bluuebunny/crossref_metadata_2025 huggingface dataset:
Synapsin condensation is governed by sequence-encoded molecular grammars
Authors: Hoffmann Christian , Ruff Kiersten M. , Edu Irina A. , Shinn Min Kyung , Tromm Johannes V. , King Matthew R. , Pant Avnika , Ausserwöger Hannes , Morgan Jennifer R. , Knowles Tuomas P. J. , Pappu Rohit V. , Milovanovic Dragomir
Published: August 2024

Multiple biomolecular condensates coexist at the pre- and post-synapse to enable vesicle dynamics and controlled neurotransmitter release in the brain. In pre-synapses, intrinsically disordered regions (IDRs) of synaptic proteins are drivers of condensation that enable clustering of synaptic vesicles (SVs). Using computational analysis, we show that the IDRs of SV proteins feature evolutionarily conserved non-random compositional biases and sequence patterns. Synapsin-1 is essential for condensation of SVs, and its C-terminal IDR has been shown to be a key driver of condensation. Focusing on this IDR, we dissected the contributions of two conserved features namely the segregation of polar and proline residues along the linear sequence, and the compositional preference for arginine over lysine. Scrambling the blocks of polar and proline residues weakens the driving forces for forming micron-scale condensates. However, the extent of clustering in subsaturated solutions remains equivalent to that of the wild-type synapsin-1. In contrast, substituting arginine with lysine significantly weakens both the driving forces for condensation and the extent of clustering in subsaturated solutions. Co-expression of the scrambled variant of synapsin-1 with synaptophysin results in a gain-of-function phenotype in cells, whereas arginine to lysine substitutions eliminate condensation. We report an emergent consequence of synapsin-1 condensation, which is the generation of interphase pH gradients realized via differential partitioning of protons between coexisting phases. This pH gradient is likely to be directly relevant for vesicular ATPase functions and the loading of neurotransmitters. Our study highlights how conserved IDR grammars serve as drivers of synapsin-1 condensation.

Research Highlights

Distinct biomolecular condensates formed by pre-synaptic proteins contain a unique bias of sequence grammars within their IDRs.

The IDR of synapsin-1, the essential protein for the clustering of synaptic vesicles, has a conserved compositional bias for Arg and blockiness of proline/polar residues.

Using sequence designs, we uncovered how conserved sequence features of the driver IDR of synapsin-1 affect condensation in vitro and in cells.

Synapsin-1 condensates are defined by a measurable interphase pH gradient.
Differential Dynamics and Roles of FKBP51 Isoforms and Their Implications for Targeted Therapies
Authors: Martinelli Silvia , Hafner Kathrin , Koedel Maik , Knauer-Arloth Janine , Gassen Nils C , Binder Elisabeth B
Published: August 2024

The expression of FKBP5, and its resulting protein FKBP51, is strongly induced by stress and glucocorticoids. Numerous studies have explored their involvement in a plethora of cellular processes and diseases, including psychiatric disorders, inflammatory conditions and cancer. However, there is a lack of knowledge on the role of the different RNA splicing variants and the two protein isoforms that originate from the human FKBP5 locus, especially in response to glucocorticoids. In this study we usein vitromodels as well as peripheral blood cells of a human cohort to show that the two expressed variants are both dynamically upregulated following dexamethasone. We also investigate the subcellular localization of the protein isoforms, their degradation dynamics as well as their differential role in known cellular pathways. The results shed light on the difference of the two variants and highlight the importance of differential analyses in future studies with implications for targeted drug design.
Polo-like kinase 1 prevents excess microtubule polymerization inC. elegansoocytes to ensure faithful meiosis
Authors: Narula Juhi G. , Wignall Sarah M.
Published: August 2024

Sexual reproduction relies on meiosis, a specialized cell division program that produces haploid gametes. Oocytes of most organisms lack centrosomes, and therefore chromosome segregation is mediated by acentrosomal spindles. Here, we explore the role of Polo-like kinase 1 (PLK-1) inC. elegansoocytes, revealing mechanisms that ensure the fidelity of this unique form of cell division. Previously, PLK-1 was shown to be required for nuclear envelope breakdown and chromosome segregation in oocytes. We now find that PLK-1 is also required for establishing and maintaining acentrosomal spindle organization and for preventing excess microtubule polymerization in these cells. Additionally, our studies revealed an unexpected new role for this essential kinase. While PLK-1 is known to be required for centrosome maturation during mitosis, we found that removal of this kinase from oocytes caused premature recruitment of pericentriolar material to the sperm-provided centrioles following fertilization. Thus, PLK-1 suppresses centrosome maturation during oocyte meiosis, which is opposite to its role in mitosis. Taken together, our work reveals multiple new roles for PLK-1 in oocytes, identifying PLK-1 as a key player that promotes faithful acentrosomal meiosis.
A targeted CRISPR screen identifies ETS1 as a regulator of HIV latency
Authors: Ashokkumar Manickam , Hafer Terry L , Felton Abby , Archin Nancie M. , Margolis David M , Emerman Michael , Browne Edward P
Published: August 2024

