bluuebunny/crossref_metadata_2025_split huggingface dataset:
Geometric and demographic effects explain contrasting fragmentation-biodiversity relationships across scales
Authors: Gelber Stav , Blowes Shane A. , Chase Jonathan M. , Huth Andreas , Schurr Frank M. , Tietjen Britta , Zeller Julian W. , May Felix 
Published: February 2024

AbstractThere is consensus that habitat loss is a major driver of biodiversity loss, while the effects of fragmentation, given a constant total habitat amount, are still debated. Here, we use a process-based metacommunity model to show how strongly scale- and context-dependent fragmentation-biodiversity relationships can emerge from the interplay of two types of fragmentation effects - geometric and demographic. Geometric effects arise from the spatial distribution of species and landscape modification, whereas demographic effects reflect long-term changes in species demographic rates following landscape modification. We introduce a novel approach to partitioning these two types of effects and assess how key ecological processes and factors, such as dispersal, habitat heterogeneity, and edge effects, influence geometric, demographic, and net fragmentation effects across spatial scales. We conclude that the framework of geometric and demographic effects can reconcile previous apparently conflicting results and hopefully unlock and advance the debate on biodiversity change in modified landscapes.
Investigating the Synergistic Role of GCN2 and HPA Axis in Regulating Integrated Stress Response in the Central Circadian Timing System
Authors: Li Yannuo , Lu Lingjun , Levy Jordan L. , Anthony Tracy G. , Androulakis Ioannis P. 
Published: February 2024

AbstractThe circadian timing and integrated stress response (ISR) systems are fundamental regulatory mechanisms that maintain body homeostasis. The central circadian pacemaker in the suprachiasmatic nucleus (SCN) governs daily rhythms through interactions with peripheral oscillators via the hypothalamus-pituitary-adrenal (HPA) axis. On the other hand, ISR signaling is pivotal for preserving cellular homeostasis in response to physiological changes. Notably, disrupted circadian rhythms are observed in cases of impaired ISR signaling. In this work, we examine the potential interplay between the central circadian system and the ISR, mainly through the SCN and HPA axis. We introduce a semi-mechanistic mathematical model to delineate the suprachiasmatic nucleus (SCN)’s capacity for indirectly perceiving physiological stress through glucocorticoid-mediated feedback from the HPA axis, and orchestrating a cellular response via the ISR mechanism. Key components of our investigation include evaluating general control nonderepressible 2 (GCN2) expression in the SCN, the effect of physiological stress stimuli on the HPA axis, and the interconnected feedback between the HPA and SCN. Simulation reveals a critical role for GCN2 in linking ISR with circadian rhythms. Notably, aGcn2deletion in mice led to swift re-entrainment of the circadian clock post simulated-jetlag. This is attributed to the diminished robustness of neuronal oscillators and an extended circadian period. Our model also offers insights into phase shifts induced by acute physiological stress and the alignment/misalignment of physiological stress with external light-dark cues. Such understanding aids in strategizing responses to stressful events, such as nutritional status changes and jetlag.
ALTering cancer by triggering telomere replication stress through the stabilization of promoter G-quadruplex inSMARCAL1
Authors: Panda Suman , Roychowdhury Tanaya , Dutta Anindya , Chakraborty Sourio , Das Tanya , Chatterjee Subhrangsu 
Published: February 2024

