bluuebunny/crossref_metadata_2025 huggingface dataset:
Iron-sensitive RNA regulation by poly C binding proteins
Authors: Forbes Kwame , Goda Grant A. , Eramo Grace A. , Breen Conner , Porter Douglas F. , Khavari Paul A. , Dominguez Daniel , Aleman Maria M.
Published: October 2024

Iron is essential for normal cellular function. Homeostatic responses to low iron availability have long been known to rely on posttranscriptional mechanisms. Poly C binding proteins (PCBPs) are essential RNA binding proteins that regulate alternative splicing, translation and RNA stability. They also serve as critical iron chaperones that manage intracellular iron flux. However, the impact of cellular iron levels on the PCBP-directed transcriptome has not been globally evaluated. We have found broad transcriptome changes in response to low iron availability consistent with numerous operant posttranscriptional mechanisms that sense iron. By comparing gene expression and alternative splicing directed by PCBPs to the iron-sensitive transcriptome, we found genes with iron-sensitive PCBP RNA regulation. Further, we demonstrate that cellular iron levels impact PCBP1 RNA binding. Our data show a large-scale RNA regulatory response to cellular iron levels and open the possibility for other iron-sensitive RNA binding proteins.
A hypothalamic circuit mechanism underlying the impact of stress on memory and sleep
Authors: Wiest Alyssa , Maurer John J. , Weber Franz , Chung Shinjae
Published: October 2024

Stress profoundly affects sleep and memory processes. Stress impairs memory consolidation, and similarly, disruptions in sleep compromise memory functions. Yet, the neural circuits underlying stress-induced sleep and memory disturbances are still not fully understood. Here, we show that activation of CRHPVNneurons, similar to acute restraint stress, decreases sleep and impairs memory in a spatial object recognition task. Conversely, inhibiting CRHPVNneurons during stress reverses stress-induced memory deficits while slightly increasing the amount of sleep. We found that both stress and stimulation of CRHPVNneurons activate neurons in the lateral hypothalamus (LH), and that their projections to the LH are critical for mediating stress-induced memory deficits and sleep disruptions. Our results suggest a pivotal role for CRHPVNneuronal pathways in regulating the adverse effects of stress on memory and sleep, an important step towards improving sleep and ameliorating the cognitive deficits that occur in stress-related disorders.
Jamaican fruit bats’ (Artibeus jamaicensis) competence for Ebola virus but not Marburg virus is driven by intrinsic differences in viral entry and IFN-I signaling antagonism
Authors: van Tol Sarah , Port Julia R. , Fischer Robert J. , Gallogly Shane , Bushmaker Trenton , Griffin Amanda , Schulz Jonathan E. , Carmody Aaron , Myers Lara , Crowley Daniel E. , Falvo Caylee A. , Riopelle Jade C. , Wickenhagen Arthur , Clancy Chad , Lovaglio Jamie , Shaia Carl , Saturday Greg , Prado-Smith Jessica , He Yi , Lack Justin , Martens Craig , Anzick Sarah L. , Kendall Lon V. , Schountz Tony , Plowright Raina K. , Marzi Andrea , Munster Vincent J.
Published: October 2024

Ebola virus (EBOV) and Marburg virus (MARV) are zoonotic filoviruses that cause hemorrhagic fever in humans. Bat species in both Chiropteran suborders host filoviruses, suggesting that bats may have coevolved with this viral family. Correlative data implicate bats as natural EBOV hosts, but neither a full-length genome nor an EBOV isolate has been found in any bats sampled. Here, we modelled filovirus infection in the Jamaican fruit bat (JFB),Artibeus jamaicensis. Bats were inoculated with either EBOV or MARV through a combination of oral, intranasal, and subcutaneous routes. EBOV-infected bats supported systemic virus replication and shed infectious virus orally. In contrast, MARV replicated only transiently and was not shed.In vitro, JFB cells replicate EBOV more efficiently than MARV, and MARV infection induced innate antiviral responses that EBOV efficiently suppressed. Experiments using VSV pseudoparticles or replicating VSV expressing the EBOV or MARV glycoprotein demonstrated an advantage for EBOV entry and replication early, respectively, in JFB cells. Overall, this study describes filovirus species-specific phenotypes for both JFB and their cells.
Models of microbiome evolution incorporating environmental microbial selection
Authors: Xiao Yao , Li Teng , Rodrigo Allen G.
Published: October 2024

The environment plays a crucial role in shaping the microbial composition of hosts. Different environments harbor distinct microbial communities, leading to variation in the availability of different microbes to potential hosts. Over the past few decades, human activities have significantly altered the environment, resulting in a decline in microbial diversity. Currently, the impact of this environmentally-induced reduction in microbial diversity on environmental microbial communities, host-microbiome interactions, and their evolutionary implications remains unclear. In this paper, we simulated how environmental microbial selection can lead to decreasing microbial diversity, using a previously-developed selection model. Our results indicate that microbial communities are influenced by both environmental conditions and host preferences. The diversity of the microbiome carried by hosts is impacted by the environment, with stronger environmental microbial selection reducing microbial diversity in the hosts, while at the same time, facilitating the emergence of mutually beneficial symbioses between microorganisms and hosts. Environmental microbial selection (EMS) leads to the survival of highly fit microorganisms in the environment, while the fitnesses of hosts and microbes within hosts remain relatively unaffected by environmental microbial selection.
Novel nanopore sequencing method for determining Human Papillomavirus integrations in tumors without the need for whole genome sequencing
Authors: Parida Preetiparna , Mukherjee Nivedita , Singh Agastya , Lewis Shirley , Sharan Krishna , Mallya Sandeep , Singh Ashima , Rao Mahadev , Higginson Daniel S. , Sabarinathan Radhakrishnan , Damerla Rama Rao
Published: October 2024