Human Immunodeficiency virus (HIV) infection is regulated by a wide array of host cell factors that combine to influence viral transcription and latency. To understand the complex relationship between the host cell and HIV latency, we performed a lentiviral CRISPR screen that targeted a set of host cell genes whose expression or activity correlates with HIV expression. We further investigated one of the identified factors - the transcription factor ETS1 and found that it is required for maintenance of HIV latency in a primary CD4 T cell model. Interestingly, ETS1 played divergent roles in actively infected and latently infected CD4 T cells, with knockout of ETS1 leading to reduced HIV expression in actively infected cells, but increased HIV expression in latently infected cells, indicating that ETS1 can play both a positive and negative role in HIV expression. CRISPR/Cas9 knockout of ETS1 in CD4 T cells from ART-suppressed people with HIV (PWH) confirmed that ETS1 maintains transcriptional repression of the clinical HIV reservoir. Transcriptomic profiling of ETS1-depleted cells from PWH identified a set of host cell pathways involved in viral transcription that are controlled by ETS1 in resting CD4 T cells. In particular, we observed that ETS1 knockout increased expression of the long non-coding RNA MALAT1 that has been previously identified as a positive regulator of HIV expression. Furthermore, the impact of ETS1 depletion on HIV expression in latently infected cells was partially dependent on MALAT1. Overall, these data demonstrate that ETS1 is an important regulator of HIV latency and influences expression of several cellular genes, including MALAT1, that could have a direct or indirect impact on HIV expression.

Author Summary

HIV latency is a major obstacle for the eradication of HIV. However, molecular mechanisms that restrict proviral expression during therapy are not well understood. Identification of host cell factors that silence HIV would create opportunities for targeting these factors to reverse latency and eliminate infected cells. Our study aimed to explore mechanisms of latency in infected cells by employing a lentiviral CRISPR screen and CRISPR/Cas9 knockout in primary CD4 T cells. These experiments revealed that ETS1 is essential for maintaining HIV latency in primary CD4 T cells and we further confirmed ETS1’s role in maintaining HIV latency through CRISPR/Cas9 knockout in CD4 T cells from antiretroviral therapy (ART)-suppressed individuals with HIV. Transcriptomic profiling of ETS1-depleted cells from these individuals identified several host cell pathways involved in viral transcription regulated by ETS1, including the long non-coding RNA MALAT1. Overall, our study demonstrates that ETS1 is a critical regulator of HIV latency, affecting the expression of several cellular genes that directly or indirectly influence HIV expression.
Structural perturbation of chromatin domains with multiple developmental regulators can severely impact gene regulation and development
Authors: Chakraborty Shreeta , Wenzlitschke Nina , Anderson Matthew J , Eraso Ariel , Baudic Manon , Thompson Joyce J , Evans Alicia A , Shatford Adams Lilly M , Chari Raj , Awasthi Parirokh , Dale Ryan K , Lewandoski Mark , Petros Timothy J , Rocha Pedro P
Published: August 2024

Chromatin domain boundaries delimited by CTCF motifs can restrict the range of enhancer action. However, disruption of domain structure often results in mild gene dysregulation and thus predicting the impact of boundary rearrangements on animal development remains challenging. Here, we tested whether structural perturbation of a chromatin domain with multiple developmental regulators can result in more acute gene dysregulation and severe developmental phenotypes. We targeted clusters of CTCF motifs in a domain of the mouse genome containing three FGF ligand genes - Fgf3, Fgf4, and Fgf15 - that regulate several developmental processes. Deletion of the 23.9kb cluster that defines the centromeric boundary of this domain resulted in ectopic interactions of the FGF genes with enhancers located across the deleted boundary that are active in the developing brain. This caused strong induction of FGF expression and perinatal lethality with encephalocele and orofacial cleft phenotypes. Heterozygous boundary deletion was sufficient to cause these fully penetrant phenotypes, and strikingly, loss of a single CTCF motif within the cluster also recapitulated ectopic FGF expression and caused encephalocele. However, such phenotypic sensitivity to perturbation of domain structure did not extend to all CTCF clusters of this domain, nor to all developmental processes controlled by these three FGF genes - for example, the ability to undergo lineage specification in the blastocyst and pre-implantation development were not affected. By tracing the impact of different chromosomal rearrangements throughout mouse development, we start to uncover the determinants of phenotypic robustness and sensitivity to perturbation of chromatin boundaries. Our data show how small sequence variants at certain domain boundaries can have a surprisingly outsized effect and must be considered as potential sources of gene dysregulation during development and disease.
Humans can use positive and negative spectrotemporal correlations to detect rising and falling pitch
Authors: Vaziri Parisa A. , McDougle Samuel D. , Clark Damon A.
Published: August 2024

To discern speech or appreciate music, the human auditory system detects how pitch increases or decreases over time. However, the algorithms used to detect changes in pitch, or pitch motion, are incompletely understood. Here, using psychophysics, computational modeling, functional neuroimaging, and analysis of recorded speech, we ask if humans can detect pitch motion using computations analogous to those used by the visual system. We adapted stimuli from studies of vision to create novel auditory correlated noise stimuli that elicited robust pitch motion percepts. Crucially, these stimuli are inharmonic and possess no persistent features across frequency or time, but do possess positive or negative local spectrotemporal correlations in intensity. In psychophysical experiments, we found clear evidence that humans can judge pitch direction based only on positive or negative spectrotemporal intensity correlations. The key behavioral result—robust sensitivity to the negative spectrotemporal correlations—is a direct analogue of illusory “reverse-phi” motion in vision, and thus constitutes a new auditory illusion. Our behavioral results and computational modeling led us to hypothesize that human auditory processing may employ pitch direction opponency. fMRI measurements in auditory cortex supported this hypothesis. To link our psychophysical findings to real-world pitch perception, we analyzed recordings of English and Mandarin speech and found that pitch direction was robustly signaled by both positive and negative spectrotemporal correlations, suggesting that sensitivity to both types of correlations confers ecological benefits. Overall, this work reveals how motion detection algorithms sensitive to local correlations are deployed by the central nervous system across disparate modalities (vision and audition) and dimensions (space and frequency).
CRISPR-Cas13d as a molecular tool to achieve targeted gene expression knockdown in chick embryos
Authors: Kim Minyoung , Hutchins Erica J.
Published: August 2024

