bluuebunny/crossref_metadata_2025 huggingface dataset:
Rare PSAP variants and possible interaction with GBA in REM sleep behavior disorder
Authors: Sosero Yuri L. , Yu Eric , Estiar Mehrdad A. , Krohn Lynne , Mufti Kheireddin , Rudakou Uladzislau , Ruskey Jennifer A. , Asayesh Farnaz , Laurent Sandra B. , Spiegelman Dan , Trempe Jean-François , Quinnell Timothy G. , Oscroft Nicholas , Arnulf Isabelle , Montplaisir Jacques Y. , Gagnon Jean-François , Desautels Alex , Dauvilliers Yves , Gigli Gian Luigi , Valente Mariarosaria , Janes Francesco , Bernardini Andrea , Sonka Karel , Kemlink David , Oertel Wolfgang , Janzen Annette , Plazzi Giuseppe , Antelmi Elena , Biscarini Francesco , Figorilli Michela , Puligheddu Monica , Mollenhauer Brit , Trenkwalder Claudia , Sixel-Döring Friederike , De Cock Valérie Cochen , Monaca Christelle Charley , Heidbreder Anna , Ferini-Strambi Luigi , Dijkstra Femke , Viaene Mineke , Abril Beatriz , Boeve Bradley F. , Postuma Ronald B. , Rouleau Guy A. , Ibrahim Abubaker , Stefani Ambra , Högl Birgit , Hu Michele T.M. , Gan-Or Ziv
Published: July 2021

PSAP encodes saposin C, the co-activator of glucocerebrosidase, encoded by GBA. Since GBA mutations are associated with idiopathic/isolated REM sleep behavior disorder (iRBD), a prodromal stage of synucleinopathy, we examined the role of PSAP mutations in iRBD. We fully sequenced PSAP and performed Optimized Sequence Kernel Association Test in 1,113 iRBD patients and 2,324 controls. We identified loss-of-function (LoF) mutations, which are very rare in PSAP, in three iRBD patients and none in controls (uncorrected p=0.018). Two variants were stop mutations, p.Gln260Ter p.Glu166Ter, and one was an in-frame deletion, p.332_333del. All three mutations have a deleterious effect on saposin C, based on in silico analysis. In addition, the two carriers of p.Glu166Ter and p.332_333del mutations also carried a GBA variant, p.Arg349Ter and p.Glu326Lys, respectively. The co-occurrence of these extremely rare PSAP LoF mutations in two (0.2%) GBA variant carriers in the iRBD cohort, is unlikely to occur by chance (estimated co-occurrence in the general population based on gnomAD data is 0.00035%). Although none of the three iRBD patients with PSAP LoF mutations have phenoconverted to an overt synucleinopathy at their last follow-up, all manifested initial signs suggestive of motor dysfunction, two were diagnosed with mild cognitive impairment and all showed prodromal clinical markers other than RBD. Their probability of prodromal PD, according to the Movement Disorder Society research criteria was 98% or more. These results suggest a possible role of PSAP variants in iRBD and potential genetic interaction with GBA, which requires additional studies.
Self-Reliance, Social Norms, and Self-Stigma as Barriers to Psychosocial Help Seeking Among Rural Cancer Survivors with Cancer-Related Distress
Authors: DeGuzman Pamela B. , Vogel David L. , Bernacchi Veronica , Scudder Margaret A. , Jameson Mark J.
Published: July 2021

Objectives

Even when technology allows rural cancer survivors to connect with supportive care providers from a distance, uptake of psychosocial referrals is low. During our telemedicine-delivered intervention aimed at identifying rural survivors with high distress and connecting them with psychosocial care, fewer than 1/3 of those with high distress accepted a referral. The purpose of this research was to examine the reasons rural cancer survivors did not accept a psychosocial referral.

Methods

We utilized a qualitative descriptive design to analyze data from interviews conducted with participants who had been offered a psychosocial referral during the intervention. Interviews were conducted 6 weeks following the intervention (n=14) and 9 months after the completion of the intervention (n=6).

Results

Ultimately, none of the rural cancer survivors in our study engaged with a psychosocial care provider, including those who had originally accepted a referral for further psychosocial care. When explaining their decisions, survivors minimized their distress, emphasizing their self-reliance and the need to handle distress on their own. They expressed a preference for dealing with distress via informal support networks, which was often limited to close family members. No survivors endorsed public stigma as a barrier to accepting psychosocial help, but several suggested that self-stigma associated with not being able to handle their own distress was a reason for not seeking care.

