bluuebunny/crossref_metadata_2025 huggingface dataset:
Update on the genus Robertmurraya: a bacterial genus honoring Dr. Robert G.E. Murray (with some personal reminiscences)
Authors: Gupta Radhey S.
Published: August 2023

The genus Robertmurraya was created by my group in 2020 to recognize the contributions of Dr. Robert G.E. Murray to the field of prokaryotic taxonomy. This manuscript updates the information regarding this genus. In addition to the seven Robertmurraya species with validly published names, the work presented here shows that two species with effectively published names, “ Bacillus yapensis” and “ Bacillus dakarensis”, and an uncharacterized Bacillus sp. Y1 are also affiliated with this genus. Based on these results, reclassification of “ Bacillus yapensis” as a novel species Robertmurraya yapensis sp. nov. is proposed. It is also suggested that “ Bacillus dakarensis”, for which strains are not available from culture collections, should also be recognized as “ Robertmurraya dakarensis”. This article also reflects on the serendipitous way I came to know Dr. Murray and his extensive interactions with me and strong support for our work for more than 10 years. Dr. Murray also introduced me and our work to his friend and contemporary Dr. Peter Sneath, who like him also contributed extensively to the field of prokaryotic taxonomy. This introduction led to a fruitful collaboration with Dr. Sneath leading to a joint publication describing the use of the Character Compatibility approach to molecular sequence data.
Impact of barrow entropy on geometrothermodynamics of specific black holes
Authors: Rani Shamaila , Jawad Abdul , Hussain Mazhar
Published: August 2023

In this paper, we study the effect of Barrow entropy on the thermodynamic properties and geometry of specific black holes along with the nonlinear source. We investigate the mass, temperature, thermodynamic variable, and electric potential of the black hole as well. Furthermore, we examine the behavior of heat capacity to check the stability of a black hole. Geometrothermodynamics allows us to describe interactions between thermodynamics, critical points, and phase transitions by considering the geometric characteristics of the thermodynamic equilibrium space. Our analysis demonstrates that these findings are consistent with the results derived from the classical thermodynamics of black holes.
$$\nu $$ Electroweak baryogenesis: the scalar singlet strikes back
Authors: Fernández-Martínez E. , López-Pavón J. , No J. M. , Ota T. , Rosauro-Alcaraz S.
Published: August 2023

We perform a comprehensive scan of the parameter space of a general singlet scalar extension of the Standard Model to identify the regions which can lead to a strong first-order phase transition, as required by the electroweak baryogenesis mechanism. We find that taking into account bubble nucleation is a fundamental constraint on the parameter space and present a conservative and fast estimate for it so as to enable efficient parameter space scanning. The allowed regions turn out to be already significantly probed by constraints on the scalar mixing from Higgs signal strength measurements. We also consider the addition of new neutrino singlet fields with Yukawa couplings to both scalars and forming heavy (pseudo)-Dirac pairs, as in the linear or inverse Seesaw mechanisms for neutrino mass generation. We find that their inclusion does not alter the allowed parameter space from early universe phenomenology in a significant way. Conversely, there are allowed regions of the parameter space where the presence of the neutrino singlets would remarkably modify the collider phenomenology, yielding interesting new signatures in Higgs and singlet scalar decays.
Restorable Shortest Path Tiebreaking for Edge-Faulty Graphs
Authors: Bodwin Greg , Parter Merav
Published: August 2023

The
restoration lemma
by Afek et al. [
3
] proves that, in an undirected unweighted graph, any replacement shortest path avoiding a failing edge can be expressed as the concatenation of two original shortest paths. However, the lemma is
tiebreaking-sensitive
: if one selects a particular canonical shortest path for each node pair, it is no longer guaranteed that one can build replacement paths by concatenating two
selected
shortest paths. They left as an open problem whether a method of shortest path tiebreaking with this desirable property is generally possible.

We settle this question affirmatively with the first general construction of
restorable tiebreaking schemes
. We then show applications to various problems in fault-tolerant network design. These include a faster algorithm for subset replacement paths, more efficient fault-tolerant (exact) distance labeling schemes, fault-tolerant subset distance preservers and + 4 additive spanners with improved sparsity, and fast distributed algorithms that construct these objects. For example, an almost immediate corollary of our restorable tiebreaking scheme is the first nontrivial distributed construction of sparse fault-tolerant distance preservers resilient to
three
faults.
Ninjinyoeito Prevents Onset of Depression‐Like Behavior and Reduces Hippocampal iNOS Expression in Senescence‐Accelerated Mouse Prone 8 Mice
Authors: Taniguchi Chise , Watanabe Takuya , Hirata Marika , Hatae Akinobu , Kubota Kaori , Katsurabayashi Shutaro , Iwasaki Katsunori
Published: August 2023

