bluuebunny/crossref_metadata_2025_split huggingface dataset:
ABCA4-Related Retinopathies in Lebanon: a novel mutation and significant heterogeneity
Authors: Ibrahim Mariam , Jaffal Lama , Assi Alexandre , Helou Charles , El Shamieh Said 
Published: November 2023

AbstractMutations inATP-binding cassette transporter type A4(ABCA4) have been linked to several forms of inherited retinal diseases (IRDs) besides the classically defined Stargardt disease (STGD), known asABCA4retinopathies.ABCA4is a sizeable locus harboring 50 exons; thus, its analysis has revealed a rich area of genetic information comprising at least 1,200 disease-causing mutations of varied severity and types. Due to the clinical and genetic heterogeneity, diagnosingABCA4retinopathies is challenging. To date, noABCA4-retinopathy has been detected in Lebanon. Using next-generation sequencing, we sought to pinpoint the mutation spectrum in seven families with different forms of IRDs: STGD, rod-cone and cone-rod dystrophies (RCD and CRD, respectively). EightABCA4mutations were found, including one novel; c.4330G>C; p.(Trp1408Cys). Three families were diagnosed with CRD, two with STGD, and two others with RCD. In conclusion, our study revealed a novel ABCA4 mutation and showed significant genotypic and phenotypic heterogeneity in Lebanon.
Post-Vaccination Syndrome: A Descriptive Analysis of Reported Symptoms and Patient Experiences After Covid-19 Immunization
Authors: Krumholz Harlan M. , Wu Yilun , Sawano Mitsuaki , Shah Rishi , Zhou Tianna , Arun Adith S. , Khosla Pavan , Kaleem Shayaan , Vashist Anushree , Bhattacharjee Bornali , Ding Qinglan , Lu Yuan , Caraballo César , Warner Frederick , Huang Chenxi , Herrin Jeph , Putrino David , Hertz Danice , Dressen Brianne , Iwasaki Akiko 
Published: November 2023

ABSTRACTIntroductionA chronic post-vaccination syndrome (PVS) after covid-19 vaccination has been reported but has yet to be well characterized.MethodsWe included 241 individuals aged 18 and older who self-reported PVS after covid-19 vaccination and who joined the online Yale Listen to Immune, Symptom and Treatment Experiences Now (LISTEN) Study from May 2022 to July 2023. We summarized their demographics, health status, symptoms, treatments tried, and overall experience.ResultsThe median age of participants was 46 years (interquartile range [IQR]: 38 to 56), with 192 (80%) identifying as female, 209 (87%) as non-Hispanic White, and 211 (88%) from the United States. Among these participants with PVS, 127 (55%) had received the BNT162b2 [Pfizer-BioNTech] vaccine, and 86 (37%) received the mRNA-1273 [Moderna] vaccine. The median time from the day of index vaccination to symptom onset was three days (IQR: 1 day to 8 days). The time from vaccination to symptom survey completion was 595 days (IQR: 417 to 661 days). The median Euro-QoL visual analogue scale score was 50 (IQR: 39 to 70). The five most common symptoms were exercise intolerance (71%), excessive fatigue (69%), numbness (63%), brain fog (63%), and neuropathy (63%). In the week before survey completion, participants reported feeling unease (93%), fearfulness (82%), and overwhelmed by worries (81%), as well as feelings of helplessness (80%), anxiety (76%), depression (76%), hopelessness (72%), and worthlessness (49%) at least once. Participants reported a median of 20 (IQR: 13 to 30) interventions to treat their condition.ConclusionsIn this study, individuals who reported PVS after covid-19 vaccination had low health status, high symptom burden, and high psychosocial stress despite trying many treatments. There is a need for continued investigation to understand and treat this condition.
Collateral effects of the COVID-19 pandemic on endocrine treatments for breast and prostate cancer in the UK: implications for bone health
Authors: Barclay Nicola L , Català Marti , Jödicke Annika M. , Prieto-Alhambra Daniel , Newby Danielle , Delmestri Antonella , Man Wai Yi , Serrano Àlvar Roselló , Moncusí Marta Pineda ,   The OPTIMA Consortium
Published: November 2023

