bluuebunny/crossref_metadata_2025 huggingface dataset:
Machine Learning in Clinical Psychology and Psychotherapy Education: A Survey of Postgraduate Students at a Swiss University
Authors: Blease Charlotte , Kharko Anna , Annoni Marco , Gaab Jens , Locher Cosima
Published: November 2020

Background

There is increasing use of for machine learning-enabled tools (e.g., psychotherapy apps) in mental health care.

Objective

This study aimed to explore postgraduate clinical psychology and psychotherapy students’ familiarity and formal exposure to topics related to artificial intelligence and machine learning (AI/ML) during their studies.

Methods

In April-June 2020, we conducted a mixed-methods web-based survey using a convenience sample of 120 clinical psychology and psychotherapy enrolled in a two-year Masters’ program students at a Swiss university.

Results

In total 37 students responded (response rate: 37/120, 31%). Among the respondents, 73% (n=27) intended to enter a mental health profession. Among the students 97% reported that they had heard of the term ‘machine learning,’ and 78% reported that they were familiar with the concept of ‘big data analytics’. Students estimated 18.61/3600 hours, or 0.52% of their program would be spent on AI/ML education. Around half (46%) reported that they intended to learn about AI/ML as it pertained to mental health care. On 5-point Likert scale, students moderately agreed (median=4) that AI/M should be part of clinical psychology/psychotherapy education.

Conclusions

Education programs in clinical psychology/psychotherapy may lag developments in AI/ML-enabled tools in mental healthcare. This survey of postgraduate clinical psychology and psychotherapy students raises questions about how curricula could be enhanced to better prepare clinical psychology/psychotherapy trainees to engage in constructive debate about ethical and evidence-based issues pertaining to AI/ML tools, and in guiding patients on the use of online mental health services and apps.
Assessment of functional capacity with cardiopulmonary exercise testing in non-severe COVID-19 patients at three months follow-up
Authors: Clavario Piero , De Marzo Vincenzo , Lotti Roberta , Barbara Cristina , Porcile Annalisa , Russo Carmelo , Beccaria Federica , Bonavia Marco , Bottaro Luigi Carlo , Caltabellotta Marta , Chioni Flavia , Santangelo Monica , Hautala Arto J. , Ameri Pietro , Canepa Marco , Porto Italo
Published: November 2020

Introduction

Long-term effects of Coronavirus Disease of 2019 (COVID-19) and their sustainability in a large number of patients are of the utmost relevance. We aimed to determine: 1)functional capacity of non-severe COVID-19 survivors by cardiopulmonary exercise testing (CPET); 2)those characteristics associated with worse CPET performance.

Methods

We prospectively enrolled the first 150 consecutive subjects with laboratory-confirmed COVID-19 infection discharged alive from March to April 2020 at Azienda Sanitaria Locale (ASL)3, Genoa, Italy. At 3-month from hospital discharge, complete clinical evaluation, trans-thoracic echocardiography, cardiopulmonary exercise testing (CPET), pulmonary function test (PFT), and dominant leg extension (DLE) maximal strength evaluation were performed.

Results

Excluding severe and incomplete/missing cases, 110 patients were analyzed. Median percent predicted peak oxygen uptake (%pVO2) was 90.9(79.2-109.0)%. Thirty-eight(34.5%) patients had %pVO2 below, whereas 72(65.5%) above the 85% predicted value (indicating normality). Median PFT parameters were within normal limits.

Eight(21.1%) patients had a mainly respiratory, 9(23.7%) a mainly cardiac, 3(7.9%) a mixed-cardiopulmonary, and 18(47.4%) a non-cardiopulmonary limitation of exercise. Eighty-one(73.6%) patients experimented at least one symptom, without relationship with %pVO2 (p>0.05).

Multivariate linear regression analysis showed age (β=0.46, p=0.020), percent weight loss (β=-0.77, p=0.029), active smoke status (β=-7.07, p=0.019), length of hospital stay (β=-0.20, p=0.042), and DLE maximal strength (β=1.65, p=0.039) independently associated with %pVO2.

Conclusions

Half of non-severe COVID-19 survivors show functional capacity limitation mainly explained by muscular impairment, albeit cardiopulmonary causes are possible. These findings call for future research to identify patients at higher risk of long-term effects, that may benefit from careful surveillance and targeted rehabilitation.

Take-home messages

at 3-month cardiopulmonary exercise testing 38/110(34.5%) non-severe COVID-19 survivors had percent predicted peak oxygen uptake (%pVO2) < 85% (indicating normality). Half of them had functional capacity limitation mainly explained by muscular impairment.
Deaths among COVID Cases in the United States: Racial and Ethnic Disparities Persist
Authors: Fabic Madeleine Short , Choi Yoonjoung , Bishai David
Published: November 2020

Using COVID-19 Case Surveillance Public Use Data by the Centers for Disease Control and Prevention, we estimate monthly age-adjusted case fatality rates (CFR) for four major groups: non-Hispanic (NH) whites, NH Blacks, NH Asians, and Hispanics. Available data show that CFRs across race/ethnic groups have become more equal over time. Nevertheless, racial and ethnic disparities persist. NH whites consistently experience lower CFRs; NH Blacks generally experience higher case fatality among younger patients; and NH Asians generally experience higher case fatality among older patients. Age-adjusted CFRs reveal dramatically different racial and ethnic disparities that are hidden by crude CFRs. Such adjustment is imperative for understanding COVID-19’s toll.
Genomic landscapes of canine splenic angiosarcoma (hemangiosarcoma) contain extensive heterogeneity within and between patients
Authors: Wong Shukmei , Ehrhart EJ , Stewart Samuel , Zismann Victoria , Cawley Jacob , Halperin Rebecca , Briones Natalia , Richter Keith , Sivaprakasam Karthigayini , Perdigones Nieves , Contente-Cuomo Tania , Facista Salvatore , Trent Jeffrey M. , Murtaza Muhammed , Khanna Chand , Hendricks William P. D.
Published: November 2020

