bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamics of baryon ejection in magnetar giant flares: implications for radio afterglows, r-process nucleosynthesis, and fast radio bursts
Authors: Cehula Jakub , Thompson Todd A , Metzger Brian D
Published: February 2024

We explore the impact of a magnetar giant flare (GF) on the neutron star (NS) crust, and the associated baryon mass ejection. We consider that sudden magnetic energy dissipation creates a thin high-pressure shell above a portion of the NS surface, which drives a relativistic shockwave into the crust, heating a fraction of these layers sufficiently to become unbound along directions unconfined by the magnetic field. We explore this process using spherically symmetric relativistic hydrodynamical simulations. For an initial shell pressure PGF we find the total unbound ejecta mass roughly obeys the relation $M_{\rm {ej}}\sim 4\!-\!9\times 10^{24}\, \rm {g}\, (P_{\rm GF}/10^{30}\, \rm {erg}\, \rm {cm}^{-3})^{1.43}$. For $P_{\rm {GF}}\sim 10^{30}\!-\!10^{31}\, \rm {erg}\, \rm {cm}^{-3}$ corresponding to the dissipation of a magnetic field of strength $\sim 10^{15.5}\!-\!10^{16}\, \rm {G}$, we find $M_{\rm {ej}}\sim 10^{25}\!-\!10^{26}\, \rm {g}$ with asymptotic velocities vej/c ∼ 0.3–0.6 compatible with the ejecta properties inferred from the afterglow of the 2004 December GF from SGR 1806-20. Because the flare excavates crustal material to a depth characterized by an electron fraction Ye ≈ 0.40–0.46, and is ejected with high entropy and rapid expansion time-scale, the conditions are met for heavy element r-process nucleosynthesis via the alpha-rich freeze-out mechanism. Given an energetic GF rate of roughly once per century in the Milky Way, we find that magnetar GFs could be an appreciable heavy r-process source that tracks star formation. We predict that GFs are accompanied by short ∼minutes long, luminous $\sim 10^{39}\, \rm {erg}\, \rm {s}^{-1}$ optical transients powered by r-process decay (nova brevis), akin to scaled-down kilonovae. Our findings also have implications for the synchrotron nebulae surrounding some repeating fast radio burst sources.
Carrageenan oligosaccharide alleviates intestinal damage via gut microflora through activating IMD/relish pathway in female Drosophila melanogaster
Authors: Wang Lu , Zhang Guocai , Li Qiaowei , Lu Fangyuan , Yang Kun , Dai Xianjun
Published: February 2024

Recent evidence suggests the anti‐inflammatory effect of carrageenan oligosaccharides (COS). The effects of COS on intestinal injury induced by 0.6% sodium dodecyl sulfate (SDS) and the molecular mechanisms involved were investigated in this study. 0.625, 1.25, and 2.5 mg/mL COS in diet had no toxic effect in flies, and they could all prolong SDS‐treated female flies' survival rate. 1.25 mg/mL COS prevented the development of inflammation by improving the intestinal barrier integrity and maintaining the intestinal morphology stability, inhibited the proliferation of intestine stem cells (ISCs), and the production of lysosomes induced by SDS, accompanied by a decrease in the expression of autophagy‐related genes. Moreover, COS decreased the active oxygen species (ROS) content in gut and increased the antioxidant activity in SDS‐induced female flies, while COS still played a role in increasing survival rate and decreasing intestinal leakage in CncC‐RNAi flies. The improvement of anti‐inflammation capacity may be associated with the regulation of intestinal microflora with COS supplementation for Drosophila melanogaster. COS changed the gut microbiota composition, and COS had no effect on germ‐free (GF) flies. It is highlighted that COS could not work in Relish‐RNAi flies, indicating relish is required for COS to perform beneficial effects. These results provide insights into the study of gut microbiota interacting with COS to modulate intestinal inflammation in specific hosts.
Digital PCR-based deep quantitative profiling delineates heterogeneity and evolution of uveal melanoma
Authors: Nell R.J. , Versluis M. , Menger N.V. , Verdijk R.M. , Kroes W.G.M. , Kapiteijn H.W. , Luyten G.P.M. , Jager M.J. , van der Velden P.A.
Published: February 2024

Uveal melanoma is an aggressive intraocular tumour characterised by a limited number of genetic alterations. However, the evolution of this malignancy remains enigmatic. In this study, we performed a deep quantitative analysis of 80 primary uveal melanomas by novel digital PCR-based approaches. Mutations were quantified by targeted and drop-off mutation assays, copy number alterations were precisely measured by quantifying the allelic imbalance of heterozygous single-nucleotide polymorphisms. By comparing the absolute abundances of genetic alterations present in a bulk tumour, the heterogeneity and early evolution could be inferred. Tumour progression was further studied by analysing matched primary and metastatic lesions from five patients.

Gαqsignalling mutations were generically and always clonally present, suggesting to be acquired in the earliest stage of uveal melanoma development (‘primary driver’). Next, three main evolutionary subtypes could be identified based on having anEIF1AXmutation,SF3B1mutation or monosomy 3p. These alterations were usually mutually-exclusive and (near-) clonally abundant, suggesting to represent distinct secondary drivers. This contrasts with gains and amplifications of chromosome 8q, which were not restricted to one of the main subtypes and showed subclonality in 31% of the affected tumours. These tertiary alterations were not required for metastatic dissemination.