Human papillomaviral (HPV) integrations into host human genome, a key event in cervical carcinogenesis, are currently mapped through laborious and expensive sequencing methodologies. We developed and validated a novel library preparation strategy for nanopore sequencing to generate long targeted reads with HPV and human chimeric sequences. Using this strategy, we validated known HPV integrations in HeLa (HPV18) and SiHa (HPV16) cell lines. We also mapped integration sites in five HPV+ cervical cancer patients, which were confirmed by whole genome and Sanger sequencing. Our nanopore-based method provides a precise and efficient strategy to capture HPV integrations crucial for understanding tumorigenesis.
The influence of downstream structured elements within mRNA on the dynamics of intersubunit rotation in ribosomes
Authors: Shebl Bassem , Pavlova Anna , Kellenberger Preston , Yu Dongmei , Menke Drew E. , Gumbart James C. , Cornish Peter V.
Published: October 2024

Proper codon/anti-codon pairing within the ribosome necessitates linearity of the transcript. Any structures formed within a messenger RNA (mRNA) must be unwound before the respective codon is interpreted. Linearity, however, is not always the norm; some intricate structures within mRNA are able to exert unique ribosome/mRNA interactions to regulate translation. Intrinsic kinetic and thermal stability in many of these structures are efficient in slowing translation causing pausing of the ribosome. Altered translation kinetics arising from atypical interactions have been shown to affect intersubunit rotation. Here, we employ single-molecule Förster Resonance Energy Transfer (smFRET), to observe changes in intersubunit rotation of the ribosome as it approaches downstream structured nucleic acid. The emergence of the hyper-rotated state is critically dependent on the distance between downstream structure and the ribosome suggesting interactions with the helicase center are allosterically coupled to intersubunit rotation. Further, molecular dynamics (MD) simulations were performed to determine ribosomal protein/mRNA interactions that may play a pivotal role in helicase activity and ultimately unwinding of downstream structure.
Deep coalescent history of the hominin lineage
Authors: Cousins Trevor , Schweiger Regev , Durbin Richard
Published: October 2024

1

Coalescent-based methods are widely used to infer population size histories, but existing analyses have limited resolution for deep time scales (>2 million years ago). Here we extend the scope of such inference by re-analysing an ancient peak seen in human and chimpanzee effective population size around 5-7 million years ago, showing that coalescent-based inference can be extended much further into the past than previously thought. This peak is consistently observed across human and chimpanzee populations, but not in gorillas or orangutans. We show that it is unlikely to be an artefact of model violations, and discuss its potential implications for understanding hominin evolutionary history, in particular the human-chimpanzee speciation.
Loss of Bicra/Gltscr1 leads to a defect in fetal liver macrophages responsible for erythrocyte maturation in mice.
Authors: Sood Surbhi , Alpsoy Aktan , Jiao Guanming , Dhiman Alisha , King Charles Samuel , Conjelko Gabriella , Hallett Judy , Utturkar Sagar , Hutchcroft Jill , Dykhuizen Emily
Published: October 2024

GLTSCR1, a protein encoded by the Bicra gene, is a defining subunit of the SWI/SNF (also called mammalian BAF) chromatin remodeling subcomplex called GBAF/ncBAF. To determine the role of GLTSCR1 during mouse development, we generated a Bicra germline knockout mouse using CRISPR/Cas9. Mice with homozygous loss of Bicra were born at Mendelian ratios but were small, pale and died within 24 hours after birth. Histology indicated blood-related defects including defective erythroblastic islands and irregularly sized red blood cells. Gene expression profiling of fetal livers pinpointed a defect in liver resident macrophages involved in the last stage of erythrocyte maturation, resulting in accumulation of nucleated erythrocytes in Bicra-/- pups. Together, these results demonstrate that Bicra is critical for fetal liver macrophage function during development.
The ribosome-associated quality control factor TCF25 imposes K48 specificity on Listerin-mediated ubiquitination of nascent chains by binding and specifically orienting the acceptor ubiquitin
Authors: Abaeva Irina S. , Bulakhov Alexander G. , Hellen Christopher U. T. , Pestova Tatyana V.
Published: October 2024

Polypeptides arising from interrupted translation undergo proteasomal degradation by the ribosome- associated quality control (RQC) pathway. The ASC-1 complex splits stalled ribosomes into 40S subunits and nascent chain-tRNA-associated 60S subunits (60S RNCs). 60S RNCs associate with NEMF that promotes recruitment of the RING-type E3 ubiquitin (Ub) ligase Listerin (Ltn1 in yeast), which ubiquitinates nascent chains. RING-type E3s mediate the transfer of Ub directly from the E2∼Ub conjugate, implying that the specificity of Ub linkage is determined by the given E2. Listerin is most efficient when it is paired with promiscuous Ube2D E2s. We previously found that TCF25 (Rqc1 in yeast) can impose K48- specificity on Listerin paired with Ube2D E2s. To determine the mechanism of TCF25’s action, we combined functional biochemical studies and AlphaFold3 modeling and now report that TCF25 specifically interacts with the RING domain of Listerin and the acceptor ubiquitin (UbA) and imposes K48-specificity by orienting UbAsuch that its K48 is directly positioned to attack the thioester bond of the Ube2D1∼Ub conjugate. We also found that TCF25 itself undergoes K48-specific ubiquitination by Listerin suggesting a mechanism for the reported upregulation of Rqc1 in the absence of Ltn1 and the observed degradation of TCF25 by the proteasomein vivo.
Single-step in vitro ribosome reconstitution mediated by two GTPase factors, EngA and ObgE
Authors: Sato Aya , Lai Weng Yu , Sakai Yusuke , Shimizu Yoshihiro
Published: October 2024