Cancer genomic heterogeneity presents significant challenges for understanding oncogenic processes and for cancer’s clinical management. Variation in driver mutation frequency between patients with the same tumor type as well as within individual patients’ cancers can limit the power of mutations to serve as diagnostic, prognostic, and predictive biomarkers. We have characterized genomic heterogeneity between and within patients in canine splenic hemangiosarcoma (HSA), a common naturally occurring cancer in pet dogs that is similar to human angiosarcoma (AS). HSA is a clinically, physiologically, and genomically complex canine cancer that may serve as a valuable model for understanding the origin and clinical impact of cancer heterogeneity. We conducted a prospective collection of 52 splenic masses from 44 dogs (28 HSA, 15 benign masses, and 1 stromal sarcoma) presenting to emergency care with hemoperitoneum secondary to a ruptured splenic mass. Multi-platform genomic analysis included matched tumor/normal cancer gene panel and exome sequencing. We found candidate somatic cancer driver mutations in 14/28 (50%) HSAs. Among recurrent candidate driver mutations,TP53was most commonly mutated (29%) followed byPIK3CA(14%),AKT1(11%), andCDKN2AIP(11%). We also identified significant intratumoral genomic heterogeneity, consistent with a branched evolution model, through multi-region exome sequencing of three distinct tumor regions from selected primary splenic tumors. These data provide new perspective on the genomic landscape and comparative value of understanding HSA in pet dogs, particularly as a naturally occurring cancer bearing intratumoral heterogeneity.
SARS-CoV-2-specific T cell memory is long-lasting in the majority of convalsecent COVID-19 individuals
Authors: Li Ziwei , Liu Jing , Deng Hui , Yang Xuecheng , Wang Hua , Feng Xuemei , Zelinskyy Gennadiy , Trilling Mirko , Sutter Kathrin , Lu Mengji , Dittmer Ulf , Wang Baoju , Yang Dongliang , Zheng Xin , Liu Jia
Published: November 2020

An unaddressed key question in the currentcoronavirus disease 2019(COVID-19) pandemic is the duration of immunity for which specific T cell responses against thesevere acute respiratory syndrome coronavirus 2(SARS-CoV-2) are an indispensable element. Being situated in Wuhan where the pandemic initiated enables us to conduct the longest analyses of memory T cell responses against SARS-CoV-2 in COVID-19 convalescent individuals (CIs). Magnitude and breadth of SARS-CoV-2 memory CD4 and CD8 T cell responses were heterogeneous between patients but robust responses could be detected up to 9 months post disease onset in most CIs. Loss of memory CD4 and CD8 T cell responses were observed in only 16.13% and 25.81% of CIs, respectively. Thus, the overall magnitude and breadth of memory CD4 and CD8 T cell responses were quite stable and not inversely correlated with the time from disease onset. Interestingly, the only significant decrease in the response was found for memory CD4 T cells in the first 6-month post COVID-19 disease onset. Longitudinal analyses revealed that the kinetics of SARS-CoV-2 memory CD4 and CD8 T cell responses were quite heterogenous between patients. Loss of memory CD4 T cell responses was observed more frequently in asymptomatic cases than after symptomatic COVID-19. Interestingly, the few CIs in which SARS-CoV-2-specific IgG responses disappeared showed more durable memory CD4 T cell responses than CIs who remained IgG-positive for month. Collectively, we provide the first comprehensive characterization of the long-term memory T cell response in CIs, suggesting that SARS-CoV-2-specific T cell immunity is long-lasting in the majority of individuals.
Early Dietary Exposures Epigenetically Program Mammary Cancer Susceptibility through IGF1-mediated Expansion of Mammary Stem Cells
Authors: Zheng Yuanning , Luo Linjie , Lambertz Isabel U. , Fuchs-Young Robin
Published: November 2020

Dietary exposures at early developmental stages have been shown to program lifetime breast cancer susceptibility. We previously reported that manipulation of gestational and postweaning diets leads to different mammary tumor outcomes in carcinogen-treated mice. The high tumor incidence (HT) groups (average 61.5% tumor incidence) received a low-fat, low-sugar, mildly restricted (12%v/v) (DR) diet during gestation, followed by a high-fat, high-sugar (HF) diet postweaning. Conversely, the low tumor incidence (LT) groups (average 20% tumor incidence) received the HF diet during gestation, followed by the DR diet postweaning. Herein, we extended these findings by demonstrating that HT animals had an expanded mammary stem cell (MaSC) population compared to LT animals before puberty, and this expansion persisted into adulthood. IGF1 expression was increased in mammary stromal cells from HT animals, which promoted the self-renewal capacity of MaSCs in a paracrine fashion. This increased IGF1 expression was programmed prepubertally through DNA hypomethylation of the IGF1 promoter 1, mediated by decreased DNMT3b levels. IGFBP5 mRNA and protein levels were also reduced in mammary tissues from HT animals, indicating an increased bioavailability of tissue IGF1. In association with these changes, mammary tissues from carcinogen-treated HT animals developed an increased proportion of mammary adenosquamous carcinomas compared to carcinogen-treated LT animals. This study provides novel mechanistic insights into how early dietary exposures program mammary cancer risk and tumor phenotypes by increasing IGF1 expression through epigenetic alterations, thereby expanding the MaSC population, resulting in a higher number of carcinogen targets susceptible to transformation in adulthood.

