bluuebunny/crossref_metadata_2025_split huggingface dataset:
From cause and effect to causes and effects
Authors: Sturmberg Joachim P. , Marcum James A. 
Published: February 2023

AbstractIt is now—at least loosely—acknowledged that most health and clinical outcomes are influenced by different interacting causes. Surprisingly, medical research studies are nearly universally designed to study—usually in a binary way—the effect of a single cause. Recent experiences during the coronavirus disease 2019 pandemic brought to the forefront that most of our challenges in medicine and healthcare deal with systemic, that is, interdependent and interconnected problems. Understanding these problems defy simplistic dichotomous research methodologies. These insights demand a shift in our thinking from ‘cause and effect’ to ‘causes and effects’ since this transcends the classical way of Cartesian reductionist thinking. We require a shift to a ‘causes and effects’ frame so we can choose the research methodology that reflects the relationships between variables of interest—one‐to‐one, one‐to‐many, many‐to‐one or many‐to‐many. One‐to‐one (or cause and effect) relationships are amenable to the traditional randomized control trial design, while all others require systemic designs to understand ‘causes and effects’. Researchers urgently need to re‐evaluate their science models and embrace research designs that allow an exploration of the clinically obvious multiple ‘causes and effects’ on health and disease. Clinical examples highlight the application of various systemic research methodologies and demonstrate how ‘causes and effects’ explain the heterogeneity of clinical outcomes. This shift in scientific thinking will allow us to find the necessary personalized or precise clinical interventions that address the underlying reasons for the variability of clinical outcomes and will contribute to greater health equity.
Identification by whole genome sequencing of genes associated with delayed postoperative hemorrhage in Scottish deerhounds
Authors: Court Michael H. , Kiser Jennifer N. , Neibergs Holly L. , Zhu Zhaohui , Dillberger John E. 
Published: February 2023

AbstractBackgroundDelayed postoperative hemorrhage (DEPOH) is an important health concern for Scottish deerhounds.Hypothesis/ObjectivesIdentify genes associated with DEPOH in Scottish deerhounds.AnimalsTwo hundred sixty‐nine privately owned Scottish deerhounds.MethodsRetrospective case‐control study. DEPOH cases and controls were identified through an owner health survey. Genome‐wide association analysis was performed using whole genome sequences from 8 cases and 17 controls. All cases and controls were genotyped for selected variants.ResultsOf 269 dogs, 10 met inclusion and exclusion criteria for DEPOH, while 62 controls had undergone similar surgical procedures without DEPOH. Genome‐wide association analysis identified a single locus on chromosome 9 spanning 40 genes. One of these genes (SERPINF2 encoding alpha‐2 antiplasmin) was directly linked to the pathophysiology of DEPOH. The entire cohort was genotyped for a missense SERPINF2 variant (c.605 C>T; p.A202V). Compared to dogs with the reference C/C genotype, the likelihood of DEPOH was significantly higher for dogs with the T/T genotype (odds ratio [OR] = 1235; 95% confidence interval [CI] = 23‐6752; P = 0.0005) and with the C/T genotype (OR = 28; 95% CI = 1.4‐542; P = 0.03).Conclusions and Clinical ImportanceSERPINF2 is associated with DEPOH in Scottish deerhounds. Genetic testing might be able to identify dogs that are susceptible to DEPOH.
MerA functions as a hypothiocyanous acid reductase and defense mechanism in Staphylococcus aureus
Authors: Shearer Heather L. , Loi Vu V. , Weiland Paul , Bange Gert , Altegoer Florian , Hampton Mark B. , Antelmann Haike , Dickerhof Nina 
Published: February 2023