Using high-resolution analyses, we identified systematic differences in the evolutionary timing of genetic events in uveal melanoma. The observed intratumour heterogeneity suggests a more complex model of gradual tumour evolution and argues for a comprehensive genetic analysis in clinical practice, which may be facilitated by the sensitive digital PCR assays developed in this study.
Cardiorespiratory Dynamics During Prone Positioning for Severe Ards: A Retrospective Cohort Study
Authors: Barros Andrew , Lee Seung Wook , Moorman J. Randall
Published: February 2024

Objectives

To elucidate the changes in cardiorespiratory dynamics during neuromuscular blockade and prone positioning and determine the associations between changes in cardiorespiratory dynamics following prone positioning and mortality.

Design

Single center retrospective cohort study of patients admitted to the medical ICU between June 1, 2020 and September 1, 2022 who received prone positioning while mechanically ventilated.

Results

Our final cohort consisted of 136 patients. Prone position was associated with an improvement in A-a gradient of 113 mmHg (95% CrI 78 – 149) between the pre-proning values and 10 hours post proning. Norepinephrine dose did not significantly change before and after prone positioning (Estimated difference: 0.04 mcg/min 95% CrI -1.00 – 1.07). For the outcome of 7-d mortality, there was a high probability that the baseline factors of increasing age, male sex, and higher baseline A-a gradient were associated with increased risk of death. Increased total vasopressor requirement and increased in PCO2 were associated with worse prognosis while a decrease in instantaneous heart rate and a decrease in heart rate variability were associated with improved prognosis.

Conclusion

The immediate changes in prone positioning primarily impact respiratory physiology, with limited influence on circulatory parameters. Predictors of short-term mortality after prone positioning include both respiratory and cardiovascular parameters suggesting that extrapulmonary effects, such as improvement in right ventricular heart function, might also contribute to the benefit of prone positioning.
AI-Driven Predictive Biomarker Discovery with Contrastive Learning to Improve Clinical Trial Outcomes
Authors: Arango-Argoty Gustavo , Bikiel Damian E. , Sun Gerald J. , Kipkogei Elly , Smith Kaitlin M. , Pro Sebastian Carrasco , Jacob Etai
Published: February 2024

Modern clinical trials can capture tens of thousands of clinicogenomic measurements per individual. Discovering predictive biomarkers, as opposed to prognostic markers, is challenging when using manual approaches. To address this, we present an automated neural network framework based on contrastive learning—a machine learning approach that involves training a model to distinguish between similar and dissimilar inputs. We have named this framework the Predictive Biomarker Modeling Framework (PBMF). This general-purpose framework explores potential predictive biomarkers in a systematic and unbiased manner, as demonstrated in simulated “ground truth” synthetic scenarios resembling clinical trials, well-established clinical datasets for survival analysis, real-world data, and clinical trials for bladder, kidney, and lung cancer. Applied retrospectively to real clinicogenomic data sets, particularly for the complex task of discovering predictive biomarkers in immunooncology (IO), our algorithm successfully found biomarkers that identify IO-treated individuals who survive longer than those treated with other therapies. In a retrospective analysis, we demonstrated how our framework could have contributed to a phase 3 clinical trial (NCT02008227) by uncovering a predictive biomarker based solely on early study data. Patients identified with this predictive biomarker had a 15% improvement in survival risk, as compared to those of the original trial. This improvement was achieved with a simple, interpretable decision tree generated via PBMF knowledge distillation. Our framework additionally identified potential predictive biomarkers for two other phase 3 clinical trials (NCT01668784,NCT02302807) by utilizing single-arm studies with synthetic control arms and identified predictive biomarkers with at least 10% improvement in survival risk. The PBMF offers a broad, rapid, and robust approach to inform biomarker strategy, providing actionable outcomes for clinical decision-making.
The heartbeat-evoked potential in young and older adults during attention orienting
Authors: Aprile Francesca , Simões Marco , Henriques Jorge , Carvalho Paulo , Castelo-Branco Miguel , Sel Alejandra , Ribeiro Maria J.
Published: February 2024

Cardiac cycle duration, or interbeat interval (IBI), is the period from one heartbeat to the next. IBI changes from cycle to cycle. Periods with longer IBI are associated with higher sensitivity to external sensory stimuli (exteroception). Warning cues induce a state of attentive anticipation characterized by an increase in IBI (anticipatory cardiac deceleration) and faster reaction times. Ageing reduces the increase in IBI induced by warning cues and response speed. However, it is unclear which mechanism, if any, connects IBI with reaction time. The heartbeat-evoked potential (HEP) is a cortical response evoked by the heartbeat, modulated by attention and associated with sensitivity to external sensory stimuli. HEP might be affected by IBI and mediate the association between cardiac output and cortical processing.

We investigated if the HEP was affected by warning cues as well as spontaneous fluctuations in IBI. To explore the impact of age-related changes in cardiac responses, we included young and older people [N = 33/29; 26/23 women; mean age 23/61 years]. We analysed the electroencephalograms and electrocardiograms simultaneously acquired during auditory cued simple reaction time and go/no-go tasks.

The warning cue did not induce significant changes in the HEP. Yet, fluctuations in IBI (not locked with the warning cue) affected the HEP and HEP amplitude was associated with average reaction time in the older group. However, on a trial-by-trial basis, reaction time was independent from IBI fluctuations.