When bacterial ribosomes are assembled in vitro, manipulation of incubation temperature and magnesium ion concentration have been an essential procedure, which is a crucial step for the assembly of active large subunits. The present study tackles with this issue to develop a single-step procedure, which can be performed in a physiological condition. We found that GTPase factors EngA and ObgE can complement the changes in temperature and magnesium ion concentrations. In the presence of these factors, ribosome assembly can proceed under physiological conditions, with magnesium ion concentrations below 10 mM, potassium concentrations around 100 mM, and temperatures of 37 °C. Both the ribosome assembly and translation processes were successfully integrated in the reconstituted cell-free protein synthesis system. Furthermore, we found that these GTPase factors can reassemble the ribosomes to an active state, whose structure was disrupted by EDTA chelation of magnesium ions, indicating that these two factors can reversibly induce the ribosome structure to an intact state. The findings are essential for the bottom-up construction of synthetic cells.
A Genes & Health pilot recall study of intrahepatic cholestasis of pregnancy and cholestatic liver disease
Authors: Constantinides Maria , Gafton Joseph , Garcia Ana Cristina Angel ,   Genes and Health, Dixon Peter H. , Williamson Catherine , Linton Kenneth , Finer Sarah , Gill Upkar S. , Zöllner Julia
Published: October 2024

Background

Cholestatic liver disease disproportionately affects South Asians, yet they remain underrepresented in genomic studies. This recall study aimed to recall volunteers from a British South Asian genetic cohort that were considered to be at high risk of cholestatic liver disease based on their genotype or phenotype.

Methods

Cases were defined as participants with rare (minor allele frequency <1%) heterozygous loss of function (LoF) variants inABCB4andABCB11(genotype re-call) or with a previous intrahepatic cholestasis of pregnancy (ICP) diagnosis (ICD10 O26.6). Cases were matched 1:1 to controls. A detailed medical and family history was taken along with fasting anthropometric and transient elastography (TE) measurements and blood samples.

Results

Out of 22 eligible volunteers, 9 (41%) participated in the recall (8/9 genotype and 1/9 phenotype recall). Among the cases there were 5ABCB4LoF, 3ABCB11LoF, and 1 ICP phenotype. Of these, 6/9 (66.7%) were newly identified with a cholestatic phenotype (genotype re-call). Specifically, 3/6 (50%) had increased liver stiffness on TE with one also demonstrating abnormal liver blood tests. 2/6 (33.3%) experienced at least 2 cholestatic symptoms and an additional 1/6 (16.7%) demonstrated abnormal liver blood tests without increased liver stiffness.

Conclusion

This pilot study demonstrated new evidence of cholestatic liver disease in 66.7% of volunteers, underscoring the potential of rare heterozygousABCB4/11variants as markers for identifying individuals at high risk of developing cholestatic liver disease. Consequently, individuals at higher genetic risk benefit from monitoring, personalised treatment and prevention strategies for cholestatic liver disease.

Plain language summary

We aimed to identify British South Asians at high risk of liver disease due to specific genetic factors, such as issues with bile production or liver problems during pregnancy. We invited these individuals to a clinic, where we collected their medical and family history, conducted liver blood tests, and performed a scan to check for early signs of liver scarring. We found that nearly two out of three participants had undetected liver disease. This finding suggests that genetic factors are linked to developing liver disease, highlighting the importance of early detection and monitoring for those at risk.
Oronasal mucosal melanoma is defined by two transcriptional subtypes in humans and dogs with implications for diagnosis and therapy
Authors: Blacklock Kelly L. Bowlt , Donnelly Kevin , Lu Yuting , del Pozo Jorge , Glendinning Laura , Polton Gerry , Selmic Laura , Tanis Jean-Benoir , Killick David , Parys Maciej , Morris Joanna , Breathnach Inge , Zago Stefano , Gould Sara M , Shaw Darren , Tivers Mickey , Malucelli Davide , Marques Ana , Purzycka Katarzyna , Cantatore Matteo , Mathers Marie E. , Stares Mark , Meynert Alison , Patton E. Elizabeth
Published: October 2024

Mucosal melanoma is a rare melanoma subtype associated with a poor prognosis and limited existing therapeutic interventions, in part due to a lack of actionable targets and translational animal models for pre-clinical trials. Comprehensive data on this tumour type is scarce, and existing data often overlooks the importance of the anatomical site of origin. We evaluated human and canine oronasal mucosal melanoma to determine whether the common canine disease could inform the rare human equivalent.

Using a human and canine primary oronasal mucosal melanoma (OMM) cohort of treatment naive archival tissue, alongside clinicopathological data, we obtained transcriptomic immunohistochemical, and microbiome data from both species. We defined the transcriptomic landscape in both species, and linked our findings to immunohistochemical, microbiome and clinical data.