Significance of Results

Rural cancer survivors’ willingness to accept a psychosocial referral may be mediated by the rural cultural norm of self-reliance, and by self-stigma. Interventions to address referral uptake may benefit from further illumination of these relationships as well as a strength-based approach that emphasizes positive aspects of the rural community and individual self-affirmation.
Clinical characterization and Genomic analysis of COVID-19 breakthrough infections during second wave in different states of India
Authors: Gupta Nivedita , Kaur Harmanmeet , Yadav Pragya , Mukhopadhyay Labanya , Sahay Rima R , Kumar Abhinendra , Nyayanit Dimpal A. , Shete Anita M. , Patil Savita , Majumdar Triparna , Rana Salaj , Gupta Swati , Narayan Jitender , Vijay Neetu , Barde Pradip , Natrajan Gita , Kumari B Amurtha , Kumari Manasa P , Biswas Debasis , Iravane Jyoti , Raut Sharmila , Dutta Shanta , Devi Sulochana , Barua Purnima , Gupta Piyali , Borkakoty Biswa , Kalita Deepjyoti , Dhingra Kanwardeep , Fomda Bashir , Joshi Yash , Goyal Kapil , John Reena , Ashok  , Dhodapkar Rahul , Pandit Priyanka , Devi Sarada , Dudhmal Manisha , Kinariwala Deepa , Khandelwal Neeta , Tiwari Yogendra Kumar , Khatri PK , Gupta Anjali , Khatri Himanshu , Malhotra Bharti , Nagasundaram Mythily , Dar Lalit , Sheikh Nazira , Aggarwal Neeraj , Abraham Priya
Published: July 2021

During March to June 2021 India has experienced a deadly second wave of COVID-19 with an increased number of post-vaccination breakthrough infections reported across the country. To understand the possible reason of these breakthroughs we collected 677 clinical samples (throat swab/ nasal swabs) of individuals who had received two doses (n=592) and one dose (n=85) of vaccines (Covishield and Covaxin,) and tested positive for COVID-19, from 17 states/Union Territories of country. These cases were telephonically interviewed and clinical data was analyzed. A total of 511 SARS-CoV-2 genomes were recovered with genome coverage of higher than 98% from both the cases. Analysis of both the cases determined that 86.69% (n=443) of them belonged to the Delta variant along with Alpha, Kappa, Delta AY.1 and Delta AY.2. The Delta variant clustered into 4 distinct sub-lineages. Sub-lineage–I had mutations: ORF1ab-A1306S, P2046L, P2287S, V2930L, T3255I, T3446A, G5063S, P5401L, A6319V and N-G215C; Sub-lineage –II : ORF1ab- P309L, A3209V, V3718A, G5063S, P5401L and ORF7a-L116F; Sub-lineage –III : ORF1ab- A3209V, V3718A, T3750I, G5063S, P5401L and Spike-A222V; Sub-lineage –IV ORF1ab- P309L, D2980N, F3138S and spike - K77T. This study indicated that majority of the clinical cases in the breakthrough were infected with the Delta variant and only 9.8% cases required hospitalization while fatality was observed in only 0.4% cases. This clearly suggests that the vaccination does provide reduction in hospital admission and mortality.
Structural Neuroplasticity Following Cognitive Behavioral Therapy for the Treatment of Chronic Musculoskeletal Pain: A Randomized Controlled Trial with Secondary MRI Outcomes
Authors: Bishop James , Shpaner Marina , Kubicki Antoni , Naylor Magdalena
Published: July 2021

The extent of white matter (WM) and Grey matter (GM) structural neuroplasticity following cognitive behavioral therapy for chronic pain management remains undetermined. In the current study, we investigated structural alterations in GM morphometry, as well as WM complexity and connectivity, before and after an 11-week group CBT for the treatment of chronic musculoskeletal pain. We hypothesized that effective pain management would influence WM structural metrics indicative of brain plasticity, particularly within cognitive and limbic circuitry as well as GM volume within pain matrix structures. To determine this, patients were randomized into two groups: 1) CBT group that received CBT once-weekly for 11-weeks, or 2) EDU group consisting of an active patient control group that received educational materials by mail. All subjects completed behavioral assessments and underwent neuroimaging at: baseline prior to any intervention (TP1), 11-weeks following either CBT or EDU (TP2), and four months following completion of the intervention (TP3). CBT resulted in significant clinical improvements, assessed via behavioral self-reports, compared to EDU. Compared to EDU, region of interest WM analysis revealed several fiber tracts that had significantly increased WM complexity following CBT intervention, including the bilateral posterior internal capsule and the left cingulum within the temporal lobe. Conversely, several tracts exhibited a decrease in WM complexity including the right external capsule, the left posterior internal capsule, and the right cingulum within the temporal lobe. Changes in clinical outcomes were predictive of alterations in WM complexity metrics immediately following intervention and at long-term follow-up. No between-group differences were observed in either WM connectivity or GM volume. In conclusion, psychotherapeutic interventions such as group CBT influence coping strategies for effective pain relief that influence WM microstructure, however, the mechanisms of these changes remain undetermined. Future studies will be required to uncover the biological underpinnings of these alterations in pain populations.

Clinicaltrialsgov

Can Therapy Alter CNS Processing of Chronic Pain: A Longitudinal Study (https://clinicaltrials.gov/ct2/show/NCT01794988?term=naylor&cntry=US&state=US%3AVT&draw=2&rank=1;NCT01794988). The study protocol was registered in the Clinical Trials Database.
Vitamin D deficiency and its association with iron deficiency in African children
Authors: Mogire Reagan M , Muriuki John Muthii , Morovat Alireza , Mentzer Alexander J , Webb Emily L , Kimita Wandia , Ndungu Francis M , Macharia Alex W , Cutland Clare L. , Sirima Sodiomon B , Diarra Amidou , Tiono Alfred B , Lule Swaib A , Madhi Shabir A , Prentice Andrew M. , Bejon Philip , Pettifor John M , Elliott Alison M , Adeyemo Adebowale , Williams Thomas N , Atkinson Sarah H
Published: July 2021