In conclusion, we found no evidence that the HEP mediates the effect of attention orienting on reaction time.
Genetic interference with HvNotch provides new insights into the role of the Notch-signalling pathway for developmental pattern formation inHydra
Authors: Pan Qin , Mercker Moritz , Klimovich Alexander , Wittlieb Jörg , Marciniak-Czochra Anna , Böttger Angelika
Published: February 2024

The Notch-signalling pathway plays an important role in pattern formation inHydra. Using pharmacological Notch inhibitors (DAPT and SAHM1), it has been demonstrated that HvNotch is required for head regeneration and tentacle patterning inHydra. HvNotch is also involved in establishing the parent-bud boundary and instructing buds to develop feet and detach from the parent. To further investigate the functions of HvNotch, we successfully constructed NICD (HvNotch intracellular domain)-overexpressing and HvNotch-knockdown transgenicHydrastrains. NICD-overexpressing transgenicHydrashowed a pronounced inhibition on the expression of predicted HvNotch-target genes, suggesting a dominant negative effect of ectopic NICD. This resulted in a “Y-shaped” phenotype, which arises from the parent-bud boundary defect seen in polyps treated with DAPT. Additionally, “multiple heads”, “two-headed” and “ectopic tentacles” phenotypes were observed. The HvNotch-knockdown transgenicHydrawith reduced expression of HvNotch exhibited similar, but not identical phenotypes, with the addition of a “two feet” phenotype. Furthermore, approximately 20% of the HvNotch-knockdown polyps were unable to regenerate a new head after decapitation. We integrated these findings into a mathematical model based on long-range gradients of signalling molecules underlying sharply defined positions of HvNotch-signalling cells at theHydratentacle and bud boundaries.
Pre-existing Immunity to Influenza Aids Ferrets in Developing Stronger and Broader Vaccine-induced Antibody Responses
Authors: Ge Yang , Lu Yao , Allen James , Einav Tal , Nkaleke Dennis Iziogo , Bai Fengwei , Handel Andreas , Ross Ted , Shen Ye
Published: February 2024

Influenza seasons occur annually, building immune history for individuals, but the influence of this history on subsequent influenza vaccine protection remains unclear. We extracted data from an animal trial to study its potential impact. The trial involved 80 ferrets, each receiving either one type of infection or a placebo before vaccination. We quantified the vaccine protection by evaluating hemagglutination inhibition (HAI) antibody titer responses. We tested whether hosts with different infection histories exhibited similar level of responses when receiving the same vaccine for all homologous and heterologous outcomes. We observed that different pre-existing immunities were generally beneficial to vaccine induced responses, but varied in magnitude. Without pre-immunity, post-vaccination HAI titers after the 1st dose of the vaccine were less likely to be above 1:40, and a booster shot was needed. Our study suggests that pre-existing immunity may strengthen and extend the homologous and heterologous vaccine protection.
Perinatal ampicillin administration modulates murine bile acid metabolismin vivo- an observational study
Authors: Thomas Sydney P , Askarian Fatemeh , Kousha Armin , Suzuki Emi , Tsai Chih Ming , Liu George , Nizet Victor , Dorrestein Pieter C , Tsunoda Shirley M.
Published: February 2024

Antibiotics are an indispensable tool of modern medicine, yet their impact extends beyond eliminating harmful bacteria to perturbing the commensal bacteria constituting the gut microbiome. This collateral damage is particularly significant in early life when the gut microbiome is still developing. In humans, antibiotic administration during infancy and childhood is associated with various long-term negative health outcomes. However, existing research has predominantly focused on the direct administration of antibiotics to infants, leaving uncertainties about whether indirect antibiotic exposure produces similar effects. Here, we use mouse models to investigate how three distinct routes of exposure to the commonly prescribed broad-spectrum antibiotic ampicillin influences parent and infant metabolism. These methods simulate major modes of both direct and indirect antibiotic exposure: intravenous antibiotic administration to the mother immediately before birth mimicking intrapartum antibiotic prophylaxis, antibiotic use by the mother during lactation, and direct administration to infants mimicking empiric antibiotic treatment for neonatal sepsis. Through untargeted metabolomics of fecal samples from mouse dams and infants, we identified one class of compounds, bile acids and related cholane steroids, as particularly sensitive to ampicillin treatment. Bile acids, produced by the host and extensively modified by the gut microbiome, serve as important mediators in the cross-talk between the microbiota and the host. Here, we detail the coordinated changes in bile acid metabolism in response to a commonly prescribed antibiotic, focusing on dams treated both pre- and postpartum. Additionally, we identify unique bile acids associated with weight gain in infant mice.

Importance

Antibiotics are widely used perinatally, administered to both parents and infants before, during, and after birth. While they can play a life-saving role, antibiotics also result in collateral damage to the beneficial microbes constituting the gut microbiome. These microbes have many important functions, particularly in the metabolism of small molecules in the body. One such group of molecules, bile acids, undergo extensive modifications by bacteria and may act as a “language” through which microbes communicate with the host. This observational study investigates the impact of the commonly prescribed antibiotic ampicillin on the metabolism of these molecules during childbirth. Our results indicate that ampicillin administration pre- or post-partum significantly alters the mother’s bile acid metabolism, but has a minimal influence on infant bile acid levels. However, in all cases, ampicillin administration significantly increased infant weight, even when the antibiotic was solely administered to the mother.
Phenomics Assistant: An Interface for LLM-based Biomedical Knowledge Graph Exploration
Authors: O’Neil Shawn T , Schaper Kevin , Elsarboukh Glass , Reese Justin T , Moxon Sierra A T , Harris Nomi L , Munoz-Torres Monica C , Robinson Peter N , Haendel Melissa A , Mungall Christopher J
Published: February 2024

We introduce Phenomics Assistant, a prototype chat-based interface for querying the Monarch knowledge graph (KG), a comprehensive biomedical database. While unaided Large Large Language models (LLMs) are prone to mistakes in factual recall, their strong abilities in summarization and tool use suggest new opportunities to help non-expert users query and interact with complex data, while drawing on the KG to improve reliability of the answers. Leveraging the ability of LLMs to interpret queries in natural language, Phenomics Assistant enables a wide range of users to interactively discover relationships between diseases, genes, and phenotypes.