The chick embryo is a classical model system commonly used in developmental biology due to its amenability to gene perturbation experiments. Pairing this powerful model organism with cutting-edge technology can significantly expand the range of experiments that can be performed. Recently, the CRISPR-Cas13d system has been successfully adapted for use in zebrafish, medaka, killifish, and mouse embryos to achieve targeted gene expression knockdown. Despite its success in other animal models, no prior study has explored the potential of CRISPR-Cas13d in the chick. Here, we present an adaptation of the CRISPR-Cas13d system to achieve targeted gene expression knockdown in the chick embryo. As proof-of-principle, we demonstrate the knockdown of PAX7, an early neural crest marker. Application of this adapted CRISPR-Cas13d technique resulted in effective knockdown of PAX7 expression and function, comparable to knockdown achieved by translation-blocking morpholino. CRISPR-Cas13d complements preexisting knockdown tools such as CRISPR-Cas9 and morpholinos, thereby expanding the experimental potential and versatility of the chick model system.
A versatile dual reporter to identify ribosome pausing motifs alleviated by translation elongation factor P
Authors: Tomasiunaite Urte , Brewer Tess , Burdack Korinna , Brameyer Sophie , Jung Kirsten
Published: August 2024

Protein synthesis is influenced by the chemical and structural properties of the amino acids incorporated into the polypeptide chain. Motifs with consecutive prolines can slow down translation speed and cause ribosome stalling. Translation elongation factor P (EF-P) facilitates peptide bond formation in these motifs, thereby alleviating stalled ribosomes and restoring regular translational speed. Ribosome pausing at various polyproline motifs has been intensively studied using a range of sophisticated techniques, including ribosome profiling, proteomics, andin vivoscreenings with reporters incorporated into the chromosome. However, the full spectrum of motifs which cause translational pausing inEscherichia colihas not yet been identified. Here we describe a plasmid-based dual reporter for rapid assessment of pausing motifs. This reporter contains two coupled genes encoding mScarlet-I and chloramphenicol acetyltransferase to screen motif libraries based on both bacterial fluorescence and survival. In combination with a diprolyl motif library, we use this reporter to reveal motifs of different pausing strengths in anE. colistrain lackingefp.Subsequently, we use the reporter for a high-throughput screen of four motif libraries, with and without prolines at different positions, sorted by fluorescence-associated cell sorting (FACS) and identify new motifs that influence translational efficiency of the fluorophore. Our study provides anin vivoplatform for rapid screening of amino acid motifs that affect translational efficiencies.
Implementation of sustainability activities in food retail chains
Authors: Boskova Iveta , Valenta Matěj , Dolanova Ivana
Published: August 2024

Purpose

This study aims to examine the implementation of sustainability activities in food retail chains operating in the Czech market and discusses the specific activities that influence their implementation.

Design/methodology/approach

Using the neo-institutional theory as a framework, the research employs qualitative content analysis with an explanatory and inductive approach based on the stratification of data collected by multiple-round, personal, face-to-face interviews by the researchers with managers of the Czech headquarters of multinational food retail chains.

Findings

There is lively development in activities in the fields of the environment and social welfare, while the activities in governance and economic resilience are more stabilised. To remain ahead of the competition, retail chains aim to implement and communicate as many activities as possible where at least some links to sustainability can be found. A lack of benchmarks and clear definitions reduce the ability to determine their degree of engagement. Thus, market actors are inundated with sustainability claims leading to inflation of the concept, while significant achievements are drowned.

Originality/value

This paper, based on empirical research, contributes to the current literature by showing inflation of the sustainability concept as one of the key effects of retail-chain competition. In this context, it also strengthens previous findings on the profitability motive behind sustainability activities. Moreover, we have developed our own stratification method, enabling differentiation between activities getting the most attention due to their progressive phase and those where development is in the background.
Construction 4.0 technology and lean construction ambidexterity capability in China’s construction industry: a sociotechnical systems perspective
Authors: Fang Yanqing , Gao Shang
Published: August 2024

Purpose

This study aims to explore the level of adoption of Construction 4.0 (C4.0) technologies and of Lean Construction (LC) ambidexterity capability in China’s construction industry. By incorporating C4.0 and LC ambidexterity into a sociotechnical systems (STS) framework, this research provides practical insights for construction practitioners and companies seeking C4.0 and LC.

Design/methodology/approach

The study adopts the questionnaire survey method. Data was obtained from Chinese construction professionals working on projects using C4.0 technologies. The data were analysed using mean score ranking and three nonparametric techniques, including the Wilcoxon signed-rank test and the Spearman rank correlation.

Findings

According to the ranking analysis, building information modelling and offsite construction have the highest adoption level, while additive manufacturing and blockchain rank lowest. Digital technology is more widely used in China’s construction industry than in physical technology. Many C4.0 technologies are significantly correlated with LC ambidexterity. Based on the STS perspective, we propose a holistic approach that incorporates C4.0 technologies and LC ambidexterity.