Significance

Early high-fat dietary exposure programs lifetime mammary cancer susceptibility before puberty through epigenetic alterations of IGF1 promoters and IGF1-mediated paracrine regulation of mammary stem cell homeostasis.
Multidimensionality in the thermal niches of dung beetles could limit species’ responses to temperature changes
Authors: Calatayud Joaquín , Hortal Joaquín , Noriega Jorge Ari , Arcones Ángel , Espinoza Verónica R. , Guil Noemí , Lobo Jorge M.
Published: November 2020

Understanding the consequences of climate change requires understanding how temperature controls species’ responses across key biological aspects, as well as the coordination of thermal responses across these aspects. We study the role of temperature in determining the species’ diel, seasonal, and geographical occurrence, using dung beetles as a model system. We found that temperature has relatively low −but not negligible− effects in the three spatiotemporal scales, once accounting for alternative factors. More importantly, the estimated thermal responses were largely incongruent across scales. This shows that species have multidimensional thermal niches, entailing that adjustments to fulfil temperature requirements for one biological aspect, such as seasonal ontogenetic cycles, may result in detrimental effects on other aspects, like diel activity. These trade-offs can expose individuals to inadequate temperatures, reducing populations’ performance. Paradoxically, the relatively weak effects of temperature we found may have serious consequences for species’ responses to warming if temperature regulates essential aspects of species’ biology in divergent ways.
Hydrogel-coating improves the in-vivo stability of electrochemical aptamer-based biosensors
Authors: Li Shaoguang , Dai Jun , Zhu Man , Arroyo-Currás Netzahualcóyotl , Li Hongxing , Wang Yuanyuan , Wang Quan , Lou Xiaoding , Kippin Tod E. , Wang Shixuan , Plaxco Kevin W. , Li Hui , Xia Fan
Published: November 2020

The ability to track the levels of specific molecules, such as drugs, metabolites, and biomarkers, in the living body, in real time and for long durations would improve our understanding of health and our ability to diagnose, treat and monitor disease. To this end, we are developing electrochemical aptamer-based (E-AB) biosensors, a general platform supporting high-frequency, real-time molecular measurements in the living body. Here we report that the addition of an agarose hydrogel protective layer to E-AB sensors significantly improves their baseline stability when deployed in the complex, highly time-varying environments found in vivo. The improved stability is sufficient that these hydrogel-protected sensors achieved good baseline stability when deployed in situ in the veins, muscles, bladder, or tumors of living rats without the use of the drift correction approaches traditionally required in such placements. Finally, this improved stability is achieved without any significant, associated “costs” in terms of detection limits, response times, or biocompatibility.
Predicting potential impacts of ocean acidification on marine calcifiers from the Southern Ocean
Authors: Figuerola Blanca , Hancock Alyce M. , Bax Narissa , Cummings Vonda , Downey Rachel , Griffiths Huw J. , Smith Jodie , Stark Jonathan S.
Published: November 2020

Understanding the vulnerability of marine calcifiers to ocean acidification is a critical issue, especially in the Southern Ocean (SO), which is likely to be the one of the first, and most severely affected regions. Since the industrial revolution, ~30% of anthropogenic CO2has been absorbed by the oceans. Seawater pH levels have already decreased by 0.1 and are predicted to decline by ~ 0.3 by the year 2100. This process, known as ocean acidification (OA), is shallowing the saturation horizon, which is the depth below which calcium carbonate (CaCO3) dissolves, likely increasing the vulnerability of many marine calcifiers to dissolution. The negative impact of OA may be seen first in species depositing more soluble CaCO3mineral phases such as aragonite and high-Mg calcite (HMC). These negative effects may become even exacerbated by increasing sea temperatures. Here we combine a review and a quantitative meta-analysis to provide an overview of the current state of knowledge about skeletal mineralogy of major taxonomic groups of SO marine calcifiers and to make predictions about how OA might affect different taxa. We consider their geographic range, skeletal mineralogy, biological traits and potential strategies to overcome OA. The meta-analysis of studies investigating the effects of the OA on a range of biological responses such as shell state, development and growth rate shows response variation depending on mineralogical composition. Species-specific responses due to mineralogical composition suggest taxa with calcitic, aragonitic and HMC skeletons may be more vulnerable to the expected carbonate chemistry alterations, and low magnesium calcite (LMC) species may be mostly resilient. Environmental and biological control on the calcification process and/or Mg content in calcite, biological traits and physiological processes are also expected to influence species specific responses.
HOX13-MEDIATEDDBX2REGULATION IN LIMBS SUGGESTS INTER-TAD SHARING OF ENHANCERS
Authors: Beccari Leonardo , Jaquier Gabriel , Lopez-Delisle Lucille , Rodriguez-Carballo Eddie , Mascrez Bénédicte , Gitto Sandra , Woltering Joost , Duboule Denis
Published: November 2020

Background

During tetrapod limb development, the HOXA13 and HOXD13 transcription factors are critical for the emergence and organization of the autopod, the most distal aspect where digits will develop. Since previous work had suggested that theDbx2gene is a target of these factors, we set up to analyze in detail this potential regulatory interaction.

