bluuebunny/crossref_metadata_2025_split huggingface dataset:
PERK arm of UPR selectively regulates ferroptosis in colon cancer cells by modulating the expression of SLC7A11 (System Xc-)
Authors: Saini Krishan Kumar , Chaturvedi Priyank , Sinha Abhipsa , Singh Manish Pratap , Khan Muqtada Ali , Verma Ayushi , Nengroo Mushtaq Ahmad , Satrusal Saumya Ranjan , Meena Sanjeev , Singh Akhilesh , Srivastava Sameer , Sarkar Jayanta , Datta Dipak 
Published: March 2023

AbstractFerroptosis, a genetically and biochemically distinct form of programmed cell death, is characterised by an iron-dependent accumulation of lipid peroxides. Therapy-resistant tumor cells display vulnerability toward ferroptosis. Endoplasmic Reticulum (ER) stress and Unfolded Protein Response (UPR) play a critical role in cancer cells to become therapy resistant. Tweaking the balance of UPR to make cancer cells susceptible to ferroptotic cell death could be an attractive therapeutic strategy. To decipher the emerging contribution of ER-stress in the ferroptotic process, we observe that ferroptosis inducer RSL3 promotes UPR (PERK, ATF6, and IRE1α), along with overexpression of cystine-glutamate transporter SLC7A11 (System Xc-). Exploring the role of a particular UPR arm in modulating SLC7A11 expression and subsequent ferroptosis, we notice that PERK is selectively critical in inducing ferroptosis in colorectal carcinoma. PERK inhibition reduces ATF4 expression and recruitment to the promoter ofSLC7A11and results in its downregulation. Loss of PERK function not only primes cancer cells for increased lipid peroxidation but also limits in vivo colorectal tumor growth, demonstrating active signs of ferroptotic cell deathin situ. Further, by performing TCGA data mining and using colorectal cancer patient samples, we demonstrate that the expression ofPERKandSLC7A11is positively correlated. Overall, our experimental data indicate that PERK is a negative regulator of ferroptosis and loss of PERK function sensitizes colorectal cancer cells to ferroptosis. Therefore, small molecule PERK inhibitors hold huge promise as novel therapeutics and their potential can be harnessed against the apoptosis-resistant condition.
Self-organized BMP signaling dynamics underlie the development and evolution of tetrapod digit patterns
Authors: Grall Emmanuelle , Feregrino Christian , Fischer Sabrina , De Courten Aline , Hiscock Tom W. , Tschopp Patrick 
Published: March 2023

AbstractRepeating patterns of synovial joints are a highly conserved feature of articulated digits, with variations in joint number and location giving rise to a diverse range of digit morphologies and limb functions across the tetrapod clade. During development, joints form iteratively within the growing digit ray, as a population of distal progenitors alternately specifies joint and phalanx cell fates to segment the digit into distinct elements. Whilst numerous molecular pathways have been implicated in this fate choice, it remains unclear how they give rise to a repeating pattern. Here, using single cell RNA-sequencing and spatial gene expression profiling, we investigate the transcriptional dynamics of interphalangeal joint specificationin vivo. Combined with mathematical modelling, we predict that interactions within the BMP signaling pathway – between the ligand GDF5, the inhibitor NOG, and the intracellular effector pSMAD – result in a self-organizing Turing system that forms periodic joint patterns. Our model is able to recapitulate the spatiotemporal gene expression dynamics observedin vivo, as well as phenocopy digit malformations caused by BMP pathway perturbations. By contrastingin silicosimulations within vivomorphometrics of two morphologically distinct digits, we show how changes in signaling parameters and growth dynamics can result in variations in the size and number of phalanges. Together, our results reveal a self-organizing mechanism that underpins tetrapod digit patterning and its evolvability, and, more broadly, illustrate how Turing systems based on a single molecular pathway may generate complex repetitive patterns in a wide variety of organisms.
Sex-dependent manifestations of intracranial aneurysms
Authors: Wälchli Thomas , Ndengera Martin , Constanthin Paul E. , Bisschop Jeroen , Morel Sandrine , Gautschi Oliver , Berhouma Moncef , Kalyvas Aristotelis , Monnier Philippe P. , Winkler Ethan A. , Kortman Hans , Bhatia Kartik , Dammann Philipp , Jägersberg Max , Gondar Renato , Schaller Karl , Kwak Brenda R. , Bijlenga Philippe 
Published: March 2023