AbstractBackgroundThe COVID-19 pandemic affected cancer screening, diagnosis and treatment pathways. This study examined the impact of the pandemic on incidence and trends of endocrine treatments in patients with breast or prostate cancer; and endocrine treatment-related side-effects.MethodsPopulation-based cohort study using UK primary care Clinical Practice Research Datalink (CPRD) GOLD database. There were 13,701 newly diagnosed breast cancer patients and 12,221 prostate cancer patients with ≥1-year data availability since diagnosis between January 2017-June 2022. Incidence rates (IR) and incidence rate ratios (IRR) were calculated across multiple time periods before and after lockdown to examine the impact of changing social restrictions on endocrine treatments and treatment-related outcomes, including osteopenia, osteoporosis and bisphosphonate prescriptions.ResultsIn patients with breast cancer, aromatase inhibitor prescriptions increased during lockdown compared to pre-pandemic (IRR: 1.22 [95% Confidence Interval: 1.11-1.34]), followed by a decrease post-first lockdown (IRR: 0.79 [95%CI: 0.69-0.89]). In patients with prostate cancer, first-generation antiandrogen prescriptions increased compared to pre-pandemic (IRR: 1.23 [95% CI: 1.08-1.4]). For breast cancer patients on aromatase inhibitors, diagnoses of osteopenia, osteoporosis and bisphosphonate prescriptions were reduced across all lockdown periods compared to pre-pandemic (IRR range: 0.31-0.62).ConclusionDuring the first two years of the pandemic, newly diagnosed breast and prostate cancer patients were prescribed more endocrine treatments compared to pre-pandemic, due to restrictions on hospital procedures replacing surgeries with bridging therapies. But breast cancer patients had fewer diagnoses of osteopenia and osteoporosis, and bisphosphonate prescriptions. These patients should be followed up in the coming years for signs of bone thinning. Evidence of poorer management of treatment-related side-effects will allow us to determine whether there is a need to better allocate resources to patients at high risk for bone-related complications.
Faltering mortality improvements at young-middle ages in high-income English-speaking countries
Authors: Timonin Sergey , Leon David A. , Banks Emily , Adair Tim , Canudas-Romo Vladimir 
Published: November 2023

AbstractBackgroundBefore the COVID-19 pandemic, stagnating life expectancy trends were reported in some high-income countries (HICs). Despite previous evidence from country-specific studies, there is a lack of comparative research that provides a broader perspective and challenges existing assumptions. This study aims to examine longevity trends and patterns in six English-speaking countries (Australia, Canada, Ireland, New Zealand, UK, USA) by combining period and cohort perspectives and to compare them with other HICs.MethodsUsing data from the Human Mortality and WHO Mortality Databases, we estimated partial life expectancy, lifespan inequality and cohort survival differences for 1970-2021, as well as the contribution of causes of death to the gap in life expectancy between English-speaking countries and the average for other HICs in 2017-19.ResultsIn the pre-pandemic period, the increase in life expectancy slowed in all English-speaking countries, except Ireland, mainly due to stagnating or rising mortality at young-middle ages. Relative to other HICs, those born in Anglophone countries since the 1970s experienced relative survival disadvantage, largely attributable to injuries (mainly suicides) and substance-related mortality (mainly poisonings). In contrast, older cohorts enjoyed advantages for females in Australia and Canada and for males in all English-speaking countries except the USA.ConclusionsAlthough future gains in life expectancy in wealthy societies will increasingly depend on reducing mortality at older ages, adverse health trends at younger ages are a cause for concern. This emerging and avoidable threat to health equity in English-speaking countries should be the focus of further research and policy action.Key messagesThe study highlights striking similarities between English-speaking high-income countries in terms of adverse health outcomes at young-middle ages compared to a group of other high-income countries (HICs).Each of the Anglophone populations has experienced a marked mortality disadvantage for cohorts born since the early 1970s relative to the average of other HICs, which contrasts with the generally better performance of the older cohorts in some English-speaking countries, particularly for men.In the most recent pre-pandemic period, i.e. 2017-19, the negative contribution of higher mortality at ages below 50 years to the gap in life expectancy at birth between English-speaking countries (excluding Ireland) and other HICs ranged from 0.15 years for Australian women to 2.06 years for US men.
Sensory kinase KdpD is a tandem serine histidine kinase controlling K+pump KdpFABC on the translational and post-transcriptional level
Authors: Silberberg Jakob M , Ketter Sophie , Böhm Paul JN , Jordan Kristin , Wittenberg Marcel , Grass Julia , Hänelt Inga 
Published: November 2023