Originality/value

Conceptually, the study incorporates C4.0 and LC ambidexterity into the STS framework. Empirically, this study fills the gap in the current literature by exploring the level of C4.0 technology adoption in the Chinese construction industry, as well as the level of LC ambidexterity capabilities. Construction companies can use this framework to make strategic decisions regarding investments in LC practices and the adoption of C4.0 technologies, such as investing in staff skill training and new technology deployment to adapt to the ever-changing environment.
Navigating the integration of ChatGPT in UAE’s government sector: challenges and opportunities
Authors: Goher Ghada Nabil
Published: August 2024

Purpose

This research examines how responsible deployment of ChatGPT in the UAE’s government sector, guided by New Public Management principles, can enhance customer journeys by integrating services across government bodies. Through semi-structured interviews with UAE government officers, the study investigates this approach’s benefits, challenges, and applications for achieving efficient and integrated public service delivery.

Design/methodology/approach

This research adopts a qualitative approach, purposive sampling strategy, and semi-structured interviews to explore the subjective viewpoints of 20 high-level UAE government authorities. The thematic analysis uncovers ChatGPT’s benefits, challenges, and applications, aligning with New Public Management principles.

Findings

Thematic analysis reveals four themes: Benefits and Applications of ChatGPT, Challenges, Strategies to Overcome Challenges, and Steps for Customer Journey Enhancement through ChatGPT.

Research limitations/implications

The analysis is based on participant responses provided during the interviews, which may be subject to biases or incomplete information. Secondly, the study focuses solely on the provided applications and participant responses, limiting the generalizability of the conclusions to other contexts.

Practical implications

The implementation of ChatGPT in the government sector has practical implications for transforming its operations and enhancing communication, efficiency, decision-making, and service offerings: citizen engagement, streamlined processes, and informed governance.

Originality/value

This study uniquely examines ChatGPT’s role in government, offering insights into communication, efficiency, decision-making, and service offerings. Identifying hurdles enriches understanding of ChatGPT’s practical integration in government.
Exploring the competitiveness of Indian technological start-ups – the case study approach
Authors: Wasi Khushnuma , Pantawane Tisha Rajeev , Parameswar Nakul , Ganesh M.P.
Published: August 2024

Purpose

Technological start-ups are significant contributor to the innovation and employment provider in an economy. Numerous technological start-ups are established every year; however, only a miniscule percentage of these technological start-ups sustain and scale up in the long run. The aim of this study is to investigate the factors that affect Indian technological start-ups’ competitiveness.

Design/methodology/approach

Case study analysis of two technological start-ups (namely, WayCool and Moglix) is undertaken to study the factors affecting the competitiveness of technological start-ups in India. Being a relatively underexplored theme of study in entrepreneurship and strategy, case analysis facilitates exploration and validation of factors influencing competitiveness. Information for case study analysis is drawn from secondary sources of information. The collected data undergoes deductive thematic analysis to systematically identify and examine recurring themes and patterns relevant to the competitiveness of Indian technological start-ups.

Findings

Case analysis reveals that innovation intensity, organisational agility and internationalisation influence competitiveness of technological start-ups. The importance of the role of each of these factors for entrepreneurial ventures has been highlighted in literature; however, their effect on competitiveness has not been examined in extant literature.

Research limitations/implications

Being among the few studies on the competitiveness of technological start-ups in specific and start-ups in general, this study highlights the gap in the literature and suggests the need for examining the competitiveness of technological start-ups.

Practical implications

For the practitioners, this study reinforces the need for entrepreneurs to emphasise fundamental factors that build competitiveness. Subsequently, the sources of competitiveness shall enable the start-up to gain a competitive advantage.

Originality/value

This is among the few studies to have explored the competitiveness of technological start-ups in the Indian context.
Planting one thousand seeds of entrepreneurs
Authors: Queen Pamela
Published: August 2024

Research methodology

This case is based on secondary information and data about the Goldman Sachs One Million Black Women initiative and youth entrepreneurship programs from press releases, news articles and websites. The protagonist has been disguised. This case has been classroom-tested in a core MBA course in both face-to-face and online delivery methods.

Case overview/synopsis

In March 2021, Goldman Sachs launched its One Million Black Women initiative which expanded its inclusive growth goals to support Black women entrepreneurs who were under-represented and under-resourced. This initiative is one of Goldman Sachs’s sponsored programs that aid existing entrepreneurs. This program would invest $10bn over the next decade to advance racial equity, promote entrepreneurial activity and increase and economic opportunities for these highly motivated and resilient Black women. With the buzz from this initiative, Johnnetta who was a Black female manager at a financial services competitor of Goldman Sachs conceived another approach to groom and grow future generations of women of color entrepreneurs. Her idea was to implement youth entrepreneurship programs in middle schools in states with high populations of students of color. Based on a psychological theory of entrepreneurship approach, these students would learn about entrepreneurship and gain hands-on experience with starting and operating a business. The program was called “Planting 1000 Seeds of Entrepreneurs” to develop a pipeline of savvy, well-prepared future women of color entrepreneurs. Johnnetta’s dilemma was whether to pitch this new youth entrepreneurship program as an employee at her employer as a diversity, equity and inclusion (DEI) initiative or start this program as an entrepreneur of a nonprofit in which she would have sole autonomy to administer this program. This case will enable students to develop ideas into a compelling business pitch while sparking debate about approaches to foster DEI initiatives that will have impactful economic benefits for women of color entrepreneurs.