AbstractBackgroundIntracranial aneurysms (IAs) are more common in females than in males, however, there is still very limited knowledge on sex-dependent differences regarding aneurysm location, multiplicity, rupture risk, risk factors and histopathology.MethodsThis prospective, consecutive cohort study examined whether IAs differ in multiplicity, location, geometry, rupture risk, risk factors and histology between sexes.ResultsWe included 982 patients (714 women, 268 men) totaling 1484 IAs (1056 unruptured, 397 ruptured). Three hundred sixty-three patients (36.97%) had multiple IAs, the proportion of which was significantly higher in females. In women, the ICA (40.79%) was the most frequent location for IAs, whereas in men most were found along the ACA territory (32.86%). Men were significantly more often diagnosed with ruptured aneurysms. Aneurysm geometry did not differ between sexes, however, ruptured aneurysms in men presented with a significantly larger neck diameter than unruptured ones. Regarding risk factors for aneurysm rupture, blood pressure control was more effective in women, whereas the effect of smoking status did not show clear sex-dependent differences. Histologically, wall-type classification analysis showed significantly more severe aneurysm wall types in men.ConclusionIA prevalence in women is significantly higher than in men. Women more often present with multiple IAs whereas men were more often diagnosed with ruptured IAs. Sex-specific differences in IA location were identified whereas geometry of IAs did not differ between sexes. IAs in men showed a more severe histological wall type. Further research is needed to unravel the molecular mechanisms underlying these important sex-dependent manifestations in IAs.
Coronavirus pathogenesis in mice explains the SARS-CoV-2 multi-organ spread by red blood cells hitch-hiking
Authors: Toro A , Arevalo AP , Pereira-Gómez M , Sabater A , Zizzi EA , Pascual G , Lage-Vickers S , Porfido JL , Achinelli I , Seniuk R , Bizzotto J , Moreno P , Costabile A , Fajardo A , Rodriguez F , Nin N , Sanchis P , Anselmino N , Labanca E , Cotignola J , Navone N , Alonso DF , Vazquez E , Gentile F , Cherkasov A , Moratorio G , Crispo M , Gueron G 
Published: March 2023

ABSTRACTSARS-CoV-2 infection causes a multisystemic disease that affects numerous organs beyond the respiratory system. Thus, it is well known that COVID-19 is associated with a wide range of hematological disorders; however, it remains unclear how the SARS-CoV-2 virus is able to navigate from tissue to tissue. In this work, we performed a comprehensive analysis of the pleiotropic effects of a prototypical coronavirus in its natural host, the validated preclinical model of murine hepatitis virus (MHV). Throughout this study we compared our results with the real-world data from COVID-19 patients (including autopsies). Thus, the presence of viral RNA was only detected in less than 25% of the human serum samples, whereas all had multiple positive nasal swabs for SARS-CoV-2. Notably, we found viral RNA not only in lungs, but also in heart and kidney of deceased COVID-19 patients. Subsequently, we investigated the association between viral organotropism and clinical manifestations employing the MHV murine model. Results from RT-qPCR and viral infectivity showcased the presence of viral RNA and infectious particles in multiple organs including liver, lung, brain, heart, kidney, spleen and pancreas, and even the blood of infected mice. Surprisingly, when comparing plasma and red blood cells (RBCs)-enriched fraction, higher viral load levels were detected in RBCs, with decreased RBC count, and hematocrit and hemoglobin levels in infected mice. Next, we treated infected mice with hemin triggering more aggressive symptoms. Strikingly, when combining hemin treatment with chloroquine (a compound that known to interact with the heme group and induces a conformational change in its structure) the infection and its clinical manifestations were distinctly attenuated. Computational docking suggested that heme is able to bind to MHV Spike protein in a similar way to the one, experimentally observed for SARS-CoV-2. Overall, our results lead to a global perspective of COVID-19 beyond the canonical focus on the respiratory system, and strongly support the multi-organ extent of coronavirus infection through specific interactions with RBC hemoproteins.
Sexual orientation and gender identity reporting in highly cited alcohol research
Authors: Connolly Dean J. , Coduri-Fulford Santino , Tugulu Connor , Yalew Meron , Moss Elizabeth , Yang Justin C. 
Published: March 2023

