bluuebunny/crossref_metadata_2025_split huggingface dataset:
The dorsolateral striatum encodes a temporal basis for the organization of behavior
Authors: Rodrigues Filipe S. , Monteiro Tiago , Motiwala Asma , Paton Joseph J. 
Published: November 2023

AbstractTo behave adaptively, the brain must register temporal structure in the environment and use it to organize behavior. The dorsolateral striatum (DLS) integrates sensorimotor input, and is necessary for accurate timing and structuring behavior in general. However, if DLS provides the basis for mapping temporal features in the environment to behavior, its activity should predict variation in that mapping. A reanalysis of DLS population activity in rats comparing the duration of two sequentially presented vibratory stimuli revealed a striking correspondence between neural activity and behavior. Varying vibration intensity of the second stimulus induced systematic biases in temporal judgments, and corresponding biases in multiple features of DLS activity during stimulus presentation, including population coding of time. In contrast, the same intensity manipulations applied to the first stimulus affected neither behavior nor neural activity. Furthermore, neuronal response profiles were best described as a continuum, arguing against hypotheses where categories of responses, e.g., ramping activity, selectively underpin temporal processing. These data represent important additional evidence that striatal population dynamics support the organization of behavior by mapping temporal information to action.
Structural insights in the GTP-driven monomerization and activation of a bacterial LRRK2 homologue using allosteric nanobodies
Authors: Galicia Christian , Guaitoli Giambattista , Fislage Marcus , Gloeckner Christian J. , Versées Wim 
Published: November 2023

AbstractThe Roco proteins are a family of GTPases, characterized by the conserved presence of a Roc-COR tandem domain. These proteins entered the limelight after mutations in human LRRK2 were identified as a major cause of familial Parkinson’s disease. LRRK2 is a large and complex protein combining a GTPase and protein kinase activity, and disease mutations increase the kinase activity, while presumably decreasing the GTPase activity. Although a cross-communication between both catalytic activities has been suggested, the underlying mechanisms and the regulatory role of the GTPase domain remain unknown. Recently, several structures of LRRK2 have been reported, but so far structures of Roco proteins in their activated GTP-bound state are lacking. Here, we use single particle cryo-EM to solve the structure of a simpler bacterial Roco protein (CtRoco) in its GTP-bound state, aided by the use of two conformation-specific nanobodies: NbRoco1and NbRoco2. This structure presents CtRoco in an active monomeric state, featuring very significant conformational changes compared to the previously solved nucleotide-free dimer structure. In particular, the structure shows a very large GTP-induced conformational change of the LRR domain, unleashing it from the Roc-COR domains, using the LRR-Roc linker as a hinge. Furthermore, this structure shows how NbRoco1and NbRoco2collaborate to activate CtRoco in an allosteric way. Altogether, our data provide important new insights in the activation mechanism of Roco proteins, with relevance to LRRK2 regulation, and suggest new routes for the allosteric modulation of their GTPase activity.
Tolerance to land-use changes through natural modulations of the plant microbiome
Authors: Zieschank Vincent , Muola Anne , Junker Robert R. 
Published: November 2023

AbstractLand-use changes pose a threat to many ecosystems and are a major driver of species loss. Adaptations to altered environments or migration to more suitable habitats are potential mechanisms to resist global change, which can, however, lag behind rapid anthropogenic alterations of the environment. Our data show that rapid natural modulations of the plant microbiome in response to land-use change directly affect plant phenotype and performance, and thus increase plant tolerance to environmental changes. In a common garden experiment, the effects of the microbiome on the plant phenotype were stronger than the direct effects of fertilizer application and mowing. This finding was confirmed in a subsequent controlled laboratory experiment using plants inoculated with land-use-specific microbiomes. Therefore, natural modulations of the plant microbiome may be the key to species persistence and ecosystem stability. A prerequisite for this microbiome-mediated tolerance is the availability of diverse local sources of microorganisms that can function as a resource for rapid modulations in response to change. Thus, conservation efforts must protect microbial diversity, which can help mitigate the effects of global change and facilitate environmental and human health.
Adeno-associated virus (AAV2) can replicate its DNA by a rolling hairpin or rolling circle mechanism, depending on the helper virus
Authors: Lkharrazi Anouk , Tobler Kurt , Marti Sara , Bratus-Neuenschwander Anna , Vogt Bernd , Fraefel Cornel 
Published: November 2023