AbstractThe major pathogen Staphylococcus aureus has to cope with host‐derived oxidative stress to cause infections in humans. Here, we report that S. aureus tolerates high concentrations of hypothiocyanous acid (HOSCN), a key antimicrobial oxidant produced in the respiratory tract. We discovered that the flavoprotein disulfide reductase (FDR) MerA protects S. aureus from this oxidant by functioning as a HOSCN reductase, with its deletion sensitizing bacteria to HOSCN. Crystal structures of homodimeric MerA (2.4 Å) with a Cys43–Cys48 intramolecular disulfide, and reduced MerACys43S (1.6 Å) showed the FAD cofactor close to the active site, supporting that MerA functions as a group I FDR. MerA is controlled by the redox‐sensitive repressor HypR, which we show to be oxidized to intermolecular disulfides under HOSCN stress, resulting in its inactivation and derepression of merA transcription to promote HOSCN tolerance. Our study highlights the HOSCN tolerance of S. aureus and characterizes the structure and function of MerA as a major HOSCN defense mechanism. Crippling the capacity to respond to HOSCN may be a novel strategy for treating S. aureus infections.
Two nucleotide sugar transporters are important for cell wall integrity and full virulence of Magnaporthe oryzae
Authors: Chen Deng , Kamran Muhammad , Chen Shen , Xing Junjie , Qu Zhiguang , Liu Caiyun , Ren Zhiyong , Cai Xuan , Chen Xiao‐Lin , Xu Jingbo 
Published: February 2023

AbstractCell wall polysaccharides play key roles in fungal development, virulence, and resistance to the plant immune system, and are synthesized from many nucleotide sugars in the endoplasmic reticulum (ER)‐Golgi secretory system. Nucleotide sugar transporters (NSTs) are responsible for transporting cytosolic‐derived nucleotide sugars to the ER lumen for processing, but their roles in plant‐pathogenic fungi remain to be revealed. Here, we identified two important NSTs, NST1 and NST2, in the rice blast fungus Magnaporthe oryzae. Both NSTs were localized in the ER, which was consistent with a function in transporting nucleotide sugar for processing in the ER. Sugar transport property analysis suggested that NST1 is involved in transportation of mannose and glucose, while NST2 is only responsible for mannose transportation. Accordingly, deletion of NSTs resulted in a significant decrease in corresponding soluble saccharides abundance and defect in sugar utilization. Moreover, both NSTs played important roles in cell wall integrity, were involved in asexual development, and were required for full virulence. The NST mutants exhibited decreasing external glycoproteins and exposure of inner chitin, which resulted in activation of the host defence response. Altogether, our results revealed that two sugar transporters are required for fungal cell wall polysaccharides accumulation and full virulence of M. oryzae.
Effects of mutant huntingtin in oxytocin neurons on non‐motor features of Huntington's disease
Authors: Bergh Sofia , Gabery Sanaz , Tonetto Simone , Kirik Deniz , Petersén Åsa , Cheong Rachel Y. 
Published: February 2023

AbstractBackgroundEarly non‐motor features including anxiety, depression and altered social cognition are present in Huntington's disease (HD). The underlying neurobiological mechanisms are not known. Oxytocin (OXT) is involved in the regulation of emotion, social cognition and metabolism, and our previous work showed that the OXT system is affected early in HD. The aim of the study was to investigate the potential causal relationship between the selective expression of mutant huntingtin (mHTT) in OXT neurons and the development of non‐motor features and neuropathology.MethodsTo express mHTT only in OXT neurons, we used a novel flex‐switch adeno‐associated viral vector design to selectively express either mHTT or wild‐type HTT in the paraventricular nucleus of the hypothalamus using OXT‐Cre‐recombinase mice. We also performed a mirror experiment to selectively delete mHTT in OXT neurons using the BACHD mouse model. Mice underwent a battery of behavioural tests to assess psychiatric and social behaviours 3 months post‐injection or at 2 months of age, respectively. Post‐mortem analyses were performed to assess the effects on the OXT system.ResultsOur results show that selective expression of mHTT in OXT neurons was associated with the formation of mHTT inclusions and a 26% reduction of OXT‐immunopositive neurons as well as increased anxiety‐like behaviours compared with uninjected mice. However, selective deletion of mHTT from OXT neurons alone was not sufficient to alter the metabolic and psychiatric phenotype of the BACHD mice at this early time point.ConclusionsOur results indicate that mHTT expression can exert cell‐autonomous toxic effects on OXT neurons without affecting the non‐motor phenotype at early time points in mice.
Volatile organic compounds as potential biomarkers of irritable bowel syndrome: A systematic review
Authors: Zhang Valencia Ru‐Yan , Ramachandran Gokula Krishnan , Loo Evelyn Xiu Ling , Soh Alex Yu Sen , Yong Wei Peng , Siah Kewin Tien Ho 
Published: February 2023