Late‐life depression is a globally prevalent disorder. Ninjinyoeito (NYT), a traditional Japanese herbal medicine, attenuates depressive symptoms in older patients. However, the mechanisms underlying the antidepressive effect of NYT are unknown. In this study, we investigated the mechanism of the action of NYT using senescence‐accelerated mouse prone 8 (SAMP8) mice, which exhibit accelerated aging. SAMP8 mice were treated with NYT starting at 12 weeks of age. Twelve‐week‐old SAMP8 mice did not show prolonged immobility time in the tail suspension test compared with age‐matched SAMR1 mice (normal aging control). At 34 weeks of age, vehicle‐treated SAMP8 mice displayed prolonged immobility time compared with SAMR1 mice. NYT‐treated SAMP8 mice showed a shorter immobility time than that of vehicle‐treated SAMP8 mice. Notably, NYT decreased hippocampal inducible nitric oxide synthase (iNOS) expression in SAMP8 mice. There was no difference in iNOS expression between SAMR1 and vehicle‐treated SAMP8 mice. Subchronic (5 days) administration of an iNOS inhibitor, 1400 W, shortened the immobility time in SAMP8 mice. These results suggest that NYT prevents an increase in immobility time of SAMP8 mice by decreasing iNOS levels in the hippocampus. Therefore, the antidepressive effect of NYT in older patients might be mediated, at least in part, by the downregulation of iNOS in the brain. Our data suggest that NYT is useful to prevent the onset of depression with aging.
Unexpected Inheritance Patterns in a Large Cohort of Patients with a Suspected Ciliopathy
Authors: Gouronc Aurélie , Javey Elodie , Leuvrey Anne-Sophie , Nourisson Elsa , Friedmann Sylvie , Reichert Valérie , Derive Nicolas , Francannet Christine , Keren Boris , Lévy Jonathan , Planes Marc , Ruaud Lyse , Amiel Jeanne , Dollfus Hélène , Scheidecker Sophie , Muller Jean
Published: August 2023

Ciliopathies are rare genetic disorders caused by dysfunction of the primary or motile cilia. Their mode of inheritance is mostly autosomal recessive with biallelic pathogenic variants inherited from the parents. However, exceptions exist such as uniparental disomy (UPD) or the appearance of a de novo pathogenic variant in trans of an inherited pathogenic variant. These two genetic mechanisms are expected to be extremely rare, and few data are available in the literature, especially regarding ciliopathies. In this study, we investigated 940 individuals (812 families) with a suspected ciliopathy by Sanger sequencing, high-throughput sequencing and/or SNP array analysis and performed a literature review of UPD and de novo variants in ciliopathies. In a large cohort of 623 individuals (511 families) with a molecular diagnosis of ciliopathy (mainly Bardet-Biedl syndrome and Alström syndrome), we identified five UPD, revealing an inherited pathogenic variant and five pathogenic variants of de novo appearance (in trans of another pathogenic variant). Moreover, from these ten cases, we reported 15 different pathogenic variants of which five are novel. We demonstrated a relatively high prevalence of UPD and de novo variants in a large cohort of ciliopathies and highlighted the importance of identifying such rare genetic events, especially for genetic counseling.
Nutritional and Metabolomic Changes of Juvenile Farmed Abalone (Haliotis iris) in New Zealand
Authors: Bullon Natalia , Seyfoddin Ali , Dezfooli Seyedehsara Masoomi , Young Tim , Alfaro Andrea C.
Published: August 2023

Seasonal variations play a crucial role in the physiology, immune responses, and nutritional profile of aquatic animals. Unpredictable water temperature fluctuations, especially those caused by climate change, may negatively affect feed consumption and growth of cultured organisms, such as abalone. In addition, metabolic and nutritional changes across different seasons may have significant effects on aquaculture production. This study aimed to investigate biochemical and metabolic alterations in healthy abalone (Haliotis iris) during 1 year of grow out in a land-based farm in New Zealand. Proximate analyses were used to identify nutritional variations in whole animal tissues, and a gas chromatography–mass spectrometry-based metabolomics approach was used to identify metabolic changes in adductor muscle of abalone during different seasons in the 1-year sampling period. Results showed that protein content was higher in warmer months compared with colder months, whereas lipid, ash, and carbohydrate contents remained generally constant throughout the year. Metabolic profile fluctuations indicated higher amounts of glutamic acid, glutathione, methionine, lysine, serine, tyrosine, and glycine in January and March compared with October and July, indicating possible amino acid breakdown and collagen degradation due to warmer temperatures. Although the proximate analyses findings revealed no signs of nutritional deficiencies in abalone among seasons, the metabolic profiles suggested possible thermal stress during summer months. This study provides a foundation for further nutritional studies to optimise seasonal diets for farmed Haliotis iris and highlights the need to monitor thermal stress effects, especially during summer and/or heatwave events.
Antioxidant and Immunomodulatory Activities of Polysaccharides from Fermented Wheat Products of Grifola frondosa: In Vitro Methods
Authors: Xu Xiaoqing , Liu Ying , Pan Chunli , Han Shaoliang , Ma Lan , Qiao Yu , Shi Bo , Peng Qing
Published: August 2023

Despite the well-known health benefits of Grifola frondosa, there is a lack of understanding regarding the potential antioxidant and immunomodulatory properties of different varieties when fermented with wheat grains. We aimed to explore the potential of G. frondosa-fermented wheat flour as a functional food. Three varieties of G. frondosa (GFA, GFB, and GFC) were fermented with wheat grains for solid-state fermentation. Polysaccharides were extracted and analyzed for total sugar content, monosaccharide composition, Mw profile, antioxidant activity, cytotoxicity, and immunomodulatory properties. Results were evaluated using HPLC, DPPH assay, MTS assay, Griess reagent, and ELISA method. Our study found variations in three different varieties of G. frondosa-fermented wheat polysaccharides. Glucose was the predominant monosaccharide, followed by galactose and mannose. Each variety had a different molecular weight distribution, with GFA-wheat mainly present in fraction II, GFB-wheat in fraction I, and GFC-wheat in fraction III. At a concentration of 1.25 mg/mL, GFA-wheat and GFB-wheat polysaccharides increased DPPH scavenging ability by 76.8% and 58.7%, respectively. The polysaccharides showed no apparent toxic effect and enhanced the production of NO, IL-6, and TNF-α in RAW 246.7 macrophages. GFB-wheat polysaccharides demonstrated remarkable immunomodulatory properties at a concentration of 5 μg/mL. Our study provides a theoretical basis for using G. frondosa in wheat staple agricultural products to improve human health.
Crataeva nurvala Bark (Capparidaceae) Extract Modulates Oxidative Stress‐Related Gene Expression, Restores Antioxidant Enzymes, and Prevents Oxidative Stress in the Kidney and Heart of 2K1C Rats
Authors: Jahan Ishrat , Saha Proma , Eysha Chisty Tammana Tabassum , Mitu Kaniz Fatima , Chowdhury Faizul Islam , Ahmed Khondoker Shahin , Hossain Hemayet , Khan Ferdous , Subhan Nusrat , Alam Md. Ashraful
Published: August 2023