To assess the reliability of our approach and compare the accuracy of different LLMs, we evaluated Phenomics Assistant answers on benchmark tasks for gene-disease association and gene alias queries. While comparisons across tested LLMs revealed differences in their ability to interpret KG-provided information, we found that even basic KG access markedly boosts the reliability of standalone LLMs. By enabling users to pose queries in natural language and summarizing results in familiar terms, Phenomics Assistant represents a new approach for navigating the Monarch KG.
Mapping domains of early-life determinants of future multimorbidity across three UK longitudinal cohort studies
Authors: Stannard S , Berrington A , Fraser SDS , Paranjothy S , Hoyle RB , Owen RK , Akbari A , Shiranirad M , Chiovoloni R , Alwan NA
Published: February 2024

Many studies use a reductionist approach to isolate the influence of one factor in childhood on multimorbidity rather than consider the combined effect of wider determinants. We explored how potential multiple early-life determinants of multimorbidity can be characterised across three UK cohort studies.

We used the National Child Development Study (NCDS), the 1970 British Cohort Study (BCS70), and the Aberdeen Children of the 1950s Study (ACONF) to identified early-life variables that fit into 12 domains of early-life determinants of multimorbidity. Variables were assigned into 12 domains; principal component analysis reduced the dimensionality of the data and structured variables into subgroups.

The data audit identified 7 domains in ACONF, 10 domains in NCDS and 12 domains in BCS70. Components included maternal fertility histories within the prenatal, antenatal and birth domain, long-term illnesses within the child health domain, educational ability within the child education and health literacy domain, ethnicity within the demography domain, parental health behaviours within the transgenerational domain, housing within the socioeconomic domain and parental-child interactions within the parental-family domain.

Conceptualising the risk of future multimorbidity as lifecourse domains composed of multiple factors can help challenge the existing understanding of disease aetiology and develop new ideas for prevention of multimorbidity.
Mitigating Machine Learning Bias Between High Income and Low-Middle Income Countries for Enhanced Model Fairness and Generalizability
Authors: Yang Jenny , Clifton Lei , Dung Nguyen Thanh , Phong Nguyen Thanh , Yen Lam Minh , Xuan Thy Doan Bui , Soltan Andrew A. S. , Thwaites Louise , Clifton David A.
Published: February 2024

Collaborative efforts in artificial intelligence (AI) are increasingly common between high-income countries (HICs) and low-to middle-income countries (LMICs). Given the resource limitations often encountered by LMICs, collaboration becomes crucial for pooling resources, expertise, and knowledge. Despite the apparent advantages, ensuring the fairness and equity of these collaborative models is essential, especially considering the distinct differences between LMIC and HIC hospitals. In this study, we show that collaborative AI approaches can lead to divergent performance outcomes across HIC and LMIC settings, particularly in the presence of data imbalances. Through a real-world COVID-19 screening case study, we demonstrate that implementing algorithmic-level bias mitigation methods significantly improves outcome fairness between HIC and LMIC sites while maintaining high diagnostic sensitivity. We compare our results against previous benchmarks, utilizing datasets from four independent United Kingdom Hospitals and one Vietnamese hospital, representing HIC and LMIC settings, respectively.
A web-based tool for real-time adequacy assessment of kidney biopsies
Authors: Ahangaran Meysam , Sun Emily , Le Khang , Sun Jiawei , Wang William M. , Tan Tian Herng , Burdine Lyle J. , Dvanajscak Zeljko , Cassol Clarissa A. , Sharma Shree , Kolachalama Vijaya B.
Published: February 2024

The escalating incidence of kidney biopsies providing insufficient tissue for diagnosis poses a dual challenge, straining the healthcare system and jeopardizing patients who may require re-biopsy or face the prospect of an inaccurate diagnosis due to an unsampled disease. Here, we introduce a web-based tool that can provide real-time, quantitative assessment of kidney biopsy adequacy directly from photographs taken with a smartphone camera. The software tool was developed using a deep learning-driven automated segmentation technique, trained on a dataset comprising nephropathologist-confirmed annotations of the kidney cortex on digital biopsy images. Our framework demonstrated favorable performance in segmenting the cortex via 5-fold cross-validation (Dice coefficient: 0.788±0.130) (n=100). Offering a bedside tool for kidney biopsy adequacy assessment has the potential to provide real-time guidance to the physicians performing medical kidney biopsies, reducing the necessity for re-biopsies. Our tool can be accessed through our web-based platform:http://www.biopsyadequacy.org.
Arsinothricin Biosynthesis Involving a Noncanonical Radical SAM Enzyme for C-As Bond Formation
Authors: Yao Yadi , He Jiale , Dong Min
Published: February 2024