AbstractBackgroundIrritable bowel syndrome (IBS) is a prevalent gastrointestinal disease characterized by intermittent abdominal pain with altered bowel habits. Due to the condition's chronicity, patients suffer from poor quality of life, while the healthcare burden continues to grow. There is currently no reliable biomarker for the diagnosis of IBS, and the current approach depends on ruling‐out organic diseases such as inflammatory bowel disease (IBD) and colorectal cancer by markers of inflammation like fecal calprotectin and C‐reactive protein, or invasive procedures like a colonoscopy. Volatile organic compounds (VOCs) are growing in popularity as a biomarker due to its accuracy and ease of use.PurposeThis systematic review of Medline and Cochrane's databases aimed to identify VOCs in the diagnosis of IBS. 57% of the studies proved that VOCs could identify IBS patients from healthy controls with AUC ranging from 0.83 to 0.99. Studies that distinguished IBS from IBD patients had slightly higher AUC of 0.87–0.98. Combining VOC into panels allowed the creation of discriminative algorithms. Though current research is limited by areas of heterogeneity in VOC sampling and small sample sizes, our review shows that VOC analysis has the potential to be a noninvasive point‐of‐care test that differentiates IBS from other organic gastrointestinal diseases.
Exploration of associations among dietary tryptophan, microbiome composition and function, and symptom severity in irritable bowel syndrome
Authors: Plantinga Anna M. , Kamp Kendra J. , Wu Qinglong , Chen Li , Yoo Linda , Burr Robert L. , Cain Kevin C. , Raftery Daniel , Carnevale Neto Fausto , Badu Shyam , So Sik Yu , Savidge Tor , Shulman Robert J. , Heitkemper Margaret M. 
Published: February 2023

AbstractBackgroundImbalance of the tryptophan (TRP) pathway may influence symptoms among patients with irritable bowel syndrome (IBS). This study explored relationships among different components that contribute to TRP metabolism (dietary intake, stool metabolite levels, predicted microbiome metabolic capability) in females with IBS and healthy controls (HCs). Within the IBS group, we also investigated relationships between TRP metabolic determinants, Bifidobacterium abundance, and symptoms of IBS.MethodsParticipants with IBS (Rome III) and HCs completed a 28‐day diary of gastrointestinal symptoms and a 3‐day food record for TRP intake. They provided a stool sample for shotgun metagenomics, 16 S rRNA analyses, and quantitative measurement of TRP by mass spectrometry.ResultsOur cohort included 115 females, 69 with IBS and 46 HCs, with a mean age of 28.5 years (SD 7.4). TRP intake (p = 0.71) and stool TRP level (p = 0.27) did not differ between IBS and HC. Bifidobacterium abundance was lower in the IBS group than in HCs (p = 0.004). Predicted TRP metabolism gene content was higher in IBS than HCs (FDR‐corrected q = 0.006), whereas predicted biosynthesis gene content was lower (q = 0.045). Within the IBS group, there was no association between symptom severity and TRP intake or stool TRP, but there was a significant interaction between Bifidobacterium abundance and TRP intake (q = 0.029) in predicting stool character.ConclusionsDietary TRP intake, microbiome composition, and differences in TRP metabolism constitute a complex interplay of factors that could modulate IBS symptom severity.
Cross‐sectional associations between physical fitness and biomarkers of inflammation in children—ThePANICstudy
Authors: Haapala Eero A. , Kuronen Emmi , Ihalainen Johanna K. , Lintu Niina , Leppänen Marja H. , Tompuri Tuomo , Atalay Mustafa , Schwab Ursula , Lakka Timo A. 
Published: February 2023