AbstractAdeno-associated virus type 2 (AAV2) is a small, non-pathogenic, helper virus-dependent parvovirus with a single-stranded (ss) DNA genome of approximately 4.7 kb. AAV2 DNA replication requires the presence of a helper virus such as adenovirus type 5 (AdV5) or herpes simplex virus type 1 (HSV-1) and is generally assumed to occur as a strand-displacement rolling hairpin (RHR) mechanism initiated at the AAV2 3’ inverted terminal repeat (ITR). We have recently shown that AAV2 replication supported by HSV-1 leads to the formation of double-stranded head-to-tail concatemers, which provides evidence for a rolling circle replication (RCR) mechanism. We have revisited AAV2 DNA replication and specifically compared the formation of AAV2 replication intermediates in presence of either HSV-1 or AdV5 as the helper virus. The results confirmed that the AAV2 DNA replication mechanism is helper virus-dependent and follows a strand-displacement RHR mechanism when AdV5 is the helper virus and primarily an RCR mechanism when HSV-1 is the helper virus. We also demonstrate that recombination plays a negligible role in AAV2 genome replication. Interestingly, the formation of high molecular weight AAV2 DNA concatemers in presence of HSV-1 as the helper virus was dependent on an intact HSV-1 DNA polymerase.ImportanceAAV is a small helper virus-dependent, non-pathogenic parvovirus. The AAV genome replication mechanism was extensively studied in presence of AdV as the helper virus and described to proceed using RHR. Surprisingly, HSV-1 co-infection facilitates RCR of the AAV2 DNA. We directly compared AdV5 and HSV-1 supported AAV2 DNA replication and show that AAV2 can adapt its replication mechanism to the helper virus. Detailed understanding of the AAV replication mechanism expands our knowledge of virus biology and can contribute to increase gene therapy vector production.
Aberrant splicing exonizesC9ORF72repeat expansion in ALS/FTD
Authors: Yang Suzhou , Wijegunawardana Denethi , Sheth Udit , Veire Austin M. , Salgado Juliana M. S. , Agrawal Manasi , Zhou Jeffrey , Pereira João D. , Gendron Tania F. , Guo Junjie U. 
Published: November 2023

ABSTRACTA nucleotide repeat expansion (NRE) in the first annotated intron of theC9ORF72gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). While C9 NRE-containing RNAs can be translated into several toxic dipeptide repeat proteins, how an intronic NRE can assess the translation machinery in the cytoplasm remains unclear. By capturing and sequencing NRE-containing RNAs from patient-derived cells, we found that C9 NRE was exonized by the usage of downstream 5ʹ splice sites and exported from the nucleus in a variety of spliced mRNA isoforms.C9ORF72aberrant splicing was substantially elevated in both C9 NRE+motor neurons and human brain tissues. Furthermore, NREs above the pathological threshold were sufficient to activate cryptic splice sites in reporter mRNAs. In summary, our results revealed a crucial and potentially widespread role of repeat-induced aberrant splicing in the biogenesis, localization, and translation of NRE-containing RNAs.
Psychometric Properties and Longitudinal Measurement Invariance of the Spanish Version of the Alcohol Expectancies Questionnaire – Short Form among Young Adult Binge Drinkers
Authors: González-Ponce Bella M. , Pilatti Angelina , Montejano Gabriela Rivarola , Bravo Adrian J. , Fernández-Calderón Fermín 
Published: November 2023