Objective. Crataeva nurvala is a medicinal plant, which contains a wide range of polyphenolic and bioactive compounds. The aim of the study was to evaluate the renal‐protective activity of Crataeva nurvala in two‐kidney, one‐clip (2K1C) rats. Methods. In this study, the ethanol extract of Crataeva nurvala bark at a dose of 100 mg/kg was orally used to treat 2K1C rats for four weeks. At the end of the experiment, all rats were sacrificed and tissue samples were collected for further biochemical and histological assessments. Results. This investigation showed that Crataeva nurvala treatment prevented the kidney dysfunction in 2K1C rats. Uric acid and creatinine concentration and CK‐MB activities increased in 2K1C rats which were normalized by Crataeva nurvala. 2K1C rats also showed increased oxidative stress, depicted by the elevated level of MDA, NO, and APOP in plasma and tissues. Oxidative stress parameters declined in 2K1C rats by the treatment of Crataeva nurvala. These results could be attributed to the restoration of antioxidant enzyme activities such as catalase and SOD. Crataeva nurvala extracts also upregulated antioxidant gene expression in the kidneys of 2K1C rats. Moreover, several anti‐inflammatory genes were suppressed by Crataeva nurvala treatment in 2K1C rats. Furthermore, fibrosis and collagen deposition in the kidneys were also lowered by the treatment of the Crataeva nurvala extract. Conclusion. The experimental data suggest that the Crataeva nurvala extract protected renal damage and oxidative stress, probably by restoring antioxidant enzymes activities in 2K1C rats.
A Single-Center Experience of Correlation of Pulse Pressure to Mortality of Stroke Hemorrhage Patients in Indonesia
Authors: Makkiyah Feda Anisah , Dicha Saraah , Nurrizzka Rahmah Hida
Published: August 2023

Introduction. The relationship between pulse pressure and mortality in acute stroke hemorrhage patients is a subject of debate. To investigate this relationship in the Indonesian context, a study was conducted due to the increasing prevalence of stroke in the country. Methods. The study sample consisted of 111 patients with acute stroke hemorrhage admitted to the hospital between January 1, 2016, and December 31, 2019. Patients with sepsis, cancer, or other hematology disorders were excluded, as were those who were lost to follow-up. Statistical analysis was performed using SPSS 22, and correlations were evaluated between various patient characteristics and laboratory values. Results. It was revealed that patients with a wider pulse pressure were more likely to die (adjusted odds ratio = 3,070) than those with a normal or constricted pulse pressure. Conclusion. Pulse pressure had an impact on the mortality of patients with acute hemorrhagic stroke.
Towards Diagnostic Aided Systems in Coronary Artery Disease Detection: A Comprehensive Multiview Survey of the State of the Art
Authors: Garavand Ali , Behmanesh Ali , Aslani Nasim , Sadeghsalehi Hamidreza , Ghaderzadeh Mustafa
Published: August 2023

Introduction. Coronary artery disease (CAD) is one of the main causes of death all over the world. One way to reduce the mortality rate from CAD is to predict its risk and take effective interventions. The use of machine learning‐ (ML‐) based methods is an effective method for predicting CAD‐induced death, which is why many studies in this field have been conducted in recent years. Thus, this study aimed to review published studies on artificial intelligence classification algorithms in CAD detection and diagnosis. Methods. This study systematically reviewed the most cutting‐edge techniques for analyzing clinical and paraclinical data to quickly diagnose CAD. We searched PubMed, Scopus, and Web of Science databases using a combination of related keywords. A data extraction form was used to collect data after selecting the articles based on inclusion and exclusion criteria. The content analysis method was used to analyze the data, and based on the study’s objectives, the results are presented in tables and figures. Results. Our search in three prevalent databases resulted in 15689 studies, of which 54 were included to be reviewed for data analysis. Most studies used laboratory and demographic data classification and have shown desirable results. In general, three ML methods (traditional ML, DL/NN, and ensemble) were used. Among the algorithms used, random forest (RF), linear regression (LR), neural networks (NNs), support vector machine (SVM), and K‐nearest networks (KNNs) have the most applications in the field of code recognition. Conclusion. The findings of this study show that these models based on different ML methods were successful despite the lack of a benchmark for comparing and analyzing ML features, methods, and algorithms in CAD diagnosis. Many of these models performed better in their analyses of CAD features as a result of a closer look. In the near future, clinical specialists can use ML‐based models as a powerful tool for diagnosing CAD more quickly and precisely by looking at its design’s technical facets. Among its incredible outcomes are decreased diagnostic errors, diagnostic time, and needless invasive diagnostic tests, all of which typically result in decreases in diagnostic expenses for healthcare systems.
Application of Data-Driven Building Information Modeling in the Visual Simulation of Disease Transmission and Route with Pipeline System
Authors: Pan Chen-Yu , Hsu Hsieh-Chih , Huang Ko-Wei , Lin Ya-Hua
Published: August 2023