Arsinothricin is a potent antibiotic secreted by soil bacteria. The biosynthesis of Arsinothricin was proposed to involve two steps. The first step is C-As bond formation between trivalent As and the 3-amino-3-carboxypropyl (ACP) group of S-adenosyl-L-methionine (SAM), which is catalyzed by the protein ArsL. However, the reaction has not been verified in vitro, and ArsL has not been characterized in detail. Interestingly, ArsL contains a CxxxCxxC motif and thus belongs to the radical SAM enzyme superfamily, the members of which cleave SAM and generate a 5′-deoxyadenosyl radical. Here, we found that ArsL cleaves the Cγ,Met–S bond of SAM and generates an ACP radical that resembles Dph2, a noncanonical radical SAM enzyme involved in diphthamid biosynthesis. As Dph2 does not contain the CxxxCxxC motif, ArsL is a unique noncanonical radical SAM enzyme that contains this motif but generates an ACP radical. Together with the methyltransferase ArsM, we successfully reconstituted arsinothricin biosynthesis in vitro. ArsL has a conserved RCCLKC motif in the C-terminal sequence and belongs to the RCCLKC-tail radical SAM protein subfamily. By truncation, we showed that this motif binds to the substrate arsenite and is highly important for its activity. Our results suggested that ArsL is a noncanonical radical SAM enzyme with a canonical radical SAM enzyme motif, implying that more noncanonical radical SAM chemistry may exist within the radical SAM enzyme superfamily.

TOC
Aging is associated with a modality-specific decline in taste
Authors: Brown Elizabeth B. , Lloyd Evan , Martin-Peña Alfonso , McFarlane Samuel , Dahanukar Anupama , Keene Alex C.
Published: February 2024

Deficits in chemosensory processing are associated with healthy aging, as well as numerous neurodegenerative disorders, including Alzheimer’s Disease (AD). In many cases, chemosensory deficits are harbingers of neurodegenerative disease, and understanding the mechanistic basis for these changes may provide insight into the fundamental dysfunction associated with aging and neurodegeneration. The fruit fly,Drosophila melanogaster, is a powerful model for studying chemosensation, aging, and aging-related pathologies, yet the effects of aging and neurodegeneration on chemosensation remain largely unexplored in this model, particularly with respect to taste. To determine whether the effects of aging on taste are conserved in flies, we compared the response of flies to different appetitive tastants. Aging impaired response to sugars, but not medium-chain fatty acids that are sensed by a shared population of neurons, revealing modality-specific deficits in taste. Selective expression of the human amyloid beta (Aβ) 1-42 peptide bearing the Arctic mutation (E693E) associated with early onset AD in the neurons that sense sugars and fatty acids phenocopies the effects of aging, suggesting that the age-related decline in response is localized to gustatory neurons. Functional imaging of gustatory axon terminals revealed reduced response to sugar, but not fatty acids. Axonal innervation of the fly taste center was largely intact in aged flies, suggesting that reduced sucrose response does not derive from neurodegeneration. Conversely, expression of the amyloid peptide in sweet-sensing taste neurons resulted in reduced innervation of the primary fly taste center. A comparison of transcript expression within the sugar-sensing taste neurons revealed age-related changes in 66 genes, including a reduction in odorant-binding protein class genes that are also expressed in taste sensilla. Together, these findings suggest that deficits in taste detection may result from signaling pathway-specific changes, while different mechanisms underly taste deficits in aged and AD model flies. Overall, this work provides a model to examine cellular deficits in neural function associated with aging and AD.
Conformational plasticity of a BiP-GRP94 chaperone complex
Authors: Brenner Joel Cyrille , Zirden Linda , Almeida-Hernandez Yasser , Kaschani Farnusch , Kaiser Markus , Sanchez-Garcia Elsa , Poepsel Simon , Hellerschmied Doris
Published: February 2024

Hsp70/Hsp90-chaperones and their regulatory co-chaperones are critical for maintaining protein homeostasis. GRP94, the sole Hsp90-chaperone in the secretory pathway of mammalian cells, is essential for the maturation of important secretory and transmembrane proteins. Without the requirement of co-chaperones, the Hsp70-protein BiP controls regulatory conformational changes of GRP94 – the structural basis of which has remained elusive. Here, we biochemically and structurally characterize the formation of a BiP-GRP94 chaperone complex and its transition to a conformation expected to support the loading of substrate proteins from BiP onto GRP94. BiP initially binds to the open GRP94 dimer via an interaction interface that is conserved among Hsp70/90 paralogs. Subsequently, binding of a second BiP protein stabilizes a semi-closed GRP94 dimer, thereby advancing the chaperone cycle. Our findings highlight a fundamental mechanism of direct Hsp70/90 cooperation, independent of co-chaperones.
DrosophilaFog/Cta and T48 pathways have overlapping and distinct contributions to mesoderm invagination
Authors: Horo Uzuki , Clarke Nat , Martin Adam C.
Published: February 2024