AbstractBackgroundLongitudinal Measurement Invariance (LMI) is critically important to evaluate changes in the alcohol expectancies over time. However, few studies have yet explored the longitudinal properties of the Spanish EQ-SF.ObjectivesTo examine the reliability, sources of validity (structural and concurrent validity), and LMI of the Spanish short version of the Alcohol Expectancy Questionnaire in a sample of young adults who engage in binge drinking.MethodsThe participants (n= 279; Mean age = 21.33,SD= 2.15; 48.4% female) completed the Spanish EQ-SF, and two months later they completed this measure again, along with measures to alcohol use, drinking motives, and protective behavioral strategies (PBS). Confirmatory Factor Analysis was used to identify which of two proposed models provided the best-fitting factor structure. We aimed to determine whether the best-fitting model was invariant across assessments and to evaluate the predictive validity and reliability of the scores.ResultsOur findings revealed that the eight-factor intercorrelated model provided the best fit. This model was invariant across assessments, providing evidence for longitudinal measurement invariance. Moreover, the scores showed adequate reliability (.68 to .90) and predictive validity (i.e., positive alcohol expectancies were positively related to alcohol use and drinking motives and negatively related to PBS).ConclusionOur results support the reliability, validity, and temporal invariance of the EQ-SF scores among Spanish young adults with binge drinking patterns. The evidence supports the suitability of this measure for accurately assessing changes in alcohol expectancies over time in interventions aimed at preventing binge drinking in young adults.
Tuberculosis-associated hemophagocytic lymphohistiocytosis: diagnostic challenges and determinants of outcome
Authors: Kurver Lisa , Seers Timothy , van Dorp Suzanne , van Crevel Reinout , Pollara Gabriele , van Laarhoven Arjan 
Published: November 2023

AbstractBackgroundTuberculosis (TB) can induce secondary hemophagocytic lymphohistiocytosis (HLH), a severe inflammatory syndrome with high mortality. To improve insight into optimal diagnostic and treatment strategies, we integrated all published reports of adult HIV-negative TB-associated HLH (TB-HLH) globally to define clinical characteristics and therapeutic approaches associated with improved survival.MethodsPubMed, Embase, and Global Index Medicus were searched for eligible records. TB-HLH cases were categorized into patients with a confirmed TB diagnosis receiving antituberculosis treatment while developing HLH, and patients presenting with HLH of unknown cause later diagnosed with TB. We integrated patients’ clinical characteristics, diagnostic test results, and pre-specified parameters associated with survival into a logistic regression model.ResultsWe identified 115 individually reported cases, 45 (39.1%) from low TB incidence countries (<10/100.000 per year). Compared to HLH patients with known TB (n=21), patients with HLH of unknown cause (n=94), more often had extrapulmonary TB (88.3% vs. 66.7%), while the opposite was true for pulmonary disease (59.6% vs. 91.5%). Overall,Mycobacterium tuberculosiswas identified in the bone marrow in 78.4% of patients for whom examination was reported (n=74). Only 10.5% (4/38) of patients tested had a positive tuberculin skin test or interferon gamma release assay. In-hospital survival was 71.9% (69/96) in those treated for TB and 0% (18/18) in those who did not receive antituberculosis treatment (p < 0.001).ConclusionsTuberculosis should be considered as a cause of unexplained HLH. TB-HLH is probably under-reported, and the diagnostic work-up of HLH patients should include bone marrow examination for evidence ofM. tuberculosisinfection. Prompt initiation of antituberculosis treatment will likely improve survival.Key pointsHemophagocytic lymphohistiocytosis is an underreported complication of tuberculosis, often manifesting as extrapulmonary or miliary disease. TST and IGRA mostly show an anergic response. Threshold should be low bone marrow investigation for evidence ofM. tuberculosis,and commencement of antituberculosis treatment.
An agent-based model to simulate the transmission dynamics of bloodborne pathogens within hospitals
Authors: Henriot Paul , El Kassas Mohammed , Anwar Wagida , Abdo Samia , Jean Kévin , Temime Laura 
Published: November 2023