Currently, preventing epidemics is an extremely critical global topic. Using present data to quickly conduct virus simulations is a difficult but interesting problem, especially when real situations are difficult to experimentally demonstrate. In the past, most studies have used package software for disease transmission simulation, but this approach is limited by availability and software cost. Therefore, we propose a visual simulation of disease transmission using building information modeling data and a 3D model using Unity. The results show that the proposed method can effectively predict the probability and route of disease transmission; it also verifies that the vertical pipeline on the floor plane is conducive to the spread of the virus (90%), and disease transmission on the plane gradually expands outward from the starting room and has a higher probability of spreading (80%) from the opposite room. In addition, a vertical pipeline was simulated using a toilet exhaust air ventilation pipeline, from which it can be observed that the adjacent floors have a higher diffusion probability (70%). It has also been confirmed that distance is the primary factor affecting disease transmission. This framework may provide designers and managers further protection against the spread of future epidemics.
A Case of Closed Pilon Fracture Resulting in Soft-Tissue Necrosis and Treated with Reverse Sural Artery Flap and Circular External Fixation
Authors: Igaki Ryu , Yasuda Tomohiro , Samejima Yuki , Irie Yuko , Murakami Yuto , Yoneya Taisuke , Takagi Shinsuke , Kawasaki Keikichi , Kanzaki Koji
Published: August 2023

Tibial pilon fractures are difficult to treat due to articular comminution and soft-tissue injuries caused by high-energy trauma. Open reduction and internal fixation is a commonly used method of treatment. However, it has a high risk of infection and soft-tissue complications due to the extensive detachment of soft tissue. We report on a case with a tibial pilon fracture and soft-tissue necrosis that we treated using limited internal fixation combined with a circular external fixator (LIFCEF) and reverse sural artery flap (RSAF) as part of an orthoplastic approach within the orthopedic surgery department alone, which obtained good results. A 51-year-old man was injured in a motorcycle accident and transported to a nearby hospital. X-rays at the time of injury showed tibial pilon fractures (AO Foundation/Orthopedic Trauma Association 43c3.3, Ruedi–Allgower: Type III). Soft-tissue necrosis with blisters on the medial side of the lower leg (AO soft-tissue classification: IC3-MT1-NV1) was observed. In addition, the patient was referred to our hospital on day 10 of the injury. LIFCEF was chosen for treating the fracture because plate fixation was accompanied by the risk of plate exposure, soft-tissue complications, and an increased skin defect area, and RSAF was chosen to reconstruct the soft tissue defect. Four years after the surgery, the American Orthopedic Foot and Ankle Score was 92 points. X-ray alignment evaluation showed mLDTA 93° and aADTA 91°. Stage 2 arthrosis was present according to the Takakura ankle osteoarthritis classification, but the patient was able to walk without pain. Tibial pilon fractures are difficult to treat due to articular comminution and soft-tissue injuries caused by high-energy trauma. The timing and choice of treatment are crucial concerning the soft tissue.
Predictors of Responsiveness to GLP-1 Receptor Agonists in Insulin-Treated Patients with Type 2 Diabetes
Authors: Gavigan Colleen , Donner Thomas
Published: August 2023

Background. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are potent antihyperglycemic agents with beneficial effects on weight, cardiovascular, and renal outcomes. Physicians lack guidance as to which patients with insulin-requiring type 2 diabetes will respond best to GLP-1 RAs with respect to glycemic control, insulin dose reduction, and weight loss. This study evaluated the efficacy of GLP-1 RAs in patients with type 2 diabetes on insulin and patient factors that may predict a beneficial clinical response. Methods. Adults with type 2 diabetes treated with insulin who had a GLP-1 RA added to their regimen were evaluated retrospectively. Baseline parameters and outcomes at 3, 6, and 12 months were collected. Results. Among the 81 patients included, there was a mean reduction in hemoglobin A1C of 0.94% (SD, 0.26;

p
=
0.0007

), 0.40% (SD, 0.21;

p
=
0.0636

), and 0.58% (SD, 0.23,

p
=
0.0154

) at 3, 6, and 12 months, respectively, following the addition of a GLP-1 RA. There was also a reduction in body weight noted at each time point. Baseline characteristics including BMI, duration of diabetes, and insulin requirement did not significantly affect A1C reduction when GLP-1 RA was added. At 3 months, patients with a random C-peptide that was normal (≥0.8 ng/ml) were significantly more likely to have discontinued insulin than those with random C-peptide that was low (<0.8 ng/ml) (11 of 23 vs. 0 of 7 patients,

p
=
0.029

). Conclusions. The addition of a GLP-1 RA reduced HbA1C, weight, and insulin requirements in this cohort of patients with type 2 diabetes on insulin. BMI, baseline insulin dose, and diabetes duration did not predict response. A C-peptide

level
≥
0.8

 ng/ml predicted a beneficial response after 3 months of therapy.
Data from Germline mutations in 12 genes and risk of ovarian cancer in three population-based cohorts
Authors: Kotsopoulos Joanne , Hathaway Cassandra A. , Narod Steven A. , Teras Lauren R. , Patel Alpa V. , Hu Chunling , Yadav Siddhartha , Couch Fergus J. , Tworoger Shelley S.
Published: August 2023

