by the Tg-AD male rats. More comprehensive studies are necessary to support the therapeutic potential of timapiprant and that of other PGD2-related compounds in the treatment of AD.
Ultra-deep Sequencing of Hadza Hunter-Gatherers Recovers Vanishing Gut Microbes
Authors: Merrill Bryan D. , Carter Matthew M. , Olm Matthew R. , Dahan Dylan , Tripathi Surya , Spencer Sean P. , Yu Brian , Jain Sunit , Neff Norma , Jha Aashish R. , Sonnenburg Erica D. , Sonnenburg Justin L.
Published: April 2022

The gut microbiome is a key modulator of immune and metabolic health. Human microbiome data is biased towards industrialized populations, providing limited understanding of the distinct and diverse non-industrialized microbiomes. Here, we performed ultra-deep metagenomic sequencing and strain cultivation on 351 fecal samples from the Hadza, hunter-gatherers in Tanzania, and comparative populations in Nepal and California. We recover 94,971 total genomes of bacteria, archaea, bacteriophages, and eukaryotes, 43% of which are absent from existing unified datasets. Analysis of in situ growth rates, genetic pN/pS signatures, high-resolution strain tracking, and 124 gut-resident species vanishing in industrialized populations reveals differentiating dynamics of the Hadza gut microbiome. Industrialized gut microbes are enriched in genes associated with oxidative stress, possibly a result of microbiome adaptation to inflammatory processes. This unparalleled view of the Hadza gut microbiome provides a valuable resource that expands our understanding of microbes capable of colonizing the human gut and clarifies the extensive perturbation brought on by the industrialized lifestyle.