AbstractBloodborne pathogens are a major public health concern as they can lead to a variety of medical conditions, including cirrhosis and cancers with significant mortality and morbidity. Three viruses are of major concern: HCV, HBV and HIV. Their transmission is mostly community-associated but the iatrogenic risk of infection is not negligible, even today. Mathematical models are widely used to describe and assess pathogens transmission, within communities and hospitals. Nevertheless, few are focusing on the transmission of pathogens through blood and even fewer on their transmission within hospital as they usually study the risk of community-associated infection in vulnerable populations such as MSM or drug users. Herein, we propose an agent-based SEI (Susceptible-Exposed-Infected) model to explore the transmission dynamics of bloodborne pathogens within hospitals. This model simulates the dynamics of patients between hospital wards, from their admission to discharge, as well as the dynamics of the devices used during at-risk invasive procedures, considering that patient contamination occurs after exposure to a contaminated device. Multiple parameters of the model, such as HCV prevalence, transition probabilities between wards or ward-specific probabilities of undergoing different invasive procedures, were informed with data collected in the University Hospital of Ain Shams in Cairo, Egypt in 2017. We explored the effect of device shortage as well as the effect of random and systematic screening with associated modification in disinfection practices on the risk of infection for patients. By modifying some parameters of the model, we then explored the case of HBV in Ethiopia. In the future, this model could be used to assess the risk of transmission of other bloodborne pathogens in other contexts.
S-acylation of NLRP3 provides a nigericin sensitive gating mechanism that controls access to the Golgi
Authors: Williams Daniel M. , Peden Andrew A. 
Published: November 2023

AbstractNLRP3 is an inflammasome seeding pattern recognition receptor activated in response to multiple danger signals which perturb intracellular homeostasis. Electrostatic interactions between the NLRP3 polybasic (PB) region and negatively charged lipids on the trans-Golgi network (TGN) have been proposed to recruit NLRP3 to the TGN. In this study, we demonstrate that membrane association of NLRP3 is critically dependant on S-acylation of a highly conserved cysteine residue (Cys-130), which traps NLRP3 in a dynamic S-acylation cycle at the Golgi, and a series of hydrophobic residues preceding Cys-130 which act in conjunction with the PB region to facilitate Cys-130 dependent Golgi enrichment. Due to segregation from Golgi localised thioesterase enzymes caused by a nigericin induced breakdown in Golgi organisation and function, NLRP3 becomes immobilised on the Golgi through reduced de-acylation of its Cys-130 lipid anchor, suggesting that disruptions in Golgi homeostasis are conveyed to NLRP3 through its acylation state. Thus, our work defines a nigericin sensitive S-acylation cycle that gates access of NLRP3 to the Golgi.
Liver sinusoidal endothelial cells constitute a major route for hemoglobin clearance
Authors: Zurawska Gabriela , Sas Zuzanna , Jończy Aneta , Mahadeva Raghunandan , Slusarczyk Patryk , Chwałek Marta , Seehofer Daniel , Damm Georg , Kulecka Maria , Rumieńczyk Izabela , Moulin Morgane , Jastrzębski Kamil , Mikula Michal , Etzerodt Anders , Serwa Remigiusz , Miączyńska Marta , Rygiel Tomasz P. , Mleczko-Sanecka Katarzyna 
Published: November 2023

AbstractMild rupture of aged erythrocytes occurs physiologically in the spleen, leading to the release of hemoglobin (Hb), while pathological hemolysis characterizes several diseases. The detoxification of Hb has traditionally been attributed to the sequestration of Hb-haptoglobin complexes by macrophages. However, this process remains incompletely studied in animal models or primary cells, leaving the precise mechanisms of Hb clearance elusive. Using mice and primary liver cell cultures (murine and human), we uncovered that Hb uptake is chiefly performed by liver sinusoidal endothelial cells (LSECs) and involves macropinocytosis. Consistently, mouse LSECs displayed proteomic signatures indicative of active heme catabolism, ferritin iron storage, antioxidant defense, and macropinocytic capacity. LSECs also exhibited high iron content and the expression of hepcidin-regulated iron exporter ferroportin. Using erythrocyte/Hb transfusion assays in mice, we demonstrated that while splenic macrophages excel in phagocytosis of erythrocytes, LSECs primarily scavenge Hb and Kupffer cells clear erythrocyte membranes, the spleen-borne hemolysis products delivered to the liver via the portal circulation. High-dose Hb injections resulted in transient hepatic iron retention, early LSEC-specific induction of heme-catabolizingHmox1and iron-sensingBmp6, culminating in hepcidin-mediated temporary hypoferremia. Transcriptional induction ofBmp6in mice was phenocopied by erythrocyte lysis upon phenylhydrazine or iron citrate injection, although the latter elicited a distinct LSEC transcriptional signature compared to Hb. In conclusion, we identify LSECs as key Hb scavengers, a function that establishes the spleen-to-liver axis for iron recycling and contributes to heme detoxification during hemolysis, coupled with the induction of the BMP6-hepcidin axis to restore iron homeostasis.
Algorithm for automatic detection of insulin granule exocytosis in human pancreatic β-cells
Authors: Makam Aishwarya A , Dubey Abhimanyu , Maharana Shovamayee , Gandasi Nikhil R. 
Published: November 2023

