bluuebunny/crossref_metadata_2025 huggingface dataset:
Survival in adult patients with BRAFV600 mutation-positive advanced melanoma: a noninterventional ambispective study of patients with cobimetinib combined with vemurafenib during the French early access program: MELANIS study
Authors: Meyer Nicolas , Pérol David , Duval-Modeste Anne-Bénédicte , El Adaoui Laïla , Lelarge Yoann , Niarra Ralph , Mateus Christine
Published: May 2022

Cobimetinib combined with vemurafenib was available in France in 2015 through a ‘Temporary Authorization for Use’ program (TAU, preapproval access pending its marketing on 2016) for patients with v-raf murine sarcoma viral oncogene homolog B1-mutant advanced melanoma. This study aimed to provide real-world outcomes in patients previously registered in this TAU. This noninterventional, ambispective, multicentre French study, conducted in patients previously registered in TAU, aimed to estimate overall survival (OS) and progression-free survival (PFS) and to describe the tolerability of the therapeutic combination. At first cobimetinib intake (in combination with vemurafenib), 88% of the 185 evaluable patients had disease stage IV (brain metastasis: 70% of them), 31% had elevated lactate dehydrogenases, and 10% had an Eastern Cooperative Oncology Group (ECOG) index ≥2. Median OS was 16.1 months (95% CI, 12.5–20.7). Brain metastasis (P < 0.001), ECOG index ≥2 (P = 0.007), and hepatic impairment (P = 0.037) were found as independent factors significantly associated with shorter survival. Median PFS was 7.3 months (95% CI, 5.2–8.4). ECOG index ≥2 (P = 0.006) was significantly associated with shorter PFS. Between cobimetinib start and inclusion, increased CPK (3% of patients), retinal serous detachment (3%), decreased left ventricular ejection fraction (3%), increased transaminases (3%), and rash (3%) were the most reported serious adverse events. This study provides real-world outcomes in France for the vemurafenib-cobimetinib combination available in patients with BRAF-mutant-advanced melanoma. Our data tend to confirm in the real-life setting that this combination therapy is effective in such patients, with a safety profile consistent with previous interventional studies.
A systematic review and meta-analysis of coronary artery disease and revascularization in lung transplant patients
Authors: Fialka Nicholas M. , Bozso Sabin J. , EL-Andari Ryaan , Kang Jimmy JH. , Laing Bryce , Meyer Steven R. , Nagendran Jayan , Nagendran Jeevan
Published: May 2022

Coronary artery disease (CAD) is common in candidates for lung transplantation (LTx) and has historically been considered a relative contraindication to transplantation. We look to review the outcomes of LTx in patients with CAD and determine the optimum revascularization strategy in LTx candidates. PubMed, Medline and Web of Science were systematically searched by three authors for articles comparing the outcomes of LTx in patients with CAD and receiving coronary revascularization. In total 1668 articles were screened and 12 were included in this review.Preexisting CAD in LTx recipients was not associated with significantly increased postoperative morbidity or mortality. The pooled estimates of mortality rate at 1, 3 and 5 years indicated significantly inferior survival in LTx recipients with a prior history of coronary artery bypass grafting (CABG) [odds ratio (OR), 1.84; 95% confidence interval (CI), 1.53–2.22; P < 0.00001; I
2 = 0%; OR, 1.52; 95% CI, 1.21–1.91; P = 0.0003; I
2 = 0%; OR, 1.62; 95% CI, 1.13–2.33; P = 0.008; I
2 = 71%, respectively). However, contemporary literature suggests that survival rates in LTx recipients with CAD that received revascularization either by percutaneous coronary intervention (PCI), previous or concomitant CABG, are similar to patients who did not receive revascularization. Trends in postoperative morbidity favored CABG in the rates of myocardial infarction and repeat revascularization, whereas rates of stroke favored PCI. The composite results of this study support the consideration of patients with CAD or previous coronary revascularization for LTx. Prospective, randomized controlled trials with consistent patient populations and outcomes reporting are required to fully elucidate the optimum revascularization strategy in LTx candidates.
Ethical considerations in the care of people with eating, drinking and swallowing difficulties
Authors: Leslie Paula , Lisiecka Dominika
Published: May 2022

Purpose of review

Eating, drinking and swallowing difficulties are low on the list of clinical headlines. Until something affects the process and then we see how pervasive and devastating such issues are. Recent guidelines have been published looking at national competencies to be structured into preregistration education. Professional bodies have addressed the topic from a risk perspective, which may be counter to the patient-centred approach of shared decision making. Our review places the literature in the wider, historical context of bioethics and our experience regarding ethical challenges as we strive to support our patients.

Recent findings

Recent literature addressing ethical care for a person with eating, drinking and swallowing difficulties, highlights shared decision-making. This is guided by patient preference, professional roles and approaches, cultural context and informed consent. Studies highlight the importance of appropriate communication and documentation, and ethical decision-making steps.