Results

We show that HOX13 proteins bind to eutherian-specific sequences at the vicinity of theDbx2locus that have enhancer activity in developing digits. However, the functional inactivation of the DBX2 protein did not elicit any particular phenotype related toHoxgenes inactivation in digits, suggesting either redundant or compensatory mechanisms. We report that the neighboringNell2andAno6genes are also expressed in distal limb buds and are, in part, controlled by the sameDbx2enhancers despite being localized into two different topologically associating domains (TADs) flanking theDbx2locus.

Conclusions

We conclude thatHoxa13andHoxdgenes cooperatively activateDbx2expression in developing digits through binding to eutherian specific regulators elements in theDbx2neighborhood. Furthermore, these enhancers can overcome TAD boundaries in either direction to co-regulate a set of genes located in distinct chromatin domains.

Bullet points

Hoxa13andHoxdgenes cooperatively regulateDbx2expression in developing digits via eutherian specific enhancers.

Dbx2is expressed in different digit joint precursors but its function there is not essential.

Dbx2enhancers also control the expression of theNell2andAno6genes, which are located in different TADs, thus overcoming the boundary effect.

Dbx2chromatin architecture and enhancers evolved in the mammalian lineage.

Grant Sponsor and Number

Swiss National Research Foundation #310030B_138662.

European Research Council grants RegulHox#588029
Threat-induced hippocampal connectivity fingerprints do not generalize to psychosocial stress
Authors: Kühnel Anne , Czisch Michael , Sämann Philipp G. ,   BeCOME study team, Binder Elisabeth B. , Kroemer Nils B.
Published: November 2020

Stress is an everyday experience and maladaptive responses play a crucial role in the etiology of affective disorders. Despite its ubiquity, the neural underpinnings of subjective stress experiences have not yet been elucidated, particularly at an individual level. In an important advance, Goldfarb et al.1showed recently that subjective stress and arousal levels in response to threatening stimuli were successfully predicted based on changes in hippocampal connectivity during the task using a machine learning approach. Crucially, stress responses were predicted by interpretable hippocampal connectivity networks, shedding new light on the role of the hippocampus in regulating stress reactivity2. However, the authors induced stress by displaying aversive pictures, while stress research often relies on the extensively validated Trier social stress task (TSST)3. The TSST incorporates crucial factors such as unpredictability of success and the social-evaluative threat of the stressor thereby eliciting cortisol responses more robustly compared to threatening images4. Towards generalization, cross validation within a sample as conducted by Goldfarb et al.1or independent replications are important steps, but the generalizability to different stressors allows to draw broader conclusions about the potential use of hippocampal connectivity to predict subjective stress5. Arguably, translating these findings to clinical applications would require a broad generalization of the results or the prediction algorithm to psychosocial stress. Here, we assessed the predictive performance of Goldfarb et al’s1algorithm for subjective stress in an independent sample using an MR adaption of the TSST6,7. In line with Goldfarb et al.1, we observed robust stress-induced changes in hippocampal connectivity. However, the spatial correlation of the changes in connectivity was low indicating little convergence across alleged stress paradigms. Critically, stress-induced changes of hippocampal connectivity were not robustly predictive of subjective stress across a multiverse of analyses based on connectivity changes. Collectively, this indicates that the generalizability of the reported stress connectivity fingerprint to other stressors is limited at best, suggesting that specific tasks might require tailored algorithms to robustly predict stress above chance levels.
Disclosing the actual efficiency of G-quadruplex-DNA–disrupting small molecules
Authors: Mitteaux Jérémie , Lejault Pauline , Pirrotta Marc , Wojciechowski Filip , Joubert Alexandra , Desbois Nicolas , Gros Claude P. , Hudson Robert H. E. , Boulé Jean-Baptiste , Granzhan Anton , Monchaud David
Published: November 2020

The quest for small molecules that avidly bind to G-quadruplex-DNA (G4-DNA, or G4), so called G4-ligands, has invigorated the G4 research field from its very inception. Massive efforts have been invested toi- screen or design G4-ligands,ii- evaluate their G4-interacting propertiesin vitrothrough a series of now widely accepted and routinely implemented assays, andiii- use them as unique chemical biology tools to interrogate cellular networks that might involve G4s. In sharp contrast, only uncoordinated efforts at developing small molecules aimed at destabilizing G4s have been invested to date, even though it is now recognized that such molecular tools would have tremendous application to neurobiology as many genetic and age-related diseases are caused by an over-representation of G4s, itself caused by a deficiency of G4-resolving enzymes, the G4-helicases. Herein, we report on our double effort toi- develop a reliablein vitroassay to identify molecules able to destabilize G4s, the G4-unfold assay, andii- fully characterize the first prototype of G4-disrupting small molecule, a phenylpyrrolcytosine (PhpC)-based G-clamp analog.
Comparative analysis of antibody- and lipid-based multiplexing methods for single-cell RNA-seq
Authors: Mylka Viacheslav , Aerts Jeroen , Matetovici Irina , Poovathingal Suresh , Vandamme Niels , Seurinck Ruth , Hulselmans Gert , Van Den Hoecke Silvie , Wils Hans , Reumers Joke , Van Houdt Jeroen , Aerts Stein , Saeys Yvan
Published: November 2020