ABSTRACTMost of the human cancers are dependent on telomerase to extend the telomeres. But ∼10% of all cancers use a telomerase-independent, homologous recombination mediated pathway called alternative lengthening of telomeres (ALT). Due to poor prognosis, the ALT status is not being considered yet in the diagnosis of cancer. No such specific treatment is available till date for ALT cancers. ALT positive cancers are dependent on replication stress to deploy DNA repair pathways to the telomeres to execute homology recombination mediated telomere extension. SMARCAL1 (SWI/SNF related, matrix-associated, actin-dependent regulator of chromatin, subfamily A-like 1) is associated with the ALT telomeres to resolve replication stress thus providing telomere stability. Thus, the dependency on replication stress regulatory factors like SMARCAL1 made it a suitable therapeutic target for the treatment of ALT positive cancers. In this study, we found a significant downregulation of SMARCAL1 expression by stabilizing the G-quadruplex (G4) motif found in the promoter ofSMARCAL1by potent G4 stabilizers, like TMPyP4 and BRACO-19. SMARCAL1 downregulation led towards the increased localization of PML (promyelocytic leukaemia) bodies in ALT telomeres and triggered the formation of APBs (ALT-associated promyelocytic leukaemia bodies) in ALT positive cell lines, thus increasing telomere replication stress and DNA damage at genomic level. Induction of replication stress and hyper recombinogenic phenotype in ALT cells mediated by G4 stabilizing molecules already highlighted their possible application as a new therapeutic window to target ALT-positive tumors. In accordance with this, our study will also provide a valuable insight towards the development of G4 based ALT-therapeutics targetingSMARCAL1.
Cilia-mediated cerebrospinal fluid flow modulates neuronal and astroglial activity in the zebrafish larval brain
Authors: D’Gama Percival P. , Jeong Inyoung , Nygård Andreas Moe , Jamali Ahmed , Yaksi Emre , Jurisch-Yaksi Nathalie 
Published: February 2024

AbstractThe brain uses a specialized system to transport cerebrospinal fluid (CSF). This system consists of interconnected ventricles lined by ependymal cells, which generate a directional flow upon beating of their motile cilia. Motile cilia act jointly with other physiological factors, including active CSF secretion and cardiac pressure gradients, to regulate CSF dynamics. The content and movement of CSF are thought to be important for brain physiology. Yet, the link between cilia-mediated CSF flow and brain function is poorly understood. In this study, we addressed the role of motile cilia-mediated CSF flow on brain development and physiology using zebrafish larvae as a model system. By analyzing mutant animals with paralyzed cilia, we identified that loss of ciliary motility did not alter progenitor proliferation, overall brain morphology, or spontaneous neural activity. Instead, we identified that cilia paralysis led to randomization of brain asymmetry. We also observed altered neuronal responses to photic stimulation, especially in the optic tectum and hindbrain. Since astroglia contact CSF at the ventricular walls and are essential for regulating neuronal activity, we next investigated astroglial activity in motile cilia mutants. Our analyses revealed a striking reduction in astroglial calcium signals both during spontaneous and light-evoked activity. Altogether, our findings highlight a novel role of motile cilia-mediated flow in regulating brain physiology through modulation of neural and astroglial networks.
Molecular basis of ligand promiscuity, structural mimicry, and atypical dimerization in the chemokine receptors
Authors: Saha Shirsha , Sano Fumiya K. , Sharma Saloni , Ganguly Manisankar , Saha Sayantan , Akasaka Hiroaki , Kobayashi Takaaki , Zaidi Nashrah , Mishra Sudha , Dalal Annu , Mohapatra Samanwita , Yadav Manish K. , Itoh Yuzuru , Leurs Rob , Chevigné Andy , Banerjee Ramanuj , Shihoya Wataru , Nureki Osamu , Shukla Arun K. 
Published: February 2024

AbstractSelectivity of natural agonists for their cognate receptors is one of the hallmarks of the members of GPCR family, and it is crucial for the specificity of downstream signal-transduction. However, this selectivity often breaks down in the chemokine receptor subfamily, wherein a high degree of promiscuity is observed with one receptor recognizing multiple chemokines and one chemokine binding to multiple receptors. The molecular determinants of such a striking promiscuity for natural ligands in the chemokine-chemokine receptor system remain mostly elusive and represent an important knowledge gap in our current understanding. Here, we carry out a comprehensive transducer-coupling analysis, testing all known C-X-C chemokines on every C-X-C type chemokine receptor, to generate a global fingerprint of the selectivity and promiscuity encoded within this system. Taking lead from our finding, we determined cryo-EM structures of the most promiscuous receptor, CXCR2, in complex with every interacting chemokine, and deciphered the conserved molecular signatures and distinct binding modalities. While most chemokines position themselves on the receptor as a dimer, CXCL6 exhibits a monomeric binding pose induced by a previously unanticipated reorientation of its carboxyl-terminal α-helix, leading to disruption of the dimer interface. Surprisingly, one of the chemokines, CXCL5, induces a ligand-swapped dimer of CXCR2, the first of its kind observed in class A GPCRs, wherein each protomer of the ligand engages its own receptor without any discernible receptor-receptor interface. These unique observations provide a possible structural mechanism for inherent functional specialization encoded in chemokines despite their convergence to a common receptor. Furthermore, we also determined cryo-EM structures of CXCR3 in complex with G-protein-biased and β-arrestin-biased small molecule agonists that elucidate distinct allosteric modulations in the receptor driving their divergent transducer-coupling bias. Guided by structural analysis and experimental validation, we discover that in contrast to previously held notion, small molecule agonists of CXCR3 display robust agonism at CXCR7, an intrinsically biased, β-arrestin-coupled receptor, making them first-in-class dual agonists for chemokine receptors with exclusive βarr-bias at CXCR7. Taken together, our study provides molecular insights into ligand promiscuity and signaling bias at the chemokine receptors, and also demonstrates a proof of principle that naturally encoded structural mimicry can be recapitulated using synthetic pharmacophores with potential implications for developing novel therapeutics.
Depth-dependent dynamics of protist communities as an integral part of spring succession in a freshwater reservoir
Authors: Mukherjee Indranil , Grujčić Vesna , Salcher Michaela M , Znachor Petr , Seďa Jaromír , Devetter Miloslav , Rychtecký Pavel , Šimek Karel , Shabarova Tanja 
Published: February 2024