We hope to widen clinicians’ perspectives and reflection on factors influencing these challenges (including own biases), and how to address them so that the patient and the clinician are satisfied. Ethical approaches require skills and knowledge, and critically also time. Resources should be allocated at the service level to ensure a robust process of informed consent and decision making.
Central venous catheter-associated deep vein thrombosis in critically ill pediatric patients: risk factors, prevention, and treatment
Authors: Johnson Rachel R. , Faustino E. Vincent S.
Published: May 2022

Purpose of review

Central venous catheter (CVC) placement and ICU admission are the two most important risk factors for pediatric deep vein thrombosis. The optimal prevention and treatment strategies for CVC-associated deep vein thrombosis (CADVT) are unclear, but recently, seminal studies have been published. This review aims to summarize the recent literature on CADVT in critically ill children.

Recent findings

Recent publications focused on three themes: risk factors, prevention, and treatment of CADVT. Newly identified risk factors for CADVT relate to Virchow's triad of hemostasis, blood vessel injury, and hypercoagulability. New risk prediction models have moderately good accuracy in predicting CADVT. Though previous data on pharmacologic CADVT prophylaxis was equivocal, recent studies indicate that low-molecular-weight heparin may be effective in preventing CADVT, particularly in critically ill children. Finally, new studies suggest that direct oral anticoagulants and shorter treatment times are noninferior to traditional agents and treatment durations in the treatment of CADVT.

Recent research suggests new ways to accurately identify children at high risk of CADVT, effectively prevent CADVT, and optimize CADVT treatment. Future research should focus on understanding the pathobiology of CADVT formation, prevention, and treatment in critically ill children.
Constraint-induced movement therapy for lower extremity use in activities of daily living in people with chronic hemiparesis: multiple case study
Authors: Duarte Pereira Natália , Ilha Jocemar , dos Anjos Sarah Monteiro , Morris Davis
Published: May 2022

Lower extremity constraint-induced movement therapy (LE-CIMT) is an intensive intervention protocol recently reported to improve lower extremity use in individuals with chronic hemiparesis. yTo test if the LE-CIMT that uses essential CIMT components, including the transfer package and intensive task-oriented training, is a feasible and potentially effective intervention to improve the lower extremity real-world use and functional ability in a group of individuals with chronic hemiparesis. A quasi-experimental pre- and post-test design study with 12 individuals with chronic stroke and impaired ambulation skills engaged in a 10-weekday LE-CIMT. Intervention feasibility was assessed, examining the training adherence, acceptability, and safety. The lower extremity motor activity log (LE-MAL), lower extremity motor function test (LE-MFT), timed up and go (TUG) and spatiotemporal gait parameters were used as clinical outcomes. Clinical data were collected at baseline, 3-day post-CIMT protocol and 30-day follow-up assessment. At baseline, LE-MAL and LE-MFT outcomes were tested over 2-week apart to ensure a stable measurement and determine the smallest real difference (SRD) in the study sample. The LE-CIMT showed excellent adherence, acceptability and safety. Ten out of 12 participants showed improvements over SRD in LE-MAL composite score (1.2 point) and eight participants in LE-MFT adjusted scores (0.8 point) in post-CIMT and 30-day follow-ups. LE-CIMT is a feasible intervention that has the potential to promote improvements in real-world use and functional ability of the paretic lower extremity in individuals with chronic stroke.
How does genetic architecture affect eco-evolutionary dynamics? A theoretical perspective
Authors: Yamamichi Masato
Published: May 2022

Recent studies have revealed the importance of feedbacks between contemporary rapid evolution (i.e. evolution that occurs through changes in allele frequencies) and ecological dynamics. Despite its inherent interdisciplinary nature, however, studies on eco-evolutionary feedbacks have been mostly ecological and tended to focus on adaptation at the phenotypic level without considering the genetic architecture of evolutionary processes. In empirical studies, researchers have often compared ecological dynamics when the focal species under selection has a single genotype with dynamics when it has multiple genotypes. In theoretical studies, common approaches are models of quantitative traits where mean trait values change adaptively along the fitness gradient and Mendelian traits with two alleles at a single locus. On the other hand, it is well known that genetic architecture can affect short-term evolutionary dynamics in population genetics. Indeed, recent theoretical studies have demonstrated that genetic architecture (e.g. the number of loci, linkage disequilibrium and ploidy) matters in eco-evolutionary dynamics (e.g. evolutionary rescue where rapid evolution prevents extinction and population cycles driven by (co)evolution). I propose that theoretical approaches will promote the synthesis of functional genomics and eco-evolutionary dynamics through models that combine population genetics and ecology as well as nonlinear time-series analyses using emerging big data.