Multiplexing of samples in single-cell RNA-seq studies allows significant reduction of experimental costs, straightforward identification of doublets, increased cell throughput, and reduction of sample-specific batch effects. Recently published multiplexing techniques using oligo-conjugated antibodies or - lipids allow barcoding sample-specific cells, a process called ‘hashing’. Here, we compare the hashing performance of TotalSeq-A and -C antibodies, custom synthesized lipids and MULTI-seq lipid hashes in four cell lines, both for single-cell RNA-seq and single-nucleus RNA-seq. Hashing efficiency was evaluated using the intrinsic genetic variation of the cell lines. Benchmarking of different hashing strategies and computational pipelines indicates that correct demultiplexing can be achieved with both lipid- and antibody-hashed human cells and nuclei, with MULTISeqDemux as the preferred demultiplexing function and antibody-based hashing as the most efficient protocol on cells. Antibody hashing was further evaluated on clinical samples using PBMCs from healthy and SARS-CoV-2 infected patients, where we demonstrate a more affordable approach for large single-cell sequencing clinical studies, while simultaneously reducing batch effects.
Establishment and characterisation of primary skeletal muscle cell cultures from patients with advanced Chronic Kidney Disease
Authors: Baker Luke A , O’Sullivan Tom F , Robinson Kate A , Redshaw Zoe , Graham-Brown Matthew , Ashford Robert U , Smith Alice C , Philp Andrew , Watson Emma L
Published: November 2020

Skeletal muscle wasting and dysfunction is a common characteristic of non-dialysis dependent chronic kidney disease (NDD-CKD). The mechanisms by which this occurs are not clearly understood and one reason for this is a lack of well controlledin-vitromethodologies to simulate NDD-CKD induced muscle wasting for mechanistic investigation at the cellular level. Here we sought to conduct the initial investigations into developing a CKD-induced skeletal muscle model for use as a mechanistic analysis tool as well as a test bed for potential novel therapeutics in this population. Human derived muscle cells (HDMCs) were isolated from n=5 NDD-CKD patients and n=3 matched healthy controls (HC) and taken through proliferation and differentiation phases in cell culture. Upon comparison of the 2 donor types, significantly greater mRNA expression of myogenic markers was noted in the NDD-CKD cultures in comparison to HC cultures, which was carried through to greater mRNA expression of myosin heavy chains (MyHCs) post differentiation. However, this was not carried over to protein expression where Pax7 and MyoD were seen to be expressed to a greater extent in HC cultures. mRNA expression markers of protein degradation were noted to be elevated in NDD-CKD cultures in comparison to HC cultures. In light of our findings, future work should seek to investigate the role of the ‘CKD environment’ as well as mechanisms implicated in transcription regulation to further advance the current model development as well as the mechanistic understanding of skeletal muscle wasting in CKD.
Biomolecular Condensation Drives Leukemia Caused by NUP98-Fusion Proteins
Authors: Terlecki-Zaniewicz Stefan , Eder Thomas , Schmöllerl Johannes , Humer Theresa , Kuchynka Natalie , Parapatics Katja , Heyes Elizabeth , Liberante Fabio G. , Müller André C. , Grebien Florian
Published: November 2020

NUP98-fusion proteins cause acute myeloid leukemia via unknown molecular mechanisms. All NUP98-fusion proteins share an intrinsically disordered region (IDR) featuring >35 repeats of Phenylalanine-Glycine (FG) in the NUP98 N-terminus. Conversely, different C-terminal NUP98-fusion partners are often transcriptional and epigenetic regulators. Given these structural features we hypothesized that mechanisms of oncogenic transformation by NUP98-fusion proteins are hard-wired in their protein interactomes. Affinity purification coupled to mass spectrometry of five distinct NUP98-fusion proteins revealed a conserved set of interactors that was highly enriched for proteins involved in biomolecular condensation. We developed biotinylated isoxazole-mediated condensome mass spectrometry (biCon-MS) to show that NUP98-fusion proteins alter the global composition of biomolecular condensates. In addition, an artificial FG-repeat containing fusion protein was able to phenocopy the induction of leukemic gene expression as mediated by NUP98-KDM5A. Thus, we propose that IDR-containing fusion proteins have evolved to uniquely combine biomolecular condensation with gene control to induce cancer.

AML, NUP98, fusion protein, AP-MS, LLPS, biCon-MS, condensate
Incidence and Risk Factors of Combined-Antiretroviral Therapy-Induced Hepatotoxicity among HIV Patients at the Bali District Hospital, Cameroon
Authors: Ngah Yayah Emerencia , Cho Frederick Nchang , Etagha Bisong Shauna , Fusi Neh Gladys , Francisca Neba , Ikomey Mondinde George , Ibrahim Njimona
Published: November 2020

Introduction

The incidence of hepatotoxicity is life-threatening and can result to an end-stage liver disease in long-term patients on combined antiretroviral therapy (cART). Our study sought to evaluate the incidence and predictors of cART-induced hepatotoxicity (CIH) among long term users on cART in a rural District hospital.

Methods

This was a hospital-based cross-sectional study in the Bali District Hospital. Spectrophotometric method was use for the quantitative measurement of alanine-aminotransferase (ALT) and aspartate-aminotransferase (AST) levels. Patients with elevations of both ALT and AST were considered CIH. The Chi (χ2) square test, ANOVA and Kaplan Meier log-ranked/ survival analyses were used to analyse the data.

Results

Of the 350 participants enrolled [156 (44.6%) males and 194 (55.4%) females], aged 43.87 ± 0.79 years (range 20 – 84 years) included in this analysis, 26 (4.4%) experienced moderate CIH. We observed 57 (16.3%), 62 (17.7%) and 238 (68%) elevated levels ALT + AST, ALT and AST respectively. Two independent predictive factors of CIH were, the male sex and alcoholism during the study period.