Human and dog OMM stratified into two distinctive transcriptional groups which we defined using a species-independent 41-gene signature. These two subgroups are termed CTLA4-high and cMET-high, and indicate actionable targets for OMM patients. To guide clinical decision-making, we developed immunohistochemical diagnostic tools which distinguish between transcriptomic subgroups.

For the first time, we find that OMM has conserved transcriptomic subtypes and biological similarity between the canine and human OMM, with significant implications for patient classification, treatment, and clinical trial design.
Research Protocol: Discrete choice modelling to understand the influence of sharing polygenic risk scores related to cardiovascular disease risk with primary care patients
Authors: Bowker-Lonnecker Lin , Dixon Padraig , Petrou Stavros , Buckell John
Published: October 2024

Introduction

Cardiovascular disease (CVD) is a leading cause of death in the UK and globally. People identified as being at high risk may receive further investigations or preventive treatment. Polygenic risk scores (PRSs) give a summary of overall underlying genetic risk, and may be used to give additional information that GPs can use alongside other information about the patient to determine which interventions, if any, would be beneficial.

Methods and Analysis

Two discrete choice experiments (DCEs) with 2000 participants recruited from the UK general adult population. The first DCE aims to determine people’s attitudes about getting their PRS in the context of cardiovascular disease, and what factors may influence this. The second DCE aims to determine how people are likely to react to this risk information, and their stated probability of undergoing further investigation or interventions for disease management. This aims to provide new, quantitative information of whether individuals’ health-related behaviour is likely to be modified by knowledge of one’s PRS. Results from the pilot study will be used to inform the design of the main study, and the analysis will use multinomial logit models. Marginal rates of substitution between attributes, and heterogeneity analysis comparing people with different demographic characteristics, will also be carried out.

Ethics and Dissemination

Ethics approval (reference: R89898/RE001) was obtained through the Medical Sciences Interdivisional Research Ethical Committee (MS IDREC) at the University of Oxford. The results of this research will be submitted to academic journals and will be presented at conferences.
Causes of Death among Cancer Patients: Emerging Trends in the 21st Century
Authors: Wang Junpu , Liu Jie , Liu Ziyu , Zhou Zongjiang , Ousmane Diabate , Liu Liu , Peng Li , Yuan Xiaoqing
Published: October 2024

Most studies examining the causes of cancer-related deaths have primarily focused on specific cancer types, often neglecting the evolving spectrum of death causes among cancer patients in the 21st century. This study, utilizing data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program, analyzed the causes of death in patients diagnosed with 36 types of cancer between 2000 and 2021. By categorizing these causes into deaths from index cancers, non-index cancers, and non-cancer causes, this study provides a comprehensive analysis of cause-of-death patterns and emerging trends, stratified by year of death, age at diagnosis, and survival duration. The findings reveal that while relative mortality rates from index cancers remain elevated for brain, pancreatic, and gallbladder cancers, significant declines were observed for lung, liver, nasopharyngeal, and esophageal cancers, as well as multiple myeloma cancers, reflecting advancements in cancer treatment. Besides, relative mortality rates from non-index cancers surpassed those from index cancers in oral cavity, oropharyngeal, vaginal, and small intestine cancers, indicating a potential benefit from enhanced surveillance and early detection of non-index cancers in these patient populations. Importantly, non-cancer-related causes of death, such as heart disease, chronic liver disease and cirrhosis, also emerged as prominent contributors to mortality among cancer patients. The results of this study offer critical and current data to inform public health policy, optimize healthcare resource allocation, and facilitate international collaboration in cancer research and control. Meanwhile, this study is of great reference value for developing countries to formulate medium– and long-term public health policies.
Prevalence of gastrointestinal symptoms is higher close to the sea: evidence from coastal Bangladesh
Authors: Fardousi Ammatul , Novak Masuma , Sagar Sharoardy , Chowdhury Srizan , Haque Rehnuma , Rahman Habibur , Kabir Iqbal , Hanifi Manzoor Ahmed
Published: October 2024

Background

Sea level rise, heavy rainfall, flooding, and temperature changes due to climate change contribute to the spread of enteric infections, disrupting normal intestinal functions and leading to gastrointestinal (GI) symptoms such as nausea, vomiting, and diarrhea etc. Coastal regions of Bangladesh are projected to be highly vulnerable to diarrheal diseases and cholera outbreaks by 2050. However, there is limited research on how coastal proximity affects GI health. Thus, we aimed to examine the association between GI symptoms and geographic distance from the sea in a coastal area of Bangladesh.

Materials and methods

This study was conducted in the Chakaria Health and Demographic Surveillance System area of icddr,b which is running since 1999. A total of 61,295 household members were interviewed between 2012 and 2016. GI symptoms were chosen as the primary outcome measure of this study. We employed chi-square tests and logistic regression analysis model.

Result

Overall, 7% reported experiencing one or more GI symptoms in the previous two weeks. Diarrhea was the most prevalent symptom (35%), followed by heartburn (22%) and abdominal pain (18%). Prevalence was significantly higher among females (8%, p<0.05), older adults (13%, p<0.05), and individuals from lower socioeconomic backgrounds (8%, p<0.05). Seasonal variation was observed, with the highest prevalence in summer (9%, p<0.05) and the lowest in winter (5%, p<0.05). Additionally, participants living within 15 kilometers (aOR: 1.35, 95% CI: 1.24-1.46) and 15-20 kilometers (aOR: 1.23, 95% CI: 1.10-1.38) of the sea had a higher risk of GI symptoms compared to those residing more than 20 kilometers away, after adjusting for other covariates.