Vitamin D regulates the master iron hormone hepcidin, and iron in turn alters vitamin D metabolism. Although vitamin D and iron deficiency are highly prevalent globally little is known about their interactions in Africa. To evaluate associations between vitamin D and iron status we measured markers of iron status, inflammation, malaria parasitemia and 25-hydroxyvitamin D (25(OH)D) concentrations in 4509 children aged 0.3 months to 8 years living in Kenya, Uganda, Burkina Faso, The Gambia and South Africa. Prevalence of iron deficiency was 35.1%, and preva- lence of vitamin D deficiency was 0.6% and 7.8% as defined by 25(OH)D concentrations of <30 nmol/L and <50 nmol/L respectively. Children with 25(OH)D concentrations of <50 nmol/L had a 98% increased risk of iron deficiency (OR 1.98 [95% CI 1.52, 2.58]) compared to those with 25(OH)D concentrations >75 nmol/L. 25(OH)D concentrations variably influenced individual markers of iron status. Inflammation interacted with 25(OH)D concentrations to predict ferritin levels. The link between vitamin D and iron status should be considered in strategies to manage these nutrient deficiencies in African children.
Antipsychotic-induced epigenomic reorganization in frontal cortex of individuals with schizophrenia
Authors: Zhu Bohan , Ainsworth Richard I. , Wang Zengmiao , Liu Zhengzhi , Sierra Salvador , Deng Chengyu , Callado Luis F. , Meana J. Javier , Wang Wei , Lu Chang , González-Maeso Javier
Published: July 2021

Genome-wide association studies have revealed >270 loci associated with schizophrenia risk, yet these genetic factors do not seem to be sufficient to fully explain the molecular determinants behind this psychiatric condition. Epigenetic marks such as post-translational histone modifications remain largely plastic during development and adulthood, allowing a dynamic impact of environmental factors, including antipsychotic medications, on access to genes and regulatory elements. However, few studies so far have profiled cell-specific genome-wide histone modifications in postmortem brain samples from schizophrenia subjects, or the effect of antipsychotic treatment on such epigenetic marks. Here we conducted ChIP-seq analyses focusing on histone marks indicative of active enhancers (H3K27ac) and active promoters (H3K4me3), alongside RNA-seq, using frontal cortex samples from antipsychotic-free (AF) and antipsychotic-treated (AT) individuals with schizophrenia, as well as individually matched controls (n = 58). Schizophrenia subjects exhibited thousands of neuronal and non-neuronal epigenetic differences at regions that included several susceptibility genetic loci, such asNRG1,DISC1,andDRD3. By analyzing the AF and AT cohorts separately, we identified schizophrenia-associated alterations in specific transcription factors, their regulatees, and epigenomic and transcriptomic features that were reversed by antipsychotic treatment; as well as those that represented a consequence of antipsychotic medication rather than a hallmark of schizophrenia in postmortem human brain samples. Notably, we also found that the effect of age on epigenomic landscapes was more pronounced in frontal cortex of AT-schizophrenics, as compared to AF-schizophrenics and controls. Together, these data provide important evidence of epigenetic alterations in the frontal cortex of individuals with schizophrenia, and remark for the first time the impact of age and antipsychotic treatment on chromatin organization.
Predicting cause of death from free-text health summaries: development of an interpretable machine learning tool
Authors: McWilliams Chris , Walsh Eleanor I. , Huxor Avon , Turner Emma L. , Santos-Rodriguez Raul
Published: July 2021

Structured Abstract

Purpose

Accurately assigning cause of death is vital to understanding health outcomes in the population and improving health care provision. Cancer-specific cause of death is a key outcome in clinical trials, but assignment of cause of death from death certification is prone to misattribution, therefore can have an impact on cancer-specific trial mortality outcome measures.

Methods

We developed an interpretable machine learning classifier to predict prostate cancer death from free-text summaries of medical history for prostate cancer patients (CAP). We developed visualisations to highlight the predictive elements of the free-text summaries. These were used by the project analysts to gain an insight of how the predictions were made.

Results

Compared to independent human expert assignment, the classifier showed >90% accuracy in predicting prostate cancer death in test subset of the CAP dataset. Informal feedback suggested that these visualisations would require adaptation to be useful to clinical experts when assessing the appropriateness of these ML predictions in a clinical setting. Notably, key features used by the classifier to predict prostate cancer death and emphasised in the visualisations, were considered to be clinically important signs of progressing prostate cancer based on prior knowledge of the dataset.

Conclusion

The results suggest that our interpretability approach improve analyst confidence in the tool, and reveal how the approach could be developed to produce a decision-support tool that would be useful to health care reviewers. As such, we have published the code on GitHub to allow others to apply our methodology to their data (https://zenodo.org/badge/latestdoi/294910364).
Mmp-13 deletion in cells of the mesenchymal lineage increases bone mass, decreases endocortical osteoclast number, and attenuates the cortical bone loss caused by estrogen deficiency in mice
Authors: Ponte Filipa , Kim Ha-Neui , Warren Aaron , Iyer Srividhya , Han Li , Mannen Erin , Gomez-Acevedo Horacio , Nookaew Intawat , Almeida Maria , Manolagas Stavros C.
Published: July 2021