This article is part of the theme issue ‘Genetic basis of adaptation and speciation: from loci to causative mutations’.
Convergent copy number increase of genes associated with freshwater colonization in fishes
Authors: Ishikawa Asano , Yamanouchi Shun , Iwasaki Wataru , Kitano Jun
Published: May 2022

Copy number variation (CNV) can cause phenotypic changes. However, in contrast to amino acid substitutions andcis-regulatory changes, little is known about the functional categories of genes in which CNV is important for adaptation to novel environments. It is also unclear whether the same genes repeatedly change the copy numbers for adapting to similar environments. Here, we investigate CNV associated with freshwater colonization in fishes, which was observed multiple times across different lineages. Using 48 ray-finned fishes across diverse orders, we identified 23 genes whose copy number increases were associated with freshwater colonization. These genes showed enrichment for peptide receptor activity, hexosyltransferase activity and unsaturated fatty acid metabolism. We further revealed that three of the genes showed copy number increases in freshwater populations compared to marine ancestral populations of the stickleback genusGasterosteus. These results indicate that copy number increases of genes involved in fatty acid metabolism (FADS2), immune function (PSMB8a) and thyroid hormone metabolism (UGT2) may be important for freshwater colonization at both the inter-order macroevolutionary scale and at the intra-genus microevolutionary scale. Further analysis across diverse taxa will help to understand the role of CNV in the adaptation to novel environments.

This article is part of the theme issue ‘Genetic basis of adaptation and speciation: from loci to causative mutations’.
Genome-wide association mapping within a local
Arabidopsis thaliana
population more fully reveals the genetic architecture for defensive metabolite diversity
Authors: Gloss Andrew D. , Vergnol Amélie , Morton Timothy C. , Laurin Peter J. , Roux Fabrice , Bergelson Joy
Published: May 2022

A paradoxical finding from genome-wide association studies (GWAS) in plants is that variation in metabolite profiles typically maps to a small number of loci, despite the complexity of underlying biosynthetic pathways. This discrepancy may partially arise from limitations presented by geographically diverse mapping panels. Properties of metabolic pathways that impede GWAS by diluting the additive effect of a causal variant, such as allelic and genetic heterogeneity and epistasis, would be expected to increase in severity with the geographical range of the mapping panel. We hypothesized that a population from a single locality would reveal an expanded set of associated loci. We tested this in a French
Arabidopsis thaliana
population (less than 1 km transect) by profiling and conducting GWAS for glucosinolates, a suite of defensive metabolites that have been studied in depth through functional and genetic mapping approaches. For two distinct classes of glucosinolates, we discovered more associations at biosynthetic loci than the previous GWAS with continental-scale mapping panels. Candidate genes underlying novel associations were supported by concordance between their observed effects in the TOU-A population and previous functional genetic and biochemical characterization. Local populations complement geographically diverse mapping panels to reveal a more complete genetic architecture for metabolic traits.

This article is part of the theme issue ‘Genetic basis of adaptation and speciation: from loci to causative mutations’.
A synthetic synthesis to explore animal evolution and development
Authors: Perkins Mindy Liu , Gandara Lautaro , Crocker Justin
Published: May 2022

Identifying the general principles by which genotypes are converted into phenotypes remains a challenge in the post-genomic era. We still lack a predictive understanding of how genes shape interactions among cells and tissues in response to signalling and environmental cues, and hence how regulatory networks generate the phenotypic variation required for adaptive evolution. Here, we discuss how techniques borrowed from synthetic biology may facilitate a systematic exploration of evolvability across biological scales. Synthetic approaches permit controlled manipulation of both endogenous and fully engineered systems, providing a flexible platform for investigating causal mechanismsin vivo. Combining synthetic approaches with multi-level phenotyping (phenomics) will supply a detailed, quantitative characterization of how internal and external stimuli shape the morphology and behaviour of living organisms. We advocate integrating high-throughput experimental data with mathematical and computational techniques from a variety of disciplines in order to pursue a comprehensive theory of evolution.

This article is part of the theme issue ‘Genetic basis of adaptation and speciation: from loci to causative mutations’.
Modelling patterns of SARS-CoV-2 circulation in the Netherlands, August 2020-February 2022, revealed by a nationwide sewage surveillance program
Authors: van Boven Michiel , Hetebrij Wouter A. , Swart Arno M. , Nagelkerke Erwin , van der Beek Rudolf F.H.J. , Stouten Sjors , Hoogeveen Rudolf T. , Miura Fuminari , Kloosterman Astrid , van der Drift Anne-Merel R. , Welling Anne , Lodder Willemijn J. , de Roda Husman Ana M.
Published: May 2022

Background

Surveillance of SARS-CoV-2 in wastewater offers an unbiased and near real-time tool to track circulation of SARS-CoV-2 at a local scale, next to other epidemic indicators such as hospital admissions and test data. However, individual measurements of SARS-CoV-2 in sewage are noisy, inherently variable, and can be left-censored.

Aim

We aimed to infer latent virus loads in a comprehensive sewage surveillance program that includes all sewage treatment plants (STPs) in the Netherlands and covers 99.6% of the Dutch population.

Methods

A multilevel Bayesian penalized spline model was developed and applied to estimate time- and STP-specific virus loads based on water flow adjusted SARS-CoV-2 qRT-PCR data from 1-4 sewage samples per week for each of the >300 STPs.

Results

The model provided an adequate fit to the data and captured the epidemic upsurges and downturns in the Netherlands, despite substantial day-to-day measurement variation. Estimated STP virus loads varied by more than two orders of magnitude, from approximately 1012(virus particles per 100,000 persons per day) in the epidemic trough in August 2020 to almost 1015in many STPs in January 2022. Epidemics at the local levels were slightly shifted between STPs and municipalities, which resulted in less pronounced peaks and troughs at the national level.