Conclusion

Our finding demonstrates that individuals residing near the coast have a higher prevalence of GI symptoms. This evidence suggests the need for targeted public health strategies to improve GI health in climate vulnerable coastal populations. Also, further research is needed to determine the causal effect as well as the underlying biological mechanisms of GI symptoms in these population.
Rapid Genome Sequencing Compared to a Gene Panel in Infants with a Suspected Genetic Disorder: An Economic Evaluation
Authors: Lavelle Tara A. , Maron Jill L. , Kingsmore Stephen F. , Lin Ching-Hsuan , Zhu Yingying , Sweigart Benjamin , Reed Dallas , Gelb Bruce D. , Vockley Jerry , Davis Jonathan M.
Published: October 2024

Introduction

Rapid genome sequencing (rGS) provides high diagnostic yield for critically ill infants with suspected genetic disorders, but it has high upfront costs and insufficient insurance coverage. Assessing the long-term costs of rGS is important for guiding coverage decisions. This study compares 1-year healthcare costs for: 1) early rGS (within 7 days of admission) for all infants, and 2) early targeted neonatal gene sequencing (NewbornDx) for all infants, followed by rGS after 7 days for undiagnosed infants.

Methods

The Genomic Medicine for Ill Neonates and Infants (GEMINI) study was a multicenter, prospective study that enrolled 400 hospitalized infants under one year with suspected genetic disorders. All participants underwent both rGS and NewbornDx. Using study data, we developed and populated a decision tree to compare 1-year costs for early rGS versus early NewbornDx followed by later rGS if necessary.

Results

The diagnostic yield and upfront testing costs were higher for rGS (49%; $12,297) than NewbornDx (27%; $2,449; p<0.05). Over 1 year, early rGS was estimated to save $158,592 per patient (95% CI: $63,701-$253,292) compared to early NewbornDx with later rGS if necessary.

Discussion

Early rGS results in substantial cost savings, highlighting the need to expand reimbursement to improve access.
Data quality and Big Data in the health industry: a scoping review protocol
Authors: Santos Lívia C. T , Bublitz Frederico M.
Published: October 2024

Introduction

Big Data is characterized by the large volume of data, the variety of types and formats, the speed with which they are generated, and the veracity and value that can be extracted from the data. However, the result obtained with this technology will depend on the quality of the information obtained from the data. Big Data has great potential in healthcare and can be used to advance diagnosis, treatment, and healthcare management. Health data is highly vulnerable due to its sensitive nature, as it contains personal and confidential information. If exposed or compromised, it could lead to privacy violations, inaccuracies, misuse, incorrect diagnoses, or misguided decision-making in patient care. It is important to prioritize confidentiality, adhere to regulatory compliance, and maintain data integrity; for that, it is essential to use efficient methods to obtain quality data and make them able to reach the proposed objective.

Objective

In this context, the scoping review protocol aims to identify and map existing strategies, methods, or models that improve the quality of medical and health data in Big Data environments. This review explores the methods to support the effective use of Big Data in healthcare while addressing the challenges to maintain data integrity and ensure safe decision-making.

Methods and analysis

This scoping review will be conducted based on the six-step process outlined in the framework proposed by Levac et al. in “Scoping Studies: Advancing the methodology” and will be reported following the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews) checklist. The research team will use Data Quality, Big Data, and Health terms to search for primary studies in the Scopus Document Search, IEEE Xplore Digital Library, and ACM Digital Library databases.
Revealing Hidden Threats: Marine Invertebrate Invasions in the Banc d’Arguin National Park (PNBA), Mauritania, Explored Through DNA Barcoding
Authors: Moura Carlos J. , Sidina Ebaye , Serrão Ester
Published: October 2024

The Banc d’Arguin National Park (PNBA) in Mauritania, a globally significant biodiversity hotspot, faces growing threats from human activities and biological invasions. This study aimed to document marine invertebrate diversity in the PNBA and identify non-native and potentially invasive species. Samples were collected during expeditions in 2021 and 2022, using scuba-diving, drag dredging, and manual intertidal collection across depths of 0 to 20 meters. Through DNA barcoding of COI and 16S genes, 17 species from three phyla—Cnidaria, Bryozoa, and Arthropoda— were identified, with several cryptic taxa detected. Evidence of human-mediated introduction was found in hydroids (Bougainvillia, Pennaria, Obelia), bryozoans (Amathia, Bugula, Schizoporella), and barnacles (Amphibalanus), suggesting invasions from regions like Brazil, and the Indo-Pacific. Notably,Amathia brasiliensisandAmathia cf. vidoviciwere recorded for the first time in West Africa, alongside the detection of two otherAmathiaspecies, raising concerns about their potential impact on the PNBA’s biodiversity and ecosystem services. The presence of these exotic species, likely introduced via international maritime traffic and fishing activities, highlights the park’s vulnerability. The study underscores the utility of DNA barcoding for detecting cryptic diversity and tracking species dispersal, recommending urgent conservation measures and biosecurity protocols to protect the PNBA’s unique marine ecosystems.
Transcriptomic diversity of amygdalar subdivisions across humans and nonhuman primates
Authors: Totty Michael S. , Juanes Rita Cervera , Bach Svitlana V. , Ameur Lamya Ben , Valentine Madeline R. , Simons Evan , Romac McKenna , Trinh Hoa , Henderson Krystal , Del Rosario Ishbel , Tippani Madhavi , Miller Ryan A. , Kleinman Joel E. , Page Stephanie Cerceo , Saunders Arpiar , Hyde Thomas M. , Martinowich Keri , Hicks Stephanie C. , Costa Vincent D.
Published: October 2024