The regulation of the cytoskeleton by multiple pathways, sometimes in parallel, is a common principle of morphogenesis. A classic example of regulation by parallel pathways isDrosophilagastrulation, where the inputs from the Folded gastrulation (Fog)/Concertina (Cta) and the T48 pathways induce apical constriction and mesoderm invagination. Whether there are distinct roles for these separate pathways in regulating the complex spatial and temporal patterns of cytoskeletal activity that accompany early embryo development is still poorly understood. We investigated the roles of the Fog/Cta and T48 pathways and found that, by themselves, the Cta and T48 pathways both promote timely mesoderm invagination and apical myosin II accumulation, with Cta being required for timely cell shape change ahead of mitotic cell division. We also identified distinct functions of T48 and Cta in regulating cellularization and the uniformity of the apical myosin II network, respectively. Our results demonstrate that both redundant and distinct functions for the Fog/Cta and T48 pathways exist.
Identification and characterization of a temperature sensitive chlorotic soybean mutant
Authors: Hancock C. Nathan , Germany Tetandianocee , Redd Priscilla , Timmons Jack , Lipford Jeffery , Burns Samantha , Cervantes-Perez Sergio Alan , Libault Marc , Shen Wenhao , An Yong-qiang Charles , Kanizay Lisa , Yerka Melinda , Parrott Wayne A.
Published: February 2024

Screening a transposon-mutagenized soybean population led to the discovery of a recessively inherited chlorotic phenotype. This “vir1” phenotype results in smaller stature, weaker stems, and a smaller root system with smaller nodules. Genome sequencing identified 15 candidate genes with mutations likely to result in a loss of function. Amplicon sequencing of a segregating population was then used to narrow the list to a single candidate mutation, a single-base change inGlyma.07G102300that disrupts splicing of the second intron. Single cell transcriptomic profiling indicates that this gene is expressed primarily in mesophyll cells and RNA sequencing data indicates it is upregulated in germinating seedlings by cold stress. Previous studies have shown that mutations toOs05g34040, the rice homolog ofGlyma.07G102300, produced a chlorotic phenotype that was more pronounced in cool temperatures. Growing soybean vir1 mutants at lower temperatures also resulted in a more severe phenotype. In addition, transgenic expression of wild typeGlyma.07G102300in the knockout mutant of the Arabidopsis homologAt4930720rescues the chlorotic phenotype, further supporting the hypothesis that the mutation inGlyma.07G102300is causal of the vir1 phenotype.
Translational T-box riboswitches bind tRNA by modulating conformational flexibility
Authors: Campos-Chavez Eduardo , Paul Sneha , Zhou Zunwu , Alonso Dulce , Verma Anjali R. , Fei Jingyi , Mondragón Alfonso
Published: February 2024

T-box riboswitches, paradigmatic non-coding RNA elements involved in genetic regulation in most Gram-positive bacteria, are adept at monitoring amino acid metabolism through direct interactions with specific tRNAs. T-box riboswitches assess tRNA aminoacylation status, subsequently regulating the transcription or translation of downstream genes involved in amino acid metabolism. Here we present single-molecule FRET studies of theMycobacterium tuberculosis IleST-box riboswitch, a model of T-box translational regulation. The data supports a two-step binding model where the tRNA anticodon is recognized first, followed by interactions with the NCCA sequence. Specifically, after anticodon recognition, tRNA in the partially bound state can transiently dock into the discriminator domain, resembling the fully bound state, even in the absence of the tRNA NCCA-discriminator interactions. Establishment of the NCCA-discriminator interactions significantly stabilizes the fully bound state. Collectively, the data suggests higher conformational flexibility in translation-regulating T-box riboswitches, compared to transcription-regulating ones, and supports a conformational selection model for NCCA recognition. Furthermore, it was found that the conserved RAG sequence is pivotal in maintaining specific interactions with the tRNA NCCA sequence by preventing sampling of an aberrant conformational state, while Stem IIA/B-linker interactions impact the conformational dynamics and the stability of both the partially bound and fully bound states. The present study provides a critical kinetic basis for how specific sequences and structural elements in T-box riboswitches enable the binding efficiency and specificity required to achieve gene regulation.
Tyrosine-sulfated peptide hormone induces flavonol biosynthesis to control elongation and differentiation in Arabidopsis primary root
Authors: Ercoli Maria Florencia , Shigenaga Alexandra M. , Teixeira de Araujo Artur , Jain Rashmi , Ronald Pamela C.
Published: February 2024

In Arabidopsis roots, growth initiation and cessation are organized into distinct zones. How regulatory mechanisms are integrated to coordinate these processes and maintain proper growth progression over time is not well understood. Here, we demonstrate that the peptide hormone PLANT PEPTIDE CONTAINING SULFATED TYROSINE 1 (PSY1) promotes root growth by controlling cell elongation. Higher levels of PSY1 lead to longer differentiated cells with a shootward displacement of characteristics common to mature cells. PSY1 activates genes involved in the biosynthesis of flavonols, a group of plant-specific secondary metabolites. Using genetic and chemical approaches, we show that flavonols are required for PSY1 function. Flavonol accumulation downstream of PSY1 occurs in the differentiation zone, where PSY1 also reduces auxin and reactive oxygen species (ROS) activity. These findings support a model where PSY1 signals the developmental-specific accumulation of secondary metabolites to regulate the extent of cell elongation and the overall progression to maturation.

Teaser

PSY1-induced flavonol biosynthesis in Arabidopsis roots modulates the distance from the root tip at which cell elongation ceases.
Quantum-inspired computing technology in operations and logistics management
Authors: Núñez-Merino Miguel , Maqueira-Marín Juan Manuel , Moyano-Fuentes José , Castaño-Moraga Carlos Alberto
Published: February 2024

Purpose

The purpose of this paper is to explore and disseminate knowledge about quantum-inspired computing technology's potential to solve complex challenges faced by the operational agility capability in Industry 4.0 manufacturing and logistics operations.