BackgroundSystemic low‐grade inflammation has been proposed as an underlying pathophysiological mechanism for cardiometabolic diseases. We investigated the associations of physical fitness with a systemic low‐grade inflammatory state in a population sample of children.MethodsAltogether 391 children aged 6–9 years were examined. Cardiorespiratory fitness (maximal power output,Wmax) was assessed by a maximal cycle ergometer test and neuromuscular fitness by hand grip strength, sit‐up, standing long jump, 50‐meter shuttle run, static balance, sit‐and‐reach, and box and block tests. Body fat percentage (BF%) and lean mass (LM) were assessed by dual‐energy X‐ray absorptiometry (DXA). High sensitivity C‐reactive protein (hs‐CRP), leptin, leptin receptor, high molecular weight adiponectin (HMW‐adiponectin), interleukin‐6 (IL‐6), tumor necrosis factor‐alpha (TNF‐α), and glycoprotein acetyls (GlycA) were assessed from fasting blood samples. The modified inflammatory score (IS) was calculated using the population‐specificz‐scores and formula (zhs‐CRP + zleptin + zIL‐6 + zTNF‐α + zGlycA)—zleptin receptor—zHMW‐adiponectin. The data were analyzed using linear regression analyses.ResultsHigherWmax/kg of body mass (β = −0.416, 95% CI = −0.514 to −0.318), higher number of completed sit‐ups (β = −0.147, 95% CI = −0.244 to −0.049), a longer distance jumped in the standing long jump test (β = −0.270, 95% CI = −0.371 to −0.169), and a shorter time in the 50‐meter shuttle run test (β = 0.123, 95% CI = 0.022 to 0.223) were associated with lower IS. None of these associations remained statistically significant after adjustment for BF%.ConclusionsHigher physical fitness is associated with a more favorable inflammatory biomarker profile in children. However, the associations were explained by BF%.
Analytical investigations on non-minimally coupled scalar fields outside neutral reflecting shells
Authors: Peng Yan 
Published: February 2023

AbstractWe study the existence of scalar fields outside neutral reflecting shells. We consider static massive scalar fields non-minimally coupled to the Gauss–Bonnet invariant. We analytically investigated properties of scalar fields through the scalar field equation. In the small scalar field mass regime, we derive a compact resonance formula for the allowed masses of scalar fields in the composed scalar field and shell configurations.
Tectonic development, thermal regimes and hydrocarbon habitat of transform margins, and their differences from rifted margins – an introduction
Authors: Nemčok M. , Doran H. , Doré A. G. , Ledvényiová L. , Rybár S. , Staniaszek S. , Gontar T. 
Published: February 2023

Abstract
Drilling, 3D seismic and deep seismic studies in recent years have significantly progressed our knowledge of continental margins. Some of the key studies are brought together in this volume, focusing on the evolution and architecture of transform faults and transform margins, giving special attention to the relationship, and differences, between transform and rift margins. Papers from a wide range of global settings consider thermal history, depositional regime, hydrocarbon prospectivity and (in a continental setting) geothermal potential. This scene-setting paper examines our current state of knowledge on transform and rift settings, and provides a brief introduction to the subject matter and context of the papers in the volume.
Hexagonal Boron Nitride as Anode for Sodium Ion Battery – A Reality Check!
Authors: Garg Shubham , Parmar Avanish Singh , Rosy Rosy 
Published: February 2023

Abstract
Sodium-ion batteries (SIBs) have gained enormous attention as an alternative electrochemical energy storage system. A significant challenge for their practical viability is finding an anode material that can provide high specific capacity along with good cycling stability. Recently, numerous theoretical works have proposed hexagonal boron nitride (hBN) as a promising anode material for SIBs. Nevertheless, there has been no reported experimental verification for these theoretical claims. To fill the knowledge gap, the electrochemical performance of hBN has been investigated under the capacity of a potential anode for SIBs. The effect of particle morphology on the electrochemical performance of hBN has also been investigated using bulk hBN powder and nanoplatelets hBN as active materials. Unexpectedly, hBN showcased minimal charging capacity with effectively no reversible intercalation/de-intercalation of Na-ions. The obtained results provide experimental insight into the ineffectiveness of hBN in serving as SIB anode material, unlike the previous theoretical claims. We believe it is essential to report these discrepancies in the computational and experimental findings for the benefit of experimentalists working enthusiastically to explore and develop new anode materials related to boron nitride systems.
Targeting Glutamine Metabolism with a Novel Na+/K+-ATPase Inhibitor RX108 in Hepatocellular Carcinoma
Authors: Wei Daoyan , Chen Dongmei , Mou Hongyuan , Chakraborty Sharmistha , Wei Bo , Tan Lin , Lorenzi Philip L. , Qian Xiangping , Yang Peiying 
Published: February 2023