The amygdaloid complex mediates learning, memory, and emotions. Understanding the cellular and anatomical features that are specialized in the amygdala of primates versus other vertebrates requires a systematic, anatomically-resolved molecular analysis of constituent cell populations. We analyzed five nuclear subdivisions of the primate amygdala with single-nucleus RNA sequencing in macaques, baboons, and humans to examine gene expression profiles for excitatory and inhibitory neurons and confirmed our results with single-molecule FISH analysis. We identified distinct subtypes ofFOXP2+interneurons in the intercalated cell masses and protein-kinase C-δ interneurons in the central nucleus. We also establish that glutamatergic, pyramidal-like neurons are transcriptionally specialized within the basal, lateral, or accessory basal nuclei. Understanding the molecular heterogeneity of anatomically-resolved amygdalar neuron types provides a cellular framework for improving existing models of how amygdalar neural circuits contribute to cognition and mental health in humans by using nonhuman primates as a translational bridge.
TRIM24 directs replicative stress responses to maintain ALT telomeres via chromatin signaling
Authors: Kim Daein , Bhargava Ragini , Wang Shih-Chun , Lee Doohyung , Patel Riya , Oh Sungtaek , Bowman Ray W. , Na Chan Hyun , O’Sullivan Roderick J. , Miller Kyle M.
Published: October 2024

An inability to replicate the genome can cause replication stress and genome instability. Here, we develop BLOCK-ID, a proteomic method to identify and visualize proteins at stressed replication forks. This approach successfully identified novel mediators of the replication stress response, including the chromatin acetylation reader protein TRIM24. In validating TRIM24 function, we uncovered its crucial role in coordinating Alternative Lengthening of Telomeres (ALT), a cancer-specific telomere extension pathway involving replication stress. Our data reveal that TRIM24 is directed to telomeres via a p300/CBP-dependent acetylation chromatin signaling cascade, where it organizes ALT-associated PML bodies (APBs) to promote telomere DNA synthesis. Strikingly, we demonstrate that when artificially tethered at telomeres, TRIM24 can stimulate new telomere DNA synthesis in a SUMO-dependent manner, independently of p300/CBP or PML-dependent APBs. Thus, this study identifies a TRIM24 chromatin signaling pathway required for ALT telomere maintenance.
DNA-Dependent Protein Kinase Inhibitors PI-103 and Samotolisib Augment CRISPR/Cas9 Knockin Efficiency in Human T Cells
Authors: Džafo Emina , Hafezi Morteza , Giordano Attianese Greta Maria Paola , Reichenbach Patrick , Grillet Stephane , Scholten Kirsten , Coukos George , Irving Melita , Gentner Bernhard
Published: October 2024

1.

The adoptive cell transfer ofex vivoexpanded tumor infiltrating lymphocytes (i.e., TIL therapy) is a promising clinical strategy and recently FDA approved for melanoma but has major limitations including that not all tumors are inflamed. Moreover, tumor-specific clones can be rare and in an exhausted state due to the suppressive tumor microenvironment. These obstacles can be overcome by engineering autologous peripheral blood T cells with pre-selected T cell receptors (TCRs) by viral vector-mediated gene insertion. While viral transduction is highly efficient, the insertional site is not specific and persistence of the T cells is oftentimes limited. In contrast, site-specific integration of the TCR into the TCR α chain (TRAC) locus by CRISPR/Cas9 has been shown to enable more consistent and physiological levels of exogenous TCR expression coupled with superior persistence and tumor control in preclinical studies. Here, we sought to improve the efficiency of CRISPR/Cas9 mediated TCR knockin (KI) into theTRAClocus of primary human T cells. In addition to the previously reported DNA-dependent protein kinase inhibitor M3814, we demonstrate that PI-103 and samotolisib markedly increase KI efficiency in a process that is GMP-compatible, while CC-115 had a variable effect. Importantly, PI-103 and samotolisib do not negatively impact cell viability, fold-expansion nor T cell phenotype and we conclude that they are suitable for the generation of gene-modified T cells for clinical use.
Analysis of RNA/DNA Hybrid Profiles in Blood From Autistic Patients Reveals Differences in mRNA and non-coding RNA Regions
Authors: Kianmehr Leila , MokhtarZadeh Kasra , Yilmaz Zeynep , Duman Ecmel Mehmetbeyoglu , Taheri Serpil , Rassoulzadegan Minoo
Published: October 2024

DNA/RNA hybrids are present in normal cellular physiology, but when misregulated in the genome, they can contribute to human pathologies such as neurodevelopmental disorders and cancer. These hybrid structures are often abundant in repetitive genomic sequences such as telomeres and centromeres, contributing to evolutionary conserved phenomena. However, excessive accumulation can lead to DNA damage and genomic instability.

Studies of autism spectrum disorders (ASDs) have revealed genome-wide disruptions, including mutations and significant deregulation of gene expression. Surprisingly, the common underlying factors remain unidentified. ASDs, which are of hereditary origin and more prevalent among boys, manifest themselves during development through disorders of various origins.