Complexity academic level

This case is best suited for upper-level undergraduate or graduate students taking business administration courses in management, entrepreneurship, women studies or other courses that cover topics or modules related to DEI initiatives involving women in business.
Wolbachia confers protection against the entomopathogenic fungus Metarhizium pingshaense in African Aedes aegypti
Authors: Bilgo Etienne , Mancini Maria Vittoria , Gnambani Jacques E. , Dokpomiwa Houeffa Adeline Tatiana , Murdochy Shivan , Lovett Brian , St. Leger Raymond , Sinkins Steven P. , Diabate Abdoulaye
Published: August 2024

Symbiotic and pathogenic microorganisms such as bacteria and fungi represent promising alternatives to chemical insecticides to respond to the rapid increase of insecticide resistance and vector‐borne disease outbreaks. This study investigated the interaction of two strains of Wolbachia, wAlbB and wAu, with the natural entomopathogenic fungi from Burkina Faso Metarhizium pingshaense, known to be lethal against Anopheles mosquitoes. In addition to showing the potential of Metarhizium against African Aedes aegypti wild‐type populations, our study shows that the wAlbB and wAu provide a protective advantage against entomopathogenic fungal infections. Compared to controls, fungal‐infected wAu and wAlbB‐carrying mosquitoes showed higher longevity, without any significant impact on fecundity and fertility phenotypes. This study provides new insights into the complex multipartite interaction among the mosquito host, the Wolbachia endosymbiont and the entomopathogenic fungus that might be employed to control mosquito populations. Future research should investigate the fitness costs of Wolbachia, as well as its spread and prevalence within mosquito populations. Additionally, evaluating the impact of Wolbachia on interventions involving Metarhizium pingshaense through laboratory and semi‐field population studies will provide valuable insights into the effectiveness of this combined approach.
Microtubule‐associated NAV3 regulates invasive phenotypes in glioblastoma cells
Authors: Škarková Aneta , Pelantová Markéta , Tolde Ondřej , Legátová Anna , Mateu Rosana , Bušek Petr , Garcia‐Borja Elena , Šedo Aleksi , Etienne‐Manneville Sandrine , Rösel Daniel , Brábek Jan
Published: August 2024

Glioblastomas are aggressive brain tumors for which effective therapy is still lacking, resulting in dismal survival rates. These tumors display significant phenotypic plasticity, harboring diverse cell populations ranging from tumor core cells to dispersed, highly invasive cells. Neuron navigator 3 (NAV3), a microtubule‐associated protein affecting microtubule growth and dynamics, is downregulated in various cancers, including glioblastoma, and has thus been considered a tumor suppressor. In this study, we challenge this designation and unveil distinct expression patterns of NAV3 across different invasion phenotypes. Using glioblastoma cell lines and patient‐derived glioma stem‐like cell cultures, we disclose an upregulation of NAV3 in invading glioblastoma cells, contrasting with its lower expression in cells residing in tumor spheroid cores. Furthermore, we establish an association between low and high NAV3 expression and the amoeboid and mesenchymal invasive phenotype, respectively, and demonstrate that overexpression of NAV3 directly stimulates glioblastoma invasive behavior in both 2D and 3D environments. Consistently, we observed increased NAV3 expression in cells migrating along blood vessels in mouse xenografts. Overall, our results shed light on the role of NAV3 in glioblastoma invasion, providing insights into this lethal aspect of glioblastoma behavior.
Reproduce to validate: A comprehensive study on the reproducibility of economics research
Authors: Herbert Sylvérie , Kingi Hautahi , Stanchi Flavio , Vilhuber Lars
Published: August 2024

Journals have pushed for transparency of research through data availability policies. Such data policies improve availability of data and code, but what is the impact on reproducibility? We present results from a large reproduction exercise for articles published in the American Economic Journal: Applied Economics, which has had a data availability policy since its inception in 2009. Out of 363 published articles, we assessed 274 articles. All articles provided some materials. We excluded 122 articles that required confidential or proprietary data or that required the replicator to otherwise obtain the data (44.5% of assessed articles). We attempted to reproduce 152 articles and were able to fully reproduce the results of 68 (44.7% of attempted reproductions). A further 66 (43.4% of attempted reproductions) were partially reproduced. Many articles required complex code changes even when at least partially reproduced. We collect bibliometric characteristics of authors, but find no evidence for author characteristics as determinants of reproducibility. There does not appear to be a citation bonus for reproducibility. The data availability policy of this journal was effective to ensure availability of materials, but is insufficient to ensure reproduction without additional work by replicators.
Deciphering the neuroprotective mechanisms of RACK1 in cerebral ischemia‐reperfusion injury: Pioneering insights into mitochondrial autophagy and the PINK1/Parkin axis
Authors: Zhao Lanqing , Chen Yu , Li Hongxi , Ding Xiaoxu , Li Jinwei
Published: August 2024

Introduction

Cerebral ischemia‐reperfusion injury (CIRI) is a common and debilitating complication of cerebrovascular diseases such as stroke, characterized by mitochondrial dysfunction and cell apoptosis. Unraveling the molecular mechanisms behind these processes is essential for developing effective CIRI treatments. This study investigates the role of RACK1 (receptor for activated C kinase 1) in CIRI and its impact on mitochondrial autophagy.