Abstract
Background: With the widespread use of multigene panel genetic testing, population-based studies are necessary to accurately assess penetrance in unselected individuals. We evaluated the prevalence of germline pathogenic or likely pathogenic variants (mutations) in 12 cancer-predisposition genes and associations with ovarian cancer risk in three population-based prospective studies (Nurses’ Health Study [NHS], NHSII, Cancer Prevention Study II).
Methods: We included women with epithelial ovarian or peritoneal cancer (n=776) and controls who were alive and had at least one intact ovary at the time of the matched case diagnosis (n=1,509). Germline DNA was sequenced for mutations in 12 genes. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for ovarian cancer risk by mutation status.
Results: The mutation frequency across all 12 genes was 11.2% in cases and 3.3% in controls (P<0.0001). BRCA1 and BRCA2 were the most frequently mutated (3.5% and 3.8% of cases and 0.3% and 0.5% of controls, respectively) and were associated with increased ovarian cancer risk (OR, BRCA1=12.38; 95%CI=4.72-32.45; OR, BRCA2=9.18; 95%CI=3.98-21.15). Mutation frequencies for the other genes were ≤1.0% and only PALB2 was significantly associated with risk (OR=5.79; 95%CI=1.09-30.83). There was no difference in survival for women with a BRCA germline mutation versus no mutation.
Conclusions: Further research is needed to better understand the role of other mutations in ovarian cancer among unselected populations.
Impact: Our data support guidelines for germline genetic testing for BRCA1 and BRCA2 among women diagnosed with epithelial ovarian cancer; testing for PALB2 may be warranted.
Data from CBF-beta mitigates PI3K-alpha-specific inhibitor killing through PIM1 in PIK3CA mutant gastric cancer
Authors: Stanland Lyla J. , Ang Hazel X. , Hoj Jacob P. , Chu Yunqiang , Tan Patrick , Wood Kris C. , Luftig Micah A.
Published: August 2023

Abstract
PIK3CA is the second most mutated gene in cancer leading to aberrant PI3K/AKT/mTOR signaling and increased translation, proliferation, and survival. Some 4-25% of gastric cancers display activating PIK3CA mutations including 80% of EBV-associated GCs. Small molecules including pan-PI3K and dual PI3K/mTOR inhibitors have shown moderate success clinically, due to broad on-target/off-tissue effects. Thus, isoform specific and mutant selective inhibitors have been of significant interest. However, drug resistance is a problem and has affected success of new drugs. There has been a concerted effort to define mechanisms of resistance and identify potent combinations in many tumor types, though gastric cancer is comparatively understudied. In this study we identified modulators of the response to the PI3K-alpha-specific inhibitor, BYL719, in PIK3CA mutant GCs. We found that loss of NEDD9 or inhibition of BCL-XL conferred hyper-sensitivity to BYL719, through increased cell cycle arrest and cell death, respectively. Additionally, we discovered that loss of CBFB conferred resistance to BYL719. CBFB loss led to up-regulation of the protein kinase PIM1, which can phosphorylate and activate several overlapping downstream substrates as AKT thereby maintaining pathway activity in the presence of PI3K-alpha inhibition. The addition of a pan-PIM inhibitor re-sensitized resistant cells to BYL719. Our data provide clear mechanistic insights into PI3K-alpha inhibitor response in PIK3CA mutant gastric tumors and can inform future work as mutant selective inhibitors are in development for diverse tumor types.

Implications: Loss of either NEDD9 or BCL-XL confers hyper-sensitivity to PI3K-alpha inhibition while loss of CBFB confers resistance through a CBFB/PIM1 signaling axis.
GABA Regulates Electrical Activity and Tumor Initiation in Melanoma
Authors: Tagore Mohita , Hergenreder Emiliano , Perlee Sarah C. , Cruz Nelly M. , Menocal Laura , Suresh Shruthy , Chan Eric , Baron Maayan , Melendez Stephanie , Dave Asim , Chatila Walid K. , Nsengimana Jeremie , Koche Richard P. , Hollmann Travis J. , Ideker Trey , Studer Lorenz , Schietinger Andrea , White Richard M.
Published: August 2023

Oncogenes can initiate tumors only in certain cellular contexts, which is referred to as oncogenic competence. In melanoma, whether cells in the microenvironment can endow such competence remains unclear. Using a combination of zebrafish transgenesis coupled with human tissues, we demonstrate that GABAergic signaling between keratinocytes and melanocytes promotes melanoma initiation by BRAFV600E. GABA is synthesized in melanoma cells, which then acts on GABA-A receptors in keratinocytes. Electron microscopy demonstrates specialized cell–cell junctions between keratinocytes and melanoma cells, and multielectrode array analysis shows that GABA acts to inhibit electrical activity in melanoma/keratinocyte cocultures. Genetic and pharmacologic perturbation of GABA synthesis abrogates melanoma initiation in vivo. These data suggest that GABAergic signaling across the skin microenvironment regulates the ability of oncogenes to initiate melanoma.

Significance:

This study shows evidence of GABA-mediated regulation of electrical activity between melanoma cells and keratinocytes, providing a new mechanism by which the microenvironment promotes tumor initiation. This provides insights into the role of the skin microenvironment in early melanomas while identifying GABA as a potential therapeutic target in melanoma.

See related commentary by Ceol, p. 2128.

This article is featured in Selected Articles from This Issue, p. 2109
Exercise as an Immune Boost: Mechanism-Driven Support for Lifestyle Interventions
Authors: Betof Warner Allison
Published: August 2023

Modifiable host factors have demonstrated promise to enhance responses to immunotherapy. In this issue, Savage et al. investigated the use of aerobic exercise to enhance antitumor immunity in a murine model of melanoma. They show that treadmill running improves tumor vasculature and alters both T-cell and myeloid-cell infiltration of the tumor via an ERK5-dependent mechanism, adding to the growing evidence supporting the immune-mediated antitumor effects of exercise.