AbstractPurposeThis study aimed to measure the frequency of high-quality and transparent sexual orientation and gender identity data collection and reporting in highly cited alcohol use research, using the extant literature to identify community-informed priorities for the measurement of these variables.MethodsA single search to identify alcohol use literature was conducted on PubMed with results restricted to primary research articles published between 2015 and 2022. The 200 most highly cited studies from each year were identified and their titles and abstracts reviewed against inclusion criteria following deduplication. Following full-text review and data extraction, the fidelity of the results was verified with a random sample prior to analyses.ResultsThe final sample comprised 580 records. Few studies reported gender identity (n=19; 33.4%) and, of these, 7.2% reported the associated gender identity measure. A two-stage approach to measuring gender was adopted in five studies and 13 studies recorded non-binary gender identities (reported by 0.9% of the whole sample). Nineteen (3.3%) studies reported sexual orientation and more than half of these provided the sexual orientation measure. Five studies adopted a two-step approach to measuring gender identity and open offered a free-text response option. Eight of 20 studies reporting gender identity and sexual orientation measures were classified as sexual and gender minority specialist research.ConclusionsTransparent and culturally competent gender identity and sexual orientation reporting is lacking in highly cited alcohol research.
Usefulness of pystan and numpyro in Bayesian item response theory
Authors: Nishio Mizuho , Ota Eiji , Matsuo Hidetoshi , Matsunaga Takaaki , Miyazaki Aki , Murakami Takamichi 
Published: March 2023

AbstractPurpose:The purpose of this study is to compare two libraries dedicated to Markov chain Monte Carlo method: pystan and numpyro.Materials and methods:Bayesian item response theory (IRT), 1PL-IRT and 2PL-IRT, were implemented with pystan and numpyro. Then, the Bayesian 1PL-IRT and 2PL-IRT were applied to two types of medical data obtained from a published paper. The same prior distributions of latent parameters were used in both pystan and numpyro. Estimation results of latent parameters of 1PL-IRT and 2PL-IRT were compared between pystan and numpyro. Additionally, the computational cost of Markov chain Monte Carlo method was compared between the two libraries. To evaluate the computational cost of IRT models, simulation data were generated from the medical data and numpyro.Results:For all the combinations of IRT types (1PL-IRT or 2PL-IRT) and medical data types, the mean and standard deviation of the estimated latent parameters were in good agreement between pystan and numpyro. In most cases, the sampling time using Markov chain Monte Carlo method was shorter in numpyro than that in pystan. When the large-sized simulation data were used, numpyro with a graphics processing unit was useful for reducing the sampling time.Conclusion:Numpyro and pystan were useful for applying the Bayesian 1PL-IRT and 2PL-IRT.
Who is responsible for nurse wellbeing in a crisis? A single centre perspective
Authors: Hughes Luke , Petrella Anika , Fern Lorna A , Taylor Rachel M 
Published: March 2023

AbstractBackgroundLeadership during the COVID-19 pandemic often manifested as a command- and-control style of leadership which had detrimental emotional impacts on staff particularly the nursing workforce. Organisational responsibility for staff wellbeing would be necessary in another pandemic and leadership emerged as a key indicator of the overall health of an organisation and its workforce. Leadership can have detrimental effects on staff wellbeing or it can greatly boost their ability to handle a crisis. We sought to explore the interrelationship between leadership and nurses’ wellbeing in an inner-city university hospital during the initial wave of the pandemic.MethodsSecondary analysis of interview data collected during a hospital-wide evaluation of barriers and facilitators to changes implemented to support the surge of COVID-19 related admissions during wave 1. Data were collected through semi-structured video interviews between May and July 2020. Interviews were analysed using Framework analysisResultsThirty-one nurses participated including matrons (n=7), sisters (n=8) and specialist nursing roles (n=16). Three overarching themes were identified: impact on nurses, personal factors and organisational factors. The impact on nurses manifested as distress and fatigue. Coping and help-seeking behaviours were found to be the two personal factors which underpinned nurses’ wellbeing. The organisational factors that impacted nurses’ wellbeing included decision-making, duty and teamwork.ConclusionsThe wellbeing of the workforce is pivotal to the health service, and it is mutually beneficial for patients, staff, and leaders. Addressing how beliefs and misconceptions around wellbeing are communicated, and accessing psychological support is a key priority to support nurses during pandemics.
Development and Validation of a novelin vitrodiagnostic test for endometriosis
Authors: Herranz-Blanco Bárbara , Daoud Elza , Viganò Paola , García-Velasco Juan Antonio , Colli Enrico 
Published: March 2023