AbstractBackgroundProtists are essential contributors to eukaryotic diversity and exert profound influence on carbon fluxes and energy transfer in freshwaters. Despite their significance, there is a notable gap in research on protistan dynamics, particularly in the deeper strata of temperate lakes.This study aimed to address this gap by integrating protists into the well-described spring dynamics of Římov reservoir, Czech Republic. Over a two-month period covering transition from mixing to established stratification, we collected water samples from three reservoir depths (0.5, 10 and 30 m) with a frequency of up to three times per week. Microbial eukaryotic and prokaryotic communities were analysed using SSU rRNA gene amplicon sequencing and dominant protistan groups were enumerated by Catalysed Reporter Deposition-Fluorescencein situHybridization (CARD-FISH). Additionally, we collected samples for water chemistry, phyto- and zooplankton composition analyses.ResultsFollowing the rapid changes in environmental and biotic parameters during spring, protistan and bacterial communities displayed swift transition from a homogeneous community to distinct strata-specific communities. Epilimnion exhibited the prevalence of auto-, mixotrophic protists dominated by cryptophytes and associated with spring algal bloom-specialized bacteria. In contrast, meta- and hypolimnion showcased the development of protist community dominated by putative parasitic Perkinsozoa, detritus or particle-associated ciliates, cercozoans and excavate protists co-occurring with bacteria associated with lake snow.ConclusionsOur high-resolution sampling matching the typical dividing time of microbes along with the combined microscopic and molecular approach and inclusion of all the components of microbial food web allowed us to follow depth-specific populations’ successions and interactions in a deep lentic ecosystem.
Mechanistic Insight into the Conformational Changes of Cas8 upon Binding to Different PAM Sequences in the Transposon-Encoded Type I-F CRISPR-Cas System
Authors: Alalmaie Amnah , Khashan Raed 
Published: February 2024

AbstractThe INTEGRATE system is a gene-editing approach that offers advantages over the widely used CRISPR-Cas9 system. It does not introduce double strand breaks in the target DNA but rather integrates the desired DNA sequence directly into it. The first step in the integration process is PAM recognition, which is critical to understanding and optimizing the system. Experimental testing revealed varying integration efficiencies of different PAM mutants, and computational simulations were carried out to gain mechanistic insight into the conformational changes of Cas8 during PAM recognition. Our results showed that the interaction between Arg246 and Guanine at position (-1) of the target strand is critical for PAM recognition. We found that unfavorable interactions in the 5’-AC-3’ PAM mutant disrupted this interaction and may be responsible for its 0% integration efficiency. Additionally, we discovered that PAM sequences not only initiate the integration process but also regulate it through an allosteric mechanism that connects the N-terminal domain and the helical bundle of Cas8. This allosteric regulation was present in all PAMs tested, even those with lower integration efficiencies, such as 5’-TC-3’ and 5’-AC-3’. We identified the Cas8 residues that are involved in this regulation. Our findings provide valuable insights into PAM recognition mechanisms in the INTEGRATE system and can help improve the gene-editing technology.
Select Gut Bacteria Promote Mosquito Larval Growth by Contributing Protease Activity and Optimal Ionic Microenvironment for Protein Digestion
Authors: Samanta Jhuma , Datta Sibnarayan 
Published: February 2024