The protective effect of estrogens against cortical bone loss is mediated via direct actions on mesenchymal lineage cells, but functional evidence for the precise molecular mechanism(s) and the mediators of these effects has only recently began to emerge. We report that the matrix metalloproteinase 13 (MMP-13) is the highest up-regulated gene in calvaria or bone marrow cells from mice lacking the estrogen receptor (ER) alpha in osteoprogenitors. We, therefore, generated mice with conditional Mmp-13 deletion in Prrx1 expressing cells (Mmp-13ΔPrrx1) and compared the effect of estrogen deficiency on their bone phenotype to that of control littermates (Mmp-13f/f). Femur and tibia length was decreased in sham-operated Mmp-13ΔPrrx1 mice as compared to Mmp-13f/f. Cortical thickness and trabecular bone volume in the femur and tibia were increased and osteoclast number at the endocortical surfaces was decreased in the sham-operated female Mmp-13ΔPrrx1 mice; whereas bone formation rate was unaffected. Ovariectomy (OVX) caused a decrease of cortical thickness in the femur and tibia of Mmp-13f/f control mice. This effect was attenuated in the Mmp-13ΔPrrx1 mice; but the decrease of trabecular bone caused by OVX was not affected. These results reveal that mesenchymal cell–derived MMP-13 regulates osteoclast number, bone resorption, and bone mass. We have recently reported that the loss of cortical, but not trabecular bone, caused by OVX is also attenuated in Cxcl12ΔPrrx1 mice. Together with the present report, this functional genetic evidence provides proof of principle that increased production of mesenchymal cell-derived factors, such as CXCL12 and MMP-13, are important mediators of the adverse effect of estrogen deficiency on cortical, but not trabecular, bone. Therefore, the mechanisms responsible for the protective effect of estrogens on these two major bone compartments are different.
Hypersensitivity of MAIT cells to Leukocidin ED indicates a Staphylococcus aureus immune evasion mechanism targeting the innate effector cell response
Authors: Boulouis Caroline , Leeansyah Edwin , Shambat Srikanth Mairpady , Norrby-Teglund Anna , Sandberg Johan K.
Published: July 2021

Mucosa-associated invariant T (MAIT) cells recognize bacterial riboflavin metabolite antigens presented by MR1 and play an important role in antimicrobial immune defense. Staphylococcus aureus is a pathobiont expressing a range of virulence factors including the secreted toxin Leukocidin ED (LukED), which binds to certain chemokine receptors and causes cell death by osmolysis. Here, we investigated the effect of LukED on subsets of human T cells and NK cells that are involved in the early innate response to infection. MAIT cells were strikingly hypersensitive to LukED-mediated lysis and rapidly lost from the peripheral blood T cell pool upon exposure to the toxin, leaving a T cell population devoid of MAIT cells. The cytolytic effect of LukED on MAIT cells was rapid, occurred at lower LukED concentration compared to effects on the overall T cell pool, and coincided with extraordinarily high and uniform expression of CCR5. Furthermore, loss of MAIT cells was efficiently inhibited by the CCR5 inhibitor Maraviroc. Interestingly, pre-activation of MAIT cells with IL-12 and IL-18 also partially rescued these cells from LukED toxicity. Among NK cells, LukED targeted the more mature and cytotoxic CD57+ NK cell subset in a CXCR1-dependent manner. Overall, these results indicate that LukED efficiently eliminates cells of the human immune system that have the capacity to respond rapidly to S. aureus in an innate fashion, and that MAIT cells are exceptionally vulnerable to this toxin. Thus, the findings support a model where LukED functions as a S. aureus immune evasion mechanism to avoid recognition by the rapid cell-mediated responses mediated by MAIT cells and NK cells.
The most comprehensive annotation of the Krill transcriptome provides new insights for the study of physiological processes and environmental adaptation
Authors: Urso Ilenia , Biscontin Alberto , Corso Davide , Bertolucci Cristiano , Romualdi Chiara , De Pittà Cristiano , Meyer Bettina , Sales Gabriele
Published: July 2021

The krill species Euphausia superba plays a critical role in the food chain of the Antarctic ecosystem, as the abundance of its biomass affects trophic levels both below it and above. Major changes in climate conditions observed in the Antarctic Peninsula region in the last decades have already altered the distribution of the krill population and its reproductive dynamics. A deeper understanding of the adaptation capabilities of this species, and of the molecular mechanisms behind it are urgently needed. The availability of a large body of RNA-seq assays gave us the opportunity to extend the current knowledge of the krill transcriptome, considerably reducing errors and redundancies. Our study covered the entire developmental process, from larval stages to adult individuals, providing information of central relevance for ecological studies. Here we describe the KrillDB2 database, a resource combining the latest annotation of the krill transcriptome with a series of analyses specifically targeting genes and molecular processes relevant to krill physiology. KrillDB2 provides in a single resource the most complete collection of experimental data and bioinformatic annotations: it includes an extended catalog of krill genes; an atlas of their expression profiles over all RNA-seq datasets publicly available; a study of differential expression across multiple conditions such as developmental stages, geographical regions, seasons, and sexes. Finally, it provides initial indications about non-coding RNAs, a class of molecules whose contribute to krill physiology has never been reported before.
An Ecological Approach to the Effects of Water-Source Locations and Time-Based Schedules on Entropy and Spatio-Temporal Behavioral Features
Authors: Hernández Varsovia , León Alejandro , Guzmán Isiris , Díaz Fryda , Avendaño Garrido Martha Lorena , Hernández Porfirio Toledo , Hernández Linares Carlos Alberto , Luna Itzel
Published: July 2021