AbstractTwo-component systems (TCSs), consisting of a histidine kinase (HK) and a response regulator, serve signal transduction in bacteria, often regulating transcription in response to environmental stimuli. Here, we identify a tandem serine histidine kinase function for KdpD, previously described as a HK of the TCS KdpDE, which controls production of the K+pump KdpFABC. We show that KdpD additionally mediates an inhibitory serine phosphorylation of KdpFABC at high K+levels, using not its C-terminal HK domain but an N-terminal atypical serine kinase (ASK) domain. Sequence analysis of KdpDs from different species highlights that some KdpDs comprise solely ASK and Usp domains. We show that, whileEscherichia coliKdpD’s ASK responds directly to K+levels, a shorter version fromDeinococcus geothermalisis controlled by second messenger cyclic di-AMP. Our findings add to the growing functional diversity of sensor kinases while simultaneously expanding the framework for regulatory mechanisms in bacterial K+homeostasis.
Interneuron migration defects during corticogenesis contribute toDyrk1ahaploinsufficiency syndrome pathogenesis via actomyosin dynamics deregulations
Authors: Hinckelmann Maria Victoria , Dubos Aline , Artot Victorine , Rudolf Gabrielle , Nguyen Thu Lan , Tilly Peggy , Nalesso Valérie , del Mar Muniz Moreno Maria , Birling Marie-Christine , Godin Juliette D. , Brault Véronique , Herault Yann 
Published: November 2023

ABSTRACTInterneuron development is a crucial step of brain corticogenesis. When affected it often leads to brain dysfunctions, such as epilepsy, intellectual disabilities and autism spectrum disorder. Such defects are observed in theDYRK1A-haploinsufficiency syndrome, caused by mutations ofDYRK1A, and commonly associated to cortical excitatory/inhibitory imbalance. However, how this imbalance is established in this syndrome remains elusive. Here, using mouse models and live imaging, we show thatDyrk1aspecifically regulates the development of the cortical GABAergic system. Unlike projection excitatory neurons, we demonstrate that interneuron tangential migration relies on Dyrk1a dosage and kinase activity through a mechanism involving actomyosin cytoskeleton remodeling. Interestingly, we further demonstrate that mice with heterozygous inactivation ofDyrk1ain interneurons show behavioral defects and epileptic activity, recapitulating phenotypes observed in human patients. Altogether, these data highlight the critical role ofDyrk1ain the development of the GABAergic system and the pathophysiology ofDYRK1A-haploinsufficiency syndrome.
Dynamic extracellular proximal interaction profiling reveals Low-Density Lipoprotein Receptor as a new Epidermal Growth Factor signaling pathway component
Authors: Al Mismar Rasha , Samavarchi-Tehrani Payman , Seale Brendon , Kasmaeifar Vesal , Martin Claire E. , Gingras Anne-Claude 
Published: November 2023