Methods

We utilized high‐throughput transcriptome sequencing and weighted gene co‐expression network analysis (WGCNA) to identify core genes associated with CIRI. In vitro experiments used human neuroblastoma SK‐N‐SH cells subjected to oxygen and glucose deprivation (OGD) to simulate ischemia, followed by reperfusion (OGD/R). RACK1 knockout cells were created using CRISPR/Cas9 technology, and cell viability, apoptosis, and mitochondrial function were assessed. In vivo experiments involved middle cerebral artery occlusion/reperfusion (MCAO/R) surgery in rats, evaluating neurological function and cell apoptosis.

Results

Our findings revealed that RACK1 expression increases during CIRI and is protective by regulating mitochondrial autophagy through the PINK1/Parkin pathway. In vitro, RACK1 knockout exacerbated cell apoptosis, while overexpression of RACK1 reversed this process, enhancing mitochondrial function. In vivo, RACK1 overexpression reduced cerebral infarct volume and improved neurological deficits. The regulatory role of RACK1 depended on the PINK1/Parkin pathway, with RACK1 knockout inhibiting PINK1 and Parkin expression, while RACK1 overexpression restored them.

Conclusion

This study demonstrates that RACK1 safeguards against neural damage in CIRI by promoting mitochondrial autophagy through the PINK1/Parkin pathway. These findings offer crucial insights into the regulation of mitochondrial autophagy and cell apoptosis by RACK1, providing a promising foundation for future CIRI treatments.
Effects of batroxobin on the antithrombotic system in patients with cerebral venous thrombosis: Clues to mechanisms
Authors: Lan Duo , Jiao Baolian , Song Siying , Wang Mengqi , Zhang Xiaoming , Huang Xiangqian , Guo Yibing , Ding Yuchuan , Ji Xunming , Meng Ran
Published: August 2024

Background and Purpose

More evidence supports the benefits of batroxobin combined with anticoagulation in correcting acute cerebral venous thrombosis (CVT). The dynamic fluctuations of peripheral blood platelets, fibrinolysis, and coagulation biomarkers during this therapy were analyzed.

Methods

We investigated batroxobin's effects on the antithrombotic system under two regimens. The pretreatment group included patients on anticoagulants for at least 1 week before starting batroxobin. The simultaneous treatment group began both treatments upon admission. The control group received only anticoagulation. Batroxobin was given on alternate days at doses of 10BU, 5BU, and 5BU, totaling three doses. Anticoagulation was continuous. Baseline data were T0; the next day after each batroxobin dose was T1, T2, and T3. Data from these four time points was analyzed.

Results

The time‐point paired sample T‐test results of the pretreatment group [n = 60; mean age (SD), 43.3(16.5); 38 (63.35%) women] showed that batroxobin significantly inhibited ADP‐induced platelet aggregation rate (T1–T0: p = 0.015; T2–T0: p = 0.025; T3–T0: p = 0.013), decreased fibrinogen level (T1–T0: p < 0.001; T2–T0: p < 0.001; T3–T0: p < 0.001), and increased D‐dimer (T1–T0:p < 0.001; T2–T0: p < 0.001; T3–T0: p < 0.001), TT (T1–T0:p = 0.046; T2–T0: p = 0.003; T3–T0: p < 0.001), and APTT (T1–T0:p = 0.021; T2–T0: p = 0.012; T3–T0: p = 0.026). Compared to the control group, the simultaneous treatment group showed significantly higher TT (T2: p = 0.002; T3: p = 0.004) and D‐dimer (T1: p < 0.001; T2: p < 0.001; T3: p < 0.001) values, while fibrinogen (T2: p < 0.001; T3: p < 0.001) levels were significantly lower. Using batroxobin can alleviate the amplitude of changes in coagulation indicators other than TT caused by anticoagulants. The above conclusions are consistent with the results of repeated measurement data analysis.

Conclusions

Batroxobin can significantly inhibit ADP‐induced platelet aggregation rate, increase D‐dimer, decrease fibrinogen, and prolong TT and APTT in the presence of anticoagulant agents. Using batroxobin can reduce the amplitude of changes in coagulation indicators caused by anticoagulants. These results reveal the potential mechanism of batroxobin combined with anticoagulation in the safe and effective treatment of CVT.
Nesfatin‐1 inhibits cerebral aneurysms by activating Nrf2 and inhibiting NF‐κB signaling
Authors: Yu Huimin , Liu Qingyuan , Xie Minghong , Fan Junquan , Luo Jiajia , Huang Junping , Chen Lei
Published: August 2024

Aims

Cerebral aneurysm (CA) has been considered one of the most common cerebrovascular diseases, affecting millions of people worldwide. A therapeutic agent is currently missing for the treatment of CA. Nesfatin‐1 (Nes‐1) is an 82‐amino acid adipokine which possesses a wide range of biological functions. However, the physiological function of Nes‐1 in CA is still unknown. Here, we aimed to assess the preventive effects of Nes‐1 in the pathological development of CA and elucidate the mechanisms behind this.

Methods

We used an elastase‐induced CA model, accompanied by a high‐salt diet to induce hypertension. Additionally, diverse experimental techniques, including Verhoeff‐Van Gieson staining, real time PCR, enzyme‐linked immuno sorbent assay (ELISA), and immunofluorescence staining, were employed to assess CA formation, gene and protein expression, as well as the macrophage infiltration.