Design/methodology/approach

A multi-case study approach is used to determine the impact of quantum-inspired computing technology in manufacturing and logistics processes from the supplier perspective. A literature review provides the basis for a framework to identify a set of flexibility and agility operational capabilities enabled by Industry 4.0 Information and Digital Technologies. The use cases are analyzed in depth, first individually and then jointly.

Findings

Study results suggest that quantum-inspired computing technology has the potential to harness and boost companies' operational flexibility to enhance operational agility in manufacturing and logistics operations management, particularly in the Industry 4.0 context. An exploratory model is proposed to explain the relationships between quantum-inspired computing technology and the deployment of operational agility capabilities.

Originality/value

This is study explores the use of quantum-inspired computing technology in Industry 4.0 operations management and contributes to understanding its potential to enable operational agility capability in manufacturing and logistics operations.
Sixteen cases of laparoscopic central pancreatectomy for benign or low‐grade malignant tumours in the pancreatic neck and proximal body
Authors: Xiang Jianqiang , Zhu Jie , Wang Haibiao , Zhou Xinhua , Li Hong
Published: February 2024

Background

The purpose of this study is to examine and analyse the outcomes and patient experiences associated with laparoscopic central pancreatectomy.

Methods

The perioperative data of 16 patients who underwent laparoscopic central pancreatectomy were retrospectively analysed at Ningbo Medical Center Lihuili Hospital (Xingning Branch and Eastern Branch) from September 2017 to July 2023.

Results

All surgical procedures were completed without the need for intraoperative conversion to open surgery. In two cases, intraoperative cholangiography was performed, while in four cases, intraoperative fluoroscopic laparoscopic assistance was utilized. The duration of the operations varied from 160 to 360 min, with an average of 281.75 min. The estimated volume of intraoperative bleeding ranged from 50 to 300 mL, with an average of 113.75 mL. The postoperative pathology results revealed that there were two cases of intraductal papillary mucinous neoplasm, six cases of serous cystic neoplasms, one case of mucinous cystic neoplasm, five cases of solid pseudopapillary neoplasms, and two cases of neuroendocrine tumours. The maximum diameter of the tumours ranged from 3.0 to 5.0 cm, with an average of 3.67 cm. There were no instances of postoperative common bile duct stenosis or biliary leakage. Among the cases, five did not exhibit pancreatic fistula, six experienced biochemical leakage, three had grade B pancreatic fistula, and two had grade C pancreatic fistula.

Conclusion

Laparoscopic central pancreatectomy, as a method to preserve pancreatic function, entails specific surgical risks and a notable likelihood of postoperative pancreatic fistula, necessitating the expertise of seasoned surgeons for its execution.
A large‐scale study on the prevalence of math anxiety in Qatar
Authors: Megreya Ahmed M. , Al‐Emadi Ahmed A. , Al‐Ahmadi Aisha M. , Moustafa Ahmed A. , Szűcs Denes
Published: February 2024

Background

Math anxiety (MA) is a worldwide appearing academic anxiety that can affect student mental health and deter students from math and science‐related career choices.

Method

Using the Arabic version of the Modified‐Abbreviated Math Anxiety Scale (m‐AMAS), the prevalence of MA was investigated in a very large sample of students (N = 10093) from grades 7 to 12 in Qatar.

Results

The results showed a better fit to the original two‐factor model of the m‐AMAS (learning MA and Evaluation MA) than to a single‐factor solution. This two‐factor model was also confirmed in each grade. Notably, the distribution of MA scores was right‐skewed, especially for learning MA. Using the inter‐quartiles ranges, norms for MA were provided: A score of ≤16 indicates low MA whereas a score of ≥30 identifies high MA. Previous studies conducted in Western countries defined high math‐anxious students as those who score above the 90th percentile corresponding to a score of 30 on the m‐AMAS. Using this cut‐off criterion, the current study found that one‐fifth of students in Qatar were highly math‐anxious, with a higher proportion of females than males. We also calculated the percentage of participants selecting each response category for each questionnaire item. Results showed that attending a long math class was the context that elicited the highest levels of learning MA. In contrast, having an unexpected math test was the situation that triggered the highest levels of evaluation MA.

Conclusion

The prevalence of MA might vary across different cultures.
Cardiovascular risk factors predict who should have echocardiographic evaluation in long COVID
Authors: Tamariz Leonardo , Ryan Mathew , Marzouka George R. , Bast Elizabeth , Klimas Nancy , Palacio Ana
Published: February 2024

Background

The need for echocardiograms among patients with long COVID is debatable. Our aim was to evaluate the prevalence of left ventricular (LV) dysfunction and identify predictors.

Methods

We conducted a cross‐sectional study and included all consecutive patients enrolled in our post‐COVID clinic. We included patients who had an echocardiogram and had no previous known heart disease. We defined LV dysfunction as a low ejection fraction or grade II to grade III diastolic dysfunction on an echocardiogram with evidence of elevated filling pressures. We calculated the prevalence of heart disease and predictors of heart disease using logistic regression.

Results

We included 217 post‐COVID patients enrolled in the clinic. The prevalence of LV dysfunction is 24%; 95% CI 18–30. Predictors of heart disease include older age and a previous history of hypertension and diabetes or having an intermediate or high ASCVD score. Patients with low ASCVD score did not have low ejection fraction on the screening echocardiograms.