See related article by Savage et al., p. 1168 (3).
Generalized Lymphatic Anomaly as a Differential Diagnosis of Lytic Lesions
Authors: Catani Greta , Waisberg Federico , Enrico Diego , Rodriguez Andrés , Pflüger Yanina , Galluzzo María Laura , Centeno María del Valle , Colmenero Isabel , Amat Mora , Paganini Lisandro , García Herrmann Anna Frida , Chacón Matías
Published: August 2023

Generalized lymphatic anomaly (GLA) is an infrequent multiorgan disease characterized by the presence of abnormal proliferation of lymphatic vessels. The diagnosis requires histological confirmation, and the treatment is controversial. We are presenting a case of a 28-year-old male patient who was diagnosed with an extragonadal mediastinal nonseminomatous germ cell tumor. He underwent chemotherapy, and during this treatment, radiologic findings evidenced lytic lesions. Multiple biopsies were performed, which revealed the presence of abnormal lymphatic vessels, characteristic of GLA. There are different etiologies of osteolytic lesions, and on some occasions, they mimic a tumoral entity. The clinical suspicion of GLA is the first step in approaching the diagnosis, particularly in young adult patients.
Cross-Cultural Disparities in Psychosocial Research with Individuals with Classical Congenital Adrenal Hyperplasia: A Scoping Review
Authors: Traino Katherine A. , Basile Nathan L. , Chang Hui-Fen , Fisher Rachel S. , Dattilo Taylor M. , Mullins Larry L. , Ediati Annastasia , Wisniewski Amy B.
Published: August 2023

Introduction: There are increased calls to address psychosocial needs among individuals with classical congenital adrenal hyperplasia (CAH). However, cross-cultural disparities exist in treatment practices and psychosocial outcomes that impact the generalizability of evidence-based recommendations. To date, this disparity has not been quantified. The present scoping review uses a dual approach to contrast rates of CAH diagnosis with CAH psychosocial research rates across countries. Methods: Six electronic database searches were conducted for: (1) CAH incidence/birth/prevalence rates; and (2) psychosocial research with affected individuals and their families. Two authors reviewed each abstract for inclusion criteria. Results: Sixty-eight and 93 full-text articles, respectively, were evaluated for incidence and country. The countries/regions with the highest reported CAH rates are Thailand, Ghana, and India. Those with the greatest portion of psychosocial publications are the USA, Germany, and the UK. Conclusion: A discrepancy exists between those countries with the highest CAH rates and those publishing psychosocial research. Specifically, increased rates of CAH are seen in non-Western countries/regions, whereas most psychosocial research arises out of Western Europe and the USA. Due to cultural differences between these regions, increased global collaboration is needed to both inform psychosocial research and translate findings in ways that are representative worldwide.
Preoperative Diagnosis and Treatment of Cholecystoduodenal Fistula
Authors: Yokoigawa Norio , Kawaguchi Yusai
Published: August 2023

The case is about an 87-year-old female. While staying at a facility, she had a fever and abdominal pain and visited our hospital for an up-close examination and treatment. An abdominal CT scan revealed gallstones, gallbladder enlargement, and common bile duct stones. Endoscopic retrograde cholangiopancreatography was performed to confirm the presence of common bile duct stones, which were extracted. At that time, she was diagnosed with a duodenal fistula of the gallbladder and underwent surgery in our department. The gallbladder and duodenum were firmly adhered, and gallstones were palpated between the gallbladder and duodenum. The gallbladder was incised at the fundus to check the lumen, and gallstones were lodged in the fistula with the duodenum. After the removal of gallstones, the gallbladder was dissected, and a fistula with the duodenum was identified. After treating the cystic duct, the fistula was removed, and the gallbladder was removed. Because the duodenal wall was fragile due to inflammation and the fistula was large and difficult to close simply, the duodenal bulb was separated with a linear stapler, and the stomach and jejunum were reconstructed with a 25-mm CDH using the Roux-en-Y technique. The patient’s postoperative course was good, and she was discharged from the hospital.
Association of Aspirin with Dementia or Mild Cognitive Impairment: A Systematic Review and Meta-Analysis of Randomized Trials
Authors: Xie Xiaolu , Kou Liqiu , Chen Xiu , Yuan Ping , Li Jun , Li Yaling
Published: August 2023

Background: At present, the effect of aspirin in preventing dementia or mild cognitive impairment (MCI) is controversial. Clarifying their association is of interest for subsequent relevant clinical trials. Methods: Four databases (PubMed, Embase, Web of Science, and the Cochrane Library) were searched from inception to May 12, 2023, for randomized controlled trials (RCTs) that explored the effects between aspirin and dementia or MCI. Two reviewers independently extracted and analyzed data using Stata software. Discrepancy was resolved by a third reviewer. The primary outcomes were dementia and MCI. The secondary outcomes were cognitive decline and changes in cognitive scores. Results: Five RCTs with 46,804 participants at randomization were included. For the primary outcomes, low-certainty evidence showed that aspirin was not associated with dementia (odds ratio [OR] = 0.93, 95% confidence interval [CI]: [0.85, 1.03], p > 0.05, I2 = 0%) or MCI (OR = 1.00, 95% CI: [0.88, 1.14], p > 0.05, I2 = 3.3%). For the secondary outcomes, moderate-certainty evidence showed that aspirin was not associated with cognitive decline (OR = 1.02, 95% CI: [0.93, 1.11], p > 0.05, I2 = 0%) and a change in global cognitive score (standard mean difference [SMD] = −0.01, 95% CI: [−0.03, 0.02], p > 0.05, I2 = 0%). Low-certainty evidence showed that aspirin was not associated with a change in verbal learning memory score (SMD = −0.04, 95% CI: [−0.09, 0.01], p > 0.05; I2 = 72.5%). Conclusions: Low- and moderate-certainty evidence showed that aspirin was not associated with dementia, MCI, cognitive decline, or better cognitive scores. Future research may need to focus more on subtypes of dementia, mainly vascular dementia or other vascular neurocognitive diseases, and assess whether aspirin has long-term clinical benefits in a large sample of patients with dementia or MCI.
The Impact of Thrombocytopenia and Lymphopenia on Mortality in Patients Infected with Influenza Virus: A Retrospective Cohort Study
Authors: Sherban Adi , Hussen Ragda , Gafter-Gvili Anat , Atamna Alla , Bishara Jihad , Raanani Pia , Ben Tikva Kagan Kim , Avni Tomer
Published: August 2023