ABSTRACTThe unique pH profile of mosquito larval midgut including the highly alkaline anterior midgut (AMG) and its significance in digestive physiology has been known for a long time. More recently, metagenomic association studies have shown that diverse assemblage of bacteria (microbiota) present in the gut influence larval nutrition, growth, development, and several other physiological processes. However, the precise functional mechanisms of these host-microbe interactions remain poorly understood. In this research, we studied the functional significance of gut associated bacteria in larval growth utilizingAedes albopictusaxenic/ gnotobiotic model. Results of our study demonstrate that, for AMG alkalinization, concurrent presence of Carbonic Anhydrase (CA) activity and ‘live’ bacteria is essential and that the later could not be substituted by either cell-free bacterial culture supernatant, or bacterial cell lysate. Further, we found that the gut pH profile and presence of proteolytic activity could be observed in larvae colonized only with select members of the microbiota that are capable of secreting extracellular protease. Collectively, our findings suggest a novel and interesting evolutionary mechanism of host-microbe interaction, in which select members of the gut microbiota promote larval nutrition, growth and development by providing protease and creating ionic microenvironment optimal for its activity.
The relationship between ethnicity and Multiple Sclerosis characteristics in the United Kingdom: a UK MS Register study
Authors: Jacobs Benjamin M , Schalk Luisa , Tregaskis-Daniels Emily , Tank Pooja , Hoque Sadid , Peter Michelle , Tuite-Dalton Katherine , Witts James ,   UK MS Register Study Group, Bove Riley , Dobson Ruth 
Published: February 2024

AbstractPrevious studies have suggested differences in Multiple Sclerosis severity between individuals from different ethnic backgrounds. However, these measures of severity have been focussed on markers of physical disability derived from clinical records. We sought to determine the association between self-reported ethnicity and Multiple Sclerosis severity across a range of domains in a prospective cohort based in the United Kingdom. Data were obtained from the United Kingdom Multiple Sclerosis Register, a longitudinal cohort study of >20,000 persons with Multiple Sclerosis. We examined the association between self-reported ethnic background and age at onset, site of onset, and a variety of participant-reported severity measures: the Expanded Disability Status Scale, the Multiple Sclerosis Impact Scale, the Multiple Sclerosis Walking Scale, the Fatigue Severity Scale, and the EuroQol-5D quality of life index. We used multivariable linear regression models adjusted for age, sex, and Multiple Sclerosis subtype (Primary Progressive vs other). We explored the association between ethnicity and impact of Multiple Sclerosis using Cox proportional hazards models to assess the rate of disability progression. Data were available for 14,264 people with Multiple Sclerosis, including 380 participants from self-reported Black (n=151) or South Asian (n=229) ethnic backgrounds. Age at Multiple Sclerosis onset and diagnosis was lower in the participants of South Asian (median onset 31.0) and Black (median onset 33.0) ethnicity compared with White ethnicity (median onset 35.0, n=13,884). We found no statistically-significant evidence for an association between ethnic background on baseline Multiple Sclerosis severity scores in any of the scores tested across a range of sensitivity analyses. In longitudinal analysis, we did not find evidence for an impact of ethnicity on five-year risk of disability progression. In this large, ethnically-diverse Multiple Sclerosis cohort with universal access to healthcare, we find no association between ethnic backgroundper seand MS severity, whether in cross-sectional or longitudinal analyses. These findings suggest that other factors, such as socioeconomic status and structural inequalities, may explain previous findings of heterogeneity between ethnic groups.
Protecting women from economic shocks to prevent HIV in Africa: Evidence from the POWER randomised controlled trial in Cameroon
Authors: Lépine Aurélia , Szawlowski Sandie , Nitcheu Emile , Cust Henry , Tamgno Eric Defo , Noo Julienne , Procureur Fanny , Mfochive Illiasou , Billong Serge , Tamoufe Ubald 
Published: February 2024