In behavior analysis, the modulation of the effect of time-based schedules by the spatial characteristics of the environment has been scarcely studied. Furthermore, the spatial organization of behavior, despite its ubiquity and ecological relevance, has not been widely addressed. The purpose of the present work was to analyze the effect of water delivery location (peripheral vs. central) on the spatial organization of water-feeding behavior under time-based schedules. One group of rats was exposed to a Fixed Time 30 s-water-delivery schedule and a second group to a Variable Time 30 s schedule. For both groups, in the first phase, the water dispenser was located in the perimetral zone. In the second condition, the water dispenser was located in the central zone. Each location was presented for 20 sessions. Rat’s trajectories, distance to the dispenser, accumulated time in regions, and entropy measures were analyzed. A differential effect of the location of water delivery in interaction with the time-based schedule was observed on all the analyzed spatial qualities of behavior. The findings are discussed in relation to the ecological proposal of Timberlake’s behavioral systems.
Mapping inter-individual functional connectivity variability in TMS targets for major depressive disorder
Authors: Harita Shreyas , Momi Davide , Mazza Frank , Griffiths John D.
Published: July 2021

Transcranial magnetic stimulation (TMS) is an emerging alternative to existing treatments for major depressive disorder (MDD). The effects of TMS on both brain physiology and therapeutic outcomes are known to be highly variable from subject to subject, however. Proposed reasons for this variability include individual differences in neurophysiology, in cortical geometry, and in brain connectivity. Standard approaches to TMS target site definition tend to focus on coordinates or landmarks within the individual brain regions implicated in MDD, such as the dorsolateral prefrontal cortex (dlPFC) and orbitofrontal cortex (OFC). Additionally considering the network connectivity of these sites has the potential to improve subject-specificity of TMS targeting and, in turn, improve treatment outcomes. We looked at the functional connectivity (FC) of dlPFC and OFC TMS targets, based on induced electrical field (E-field) maps, estimated using the SimNIBS library. We generated individualized E-field maps on the cortical surface for 121 subjects from the Human Connectome Project database using tetrahedral head models generated from T1-weighted MR images. We analyzed inter-subject variability in the shape and location of these TMS target E-field patterns, their FC, and the major functional networks to which they belong. Our results revealed the key differences in TMS target FC between the dlPFC and OFC, and also how this connectivity varies across subjects. Three major functional networks were targeted across the dlPFC and OFC: the ventral attention, fronto-parietal and default-mode networks in the dlPFC, and the fronto-parietal and default mode networks in the OFC. Inter-subject variability in cortical geometry and in FC was high. Our results characterize the FC patterns of canonical therapeutic TMS targets, and the key dimensions of their variability across subjects. The high inter-individual variability in cortical geometry and FC, leading to high variability in distributions of targeted brain networks, may account for the high levels of variability in physiological and therapeutic TMS outcomes. These insights should, we hope, prove useful as part of the broader effort by the psychiatry, neurology, and neuroimaging communities to help improve and refine TMS therapy, through a better understanding of the technology and its neurophysiological effects.

Highlights

E-field modelling and functional connectivity used to study TMS targets (dlPFC,OFC)

Considerable variability in TMS target E-field patterns seen across subjects

Large inter-subject differences in target connectivity observed and characterized

Major functional networks targeted by dlPFC, OFC TMS were the VAN, FPN and DMN

Insights can contribute to improved and more personalized TMS therapies in the future
GPR39 Localization in Aging Human Brain and Correlation of Expression and Polymorphism with Vascular Cognitive Impairment
Authors: Davis Catherine M , Bah Thierno M , Zhang Wenri H , Nelson Jonathan W , Golgotiu Kirsti , Nie Xiao , Alkayed Farah N , Young Jennifer M , Woltjer Randy L , Silbert Lisa C , Grafe Marjorie R , Alkayed Nabil J
Published: July 2021

INTRODUCTION

The pathogenesis of vascular cognitive impairment (VCI) is not fully understood. GPR39, an orphan G-protein coupled receptor, is implicated in neurological disorders but its role in VCI is unknown.

METHODS

We performed GPR39 immunohistochemical analysis in postmortem brain samples from mild cognitive impairment (MCI) and control subjects. DNA was analyzed for GPR39 SNPs, and correlated with white matter hyperintensity (WMH) burden on premortem MRI.

RESULTS

GPR39 is expressed in aged human dorsolateral prefrontal cortex, localized to microglia and peri-capillary cells resembling pericytes. GPR39-capillary colocalization, and density of GPR39-expressing microglia was increased in aged brains compared to young. SNP distribution was equivalent between groups; however, homozygous SNP carriers were present only in the MCI group, and had higher WMH volume than WT or heterozygous SNP carriers.

DISCUSSION

GPR39 may play a role in aging-related VCI, and may serve as a therapeutic target and biomarker for the risk of developing VCI.
Modeling transcriptional profiles of gene perturbation with deep neural network
Authors: Liu Wenke , Wang Xuya , Mani D R , Fenyö David
Published: July 2021

Background

Cell line perturbation data could be utilized as a reference for inferring underlying molecular processes in new gene expression profiles. It is important to develop accurate and computationally efficient algorithms to exploit biological knowledge in the growing compendium of existing perturbation data and harness these for new predictions.