In this study, we used whole-genome transcriptomic analysis of DNA/RNA hybrids from blood samples of autistic patients and healthy controls. we identified differences between numerous hybrid genomic regions with varying sequence compositions. Additionally, we observed local specificity in genomic regions, where RNA could either inhibit or enhance transcription. Our analysis of short RNAs hybridized with DNA revealed a striking example of transcriptional activity, where each gene is stably transcribed. We propose that non-coding RNAs originating from exons, introns or intergenic regions bind to DNA as hybrids (DNA/RNA) and influence gene expression. The specific levels of these short RNAs may regulate their own transcription, likely affecting cell fate.
Context-dependent epigenome rewiring during neuronal differentiation
Authors: Manelli Vera , Diwakar Jeisimhan , Beşkardeş Sude , Alonso-Gil Dácil , Forné Ignasi , Chong Faye , Imhof Axel , Bonev Boyan
Published: October 2024

Transcription factors (TFs) are pivotal in orchestrating lineage decisions and their binding is often accompanied by chromatin remodeling. However, a comprehensive understanding of how cellular and epigenetic contexts influence TF binding and the subsequent activation of lineage-specific programs remains lacking. Here, we dissected the molecular mechanisms underlying the binding of one such TF – Neurog2 and its functional consequences in two cell-types: mouse embryonic stem cells and neural progenitor cells. Our findings reveal that cell-type-specific chromatin accessibility and motif syntax are key determinants for TF binding. While Neurog2 binding primarily leads to chromatin opening, DNA demethylation and increased chromatin interactions, we also uncovered strong indirect, cell-type-specific effects, which ultimately result in vastly different epigenetic landscape. Furthermore, we identify shared and cell-type-specific Neurog2 interactors, including the SWI/SNF and NuRD complexes. Our study shed light on how cellular environment can modulate TF function to establish lineage identity during development.
Elevated Ubiquitin Phosphorylation by PINK1 Contributes to Proteasomal Impairment and Promotes Neurodegeneration
Authors: Chen Cong , Gao Tong-Yao , Yi Hua-Wei , Zhang Yi , Wang Tong , Lou Zhi-Lin , Wei Tao-Feng , Lu Yun-Bi , Li Ting-Ting , Tang Chun , Zhang Wei-Ping
Published: October 2024

Ubiquitin (Ub), a key player of protein turnover, can be phosphorylated by PINK1 kinase to generate S65-phosphorylated ubiquitin (pUb). Elevated pUb levels have been observed in aged human brains and human brains with Parkinson’s disease. However, how pUb is involved in neurodegeneration remains elusive. Here we show that elevation of pUb is pervasive in a multitude of neurodegenerative conditions, including Alzheimer’s disease, aging, and ischemic injury. In cultured cells, proteasomal inhibition by MG132 leads to sPINK1 accumulation, the cytosolic fragment of PINK1, thus promoting Ub phosphorylation. Elevated pUb impairs proteasomal degradation by disrupting covalent ubiquitin chain elongation and noncovalent proteasome-substrate interaction. Conversely,pink1knockout mitigates protein aggregation in both aging and ischemic mouse brains, as well as cells treated with MG132. Using AAV2/9 vector to specifically express sPINK1 in mouse hippocampus neurons, we observed cumulative pUb elevation, accompanied by protein aggregation, proteostasis disturbance, neuronal injury, neuroinflammation, and cognitive impairment. These sPINK1-induced impairments were reversed by co-expressing Ub/S65A phospho-null Ub mutant but exacerbated by Ub/S65E phospho-mimic mutant. As such, pUb elevation can result from declined proteasomal activity in neurodegenerative conditions, while a constant elevation of pUb actively drives neurodegeneration by further inhibiting proteasomal degradation. Our study reveals a new pathogenic pathway of neurodegeneration, highlighting the pUb-mediated feedforward loop as a promising therapeutic target for pharmaceutical intervention.
Heterogeneity and Metabolic Diversity amongEnterococcusSpecies during Long-term Colonization
Authors: Karlsson Philip A. , Zhang Taoran , Järhult Josef D. , Joffré Enrique , Wang Helen
Published: October 2024

Urinary tract infections (UTIs), traditionally dominated by Gram-negative pathogens, are increasingly complicated by antimicrobial-resistantEnterococcusspp. in hospital settings. This study screened urine samples from 210 ICU patients at Uppsala University Hospital (June 2020 - September 2021), identifying 39 unique PhenePlate™-RF types acrossE. faecium,E. faecalis, andE. durans.E. faeciumisolates showed considerable genetic diversity, primarily within clonal complex 17 (CC17), known for its virulence and antibiotic resistance. We identified multiple lineages and sequence types (STs), such as in patient HWP143, who had isolates from both ST80 and ST22 (an ancestral CC17 lineage). Notably, metabolic adaptations, such as increased L-arabinose metabolism, and shifts in antibiotic resistance were observed. Variations and similarities in plasmid content between individual linages suggest horizontal gene transfer.E. faecalisisolates exhibited less genetic diversity but significant metabolic variability across patients and mixed infections, as seen in patient HWP051, colonized by both ST16 (CC58) and ST287.E. durans, though less common, shared important metabolic traits withE. faeciumand displayed polyclonal characteristics, highlighting its potential role in UTIs and the complexity of enterococcal infections.E. duranswas sometimes misidentified, underscoring the need for accurate identification methods. This research underscores the importance of understanding genetic and metabolic diversity, plasmid variations, and horizontal gene transfer inEnterococcusspp., which influence antibiotic resistance, virulence, and ultimately, treatment outcomes.