Conclusion

Although substantial day-to-day variation is observed in virus load measurements, wastewater-based surveillance of SARS-CoV-2 can track long-term epidemic progression at a local scale in near real-time, especially at high sampling frequency.
Historical forest disturbance results in variation in functional resilience of seed dispersal mutualisms
Authors: Buono Carmela M. , Lofaso Jesse , Smisko Will , Gerth Carly , Santare John , Prior Kirsten M.
Published: May 2022

Mutualistic interactions provide essential ecosystem functions, such as promoting and maintaining diversity. Understanding if functionally important mutualisms are resilient (able to resist and recover) to anthropogenic disturbance is important to understand the capacity for diversity to recover. Animal-mediated seed dispersal supports plant population growth and community structure, and disturbance of this function can threaten plant diversity and contribute to low resiliency. Ant-mediated seed dispersal mutualisms are particularly sensitive to anthropogenic disturbance, as they rely on one to a few high-quality dispersal partners. In North American eastern deciduous forests (NAEDF), ants in the genusAphaenogasterare “keystone dispersers” of 30-40% of understory forbs adapted to dispersal by ants (myrmecochores). The majority of present day NAEDF have regenerated from previous disturbance in the form of historical land use change (HLUC), due to clearing for agriculture. Previous studies have revealed that myrmecochore diversity is not resilient to HLUC. Here, we ask if seed dispersal mutualisms are resilient to HLUC and if decreases in mutualistic interactions with partners,Aphaenogastersp., or increases in antagonistic interactions cause degradation of function. In a large-scale natural experiment (20 sites), we measured seed removal, the abundance of mutualistic partners and other invertebrates interacting with seeds, myrmecochore cover and diversity, along with ant habitat and forest structure. We found lower and more variable seed removal in secondary forests compared to remnant forests. A path analysis of all forests revealed that abundance of mutualists was the primary determinant of variation in seed removal, and that seed damage by antagonists (invasive slugs) negatively affected dispersal and was higher in secondary forests. In a path analysis of remnant forests, the link between mutualist abundance and seed removal was absent, but present in the secondary forest path, suggesting that seed dispersal is more variable and dependent on mutualist abundance in secondary forests and is stable and high in remnant forests. Here we show that functional resilience to HLUC is variable and may impede recovery of understory plant communities. This work provides key insights on the effects of anthropogenic disturbance on mutualistic interactions and how the resilience of critical ecosystem functions impacts diversity resiliency.
Variation in mutational (co)variances
Authors: Mallard François , Noble Luke , Baer Charles F. , Teotónio Henrique
Published: May 2022

1

Because of pleiotropy, mutations affect the expression and inheritance of multiple traits and are expected to determine the structure of standing genetic variation and phenotypic evolution. It is thus important to find if the M matrix, describing mutational (co)variances between traits, varies between genotypes. We here estimate the M matrix for six locomotion behavior traits in two genotypes of the nematode Caenorhabditis elegans. We find significant mutational variance along at least one phenotypic dimension of the M matrix, but its size and orientation was similar between genotypes. We then tested if the M matrices were similar to one G matrix describing the standing genetic (co)variances of a domesticated population derived by the hybridization of several genotypes and adapted to a lab defined environment for 140 generations. M and G are different in part because the genetic covariances caused by mutational pleiotropy in the two genotypes are smaller than those caused by standing linkage disequilibrium in the lab population. If generalized to other genotypes, these observations indicate that selection is unlikely to shape the evolution of the M matrix for locomotion behavior and suggests that the genetic restructuring due to the hybridization of C. elegans genotypes allows for selection in the lab on new phenotypic dimensions of locomotion behavior, phenotypic dimensions which are inaccessible to natural populations.
Selection and the direction of phenotypic evolution
Authors: Mallard François , Afonso Bruno , Teotónio Henrique
Published: May 2022

1

Predicting phenotypic evolution on the short-term of tens to hundreds of generations, particularly in changing environments and under finite population sizes, is an important theoretical goal. Because organisms are not simply collections of independent traits, making headway into this goal requires understanding if the phenotypic plasticity of ancestral populations aligns with the phenotypic dimensions that contain more genetic variation for selection to be effective and eventually feedback on the maintenance of genetic variation and promote adaptation or rescue from extinction. By performing 50 generations of experimental evolution in a changing environment we show that ancestral phenotypic plasticity for locomotion behavior in the partially-outcrossing nematodeCaenorhabditis elegansis nonadaptive because it does not align with the phenotypic dimension encompassing most genetic variance in the ancestral population and is of no consequence to future phenotypic divergence. Despite evolution of the genetic structure of locomotion behavior we are able to predict the direction of phenotypic divergence, but not the magnitude, based on the genetic covariances between the component traits of locomotion behavior and fitness of the ancestral population. We further demonstrate that indirect selection on the component traits of locomotion behavior with unobserved trait(s) is responsible for the observed phenotypic divergence on them. Our findings indicate that selection theory can predict the direction of short-term adaptive phenotypic evolution.
Improved methods for bulk cultivation and fixation of Loxodes ciliates for fluorescence microscopy
Authors: Seah Brandon Kwee Boon , Emmerich Christiane , Singh Aditi , Swart Estienne
Published: May 2022