Results

We reframed the problem of inferring possible gene perturbation based on a reference perturbation database into a classification task and evaluated the application of deep neural network models to address this problem. Our results showed that a fully-connected multi-layer neural network was able to achieve up to 74.9% accuracy in a holdout test set, but the model generalizability was limited by consistency between training and testing data.

Conclusion

Capacity and flexibility enables neural network models to efficiently represent transcriptomic features associated with single gene knockdown perturbations. With consistent signals between training and testing sets, neural networks may be trained to classify new samples to experimentally confirmed molecular phenotypes.
Crosstalk between Flavonoids and the Plant Circadian Clock
Authors: Hildreth Sherry B. , Littleton Evan S. , Clark Leor C. , Puller Gabrielle C. , Kojima Shihoko , Winkel Brenda S.J.
Published: July 2021

Flavonoids are a well-known class of specialized metabolites that play key roles in plant development, reproduction, and survival. Flavonoids are also of considerable interest from the perspective of human health, both as phytonutrients and pharmaceuticals. RNA-Seq analysis of an Arabidopsis null allele for chalcone synthase (CHS), which catalyzes the first step in flavonoid biosynthesis, has uncovered evidence that these compounds influence the expression of circadian clock genes in plants. Analysis of promoter-luciferase constructs showed that the transcriptional activity of genes encoding two components of the central clock,CCA1andTOC1, across the day/night cycle is altered in CHS-deficient seedlings. The effect of flavonoids on circadian function was furthermore reflected in photosynthetic activity, with chlorophyll cycling abolished in the mutant line. Analysis of a mutant lacking flavonoid 3’-hydroxylase (F3’H) activity, and thus able to synthesize mono- but not di-hydroxylated B-ring flavonoids, suggests that the latter are at least partially responsible, as further supported by the effects of quercetin onCCA1promoter activity in wild-type seedlings. Collectively, these experiments point to a previously-unknown connection between flavonoids and circadian cycling in plants and open the way to better understanding of the molecular basis of flavonoid action.
GuPPy, a Python toolbox for the analysis of fiber photometry data
Authors: Sherathiya Venus N. , Schaid Michael D. , Seiler Jillian L. , Lopez Gabriela C. , Lerner Talia N.
Published: July 2021

Fiber photometry (FP) is an adaptable method for recording in vivo neural activity in freely behaving animals. It has become a popular tool in neuroscience due to its ease of use, low cost, the ability to combine FP with freely moving behavior, among other advantages. However, analysis of FP data can be a challenge for new users, especially those with a limited programming background. Here, we present Guided Photometry Analysis in Python (GuPPy), a free and open-source FP analysis tool. GuPPy is provided as a Jupyter notebook, a well-commented interactive development environment (IDE) designed to operate across platforms. GuPPy presents the user with a set of graphic user interfaces (GUIs) to load data and provide input parameters. Graphs produced by GuPPy can be exported into various image formats for integration into scientific figures. As an open-source tool, GuPPy can be modified by users with knowledge of Python to fit their specific needs.
Data-independent acquisition protease-multiplexing enables increased proteome sequence coverage across multiple fragmentation modes
Authors: Richards Alicia L. , Chen Kuei-Ho , Wilburn Damien B. , Stevenson Erica , Polacco Benjamin J. , Searle Brian C. , Swaney Danielle L.
Published: July 2021

The use of multiple proteases has been shown to increase protein sequence coverage in proteomics experiments, however due to the additional analysis time required, it has not been widely adapted in routine data-dependent acquisition (DDA) proteomic workflows. Alternatively, data-independent acquisition (DIA) has the potential to analyze multiplexed samples from different protease digests, but has been primarily optimized for fragmenting tryptic peptides. Here we evaluate a DIA multiplexing approach that combines three proteolytic digests (Trypsin, AspN, and GluC) into a single sample. We first optimize data acquisition conditions for each protease individually with both the canonical DIA fragmentation mode (beam type CID), as well as resonance excitation CID, to determine optimal consensus conditions across proteases. Next, we demonstrate that application of these conditions to a protease-multiplexed sample of human peptides results in similar protein identifications and quantitative performance as compared to trypsin alone, but enables up to a 63% increase in peptide detections, and a 27% increase non-redundant amino acid detections. Importantly, this resulted in 100% sequence coverage for numerous proteins, suggesting the utility of this approach in applications where sequence coverage is critical, such as proteoform analysis.
Cellular signaling beyond the Wiener-Kolmogorov limit
Authors: Weisenberger Casey , Hathcock David , Hinczewski Michael
Published: July 2021