AbstractBackgroundWomen in Sub-Saharan Africa are disproportionately affected by the HIV epidemic. Young women are twice as likely to be living with HIV than men of the same age and account for 64% of new HIV infections among young people. Many studies suggest that financial needs, alongside biological susceptibility, are the main causes of the gender disparity in HIV acquisition. While the literature shows a limited understanding of the link between poverty and HIV, there is some new robust evidence demonstrating that women adopt risky sexual behaviours as a way to cope with economic shocks.MethodsWe recruited 1,506 adolescent girls and women engaging in transactional or in commercial sex in Yaounde, Cameroon, using snowball sampling. Half of the study participants were randomly allocated to receive a free health insurance product covering themselves and their economic dependents over 12 months. We collected data on socio-economics, health and sexual behaviours and sexually transmitted infection and HIV biomarkers at baseline, 6-month post randomisation (midline) and 12-month post randomisation (endline).ResultsWe found that study participants engaging in transactional sex allocated to the treatment group were less likely to be infected with HIV (OR=0.109, p-value<0.05). We showed that the intervention allowed women to leave transactional sex. In addition, we found that for the participants remaining in transactional sex, the intervention increased condom use and reduced sex acts, these results were however only statistically significant at 10% given our sample size. There was no evidence of a change in risky sexual behaviours or in a reduction of HIV incidence among female sex workers.ConclusionThe study provides the first evidence of the effectiveness of a formal shock-coping strategy to prevent HIV among women in Africa. We showed that the intervention effectiveness operates through the reduction in health shocks since the increase in healthcare use following the intervention was low. We estimated that in our trial, the cost for each HIV infection averted is £4,667 among the cohort of women engaging in transactional sex. Policymakers should consider formal shock-coping strategies to prevent HIV among women in Africa.
Mendelian segregation and high recombination rates facilitate genetic analyses inCryptosporidium parvum
Authors: Kimball Abigail , Funkhouser-Jones Lisa , Huang Wanyi , Xu Rui , Witola William H. , Sibley L. David 
Published: February 2024

ABSTRACTVery little is known about the process of meiosis in the apicomplexan parasiteCryptosporidiumdespite the essentiality of sex in its life cycle. Most cell lines only support asexual growth ofCryptosporidium parvum(C. parvum), but stem cell derived intestinal epithelial cells grown under air-liquid interface (ALI) conditions support the sexual cycle. To examine chromosomal dynamics during meiosis inC. parvum, we generated two transgenic lines of parasites that were fluorescently tagged with mCherry or GFP on chromosomes 1 or 5, respectively. Infection of ALI cultures orIfngr1-/-mice with mCherry and GFP parasites produced “yellow” oocysts generated by cross-fertilization. Outcrossed oocysts from the F1generation were purified and used to infect HCT-8 cultures, and phenotypes of the progeny were observed by microscopy. All possible phenotypes predicted by independent segregation were represented equally (∼25%) in the population, indicating thatC. parvumchromosomes exhibit a Mendelian inheritance pattern. Unexpectedly, the most common pattern observed from the outgrowth of single oocysts included all possible parental and recombinant phenotypes derived from a single meiotic event, suggesting a high rate of crossover. To estimate the frequency of crossover, additional loci on chromosomes 1 and 5 were tagged and used to monitor intrachromosomal crosses inIfngr1−/−mice. Both chromosomes showed a high frequency of crossover compared to other apicomplexans with map distances (i.e., 1% recombination) of 3-12 kb. Overall, a high recombination rate may explain many unique characteristics observed inCryptosporidiumspp. such as high rates of speciation, wide variation in host range, and rapid evolution of host-specific virulence factors.AUTHOR SUMMARYAlthough sex is essential for the transmission and maintenance of infection ofCryptosporidium, it has been historically challenging to study the process of meiosis in this medically relevant protist. We utilize recent methodological advances such as a specializedin vitroculture system, cell sorting, and the generation of transgenic parasites to cross identical strains of parasites in the absence of selection pressure to identify intrinsic chromosome behavior during meiosis. By specifically examining the phenotypes from the first generation of parasites, we reveal that cross-fertilization frequently occurs in parasite populations, chromosomes segregate in a Mendelian manner, and the rate of crossover is high on Chromosomes 1 and 5. Understanding these baseline meiotic mechanisms is essential for planning and interpreting future genetic studies ofCryptosporidiumseeking to identify genes associated with phenotypes of interest.