Conclusion

The prevalence of CIH in HIV-infected patients in Bali was lower than that observed in previous studies. The duration of therapy had no influence on the frequency of CIH. Alcoholism and smoking showed significant differences in the development of CIH.
Apoptotic Cells May Drive Cell Death in Hair Follicles During their Regression Cycle
Authors: Keister Bradley D. , Mesa Kailin R. , Blagoev Krastan B.
Published: November 2020

Intravital microscopy in live mice have shown that the elimination of epithelial cells during hair follicle regression involves supra-basal cell differentiation and basal cell apoptosis through synergistic action of TGF-β (transforming growth factor) and mesenchymal-epithelial interactions. In this process the basal epithelial cells are not internally committed to death and the mesenchymal dermal papilla (DP) plays essential role in death induction. Because the DP cells are not necessary for completion of the cycle but only for its initiation it is still an open question what is the mechanism leading to the propagation of apoptosis towards the “immortal” stem cell population. Here, we use a quantitative analysis of the length of hair follicles during their regression cycle. The data is consistent with a propagation mechanism driven by apoptotic cells inducing apoptosis in their neighboring cells. The observation that the apoptosis slows down as the apoptotic front approaches the stem cells at the end of the follicle is consistent with a gradient of a pro-survival signal sent by these stem cells. An experiment that can falsify this mechanism is proposed.
Agricultural production and CO2 emissions causes in the developing and developed countries: New insights from quantile regression and decomposition analysis
Authors: Khan Rabnawaz
Published: November 2020

Agriculture is the dominant economic activity of the economies. The developing and developed countries are responsible for the most greenhouse gasses emitted in the developing areas. Are there heterogeneous determinants of environmental degradation and CO2 emitters in developing and developed countries? and estimating the significance of agricultural production, renewable energy consumption, the industrial revolution, and economic growth. In this study, 22 countries’ environmental degradation analyze by two (per-capita and liquid) sources of CO2 emissions and using panel data from 1991 through 2016. This study adopts a panel regression (non-additive effects) and quantile regression techniques to explore the connection between agriculture and economic factors. And the extent of the CO2 emitter gap between developing and developed countries. The outcome of agriculture has a positive and significant influence on CO2 emission from liquid with a 36.75% increase in environmental degradation and a negative impact on CO2 emission in the total emissions by 19.12%. The agriculture-related activities negatively influence the environment, such as deforestation for feed cropping, burning of biomass, and deep soil cropping in the developing countries. Furthermore, the quantiles decomposition procedure in agriculture production is signifying heterogeneity of the determinants of environmental degradation, low and high CO2 emitters.
ARID1A regulates R-loop associated DNA replication stress
Authors: Tsai Shuhe , Chang Emily Yun-chia , Fournier Louis-Alexandre , Wells James P. , Minaker Sean W. , Zhu Yi Dan , Wang Alan Ying-Hsu , Wang Yemin , Huntsman David G. , Stirling Peter C.
Published: November 2020

ARID1A is lost in up to 7% of all cancers, and this frequency increases in certain cancer types, such as clear cell ovarian carcinoma where ARID1A protein is lost in about 50% of cases. While the impact of ARID1A loss on the function of the BAF chromatin remodeller complexes is likely to drive oncogenic gene expression programs in specific contexts, ARID1A also binds genome stability regulators such as ATR and TOP2. Here we show that ARID1A loss leads to DNA replication stress associated with R-loops and transcription-replication conflicts in human cells. These effects correlate with altered transcription and replication dynamics in ARID1A knockout cells and to reduced TOP2A binding at R-loop sites. Together this work extends mechanisms of replication stress in ARID1A deficient cells with implications for targeting ARID1A deficient cancers.
Selection for Decreased BRCA2 Functional Activity inHomo sapiensAfter Divergence from the Chimpanzee-Human Last Common Ancestor
Authors: Huang Jinlong , Zhong Yi , Makohon-Moore Alvin P. , White Travis , Jasin Maria , Norell Mark A. , Wheeler Ward C. , Iacobuzio-Donahue Christine A.
Published: November 2020

Humans have an increased incidence of epithelial neoplasia compared to non-human primates. We performed a comparative analysis of 21 non-human primate genomes and 54 ancient human genomes to identify variations in known cancer genes that may explain this difference. We identified 299 human-specific fixed non-silent single nucleotide polymorphisms. Bioinformatics analyses for functional consequences identified a number of variants predicted to have altered protein function, one of which was located at the most evolutionarily conserved domain of human BRCA2. This variant, in which a polar threonine residue replaces a hydrophobic methionine residue to codon 2662 within the DSS1 binding domain, decreases the interactions of BRCA2 with other proteins, specifically the binding of BRCA2 and RAD51, as well as the repairing ability of cells for DNA double-strand breaks. We conclude that a 20% reduction in BRCA2 DNA repair ability was positively selected for in the course of human evolution.