Loxodes is one of the best ecologically characterized ciliate genera with numerous intriguing physiological abilities, including gravity-sensing organelles and nitrate respiration. However, these cells have been considered challenging to cultivate in bulk, and are poorly preserved by conventional fixatives used for fluorescence microscopy. Here we describe methods to grow and harvest Loxodes cells in bulk with liquid soil extract medium, as well as a new fixative called ZFAE (zinc sulfate, formaldehyde, acetic acid, ethanol) that can fix Loxodes cells more effectively than buffered formaldehyde or methanol. We show that ZFAE is compatible with immunofluorescence and the nuclear stain DAPI. Loxodes is thus now amenable to long-term maintenance, large-scale growth, and modern cell biology investigations of monoclonal strains in laboratory conditions.
Transcriptome profiling of histone writers/erasers enzymes across spermatogenesis, mature sperm and pre-cleavage embryo: Implications in paternal epigenome transitions and inheritance mechanisms
Authors: Barbero Gastón , de Sousa Serro Maximiliano , Lujan Camila Perez , Vitullo Alfredo D. , González Candela R. , González Betina
Published: May 2022

Accumulating evidence points out that sperm carry epigenetic instructions to embryo in the form of retained histones marks and RNA cargo that can transmit metabolic and behavioral traits to offspring. However, the mechanisms behind epigenetic inheritance of paternal environment are still poorly understood. Here, we curated male germ cells RNA-seq data and analyzed the expression profile of all known histone lysine writers and erasers enzymes across spermatogenesis, unraveling the developmental windows at which they are upregulated, and the specific activity related to canonical and non-canonical histone marks deposition and removal. We also characterized the epigenetic enzymes signature in the mature sperm RNA cargo, showing most of them positive translation at pre-cleavage zygote, suggesting that paternally-derived enzymes mRNA cooperate with maternal factors to embryo chromatin assembly. Our study shows several histone modifying enzymes not described yet in spermatogenesis and even more, important mechanistic aspects behind transgenerational epigenetics. Epigenetic enzymes not only can respond to environmental stressors, but could function as vectors of epigenetic information and participate in chromatin organization during maternal-to-zygote transition.
Potentiating the cross-reactive IFN-γ T cell and polyfunctional T cell responses by heterologous GX-19N DNA booster in mice primed with either a COVID-19 mRNA vaccine or inactivated vaccine
Authors: Seo Yong Bok , Ko Ara , Shin Duckhyang , Kim Junyoung , Suh You Suk , Na Juyoung , Ryu Ji In , Sung Young Chul
Published: May 2022

Waning vaccine-induced immunity, coupled with the emergence of SARS-CoV-2 variants, has inspired the widespread implementation of COVID-19 booster vaccinations. Here, we evaluated the potentials of the GX-19N DNA vaccine as a heterologous booster to enhance the protective immune response to SARS-CoV-2 in mice primed with either an inactivated virus particle (VP) or mRNA vaccine. We found that in the VP-primed condition, GX-19N enhanced the response of both vaccine-specific antibodies and cross-reactive T-cells to the SARS-CoV-2 variant of concern (VOC) compared to the homologous VP vaccine prime-boost. Under the mRNA-primed condition, GX-19N induced higher vaccine-induced T-cell responses but lower antibody responses than the homologous mRNA vaccine prime-boost. Furthermore, heterologous GX-19N boost induced higher S-specific polyfunctional CD4+ and CD8+ T cell responses than the homologous VP or mRNA prime-boost vaccinations. Our results provide new insights into booster vaccination strategies for the management of novel COVID-19 variants.
P-TEFb promotes cell survival upon p53 activation by suppressing intrinsic apoptosis pathway
Authors: Wang Zhijia , Mačáková Monika , Bugai Andrii , Kuznetsov Sergey G. , Hassinen Antti , Lenasi Tina , Potdar Swapnil , Friedel Caroline C. , Barborič Matjaž
Published: May 2022

Positive transcription elongation factor b (P-TEFb) is the crucial player in RNA polymerase II (Pol II) pause release that has emerged as a promising target in cancer. Because single-agent therapy may fail to deliver durable clinical response, targeting of P-TEFb shall benefit when deployed as a combination therapy. We screened a comprehensive oncology library and identified clinically relevant antimetabolites and Mouse double minute 2 homolog (MDM2) inhibitors as top compounds eliciting p53-dependent death of colorectal cancer cells in synergy with selective inhibitors of P-TEFb. While the targeting of P-TEFb augments apoptosis by antimetabolite 5-fluorouracil, it switches the fate of cancer cells by the non-genotoxic MDM2 inhibitor Nutlin-3a from cell-cycle arrest to apoptosis. Mechanistically, the fate switching is enabled by the induction of p53-dependent pro-apoptotic genes and repression of P-TEFb-dependent pro-survival genes of the PI3K-AKT signaling cascade, which stimulates Caspase 9 and intrinsic apoptosis pathway in BAX/BAK-dependent manner. Finally, combination treatments trigger apoptosis of cancer cell spheroids. Together, co-targeting of P-TEFb and suppressors of intrinsic apoptosis could become a viable strategy to eliminate cancer cells.
Defining specific cell states of MPTP-induced Parkinson’s disease by single-nucleus RNA sequencing
Authors: Guo Yunxia , Ma Junjie , Huang Hao , Xu Jitao , Ye Kaiqiang , Chang Ning , Ge Qinyu , Wang Guangzhong , Zhao Xiangwei
Published: May 2022