Abstract

The poor prognosis and limited therapeutic options for human hepatocellular carcinoma (HCC), the most common form of liver cancer, highlight the urgent need to identify novel therapeutic modalities. Here, we describe the antitumor activity and underlying molecular mechanisms of a novel Na+/K+-ATPase inhibitor RX108 in human HCC cells and its xenograft model. RX108 dose-dependently inhibited HCC cell proliferation in vitro and tumor growth in a xenograft mouse model, and that the inhibition was associated with induction of apoptosis. Mechanistically, RX108 significantly downregulated alanine serine cysteine transporter 2 (ASCT2) protein expression and reduced glutamine and glutamate concentration in HCC cells and tumors. In addition, RX108 exposure led to a significant decrease in cell energy metabolism in Huh7 and Hep3B cells, including decreased levels of glutathione, NADH, NADPH, and mitochondrial respiration oxygen consumption rate. Furthermore, HCC cells exhibited evidence of glutamine addiction; the antiproliferative effect of RX108 was dependent on glutamine transport. Clinically, elevated ASCT2 mRNA expression in HCCs was associated with unfavorable survival. Taken together, these findings reveal a novel approach to target glutamine metabolism through inhibiting Na+/K+-ATPase and provide a rationale for using RX108 to treat HCC in patients whose tumors express ASCT2 at high levels. RX108 is currently under clinical development.
Adult Low-Hypodiploid Acute Lymphoblastic Leukemia Evolves fromTP53-Mutated Clonal Hematopoiesis
Authors: Saiki Ryunosuke , Ogawa Seishi 
Published: February 2023

Summary:Low-hypodiploid acute lymphoblastic leukemia (LH-ALL) in both children and adults is characterized by biallelic TP53 alterations in virtually all cases. However, in contrast to a common germline origin of the TP53 mutations in pediatric cases, those in adult cases are mostly somatic and are derived from age-related clonal hematopoiesis (ARCH), highlighting the role of TP53-mutant ARCH in the development not only of myeloid leukemogenesis but also of LH-ALL in aged populations.See related article by Kim et al., p. 134 (4).
Analysis of N-linked Glycan Alterations in Tissue and Serum Reveals Promising Biomarkers for Intrahepatic Cholangiocarcinoma
Authors: Ochoa-Rios Shaaron , Blaschke Calvin R.K. , Wang Mengjun , Peterson Kendell D. , DelaCourt Andrew , Grauzam Stéphane Elie , Lewin David , Angel Peggi , Roberts Lewis R. , Drake Richard , Mehta Anand S. 
Published: February 2023

There is an urgent need for the identification of reliable prognostic biomarkers for patients with intrahepatic cholangiocarcinoma (iCCA) and alterations in N-glycosylation have demonstrated an immense potential to be used as diagnostic strategies for many cancers, including hepatocellular carcinoma (HCC). N-glycosylation is one of the most common post-translational modifications known to be altered based on the status of the cell. N-glycan structures on glycoproteins can be modified based on the addition or removal of specific N-glycan residues, some of which have been linked to liver diseases. However, little is known concerning the N-glycan alterations that are associated with iCCA. We characterized the N-glycan modifications quantitatively and qualitatively in three cohorts, consisting of two tissue cohorts: a discovery cohort (n = 104 cases) and a validation cohort (n = 75), and one independent serum cohort consisting of patients with iCCA, HCC, or benign chronic liver disease (n = 67). N-glycan analysis in situ was correlated to tumor regions annotated on histopathology and revealed that bisected fucosylated N-glycan structures were specific to iCCA tumor regions. These same N-glycan modifications were significantly upregulated in iCCA tissue and serum relative to HCC and bile duct disease, including primary sclerosing cholangitis (PSC) (P &lt; 0.0001). N-glycan modifications identified in iCCA tissue and serum were used to generate an algorithm that could be used as a biomarker of iCCA. We demonstrate that this biomarker algorithm quadrupled the sensitivity (at 90% specificity) of iCCA detection as compared with carbohydrate antigen 19-9, the current “gold standard” biomarker of CCA.Significance:This work elucidates the N-glycan alterations that occur directly in iCCA tissue and utilizes this information to discover serum biomarkers that can be used for the noninvasive detection of iCCA.