STRUCTURED ABSTRACTObjectiveTo develop a non-invasive diagnostic test for endometriosis.DesignWe conducted two studies: the development study (study 1) aimed at (i) evaluating the ability of CA125, brain-derived neurotrophic factor (BDNF) and clinical variables in segregating between cases and controls and (ii) developing a diagnostic algorithm based on those results. In the validation study (study 2), the clinical performance of the developedin vitrodiagnostic (IVD) test, in diagnosing endometriosis was validated.InterventionsSerum samples and clinical variables extracted from psychometric questionnaires were collected from the Oxford Endometriosis CaRe Centre biobank (UK). Case/control classification was performed based on laparoscopy and histological verification of endometrial glands and/or stroma in the excised lesions.Main outcome measuresStudy 1 and 2 includedn=204 andn=79 patients, respectively. CA125 and BDNF concentrations were determined using the endometriosis IVD ELISA kit. In study 2, serum CA125 and BDNF concentrations and clinical variables were introduced into the IVD test software hosting the data treatment algorithm, which generates the qualitative diagnostic result (“positive” or “negative”).ResultsResults from study 1 showed that, for both biomarkers levels, a statistically significant difference was found between cases and controls. Among all clinical variables related to patients’ medical history considered, six were significantly different between cases and controls: record of a previous surgery to investigate endometriosis presence, painful periods leading to referral for endometriosis presence, severity of menstrual pain during last cycle, age at first experience of intercourse pain, age at first regular use of painkillers and age at first diagnosis of ovarian cyst. In study 2, the novel endometriosis IVD test demonstrated sensitivity and specificity values of 46.2% (25.5-66.8%) and 100% (86.7-100%), respectively.ConclusionBDNF and CA125, together with patient’s clinical variables allowed efficient segregation between controls and endometriosis cases. Due to its high specificity, the novel endometriosis IVD test is an accurate rule-in non-invasive method, potentially contributing to diagnose endometriosis.
Genetic structure and genome-wide association study of the traditional Kazakh horses
Authors: Pozharskiy A. , Abdrakhmanova A. , Beishova I. , Shamshidin A. , Nametov A. , Ulyanova T. , Bekova G. , Kikebayev N. , Kovalchuk A. , Ulyanov V. , Turabayev A. , Khusnitdinova M. , Zhambakin K. , Sapakhova Z. , Shamekova M. , Gritsenko D. 
Published: March 2023

AbstractHorses are traditionally used in Kazakhstan as a source of food and as working and saddle animals as well. Here, for the first time, microarray-based medium-density SNP genotyping of six traditionally defined types and breeds of indigenous Kazakh horses was conducted to reveal their genetic structure and find markers associated with animal size and weight. The results showed that the pre-defined separation between breeds and sampled populations was not supported by the molecular data. The lack of genetic variation between breeds and populations was revealed by the principal component analysis (PCA), ADMIXTURE, and distance based analyses, as well as the general population parameters expected and observed heterozygosity (HeandHo)and between group fixation index (Fst). The comparison with previously published data on global horse breed diversity revealed the relatively high level of individual diversity of Kazakh horses in comparison with the wellknown foreign breeds. The Mongolian and Tuva breeds were identified as the closest horse landraces, demonstrating similar patterns of internal variability. The genome-wide association analysis was performed for animal size and weight as the traits directly related with meat productivity of horses. The analysis identified a set of 60 SNPs linked with horse genes involved in the regulation of processes of development of connective tissues and the bone system, neural system, immune system regulation, and other processes. The present study is novel and introduces Kazakh horses as a promising genetic source for horse breeding and selection.
Methylglyoxal is the main culprit to impairing neuronal function: mediated through tryptophan depletion
Authors: Samsuzzaman Md. , Lee Jae Hyuk , Hong Seong-Min , Park Hyun jun , Chang Keun-A , Kim Hyun-Bum , Park Myoung Gyu , Eo Hyeyoon , Oh Myung Sook , Kim Sun Yeou 
Published: March 2023