Introduction: Influenza virus causes significant global annual morbidity and mortality. Thrombocytopenia is recognized as a poor prognostic factor in sepsis and is associated with mortality, while lymphopenia has been established as a poor prognostic factor in other viral infections. We aimed to assess the incidence of thrombocytopenia and lymphopenia in seasonal influenza and their effect on clinical outcomes. Methods: This single-center, retrospective, cohort study included consecutive adult patients, hospitalized in Rabin Medical Center between October 2017 and April 2018, with laboratory-confirmed influenza. Patients were grouped according to blood counts on admission: (1) thrombocytopenia (<150 K/mL), (2) lymphopenia (<0.5 K/mL), and (3) both thrombocytopenia and lymphopenia. Patients without thrombocytopenia and lymphopenia were designated as controls. The primary outcome was 30-day all-cause mortality. Risk factors were identified by univariable and multivariable analyses, using logistic regression and reported as odds ratios (ORs) and 95% confidence intervals (CIs). Results: A total of 625 patients were included, 112 (18%) had thrombocytopenia, 98 (15.6%) had lymphopenia, and 107 (17%) had both. The crude 30-day all-cause mortality was 7.6% (48/625). Mortality rates were 7.1% (8/112) for the thrombocytopenia group, 11.2% (11/98) for the lymphopenia group, and 14.9% (16/107) for patients with both versus 4.2% (13/308) in the control (p = 0.000 for all). In a multivariable regression model, significant thrombocytopenia (<100 K/μL) [OR 5.07 (95% CI 1.5–16.2)], age [OR 1.07 (95% CI 1.02–1.11)], time to oseltamivir [OR 1.006 (95% CI 1.002–1.11)], and significant respiratory support [OR 8.85 (3.4–22.6)] were associated with 30-day all-cause mortality. Conclusion: Patients hospitalized with seasonal influenza and thrombocytopenia <100 K/mL on admission, have an increased 30-day all-cause mortality.
PROX1 Inhibits PDGF-B Expression to Prevent Myxomatous Degeneration of Heart Valves
Authors: Ho Yen-Chun , Geng Xin , O’Donnell Anna , Ibarrola Jaime , Fernandez-Celis Amaya , Varshney Rohan , Subramani Kumar , Azartash-Namin Zheila J. , Kim Jang , Silasi Robert , Wylie-Sears Jill , Alvandi Zahra , Chen Lijuan , Cha Boksik , Chen Hong , Xia Lijun , Zhou Bin , Lupu Florea , Burkhart Harold M. , Aikawa Elena , Olson Lorin E. , Ahamed Jasimuddin , López-Andrés Natalia , Bischoff Joyce , Yutzey Katherine E. , Srinivasan R. Sathish
Published: August 2023

BACKGROUND:

Cardiac valve disease is observed in 2.5% of the general population and 10% of the elderly people. Effective pharmacological treatments are currently not available, and patients with severe cardiac valve disease require surgery. PROX1 (prospero-related homeobox transcription factor 1) and FOXC2 (Forkhead box C2 transcription factor) are transcription factors that are required for the development of lymphatic and venous valves. We found that PROX1 and FOXC2 are expressed in a subset of valvular endothelial cells (VECs) that are located on the downstream (fibrosa) side of cardiac valves. Whether PROX1 and FOXC2 regulate cardiac valve development and disease is not known.

METHODS:

We used histology, electron microscopy, and echocardiography to investigate the structure and functioning of heart valves from

Prox1
ΔVEC

mice in which
Prox1
was conditionally deleted from VECs. Isolated valve endothelial cells and valve interstitial cells were used to identify the molecular mechanisms in vitro, which were tested in vivo by RNAScope, additional mouse models, and pharmacological approaches. The significance of our findings was tested by evaluation of human samples of mitral valve prolapse and aortic valve insufficiency.

RESULTS:

Histological analysis revealed that the aortic and mitral valves of

Prox1
ΔVEC

mice become progressively thick and myxomatous. Echocardiography revealed that the aortic valves of

Prox1
ΔVEC

mice are stenotic
. FOXC2
was downregulated and PDGF-B (platelet-derived growth factor-B) was upregulated in the VECs of

Prox1
ΔVEC

mice. Conditional knockdown of FOXC2 and conditional overexpression of PDGF-B in VECs recapitulated the phenotype of

Prox1
ΔVEC

mice. PDGF-B was also increased in mice lacking FOXC2 and in human mitral valve prolapse and insufficient aortic valve samples. Pharmacological inhibition of PDGF-B signaling with imatinib partially ameliorated the valve defects of

Prox1
ΔVEC

mice.