One Sentence Summary

Reduction of BRCA2 functional activity has been selected for during human evolution since the chimpanzee-human last common ancestor.
Transmission of SARS-CoV-2 from humans to animals and potential host adaptation
Authors: Tan Cedric C.S. , Lam Su Datt , Richard Damien , Owen Christopher , Berchtold Dorothea , Orengo Christine , Nair Meera Surendran , Kuchipudi Suresh V. , Kapur Vivek , van Dorp Lucy , Balloux François
Published: November 2020

SARS-CoV-2, the agent of the COVID-19 pandemic, can infect a wide range of mammals. Since its spread in humans, secondary host jumps of SARS-CoV-2 from humans to a variety of domestic and wild populations of mammals have been documented. The evolution of SARS-CoV-2 in different host species is of fundamental interest while also providing indication of how SARS-CoV-2 may have adapted to human hosts soon after the initial host jump, a time window for which there are no genome sequences available. Moreover, the study of SARS-CoV-2 circulating in animals is critical to assess the risk that the transmission of animal-adapted viral lineages back into humans (i.e., spillback) may pose. Here, we compared the genomic landscapes of SARS-CoV-2 isolated from animal species relative to that in humans, profiling the mutational biases indicative of potentially different selective pressures in animals. We focused on viral genomes collected in infected mink (Neovison vison) and white-tailed deer (Odocoileus virginianus) for which reports of multiple independent spillover events and subsequent animal-to-animal transmission are available. We identified six candidate mutations for animal-specific adaptation in mink (NSP9_G37E, Spike_F486L, Spike_N501T, Spike_Y453F, ORF3a_T229I, ORF3a_L219V), and one in deer (NSP3a_L1035F), though these mutations appear to confer minimal advantage for circulation in humans. Additionally, circulation of SARS-CoV-2 in mink and deer has not caused considerable changes to the evolutionary trajectory of SARS-CoV-2 thus far. Finally, our results suggest that minimal adaptation was required for human-to-animal spillover and subsequent onward transmission in mink and deer, highlighting the ‘generalist’ nature of SARS-CoV-2 as a pathogen of mammalian hosts.
The impact of identity-by-descent on fitness and disease in natural and domesticatedCanidpopulations
Authors: Mooney Jazlyn A. , Yohannes Abigail , Lohmueller Kirk E.
Published: November 2020

Domestic dogs have experienced population bottlenecks, recent inbreeding, and strong artificial selection. These processes have simplified the genetic architecture of complex traits, allowed deleterious variation to persist, and increased both identity-by-descent (IBD) segments and runs of homozygosity (ROH). As such, dogs provide an excellent model for examining how these evolutionary processes influence disease. We assembled a dataset containing 4,414 breed dogs, 327 village dogs, and 380 wolves genotyped at 117,288 markers and phenotype data for clinical and morphological phenotypes. Breed dogs have an enrichment of IBD and ROH, relative to both village dogs and wolves and we use these patterns to show that breed dogs have experienced differing severities of bottlenecks in their recent past. We then found that ROH burden is associated with phenotypes in breed dogs, such as lymphoma. We next test the prediction that breeds with greater ROH have more disease alleles reported in Online Mendelian Inheritance in Animals (OMIA). Surprisingly, the number of causal variants identified correlates with the popularity of that breed rather than the ROH or IBD burden, suggesting an ascertainment bias in OMIA. Lastly, we use the distribution of ROH across the genome to identify genes with depletions of ROH as potential hotspots for inbreeding depression and find multiple exons where ROH are never observed. Our results suggest that inbreeding has played a large role in shaping genetic and phenotypic variation in dogs, and that there remains an excess of understudied breeds that can reveal new disease-causing variation.

Significance Statement

Dogs and humans have coexisted together for thousands of years, but it was not until the Victorian Era that humans practiced selective breeding to produce the modern standards we see today. Strong artificial selection during the breed formation period has simplified the genetic architecture of complex traits and caused an enrichment of identity-by-descent (IBD) segments in the dog genome. This study demonstrates the value of IBD segments and utilizes them to infer the recent demography of canids, predict case-control status for complex traits, locate regions of the genome potentially linked to inbreeding depression, and to identify understudied breeds where there is potential to discover new disease-associated variants.
Developmental Genetics of Color Pattern Establishment in Cats
Authors: Kaelin Christopher B. , McGowan Kelly A. , Barsh Gregory S.
Published: November 2020

Intricate color patterns are a defining aspect of morphological diversity in the Felidae. We applied morphological and single-cell gene expression analysis to fetal skin of domestic cats to identify when, where, and how, during fetal development, felid color patterns are established. Early in development, we identify stripe-like alterations in epidermal thickness preceded by a gene expression pre-pattern. The secreted Wnt inhibitor encoded by Dickkopf 4 (Dkk4) plays a central role in this process, and is mutated in cats with the Ticked pattern type. Our results bring molecular understanding to how the leopard got its spots, suggest that similar mechanisms underlie periodic color pattern and periodic hair follicle spacing, and identity new targets for diverse pattern variation in other mammals.
Methyltransferase SMYD5 Exaggerates IBD by Downregulating Mitochondrial Functions via Post-translational Control of PGC-1α Stability
Authors: Hou Yuning , Sun Xiaonan , Gheinani Pooneh Tavakoley , Guan Xiaoqing , Sharma Shaligram , Zhou Yu , Jin Chengliu , Yang Zhe , Naren Anjaparavanda P. , Yin Jun , Denning Timothy L. , Gewirtz Andrew T. , Xie Zhonglin , Li Chunying
Published: November 2020

Background and Aims

The expression and role of methyltransferase SET and MYND domain-containing protein 5 (SMYD5) in inflammatory bowel diseases (IBD) is completely unknown. Here, we investigated the role and the underlying mechanism of epithelial SMYD5 in IBD pathogenesis and progression.