IMPORTANCE STATEMENT

Our study uncovers novel insights into the genetic and metabolic diversity ofEnterococcusspecies within individual patients, focusing onE. faecium,E. faecalis, andE. durans. Unlike prior studies, which often focused on single lineages, we reveal multiple clones and lineages across individual patients, including clones from clonal complex 17 and the emerging sequence type (ST) 192, highlighting notable metabolic adaptations and shifts in antibiotic resistance. The detection of mixed colonization with varied ST-types, andE. duransmisidentification by MALDI-TOF, later corrected by sequencing, further emphasizes the challenges inEnterococcusspecies identification. For the first time, we demonstrate likely horizontal gene transfer amongE. faecium,E. faecalis, andE. duranswithin the same patient, underscoring the dynamic nature of these infections. Our findings have significant implications for understanding the complexity ofEnterococcusinfections, stressing the need to consider genetic and metabolic diversity to improve disease management and treatment outcomes.
Shh signaling directs dorsal ventral patterning in the regeneratingX. tropicalisspinal cord
Authors: Angell Swearer Avery , Perkowski Samuel , Wills Andrea
Published: October 2024

Tissue development and regeneration rely on the deployment of embryonic signals to drive progenitor activity and thus generate complex cell diversity and organization. One such signal is Sonic Hedgehog (Shh), which establishes the dorsal-ventral (D/V) axis of the spinal cord during embryogenesis. However, the existence of this D/V axis and its dependence on Shh signaling during regeneration varies by species. Here we investigate the function of Shh signaling in patterning the D/V axis during spinal cord regeneration inXenopus tropicalistadpoles. We find that neural progenitor markers Msx1/2, Nkx6.1, and Nkx2.2 are confined to dorsal, intermediate and ventral spatial domains, respectively, in both the uninjured and regenerating spinal cord. These domains are altered by perturbation of Shh signaling. Additionally, we find that these D/V domains are more sensitive to Shh perturbation during regeneration than uninjured tissue. The renewed sensitivity of these neural progenitor cells to Shh signals represents a regeneration specific response and raises questions about how responsiveness to developmental patterning cues is regulated in mature and regenerating tissues.
Investigating the determinants of consumer confidence and online impulse buying intentions: an experimental study
Authors: Jamil Raja Ahmed , Qayyum Abdul , Ahmad Zia , Shah Adnan Muhammad
Published: October 2024

Purpose

This study examines the effects of risk reduction, seller reputation, eWOM and warranties on consumer confidence and online impulse buying intentions through the lens of the stimulus-organism-response (SOR) model. It also explores the role of installment options in online impulse buying.

Design/methodology/approach

We performed a between-subjects experiment (installment vs. no-installment option). Data were collected from 199 consumers and analyzed using SmartPLS 3.3.9.

Findings

The results show that risk reduction, eWOM and warranty positively affect consumer confidence (CC) in online shopping and that CC positively predicts online impulse buying intentions. It was also found that the effect of CC on online impulse buying intentions was stronger when consumers were offered an installment option than a no-installment option.

Practical implications

Findings suggest that online sellers should invest more resources in building consumer confidence, which affects online impulse buying intentions. Moreover, online sellers should offer installment options to consumers, thereby reaping stronger effects of consumer confidence on online impulse buying intentions.

Originality/value

Employing the experimental approach, this study makes a novel attempt to examine the role of the installment option in fostering online impulse buying intentions among Pakistani consumers. Likewise, this is one of the early studies to explore the effects of risk reduction, seller reputation, eWOM and warranties on CC among Pakistani consumers using the SOR model.
The socio-spatial dynamics of coliving: examining fractality, visual integration and copresence in a large-scale purpose-built shared living building
Authors: Alyedreessy Emad
Published: October 2024

Purpose

“Coliving” is a rapidly developing cohousing typology, characterised by high-density private micro-units integrated with shared, mixed-use amenity spaces. This research examines the interrelationship between spatial configuration, space typologies and the frequency and intensity of copresence within a large coliving building-also known as large-scale purpose-built shared living (LSPBSL).

Design/methodology/approach

Using a UK-based case study, quantitative methods drawn from space syntax theory-namely, visibility graph analysis (VGA) and systematically structured ethnographic observations-were adopted to measure visual integration (HH) and copresence.

Findings

A positive correlation (rs = 0.43, p = 0.07) and no statistically significant difference in distribution (V = 76, p = 0.70) was identified between macro- and micro-level visual integration (HH), indicating that “fractality” exists in the building. Positive correlations were also identified between visual (HH) and spatial (1/RRA) integration (rs = 0.62, p < 0.01); visual integration and copresence frequency (rs = 0.55, p = 0.12); copresence frequency and intensity (rs = 0.63, p < 0.01) and copresence intensity (CI) and frequencies of large group interactions.

Originality/value

No existing research examines the relationship between spatial configurations and the frequencies, intensities and patterns of copresence within coliving buildings. Thus, this article contributes to spatial theory by (1) identifying correlations between these variables within an uncharted spatial context, and (2) introducing a novel syntactic concept – “fractality” – alongside a method for its calculation. By identifying the space typologies and spatial configurations that facilitate the greatest opportunities for social encounter, this study also contributes towards our knowledge of shared living environments.