AbstractDepression is a common and prevalent illness and the exact cause of major depressive disorder is not known. Here, we investigated how methylglyoxal (MGO) stress induces depression and unveiled the potential molecular mechanism. Ourin vivoresults suggested that MGO caused depression in mice, confirmed by several behavioral tests. Interestingly, it halted the mice’s brain’s tryptophan levels and its related neurotransmitters. In addition, MGO induced a reduction in the number of cells in different hippocampal regions. Moreover, it decreased tryptophan hydroxylase 1 (TPH1) and tryptophan hydroxylase 1 (TPH2) levels in the brain and large intestine. Surprisingly, MGO showed the highest affinity and trapping ability toward tryptophan. Most importantly, combined treatment with MGO-tryptophan displayed similar effects as those exhibited by the tryptophan-null treatment in neuronal cells, which included neuronal apoptosis, decrease TPH1 and TPH2 levels, and inhibition of neuronal outgrowth. However, tryptophan treatment improved MGO induced depression-like behavior of mice and recovered the loss of neuronal and hippocampal cells. Subsequently, it also induced MGO detoxifying factors, tryptophan levels, and reduces inflammation in the intestine. Collectively, our data revealed that MGO induced depression facilitated by neuronal and synaptic dysfunction is mediated through the disturbance of tryptophan metabolism in the brain and intestine.
Water-soluble 4-(dimethylaminomethyl)heliomycin exerts greater antitumor effects than parental heliomycin by targeting the tNOX-SIRT1 axis and apoptosis in oral cancer cells
Authors: Islam Atikul , Chang Yu-Chun , Chen Xiao-Chi , Weng Chia-Wei , Chen Chien-Yu , Wang Che-Wei , Chen Mu-Kuan , Tikhomirov Alexander S. , Shchekotikhin Andrey E. , Chueh Pin Ju 
Published: March 2023

AbstractThe antibiotic heliomycin (resistomycin), which is generated fromStreptomyces resistomycificus, has multiple activities, including anticancer effects. Heliomycin was first described in the 1960s, but its clinical applications have been hindered by extremely low solubility. A series of 4-aminomethyl derivatives of heliomycin were synthesized to increase water solubility; studies showed that they had anti-proliferative effects, but the drug targets remained unknown. In this study, we conducted cellular thermal shift assays (CETSA) and molecular docking simulations to identify and validate that heliomycin and its water-soluble derivative, 4-(dimethylaminomethyl)heliomycin (designated compound 4-dmH) engaged and targeted with sirtuin-1 (SIRT1) in p53-functional SAS and p53-mutated HSC-3 oral cancer cells. We further addressed the cellular outcome of SIRT1 inhibition by these compounds and found that, in addition to SIRT1, the water-soluble 4-dmH preferentially targeted a tumor-associated NADH oxidase (tNOX, ENOX2). The direct binding of 4-dmH to tNOX decreased the oxidation of NADH to NAD+which diminished NAD+-dependent SIRT1 deacetylase activity, ultimately inducing apoptosis and significant cytotoxicity in both cell types, as opposed to the parental heliomycin-induced autophagy. We also observed that tNOX and SIRT1 were both upregulated in tumor tissues of oral cancer patients compared to adjacent normal tissues, suggesting their clinical relevance. Finally, the better therapeutic efficacy of 4-dmH was confirmed in tumor-bearing mice, which showed greater tNOX and SIRT1 downregulation and tumor volume reduction when treated with 4-dmH compared to heliomycin. Taken together, ourin vitroandin vivofindings suggest that the multifaceted properties of water-soluble 4-dmH enable it to offer superior antitumor value compared to parental heliomycin, and indicated that it functions through targeting the tNOX-NAD+-SIRT1 axis to induce apoptosis in oral cancer cells.