Methods

The expression and subcellular localization of SMYD5 and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) were examined by Western blot analysis, immunofluorescence staining, and immunohistochemistry in intestinal epithelial cells (IECs) and in colon tissues from human IBD patients and mice with experimental colitis. Mice with Smyd5 conditional knockout in IECs and littermate controls were subjected to DSS-induced experimental colitis and the disease severity and inflammation were assessed. SMYD5-regulated mitochondrial biogenesis was examined by RT-qPCR and transmission electron microscopy and mitochondrial oxygen consumption rate was measured in a Seahorse Analyzer system. The interaction between SMYD5 and PGC-1α was determined by co-immunoprecipitation assay. PGC-1α degradation and turnover (half-life) were analyzed by cycloheximide chase assay. SMYD5-mediated PGC-1α methylation was measured viain vitromethylation followed by mass spectrometry to identify the specific lysine residues that were methylated.

Results

Up-regulated SMYD5 and down-regulated PGC-1α were observed in IECs from IBD patients and mice with experimental colitis. However, Smyd5 depletion in IECs protected mice from DSS-induced colitis. SMYD5 was critically involved in regulating mitochondrial biology such as mitochondrial biogenesis, respiration, and apoptosis. Mechanistically, SMYD5 regulated mitochondrial functions in a PGC-1α dependent manner. Further, SMYD5 mediated lysine methylation of PGC-1α and facilitated its ubiquitination and proteasomal degradation.

Conclusion

SMYD5 attenuates mitochondrial functions in IECs and promotes IBD progression by enhancing the proteasome-mediated degradation of PGC-1α protein in methylation-dependent manner. Strategies to decrease SMYD5 expression and/or increase PGC-1α expression in IECs might be a promising therapeutic approach to treat patients with IBD.
TheC. eleganshomolog ofTMEM132D, a human panic-disorder and anxiety risk gene, modulates neuronal morphogenesis through the WAVE-regulatory complex
Authors: Wang Xin , Jiang Wei , Luo Shuo , Yang Xiaoyu , Wang Changnan , Wang Bingying , Dang Yongjun , Shen Yin , Ma Dengke K.
Published: November 2020

TMEM132Dis a human gene identified with multiple risk alleles for panic disorders, anxiety and major depressive disorders. Belonging to a conserved family of transmembrane proteins, TMEM132D and its homologs are still of unknown molecular functions. By generating loss-of-function mutants of the sole TMEM132 ortholog inC. elegans, we identify abnormal morphologic phenotypes in the dopaminergic PDE neurons. Using a yeast two-hybrid screen, we find that NAP1 directly interacts with the cytoplasmic domain of human TMEM132D, and mutations inC. elegans tmem-132that disrupt the interaction with NAP1 cause similar morphologic defects in the PDE neurons. NAP1 is a component of the WAVE regulatory complex (WRC) that controls F-actin cytoskeletal dynamics. Decreasing activity of WRC rescues the PDE defects intmem-132mutants, whereas gain-of-function ofTMEM132Din mammalian cells inhibits WRC, leading to decreased abundance of selective WRC components, impaired actin nucleation and cell motility. We propose that metazoan TMEM132 family proteins play evolutionarily conserved roles in regulating NAP1 protein homologs to restrict inappropriate WRC activity, cytoskeletal and morphologic changes in the cell.
Multiple epitaxial lateral overgrowth of GaN thin films using a patterned graphene mask by metal organic chemical vapor deposition
Authors: Lee Jun-Yeob , Min Jung-Hong , Bae Si-Young , Park Mun-Do , Jeong Woo-Lim , Park Jeong-Hwan , Kang Chang-Mo , Lee Dong-Seon
Published: November 2020

Single-crystal gallium nitride (GaN) thin films were grown using a graphene mask via multiple epitaxial lateral overgrowth (multiple-ELOG). During the growth process, the graphene mask self-decomposed to enable the emergence of a GaN film with a thickness of several hundred nanometres. This is in contrast to selective area growth of GaN using an SiO2 mask leading to the well known hexagonal-pyramid shape under the same growth conditions. The multiple-ELOG GaN had a single-crystalline wurtzite structure corresponding to the crystallinity of the GaN template, which was confirmed with electron backscatter diffraction measurements. An X-ray diffraction rocking curve of the asymmetric 102 reflection showed that the FWHM for the multiple-ELOG GaN decreased to 405 from 540′′ for the underlying GaN template. From these results, the self-decomposition of the graphene mask during ELOG was experimentally proven to be affected by the GaN decomposition rather than the high-temperature/H2 growth conditions.
Crystal structure of bis(tetramethylthiourea-κS)bis(thiocyanato-κN)nickel(II)
Authors: Jochim Aleksej , Radulovic Rastko , Jess Inke , Näther Christian
Published: November 2020

In the course of our investigations regarding transition-metal thiocyanates with thiourea derivatives, the title compound, [Ni(NCS)2(C5H12N2S)2], was obtained. The asymmetric unit consists of one thiocyanate anion and one tetramethylthiourea molecule on general positions, as well as one NiII cation that is located on a twofold rotational axis. In this compound, discrete complexes are formed in which the NiII cations are surrounded by two trans-N-bonding thiocyanate anions as well as two trans-S-bonding tetramethylthiourea molecules within a distorted square-planar coordination geometry. The discrete complexes are linked by pairs of weak C—H...S hydrogen bonds between the thiocyanate S and one of the tetramethylthiourea methyl hydrogen atoms into chains along the crystallographic a- and c-axis directions, which are combined into layers parallel to the ac plane. X-ray powder diffraction proves that a pure crystalline phase was obtained and measurements using thermogravimetry and differential thermoanalysis reveal that the compound decomposes at about 408 K, where all tetramethylthiourea molecules are lost.