Parkinson’s disease (PD), a neurodegenerative disease with the impairment of movement execution that is related to age, genetic and environmental factors. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyri-dine (MPTP) is a neurotoxin widely used to induce PD models, but the effect of MPTP on cell-gene of PD has not been fully elucidated. By single-nucleus RNA sequencing, we uncovered the PD-specific cells and revealed remarkable changes in their cellular states, including astrocytosis, endothelial cells absence, as well as a cluster of PD-exclusive medium spiny neuron cells. Furthermore, trajectory analysis of astrocyte and endothelial cells populations predicted candidate target gene sets that might be associated with PD. Notably, the detailed regulatory roles of astrocyte-specific transcription factors Dbx2 and Sox13 in PD were first revealed in our work. Finally, we characterized the cell-cell communications of PD-specific cells and found that the overall communication strength was enhanced in PD compared with matched control, especially the signaling pathways of NRXN and NEGR. Our work provides comprehensive overview on the changes of cellular states of the MPTP-induced mouse brain.
Confounding factors of Alzheimer’s disease plasma biomarkers and their impact on clinical performance
Authors: Binette Alexa Pichet , Janelidze Shorena , Cullen Nicholas , Dage Jeffrey L. , Bateman Randall J. , Zetterberg Henrik , Blennow Kaj , Stomrud Erik , Mattsson-Carlgren Niklas , Hansson Oskar
Published: May 2022

INTRODUCTION

Plasma biomarkers will likely revolutionize the diagnostic work-up of Alzheimer’s disease (AD) globally. Before widespread use, we need to determine if confounding factors affect the levels of these biomarkers, and their clinical utility.

METHODS

Participants with plasma and CSF biomarkers, creatinine, body mass index (BMI), and medical history data were included (BioFINDER-1: n=748, BioFINDER-2: n=421). We measured beta-amyloid (Aβ42, Aβ40), phosphorylated tau (p-tau217, p-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP).

RESULTS

In both cohorts, creatinine and BMI were the main factors associated with NfL, GFAP, and to a lesser extent with p-tau. However, adjustment for BMI and creatinine had only minor effects in models predicting either the corresponding levels in CSF or subsequent development of dementia.

DISCUSSION

Creatinine and BMI are related to certain plasma biomarkers levels, but they do not have clinically relevant confounding effects for the vast majority of individuals.
Deciphering the conformational dynamics of gephyrin-mediated collybistin activation
Authors: Imam Nasir , Choudhury Susobhan , Hemmen Katherina , Heinze Katrin G. , Schindelin Hermann
Published: May 2022

Efficient neuronal signaling depends on the proper assembly of the postsynaptic neurotransmitter machinery and at inhibitory GABAergic synapses is controlled by the scaffolding protein gephyrin and collybistin, a Dbl-family guanine nucleotide exchange factor and neuronal adaptor protein. Collybistin usually contains an N-terminal SH3 domain and exists in closed/inactive or open/active states. Here, we elucidate the molecular basis of the gephyrin-collybistin interaction with newly designed collybistin FRET sensors. Using fluorescence lifetime-based FRET measurements, we deduce the affinity of the gephyrin-collybistin complex, thereby confirming that the C-terminal dimer-forming E domain binds collybistin, an interaction, which does not require E domain dimerization. Simulations based on fluorescence lifetime and sensor distance distributions reveal a dynamic behavior of the SH3 domain already in the closed state of collybistin. Finally, our data provide strong evidence for a collybistin-gephyrin communication network, where, unexpectedly, switching of collybistin from closed/inactive to open/active states is efficiently triggered by gephyrin.
LOMAR: LOcalization Microscopy Analysis in R
Authors: Theiss Maria , Brazma Alvis , Uhlmann Virginie , Hériché Jean-Karim
Published: May 2022

In single molecule localization microscopy data (SMLM), individual instances of a macromolecular complex come in the form of point sets. Particle averaging, which combines localization data from a large number of instances, is often used to overcome experimental noise and obtain a refined view of the underlying structure. However, SMLM point sets are often heterogeneous due to biological variations in the structure they represent and must be partitioned into groups with similar structure before averaging which calls for being able to compute structurally-relevant similarity measures between sets of points. Here we introduce LOMAR (LOcalization Microscopy Analysis in R) a software package for the R programming language that enables comparison of point sets through implementation of several point sets registration methods and similarity measures derived from topological data analysis. We demonstrate use of the package on real and simulated SMLM data of nuclear pore complexes.
Glycolysis-derived alanine from glia fuels neuronal mitochondria for memory in Drosophila
Authors: Rabah Yasmine , Frances Raquel , Plaçais Pierre-Yves , Preat Thomas
Published: May 2022