Accurate propagation of signals through stochastic biochemical networks involves significant expenditure of cellular resources. The same is true for regulatory mechanisms that suppress fluctuations in biomolecular populations. Wiener-Kolmogorov (WK) optimal noise filter theory, originally developed for engineering problems, has recently emerged as a valuable tool to estimate the maximum performance achievable in such biological systems for a given metabolic cost. However, WK theory has one assumption that potentially limits its applicability: it relies on a linear, continuum description of the reaction dynamics. Despite this, up to now no explicit test of the theory in nonlinear signaling systems with discrete molecular populations has ever seen performance beyond the WK bound. Here we report the first direct evidence the bound being broken. To accomplish this, we develop a theoretical framework for multi-level signaling cascades, including the possibility of feedback interactions between input and output. In the absence of feedback, we introduce an analytical approach that allows us to calculate exact moments of the stationary distribution for a nonlinear system. With feedback, we rely on numerical solutions of the system’s master equation. The results show WK violations in two common network motifs: a two-level signaling cascade and a negative feedback loop. However the magnitude of the violation is biologically negligible, particularly in the parameter regime where signaling is most effective. The results demonstrate that while WK theory does not provide strict bounds, its predictions for performance limits are excellent approximations, even for nonlinear systems.
Functional analyses of phosphatidylserine/PI(4)P exchangers with diverse lipid species and membrane contexts set unanticipated rules on lipid transfer
Authors: Ikhlef Souade , Lipp Nicolas-Frédéric , Delfosse Vanessa , Fuggetta Nicolas , Bourguet William , Magdeleine Maud , Drin Guillaume
Published: July 2021

Several members of the oxysterol-binding protein-related proteins (ORPs)/oxysterol-binding homology (Osh) family exchange phosphatidylserine (PS) and phosphatidylinositol 4-phosphate (PI(4)P) at the endoplasmic reticulum/plasma membrane (PM) interface. It is unclear whether they preferentially exchange PS and PI(4)P with specific acyl chains to tune the features of the PM, whether they use phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) instead of PI(4)P for exchange processes and whether their activity is influenced by the association of PS with sterol in the PM. Here, we measured in vitro how the yeast Osh6p and human ORP8 transported diverse PS and PI(4)P subspecies, including major cellular species, between membranes. We established how their activity is impacted by the length and unsaturation degree of these lipids. Surprisingly, the speed at which they individually transfer these ligands inversely depends on their affinity for them. To be fast, the transfer of high-affinity ligands requires their exchange for a counterligand of equivalent affinity. Besides, we determined that Osh6p and ORP8 cannot use PI(4,5)P2 for intracellular lipid exchange, as they have a low affinity for this lipid compared to PI(4)P, and do not transfer more PS into sterol-rich membranes. This study provides insights into PS/PI(4)P exchangers and sets unanticipated rules on how the activity of lipid transfer proteins relates to their affinity for ligands.
The gut microbiota of environmentally enriched mice regulates visual cortical plasticity
Authors: Lupori Leonardo , Cornuti Sara , Mazziotti Raffaele , Borghi Elisa , Ottaviano Emerenziana , Sagona Giulia , Pizzorusso Tommaso , Tognini Paola
Published: July 2021

Exposing animals to an enriched environment (EE) has dramatic effects on brain structure, function and plasticity. The poorly known “EE derived signals” mediating the EE effects are thought to be generated within the central nervous system. Here, we shift the focus to the body periphery, revealing that gut microbiota signals are crucial for EE-driven plasticity. Developmental analysis of intestinal bacteria composition in EE mice revealed striking differences from standard condition (ST) animals and enhanced levels of short-chain fatty acids (SCFA). Depleting the EE mice gut microbiota with an antibiotic cocktail decreased SCFA and prevented EE induction of adult ocular dominance (OD) plasticity, spine dynamics and microglia rearrangement. SCFA treatment in ST mice mimicked the EE induction of adult OD plasticity and morphological microglial rearrangement. Remarkably, transferring the microbiota of EE mice to ST recipients activated adult OD plasticity. Thus, taken together our data suggest that experience-dependent changes in gut microbiota regulate brain plasticity.
DNA methylation cues in nucleosome geometry, stability, and unwrapping
Authors: Li Shuxiang , Peng Yunhui , Landsman David , Panchenko Anna R.
Published: July 2021

Cytosine methylation at the 5-carbon position is an essential DNA epigenetic mark in many eukaryotic organisms. Although countless structural and functional studies of cytosine methylation have been reported in both prokaryotes and eukaryotes, our understanding of how it influences the nucleosome assembly, structure, and dynamics remains obscure. Here we investigated the effects of cytosine methylation at CpG sites on nucleosome dynamics and stability. By applying long molecular dynamics simulations (five microsecond long trajectories, 60 microseconds in total), we generated extensive atomic level conformational full nucleosome ensembles. Our results revealed that methylation induces pronounced changes in geometry for both linker and nucleosomal DNA, leading to a more curved, under-twisted DNA, shifting the population equilibrium of sugar-phosphate backbone geometry. These conformational changes are associated with a considerable enhancement of interactions between methylated DNA and the histone octamer, doubling the number of contacts at some key arginines. H2A and H3 tails play important roles in these interactions, especially for DNA methylated nucleosomes. This, in turn, prevents a spontaneous DNA unwrapping of 3-4 helical turns for the methylated nucleosome with truncated histone tails, otherwise observed in the unmethylated system on several microsecond time scale.
Withanolides from Physalis angulata L.
Authors: Okmanov R. Ya. , Makhmudova M. M. , Bobaev I. D. , Tashkhodjaev B.
Published: July 2021