Results

Our results indicate that administration of Nes‐1 significantly decreased the aneurysm size. Additionally, Nes‐1 prevented inflammatory response by inhibiting the expression of interleukin‐6 (IL‐6), tumor necrosis factor‐α (TNF‐α), and monocyte chemoattractant protein 1 (MCP‐1) at both the mRNA and protein levels in the Circle of Willis (COW) region. Also, the increased levels of matrix metalloproteinase‐2 (MMP‐2) and matrix metalloproteinase‐9 (MMP‐9) in the COW region were reduced by Nes‐1. We found that Nes‐1 administration suppressed the invasion of macrophages. Mechanistically, Nes‐1 activated Nrf‐2 by promoting its nuclear translocation but prevented the activation of the IκBα/NF‐κB signaling pathway.

Conclusion

These findings suggest that Nes‐1 might be used as a promising agent for the prevention of CA.
Treating activated regulatory T cells with pramipexole protects human dopaminergic neurons from 6‐OHDA‐induced degeneration
Authors: Guevara‐Salinas Adrián , Netzahualcoyotzi Citlalli , Álvarez‐Luquín Diana Denisse , Pérez‐Figueroa Erandi , Sevilla‐Reyes Edgar E. , Castellanos‐Barba Carlos , Vega‐Ángeles Vera Teresa , Terán‐Dávila Edgar , Estudillo Enrique , Velasco Iván , Adalid‐Peralta Laura
Published: August 2024

Background

Parkinson's disease (PD) is a chronic neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra, which promotes a sustained inflammatory environment in the central nervous system. Regulatory T cells (Tregs) play an important role in the control of inflammation and might play a neuroprotective role. Indeed, a decrease in Treg number and function has been reported in PD. In this context, pramipexole, a dopaminergic receptor agonist used to treat PD symptoms, has been shown to increase peripheral levels of Treg cells and improve their suppressive function. The aim of this work was to determine the effect of pramipexole on immunoregulatory Treg cells and its possible neuroprotective effect on human dopaminergic neurons differentiated from human embryonic stem cells.

Methods

Treg cells were sorted from white blood cells of healthy human donors. Assays were performed with CD3/CD28‐activated and non‐activated Treg cells treated with pramipexole at concentrations of 2 or 200 ng/mL. These regulatory cells were co‐cultured with in vitro‐differentiated human dopaminergic neurons in a cytotoxicity assay with 6‐hydroxydopamine (6‐OHDA). The role of interleukin‐10 (IL‐10) was investigated by co‐culturing activated IL‐10‐producing Treg cells with neurons. To further investigate the effect of treatment on Tregs, gene expression in pramipexole‐treated, CD3/CD28‐activated Treg cells was determined by Fluidigm analysis.

Results

Pramipexole‐treated CD3/CD28‐activated Treg cells showed significant protective effects on dopaminergic neurons when challenged with 6‐OHDA. Pramipexole‐treated activated Treg cells showed neuroprotective capacity through mechanisms involving IL‐10 release and the activation of genes associated with regulation and neuroprotection.

Conclusion

Anti‐CD3/CD28‐activated Treg cells protect dopaminergic neurons against 6‐OHDA‐induced damage. In addition, activated, IL‐10‐producing, pramipexole‐treated Tregs also induced a neuroprotective effect, and the supernatants of these co‐cultures promoted axonal growth. Pramipexole‐treated, activated Tregs altered their gene expression in a concentration‐dependent manner, and enhanced TGFβ‐related dopamine receptor regulation and immune‐related pathways. These findings open new perspectives for the development of immunomodulatory therapies for the treatment of PD.
Determining the role of statins in Parkinson's disease risk reduction and disease modification: A comprehensive meta‐analysis of 4 million participants' data
Authors: Mady Abdelrahman , Nabil Yehia , Daoud Asma , Alnajjar Asmaa Zakria , Alsalloum Taleb , Marwan Menna , Abdelmeseh Maickel , Elsayed Moaz , Krayim Abdulrahman , Alaa Mohamed , Masoud Mahmoud , Bushara Nagham , Faisal Roaa , Ahmed Hayat , Saad Mohamed , Belabaci Zineddine , Barrett Matthew J. , Berman Brian , Negida Ahmed
Published: August 2024

Background

Many observational studies have examined the association between statins and the incidence of Parkinson's disease (PD) in high‐risk populations. On the other hand, clinical trials as well as other observational studies investigated the safety and efficacy of statins in slowing disease progression in PD patients. However, the evidence has been inconclusive in both questions. To that end, we conducted this systematic review and meta‐analysis to synthesize evidence on the role of statins in decreasing the risk of PD among high‐risk populations and as a possible disease‐modifying agent for patients with PD.

Methods

A comprehensive literature search of electronic databases including PubMed, Scopus, Cochrane, and Web of Science has been performed. Relevant studies were chosen and data were extracted and analyzed using RevMan software version 5.4.1.

Results

Twenty‐five studies (14 cohort, 9 case–control, and 2 randomized controlled trials) have been included in the present systematic review. Of them, 21 studies reported the association between statins and PD risk. Statins were found to significantly reduce the risk of developing PD (pooled RR 0.86, 95% CI [0.77–0.95], p < 0.005). Four studies investigated statins as a disease‐modifying agent. The pooled mean difference (MD) in the UPDRS‐III from baseline to endpoint did not differ significantly between the statin and control groups (MD −1.34 points, 95% CI [−3.81 to 1.14], p = 0.29).