CONCLUSIONS:

PROX1 antagonizes PDGF-B signaling partially via FOXC2 to maintain the extracellular matrix composition and prevent myxomatous degeneration of cardiac valves.
Epigenetic Induction of Smooth Muscle Cell Phenotypic Alterations in Aortic Aneurysms and Dissections
Authors: Chakraborty Abhijit , Li Yanming , Zhang Chen , Li Yang , Rebello Kimberly R. , Li Shengyu , Xu Samantha , Vasquez Hernan G. , Zhang Lin , Luo Wei , Wang Guangyu , Chen Kaifu , Coselli Joseph S. , LeMaire Scott A. , Shen Ying H.
Published: August 2023

BACKGROUND:

Smooth muscle cell (SMC) phenotypic switching has been increasingly detected in aortic aneurysm and dissection (AAD) tissues. However, the diverse SMC phenotypes in AAD tissues and the mechanisms driving SMC phenotypic alterations remain to be identified.

METHODS:

We examined the transcriptomic and epigenomic dynamics of aortic SMC phenotypic changes in mice with angiotensin II–induced AAD by using single-cell RNA sequencing and single-cell sequencing assay for transposase-accessible chromatin. SMC phenotypic alteration in aortas from patients with ascending thoracic AAD was examined by using single-cell RNA sequencing analysis.

RESULTS:

Single-cell RNA sequencing analysis revealed that aortic stress induced the transition of SMCs from a primary contractile phenotype to proliferative, extracellular matrix–producing, and inflammatory phenotypes. Lineage tracing showed the complete transformation of SMCs to fibroblasts and macrophages. Single-cell sequencing assay for transposase-accessible chromatin analysis indicated that these phenotypic alterations were controlled by chromatin remodeling marked by the reduced chromatin accessibility of contractile genes and the induced chromatin accessibility of genes involved in proliferation, extracellular matrix, and inflammation. IRF3 (interferon regulatory factor 3), a proinflammatory transcription factor activated by cytosolic DNA, was identified as a key driver of the transition of aortic SMCs from a contractile phenotype to an inflammatory phenotype. In cultured SMCs, cytosolic DNA signaled through its sensor STING (stimulator of interferon genes)-TBK1 (tank-binding kinase 1) to activate IRF3, which bound and recruited EZH2 (enhancer of zeste homolog 2) to contractile genes to induce repressive H3K27me3 modification and gene suppression. In contrast, double-stranded DNA–STING-IRF3 signaling induced inflammatory gene expression in SMCs. In

Sting
–/–

mice, the aortic stress–induced transition of SMCs into an inflammatory phenotype was prevented, and SMC populations were preserved. Finally, profound SMC phenotypic alterations toward diverse directions were detected in human ascending thoracic AAD tissues.

CONCLUSIONS:

Our study reveals the dynamic epigenetic induction of SMC phenotypic alterations in AAD. DNA damage and cytosolic leakage drive SMCs from a contractile phenotype to an inflammatory phenotype.
Multilingual Coreference Resolution in Multiparty Dialogue
Authors: Zheng Boyuan , Xia Patrick , Yarmohammadi Mahsa , Durme Benjamin Van
Published: August 2023

Existing multiparty dialogue datasets for entity coreference resolution are nascent, and many challenges are still unaddressed. We create a large-scale dataset, Multilingual Multiparty Coref (MMC), for this task based on TV transcripts. Due to the availability of gold-quality subtitles in multiple languages, we propose reusing the annotations to create silver coreference resolution data in other languages (Chinese and Farsi) via annotation projection. On the gold (English) data, off-the-shelf models perform relatively poorly on MMC, suggesting that MMC has broader coverage of multiparty coreference than prior datasets. On the silver data, we find success both using it for data augmentation and training from scratch, which effectively simulates the zero-shot cross-lingual setting.
Notation Methods and Reference Systems: On the Phenomenon of Cultural Translation in the Eastern Mediterranean
Authors: Jäger Ralf Martin
Published: August 2023

Traditional art music in the Ottoman Empire was essentially shaped by phenomena of transculturality. It can be assumed that dynamic cultural transfer processes took place between the cultural groups involved, including Armenians, Greeks, Jews, and Arabs, in addition to Turks, and that these processes are visible today through circumstantial evidence.

Each cultural group has an individual-specific music-theoretical, as well as music-historical background, so that the cultural intersection of Ottoman art music is considered from different perspectives. Using Greek sources from the 18th and 19th centuries as examples, this contribution is devoted to the phenomenon of cultural translation that accompanies the transfer processes. The central question is whether and in what form the detailed information given on the pitch system can contribute to a better understanding of Ottoman music theory in the nineteenth century, and how it can be made useful for the critical edition of music practical sources from the period.
Southern Rhodesia’s Adherence to the 1929 Geneva Convention on the Treatment of Italian and German Internees, 1939–1945
Authors: Takura Enest , Mujere Joseph , Bishi George
Published: August 2023

The article looks at the Southern Rhodesian government’s efforts to implement the 1929 Geneva Convention’s provisions in establishing and administering internment camps during Second World War, despite the fact that the convention did not apply to civilian internees. The article contends that, although the Southern Rhodesian government was committed to the Geneva Convention of 1929, which specified the guidelines and norms for the treatment of prisoners of war, this was fraught with ambiguities. This was partially due to the fact that internees were not initially considered prisoners of war and also because the pro-British Southern Rhodesia white community had conflicting feelings towards Germans and Italians. Hence, although the Geneva Convention obliged capturing states to adhere to certain norms, there was a limit to how far Southern Rhodesia could go in terms of executing these stipulations. This article is based on archival documents from the National Archives of Zimbabwe.