The compounds (17S,20R,22R,24R,25S)-5β,6β:20,24-diepoxy-4β,25-dihydroxy-1-oxowith-2-en-26,22-olide and (20R,22R)-5α,14α,20-Trihydroxy-1-oxo-6α,7α-epoxywitha-2-enolide were isolated from a chloroform extract of the aerial parts of Physalis angulata L. (Solanaceae). Two products were isolated from the chromatographic separation extract. Compound I corresponds to physangulide B chloroform monosolvate, C28H38O7·CHCl3, while compound II is 14α-hydroxyixocarpanolide, C28H40O7. In the two molecular structures, the conformation of the steroid part (rings A, B, C, D) does not differ. In both crystals, molecules are linked by intermolecular O—H...O hydrogen bonds along the c-axis direction and form a two-dimensional network parallel to the ac plane. The absolute configuration was determined from X-ray diffraction data.
Crystal structures of two polymorphs of tixocortol pivalate
Authors: Rousselin Yoann , Yolka Sylvie , Clavel Alexandre
Published: July 2021

Two polymorphs, (I) and (II), of (S)-{2-[(8S,9S,10R,11S,13S,14S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-2,6,7,8,9,11,12,14,15,16-decahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} 2,2-dimethylpropanethioate, C26H38O5S, have been identified. They are orthorhombic, non-centrosymmetric (P212121). The structures display layers of molecules conected via O—H...O hydrogen bonds along the b-axis direction in polymorph (I) and along the c-axis direction in polymorph (II). The structure of (II) exhibits disorder of the main molecule.
Synthesis and crystal structure of 1-hydroxy-8-methyl-9H-carbazole-2-carbaldehyde
Authors: Thiruvalluvar Aravazhi Amalan , Sridharan M. , Rajendra Prasad K. J. , Zeller M.
Published: July 2021

Two crystallographically independent molecules are present in the asymmetric unit of the title compound, C14H11NO2, with virtually identical geometries. The carbazole units are planar. The hydroxy group at position 1, carbaldehyde group at position 2, and methyl group at position 8 (with the exception of two H atoms) are coplanar with the attached benzene rings. The dihedral angle between the two benzene rings is 2.20 (9)° in molecule A and 2.01 (9)° in molecule B. The pyrrole ring makes dihedral angles of 0.82 (10) and 1.40 (10)° [0.84 (10) and 1.18 (10)° in molecule B] with the (–CH3)-substituted and (–OH and –CHO) substituted benzene rings, respectively. The molecular structure is stabilized by the intramolecular O—H...O hydrogen bonds, while the crystal structure features N—H...O and C—H...O hydrogen bonds. A range of π–π contacts further stabilizes the crystal structure.
Effects of developmental HR practices on management innovation: a scenario experiment study
Authors: Huang Jie , Tang Chunyong , Deng Ting
Published: July 2021

Purpose

This research aims to examine the influence of developmental human resources (HR) practices on management innovation. Drawing on social exchange theory, this paper analyzes the mediating role of responsibility for change and the moderating role of resource availability.

Design/methodology/approach

The authors conducted a scenario experiment using a sample of 329 part-time MBA students from various Chinese companies in Southwest China, using analysis of variance and regression to examine the hypotheses.

Findings

The results find a positive relationship between developmental HR practices and management innovation and responsibility for change mediates this relationship. Moreover, it examines the moderating role of resource availability. Resource availability positively moderates the correlation between responsibility for change and management innovation and moderates the mediation effect of responsibility for change on the correlation between developmental HR practices and management innovation.

Practical implications

Organizations should enhance the actual use of developmental HR practices to ensure the provision of appropriate training and development opportunities for all levels of employees in a fair and equal environment. It is better to take up an individual approach when offering these practices. Organizations should provide enough resources for employees, such as financial, spatial and temporal, and ensure the fair distribution of these resources. Organizations should cultivate the responsibility for change of middle-senior managers who can serve as role models for subordinates.

Originality/value

This study broadens the research on developmental HR practices, confirming that it has a positive impact on management innovation. It also provides more insight into the “black box” of developmental HR practices affecting management innovation, namely, the mediating effect of responsibility for change. This study shows that resources are critical to understanding how developmental HR practices can contribute to management innovation through responsibility for change. Using social exchange theory, the research deduces the conditional indirect effect of the model and uses a scenario experiment method to conclude causality.
Transnationality in the XXI century. Concept and indicators
Authors: Ietto-Gillies Grazia
Published: July 2021

Purpose

The purpose of this paper is to analyse the impact of major structural changes on the conceptualization of the transnational corporation (TNC) based on foreign direct investment (FDI) and on indicators of transnationality.

Design/methodology/approach

Analysis of three major structural changes which impact the current conception of transnationality. They are: the rise of digital companies; the increased role of finance in the economy; externalization of activities via non-equity modalities (NEMs) with an impact on FDI and on the labour market.

Findings

The paper finds that the current concept of transnationality needs widening to take account of companies with a low degree of fixed assets abroad such as the digital and the financial companies and those internationalizing via NEMs, as well as to take account of the evolving relationship between TNCs and labour.

Research limitations/implications

Future research along the lines proposed should consider: working explicitly with the new, inclusive concept of transnationality and arrive at an empirical estimate of the proposed indices of transnationality which modify and amplify the current United Nations Conference on Trade and Development indices.

Social implications

Useful for understanding the nature of transnationality in the twenty-first century and for developing policies.

Originality/value

The paper proposes a new concept of transnationality and of the TNC, one that allows for new ways of organizing direct business activities abroad. It also proposes broadening the list of indicators of transnationality.