Conclusion

Although epidemiological observational studies showed that statin use was associated with a reduced risk of PD, current evidence is insufficient to support the role of statins in slowing the progression of PD. These findings are limited by the fact that most of the included studies are observational studies which carry a high risk of confounding bias which highlights the need for future well‐designed RCTs.
Serotonin (5‐HT)2A/2C receptor agonist 2,5‐dimethoxy‐4‐iodophenyl‐2‐aminopropane hydrochloride improves detrusor sphincter dyssynergia by inhibiting L‐type voltage‐gated calcium channels in spinal cord injured rats
Authors: Lv Rong , Li Mingzhuo , Chen Xun , Li Shengtian , Cao Nailong , Gu Baojun
Published: August 2024

Aims

To explore the role of voltage‐gated calcium channels (VGCC) in 5‐HT2A/2C receptor agonist 2,5‐dimethoxy‐4‐iodophenyl‐2‐aminopropane hydrochloride's improvement of spinal cord injury (SCI) induced detrusor sphincter dyssynergia and the expressions of the 5‐hydroxy tryptamine (5‐HT) 2A receptors and VGCCs in lumbosacral cord after SCI.

Methods

Female Sprague–Dawley rats were randomized into normal control group and SCI group (N = 15 each). Cystometrogram (CMG), simultaneous CMG, and external urethral sphincter electromyography (EUS‐EMG) were conducted in all groups under urethane anesthesia. Drugs were administered intrathecally during CMG and EUS‐EMG. Rats were euthanized and L6‐S1 spinal cord were acquired for immunofluorescence.

Results

In SCI rats, intrathecal administration of 2,5‐dimethoxy‐4‐iodophenyl‐2‐aminopropane hydrochloride or L‐type VGCC blocker, nifedipine, could significantly increase voiding volume, voiding efficiency, and the number of high‐frequency oscillations. They could also prolong EUS bursting activity duration on EUS‐EMG. Moreover, the effect of 2,5‐dimethoxy‐4‐iodophenyl‐2‐aminopropane hydrochloride can be eliminated with the combined administration of L‐type VGCC agonist, (±)‐Bay K 8644. No significant differences were observed in CMG after intrathecal administration of T‐type VGCC blocker TTA‐P2. Additionally, immunofluorescence of the lumbosacral cord in control and SCI rats showed that the 5‐HT2A receptor and Cav1.2 immunolabeling‐positive neurons in the anterior horn of the lumbosacral cord were increased in SCI rats.

Conclusions

Our study demonstrated that 5‐HT2A/2C agonist 2,5‐dimethoxy‐4‐iodophenyl‐2‐aminopropane hydrochloride may improve SCI‐induced DSD by inhibiting the L‐type voltage‐gated calcium channel in lumbosacral cord motoneurons.
Progress and recognition of idiopathic intracranial hypertension: A narrative review
Authors: Zhou Chenxia , Zhou Yifan , Liu Lu , Jiang Huimin , Wei Huimin , Zhou Chen , Ji Xunming
Published: August 2024

Background

Idiopathic intracranial hypertension (IIH) mainly affects obese young women, causing elevated intracranial pressure, headaches, and papilledema, risking vision loss and severe headaches. Despite weight loss as the primary treatment, the underlying mechanisms remain unclear. Recent research explores novel therapeutic targets.

Aims

This review aimed to provide a comprehensive understanding of IIH's pathophysiology and clinical features to inform pathogenesis and improve treatment strategies.

Methods

Recent publications on IIH were searched and summarized using PubMed, Web of Science, and MEDLINE.

Results

The review highlights potential pathomechanisms and therapeutic advances in IIH.

Conclusion

IIH incidence is rising, with growing evidence linking it to metabolic and hormonal disturbances. Early diagnosis and treatment remain challenging.
Transcriptional expression patterns of the cortical morphometric similarity network in progressive supranuclear palsy
Authors: Qu Junyu , Qu Yancai , Zhu Rui , Wu Yongsheng , Xu Guihua , Wang Dawei
Published: August 2024

Background

It has been demonstrated that progressive supranuclear palsy (PSP) correlates with structural abnormalities in several distinct regions of the brain. However, whether there are changes in the morphological similarity network (MSN) and the relationship between changes in brain structure and gene expression remain largely unknown.

Methods

We used two independent cohorts (discovery dataset: PSP: 51, healthy controls (HC): 82; replication dataset: PSP: 53, HC: 55) for MSN analysis and comparing the longitudinal changes in the MSN of PSP. Then, we applied partial least squares regression to determine the relationships between changes in MSN and spatial transcriptional features and identified specific genes associated with MSN differences in PSP. We further investigated the biological processes enriched in PSP‐associated genes and the cellular characteristics of these genes, and finally, we performed an exploratory analysis of the relationship between MSN changes and neurotransmitter receptors.

Results

We found that the MSN in PSP patients was mainly decreased in the frontal and temporal cortex but increased in the occipital cortical region. This difference is replicable. In longitudinal studies, MSN differences are mainly manifested in the frontal and parietal regions. Furthermore, the expression pattern associated with MSN changes in PSP involves genes implicated in astrocytes and excitatory and inhibitory neurons and is functionally enriched in neuron‐specific biological processes related to synaptic signaling. Finally, we found that the changes in MSN were mainly negatively correlated with the levels of serotonin, norepinephrine, and opioid receptors.

Conclusions

These results have enhanced our understanding of the microscale genetic and cellular mechanisms responsible for large‐scale morphological abnormalities in PSP patients, suggesting potential targets for future therapeutic trials.