Glucose is the primary source of energy for the brain. However, it remains controversial whether, upon neuronal activation, glucose is primarily used by neurons for ATP production, or if it is partially oxidized in astrocytes, as proposed by the astrocyte-neuron lactate shuttle model for glutamatergic neurons. Thus, an in vivo picture of glucose metabolism during cognitive processes is missing. Here, we uncover in Drosophila a glia-to-neuron alanine transfer that sustains memory formation. Following associative conditioning, glycolysis in glial cells produces alanine, which is back-converted into pyruvate in mushroom body cholinergic neurons to uphold their increased mitochondrial needs. Alanine, as a mediator of glia-neuron coupling, could be an alternative to lactate in cholinergic systems. In parallel, a dedicated glial glucose transporter imports glucose specifically for long-term memory, by directly transferring it to neurons for use by the pentose phosphate pathway. Our results demonstrate in vivo the compartmentalization of glucose metabolism between neurons and glial cells during memory formation.
The optimal clutch size revisited: separating individual quality from the parental survival costs of reproduction
Authors: Winder Lucy A. , Simons Mirre J.P. , Burke Terry
Published: May 2022

Life-history theory, central to our understanding of diversity in morphology, behaviour and senescence, describes how traits evolve through the optimisation of trade-offs in investment. Despite considerable study, there is only minimal support for trade-offs within species between the two traits most closely linked to fitness – reproductive effort and survival – questioning the theory’s general validity. We used a meta-analysis to separate the effects of individual quality (positive survival/reproduction correlation) from the costs of reproduction (negative survival/reproduction correlation) using studies of reproductive effort and parental survival in birds. Experimental enlargement of brood size caused reduced parental survival. However, the effect size of brood size manipulation was small and opposite to the effect of phenotypic quality, as we found that individuals that naturally produced larger clutches also survived better. The opposite effects on parental survival in experimental and observational studies of reproductive effort provides the first meta-analytic evidence for theory suggesting that quality differences mask trade-offs. Fitness projections using the overall effect size revealed that reproduction presented negligible costs, except when reproductive effort was forced beyond the maximum level observed within species, to that seen between species. We conclude that there is little support for the most fundamental life-history trade-off, between reproductive effort and survival, operating within a population. We suggest that within species, the fitness landscape of the reproduction–survival trade-off is flat until it reaches the boundaries of the between-species fast–slow life-history continuum. Our results provide a quantitative explanation as to why the costs of reproduction are not apparent and why variation in reproductive effort persists within species.
Hippocampal-medial entorhinal circuit is differently organized along the dorsoventral axis in rodents
Authors: Ohara Shinya , Rannap Märt , Tsutsui Ken-ichiro , Draguhn Andreas , Egorov Alexei V. , Witter Menno P.
Published: May 2022

The general understanding of hippocampal circuits is that the hippocampus and the entorhinal cortex (EC) are topographically connected through parallel identical circuits along the dorsoventral axis. Our anterograde tracing and in vitro electrophysiology data, however, show a markedly different dorsoventral organization of the hippocampal projection to the medial EC (MEC). Whereas dorsal hippocampal projections are confined to the dorsal MEC and preferentially target layer Vb (LVb) over layer Va (LVa) neurons, the ventral hippocampus innervates the entire dorsoventral extent of MEC. In the ventral MEC, these projections innervate neurons in both LVa and LVb. In contrast, in the dorsal MEC, ventral hippocampal projections target mainly LVa neurons. As LVa neurons project to telencephalic structures, our findings indicate that the ventral hippocampus regulates LVa-mediated entorhinal-neocortical output from both the dorsal and ventral MEC. Overall, the marked dorsoventral differences in hippocampal-entorhinal connectivity impose important constraints on signal flow in hippocampal-neocortical circuits.
Pentameric assembly of the Kv2.1 tetramerization domain
Authors: Xu Zhen , Khan Saif , Schnicker Nicholas J. , Baker Sheila
Published: May 2022

The Kv family of voltage-gated potassium channels regulate neuronal excitability. The biophysical characteristics of Kv channels can be matched to the needs of different neurons by forming homotetrameric or heterotetrameric channels within one of four subfamilies. The cytoplasmic tetramerization (T1) domain plays a major role in dictating the compatibility of different Kv subunits. The only Kv subfamily lacking a representative structure of the T1 domain is the Kv2 family. Here, X-ray crystallography was used to solve the structure of the human Kv2.1 T1 domain. The structure is similar to those of other T1 domains, but surprisingly formed a pentamer instead of a tetramer. In solution the Kv2.1 T1 domain also formed a pentamer, as determined by inline SEC–MALS–SAXS and negative-stain electron microscopy. The Kv2.1 T1–T1 interface involves electrostatic interactions, including a salt bridge formed by the negative charges in a previously described CDD motif, and inter-subunit coordination of zinc. It is shown that zinc binding is important for stability. In conclusion, the Kv2.1 T1 domain behaves differently from the other Kv T1 domains, which may reflect the versatility of Kv2.1, which can assemble with the regulatory KvS subunits and scaffold ER–plasma membrane contacts.
Can venting hamper high emotionally intelligent recipient's reattachment to work?
Authors: Shah Syed Jamal , Huang Cheng
Published: May 2022