ABSTRACTImage processing and analysis are two significant areas that are highly important for interpreting enormous amounts of data obtained from microscopy-based experiments. Several image analysis tools exist for the general detection of fundamental cellular processes, but tools to detect highly distinct cellular functions are few. One such process is exocytosis, which involves the release of vesicular content out of the cell. The size of the vesicles and the inherent differences in the imaging parameters demand specific analysis platforms for detecting exocytosis. In this direction, we have developed an image-processing algorithm based on Lagrangian particle tracking. The tool was developed to ensure that there is efficient detection of punctate structures initially developed by mathematical equations, fluorescent beads and cellular images with fluorescently labelled vesicles that can exocytose. The detection of these punctate structures using the tool was compared with other existing tools, such as find maxima in ImageJ and manual detection. The tool not only met the precision of existing solutions but also expedited the process, resulting in a more time-efficient solution. During exocytosis, there is a sudden increase in the intensity of the fluorescently labelled vesicles that look like punctate structures. The algorithm precisely locates the vesicles’ coordinates and quantifies the variations in their respective intensities. Subsequently, the algorithm processes and retrieves pertinent information from large datasets surpassing that of conventional methods under our evaluation, affirming its efficacy. Furthermore, the tool exhibits adaptability for the image analysis of diverse cellular processes, requiring only minimal modifications to ensure accurate detection of exocytosis.
Lead-time management, information sharing and performance of the motor industry in Zimbabwe
Authors: Kanyepe James , Zizhou Brave , Alphaneta Mikel , Chifamba Neater 
Published: November 2023

PurposeThis study examines the moderating role of information sharing on the effect of lead-time management on the performance of firms in the Zimbabwean motor industry.Design/methodology/approachData were collected using Likert-based structured questionnaires from a sample of 105 employees in Zimbabwe. In addition, Pearson Correlation, Linear Regression and Moderation Regression analysis were employed to test the relationship between study variables.FindingsThe study found that fixed lead time, preprocessing lead time, processing lead time and postprocessing lead time significantly influence the performance of firms in the motor industry. The results also demonstrate that information sharing moderates the effect of lead-time management on firm performance in the motor industry.Practical implicationsFirms in the motor industry should establish long-term relationships with their suppliers and implement effective communication channels for timely and frequent information exchange regarding production schedules, inventory levels, quality standards and potential disruptions.Originality/valueThe current study aims to contribute to the scientific discourse on lead-time management, information sharing and performance in the motor industry. Furthermore, it extends knowledge on the performance of the motor industry in the African region.
Public leaders in accelerated times: a qualitative study on their reflective practices in the Netherlands
Authors: van der Steen Barbara , van Saane Joke , van Dijk Gerda 
Published: November 2023

PurposeThe purpose of this article is to phenomenologically explore the reflective practices of leaders in public organisations amidst a complex societal context in combination with rapid changes. In this article, the authors specifically explore the lived experiences of public leaders to generate new hypotheses concerning their reflective practices.Design/methodology/approachThe phenomenological methodology consists of analysing the lived experiences of 13 public leaders, collected in an in-depth interview and written reflections.FindingsThe thick data offer new and up-to-date insights into the daily experiences of public leaders concerning their challenges, the effect of the addictive and alienating forces, their reflex to withdrawal when facing emotional incidents and the effects of their contradictory mindsets.Practical implicationsThe practical implication is a critical approach towards reflective practices of public leaders. The risk is that reflectivity is approached as a socially desirable instrumental ritual. Considering the needs and desires the public leaders shared, the authors wonder: Is there a growing importance of reflective time and space – or, above all, meaningful relations and resonant moments amidst the alienation forces?Originality/valueThe phenomenological exploration offers concrete insights into the daily experience of public leaders', as opposed to the often-abstract theory. The new hypotheses provide a new starting point for further critical phenomenological research.