ABSTRACTPlasma membrane proteins are critical mediators of cell-cell and cell-environment interactions, pivotal in intracellular signal transmission vital for cellular functionality. Proximity-dependent biotinylation approaches such as BioID combined with mass spectrometry have begun illuminating the landscape of proximal protein interactions within intracellular compartments. However, their deployment in studies of the extracellular environment remains scarce. Here, we present extracellular TurboID (ecTurboID), a method designed to profile cell surface interactions in living cells on short timescales. We first report on the careful optimization of experimental and data analysis strategies that enable the capture of extracellular protein interaction information. Leveraging the ecTurboID technique, we unveiled the proximal interactome of multiple plasma membrane proteins, notably the epidermal growth factor receptor (EGFR). This led to identifying the low-density lipoprotein receptor (LDLR) as a newfound extracellular protein associating with EGFR, contingent upon the presence of the EGF ligand. We showed that 15 minutes of EGF stimulation induced LDLR localization to the plasma membrane to associate with proteins involved in EGFR regulation. This modified proximity labelling methodology allows us to dynamically study the associations between plasma membrane proteins in the extracellular environment.One Sentence SummaryWe developed extracellular TurboID (ecTurboID) as a new proximity dependent biotinylation approach that can capture dynamic interactions at the cell surface, identifying Low-Density Lipoprotein Receptor as a new ligand-dependent extracellular partner of Epidermal Growth Factor Receptor.
Fibroblast Nrf2 inhibits profibrotic transcription with Ddx54 and mitigates pathological fibrosis in the mouse heart and kidney
Authors: Nishiji Toshiyuki , Hoshino Atsushi , IKemura Nariko , Alcantara Mellissa C , Higuchi Yusuke , Uchio Yuki , Kirita Yuhei , Taminishi Shunta , Ozaki Yuki , Motooka Daisuke , Kobayashi Ryosuke , Horii Takuro , Hatada Izuho , Matoba Satoaki 
Published: November 2023

AbstractBackgroundTissue fibrosis is a common feature of many organ dysfunctions, such as heart failure and chronic kidney disease. However, no fundamental treatment has been developed. This study aims to identify novel molecular mechanisms for antifibrotic intervention, focusing on fibroblast activation.MethodsWe performed a forward genetic screen using a genome-wide CRISPR library in the context of transforming growth factor β (TGF-β)-mediated connective tissue growth factor (CTGF) expression, and used unbiased techniques such as Cleavage Under Targets and Tagmentation (CUT&Tag) and proximity-dependent biotin labeling by TurboID to reveal the detailed molecular mechanisms.ResultsCRISPR library screening identified a number of players in both the canonical Smad pathway and the non-canonical pathway. In addition to the known factors, the Keap1-Nrf2 pathway was identified as a predominant regulator of TGF-β-mediated CTGF expression.Keap1deletion and consequent Nrf2 activation broadly suppressed profibrotic gene expression, independently of conventional antioxidant effects. CUT&Tag revealed that Nrf2 bound to the proximity of fibrosis-related genes includingCtgfandFn1.Subsequent individual analysis revealed Smad3 and RNA polymerase II binding to the Nrf2 peak site, which was attenuated byKeap1deletion. TurboID experiments further discovered that Nrf2 interacts with Ddx54, which acts as a corepressor. Consistently,Keap1deletion-mediated repression of profibrotic gene expression was reversed by additionalDdx54deletion. The impact of the Keap1-Nrf2 pathway on pathological fibrosis was examined using tamoxifen-inducible fibroblast-specificKeap1knockout mice. Pressure overload for 4 weeks robustly induced cardiac hypertrophy, fibrosis and contractile dysfunction. However, deletion ofKeap1in thePostnlineage attenuated these cardiac pathologies. The anti-fibrotic effects of Keap1 deletion were also confirmed in renal fibrosis in the unilateral ureteral obstruction (UUO) model.ConclusionsFibroblast Nrf2 transcriptionally represses fibrosis-related genes in cooperation with the corepressor Ddx54. Fibroblast-specific deletion ofKeap1attenuated pathological fibrosis in pressure overload heart failure and renal fibrosis.
An elevated rate of whole-genome duplications associated with carcinogen exposure in Black cancer patients
Authors: Brown Leanne M. , Hagenson Ryan A. , Koklič Tilen , Urbančič Iztok , Strancar Janez , Sheltzer Jason M. 
Published: November 2023