Purpose

This study investigates how healthcare workers' venting - an emotion-focused form of coping during non-working hours - has unintended costs via its effect on spouses' reattachment to work if life partners are dual-earners. Research also examined anxiety as a causal mechanism that connects the receipt of venting with failure in reattachment to work. Lastly, our theory suggests that not everyone has the same experience with venting; the effect varies at different levels of emotional intelligence.

Design/methodology/approach

Multilevel path analysis using MPlus 8.3 was conducted to examine the daily survey data obtained from 101 spouses of healthcare workers over four consecutive workdays using the experience sampling technique.

Findings

The results suggested that receipt of venting increases anxiety and adversely influences reattachment to work through increased anxiety. The findings supported the suggested model's predictions, indicating that anxiety mediated the link between the receipt of venting and reattachment to work, and the mediation was partial. Further, emotional intelligence buffers the positive effect of receipt of venting on anxiety and the negative on reattachment to work. Lastly, the findings indicate that moderated mediation exists: the indirect effect of receipt of venting on reattachment to work is not as strong at higher levels of emotional intelligence.

Originality/value

This study is the first attempt that identified the receipt of venting as a predictor of reattachment to work. Moreover, up till now, no study has examined the mediating role of anxiety in the relationship between receipt of venting and reattachment to work. Finally, this is the preliminary effort that validated the moderating role of emotional intelligence on the above-mentioned links.
Business model innovation based on new technologies – is it resources driven and dependent?
Authors: Mielcarek Paweł , Dymitrowski Adam
Published: May 2022

Purpose

The purpose of this paper is to analyse the significance and impact of different resource types and their features on the operation of business model innovation (BMI) based on new technologies and their effects. Specifically, the relationships of nine different types of resources, as well as their features in terms of VRIO and VARIM concepts, and 10 BMI effects of operation were examined. The significance and impact of resources on the operation of BMI are pretty well established in the literature. However, when the analysis is narrowed down to BMI based on new technologies, there is very little research in this field. This is partly because of the subject’s novelty and the wide range and complexity of this phenomenon.

Design/methodology/approach

The research covers 483 Polish companies that implement BMI based on new technology. For gathering data, the computer-assisted telephone interview method was used. Analysis is based on Spearman correlation. Results meet the requirement of p-value = 0.01 and are statistically significant and representative.

Findings

The main findings of this paper is that there is a need for building interdependency and synergy between individual types and features of resources and thus properly arrange and orchestrate them to succeed. Moreover, there are several patterns that stand out from the analysis, with the leading role of employees, technology, dynamic capabilities and know-how being the key enablers of BMI transformation.

Practical implications

The paper presents several compounds and relationships that shed light on the application and effects of BMI based on new technologies in terms of resource utilization, which can help business owners and senior managers to make consistent decisions in matching and orchestrating resources.

Originality/value

This study clarifies theoretical concepts building a resource-based view (VRIO, VARIM, dynamic capabilities, etc.) and their impact on BMI based on new technology. The results expand and complement existing research by shedding new light on resource utilization and orchestration.
The mediating role of self-efficacy in the relationship between emotional intelligence and organizational commitment
Authors: Hameli Kujtim , Ordun Güven
Published: May 2022

Purpose

This study examines the relationship between emotional intelligence, self-efficacy and organizational commitment, focusing on the mediating role of self-efficacy in the relationship between emotional intelligence and organizational commitment.

Design/methodology/approach

The authors used an online survey to collect data for this purpose. The sample consisted of 145 employees of different organizations in Kosovo. To test the hypothetical model, a mediation analysis was conducted using PROCESS Model Type 4.

Findings

The results show that emotional intelligence is positively related to self-efficacy and that self-efficacy is positively related to organizational commitment. Furthermore, the results of the mediation analysis confirm that the relationship between emotional intelligence and organizational commitment is mediated by self-efficacy.

Research limitations/implications

For future research, the authors recommend using the sub-dimensions of the above variables to test this model, and multiple models could be formulated. At the same time, the survey can be applied to managers to examine their emotional intelligence and to determine whether emotional intelligence influences their organizational commitment through self-efficacy. Consistent with the findings of this study, managers and executives in organizations should consider the emotional intelligence of their employees and that the employees with higher emotional intelligence have higher self-efficacy and can perform better.

Originality/value

This study extends the current literature in organizational behavior and provides a comprehensive understanding of the relationship between emotional intelligence, self-efficacy and organizational commitment. This study was also conducted in a developing country context, which can always lead to different results than studies conducted in developed countries.