Conclusion

Our study found a considerable number of patients with LV dysfunction. Older patients with cardiovascular risk factors are at risk of long COVID associated heart disease.
Biochemical characteristics of sorghum cultivars affect life table parameters, feeding performance, and digestive enzyme activities of Helicoverpa armigera
Authors: Bonvari Ali , Hemmati Seyed Ali , Shishehbor Parviz
Published: February 2024

The cotton bollworm, Helicoverpa armigera (Hübner) (Lepidoptera: Noctuidae), is a major insect pest of various agricultural crops worldwide. In this study, the effects of eight sorghum [Sorghum bicolor (L.) Moench, Poaceae] cultivars (Payam, Pegah, Sepideh, Spidfid, Kimia, KGS23, KFS2, and KFS18) on life table parameters, feeding performance, and activities of digestive enzymes in H. armigera were assessed under laboratory conditions. The insects were fed grains of the eight cultivars. Furthermore, the phytochemicals starch, proteins, flavonoids, and phenolic compounds in the grains were quantified to investigate their relationship with ecological and physiological parameters in H. armigera. Our results revealed that H. armigera had the shortest development time when reared on cv. Sepideh and the longest development time when reared on cv. Payam. The insects reached the highest and lowest intrinsic rate of increase (r) on cv. Sepideh and Payam, respectively. The relative growth rate (RGR) and efficiency of conversion of digested food (ECD) of larvae were highest and lowest on cv. Sepideh and Payam, respectively. Larval proteolytic activity was highest on cv. KFS18 and lowest on cv. Sepideh. Concerning phytochemicals, protein content was highest in cv. KFS18 and lowest in cv. Payam and KGS 23. Total phenolic levels were highest in cv. Payam and lowest in cv. Sepideh. According to the correlation analysis, overall, plant protein content was negatively correlated with insect development time, but positively correlated with pupal weight and r. Total phenolic content was positively correlated with insect development time, and negatively correlated with r and RGR. Cluster analysis indicated that cv. Sepideh was the most susceptible host, whereas cv. Payam was the most resistant. Therefore, cv. Payam may be a candidate for use in integrated pest management (IPM) against H. armigera.
“Masculinity is responsibility toward your family”: Masculinity in the shadow of Bedouin patriarchy in Israel
Authors: Alhuzail Nuzha Allassad , Segev Einav
Published: February 2024

Objective

The aim of this study is to examine how the patriarchal structure affects Bedouin men's role in the family and how this role affects their masculinity.

Background

How the patriarchal structure affects Bedouin women and constrains them has been studied extensively, but there is a dearth of research on how it affects young Bedouin men—especially those who are the sons of men with higher education—who have been influenced by modernization and exposure to Israeli society.

Method

This is a qualitative study in the phenomenological tradition, using a semistructured in‐depth interview, of 20 young Bedouin men.

Results

Four themes were identified. “Power that I did not choose”: The patriarchal structure gives young men power and authority that they do not choose and cannot oppose. “The mirror of the older men is important”: Fulfilling the traditional Bedouin man's role is crucial for obtaining their elders' approval of their masculinity. “Responsibility”: The men have responsibility. “Masculine juggling”: The young men must negotiate their aspirations that conflict with society's expectations.

Conclusion

The change that traditional Bedouin society is undergoing creates many challenges for young Bedouin men. These include having to be the authority figure in a patriarchal structure and the protector of the female family members, roles that often conflict with the men's personal desire for equality between the sexes and among family members.

Implications

The findings may be useful in planning support programs for educated young Bedouin men and may contribute to the understanding of the challenges facing men in Bedouin families.
Translation regulation in response to stress
Authors: Williams Thomas D. , Rousseau Adrien
Published: February 2024

Cell stresses occur in a wide variety of settings: in disease, during industrial processes, and as part of normal day‐to‐day rhythms. Adaptation to these stresses requires cells to alter their proteome. Cells modify the proteins they synthesize to aid proteome adaptation. Changes in both mRNA transcription and translation contribute to altered protein synthesis. Here, we discuss the changes in translational mechanisms that occur following the onset of stress, and the impact these have on stress adaptation.
A modified geometric technique to increase peri‐implant keratinized mucosa
Authors: Tang Chenxi , Zhang Peng , Zhang Xiaohan , Peng Lin
Published: February 2024

Objective

The free gingival graft (FGG) has been identified as the most effective method for increasing keratinized mucosa width (KMW). However, the challenge emerges in cases of extensive keratinized mucosa deficiency, where efficient utilization of the patient's limited keratinized tissue to achieve optimal results is crucial. This article introduces a modified geometric technique to address this clinical issue.

Clinical Considerations

Utilizing geometric principles, the modified technique involves dividing the rectangular graft into two triangular or trapezoidal sections, which are then reassembled to form an approximate diamond shape. Through strategic cut and splice, the graft is reshaped to suit the recipient site.

Conclusion

Preliminary observations in cases employing the modified geometric technique have increased the KMW around implants. This method enhances graft utilization and offers a viable clinical option for surgical plans aimed at widening keratinized mucosa in instances of large‐area KMW deficiency.

Clinical Significance

This article proposed a modified method to increase KMW, which may be an optimal choice for patients with insufficient KMW in large area, avoiding the waste of limited graft, decreasing patient morbidity, and effectively widening keratinized mucosa.