ABSTRACTIn the United States, Black individuals have higher rates of cancer mortality than any other racial or ethnic group. The sources of these significant racial disparities are not fully understood, and may include social, environmental, and genetic factors that influence cancer onset, diagnosis, and treatment. Here, we examined genomic data from several large-scale cancer patient cohorts to search for racial associations in chromosome copy number alterations. We found that tumors from self-reported Black patients were significantly more likely to exhibit whole-genome duplications (WGDs), a genomic event that enhances metastasis and aggressive disease, compared to tumors from self-reported white patients. Among patients with WGD-positive cancers, there was no significant difference in survival between self-reported Black and white patients, suggesting that the increased incidence of WGD events could contribute to the disparities in patient outcome. We further demonstrate that combustion byproducts are capable of driving genome-duplication events in cell culture, and cancers from self-reported Black patients exhibit mutational patterns consistent with increased exposure to these carcinogens. In total, these findings identify a class of genomic alterations that are associated with environmental exposures and that may influence racial disparities in cancer patient outcome. Additionally, as cancers that have undergone WGD events exhibit unique genetic vulnerabilities, therapies that selectively target WGD-positive cancers may be particularly effective at treating aggressive malignancies in Black patients.
Ocrelizumab B cell depletion has no effect on HERV RNA expression in PBMC in MS patients
Authors: Tarlinton Rachael , Tanasescu Radu , Shannon-Lowe Claire , Gran Bruno 
Published: November 2023

AbstractBackgroundEpstein Barr Virus (EBV) infection of B cells is now understood to be one of the triggering events for the development of Multiple Sclerosis (MS), a progressive immune-mediated disease of the central nervous system. EBV infection is also linked to expression of Human endogenous retroviruses (HERVs) of the HERV-W group, a further risk factor for the development of MS (Ocrelizumab is a high-potency disease-modifying treatment (DMT) for MS, which depletes B cells by targeting CD20.ObjectivesWe studied the effects of ocrelizumab on gene expression in peripheral blood mononuclear cells (PBMC) from paired samples from 20 patients taken prior to and 6 months after beginning Ocrelizumab therapy. We hypothesised that EBV and HERV-W loads would be lower in post-treatment samples.MethodsSamples were collected in Paxgene tubes, subject to RNA extraction and Illumina paired end short read mRNA sequencing with mapping of sequence reads to the human genome using Salmon and Differential Gene expression compared with DeSeq2. Mapping was also performed separately to the HERV-D database of HERV sequences and the EBV reference sequence.ResultsPatient samples were more strongly clustered by individual rather than disease type (relapsing/remitting or primary progressive), treatment (pre and post), age, or sex. Fourteen genes, all clearly linked to B cell function were significantly down regulated in the post treatment samples. Interestingly only one pre-treatment sample had detectable EBV RNA and there were no significant differences in HERV expression (of any group) between pre- and post-treatment samples.ConclusionsWhile EBV and HERV expression are clearly linked to triggering MS pathogenesis, it does not appear that high level expression of these viruses is a part of the ongoing disease process or that changes in virus load are associated with Ocrelizumab treatment.
Agricultural value chain participation and farmers' access to credit in northern Ghana
Authors: Osei Timothy Anakwa , Donkoh Samuel A. , Ansah Isaac Gershon Kodwo , Awuni Joseph A. , Cobbinah Mensah Tawiah 
Published: November 2023

PurposePromoted for its inclusivity, agricultural value chain (AVC) financing leverages social capital and mechanisms such as off-take agreements and forward contracts to reduce borrowing and lending costs and risks for both farmers and lending institutions. AVC financing has been defined as the flow of financial products and services to and among the various actors within the AVC to address constraints of production and distribution and fulfill the needs of those involved in the chain by reducing risk and improving efficiency. This paper investigates how farmers' involvement in AVC affects their access to credit.Design/methodology/approachThe authors collected primary data from 400 crop farmers in northern Ghana through a semi-structured questionnaire and analyzed the data, using the multinomial endogenous switching regression model.FindingsJoint participation in AVC increased the amount of formal and informal credit received by 64 and 78%, respectively, compared to nonparticipation. Similarly, participation in AVC horizontal linkage and AVC vertical linkage increased the amount of formal and informal credit received by 40 and 47% and 46 and 74%, respectively, compared to nonparticipation. Irrigation farming, extension visits, knowledge of AVC in the community, access to a storage facility and trust in contract farming significantly influenced farmers' participation in AVC.Originality/valueThe authors’ work offers valuable insights into how different dimensions of value chain participation can impact smallholder farmers' access to credit. This work also underscores the importance of considering both formal and informal credit sources when analyzing the outcomes of value chain participation. The findings could enable formal financial providers to identify, liaise and/or resource informal financial players such as value chain actors to supply both formal and informal credit to farmers in AVCs.