bluuebunny/crossref_metadata_2025 huggingface dataset:
First on-sky interference fringes at 810 nm with the CHARA array using servo controlled hectometric outdoor fibre links
Authors: Magri Julie , Grossard Ludovic , Reynaud François , Fabert Marc , Lehmann Lucien , Delage Laurent , Ligon Robert , Vargas Norm , Majoinen Olli , ten Brummelaar Theo , Farrington Christopher D , Scott Nicholas J , Anugu Narsireddy , Schaefer Gail , Gies Douglas , Woods Craig , Golden Steve , Castillo Victor , Anderson Matt , Krawczyk Rodolphe , Le Duigou Jean-Michel
Published: November 2024

In the framework of the ALOHA (Astronomical Light Optical Hybrid Analysis) project, we have implemented a fibre-linked interferometer connecting two telescopes of the CHARA (Center for High Angular Resolution Astronomy) array to the recombination beam facility using servo controlled hectometric outdoor fibres (240 m). During two consecutive nights, on-sky fringes at 810 nm were recorded on the star Vega (mag 0), with servo control of the fibre lengths. The optical path difference was set close to zero using internal fringes found before the on-sky observations. The repeatability of the delay line position offset between internal and on-sky fringes was less than 0.2 mm. The efficiency of the servo control systems has been demonstrated, leading to an enhancement of the signal-to-noise ratio from 68.9 with the servo off to 91.6 with the servo on. This result is a cornerstone for the ALOHA project goal of interferometry at 3.5 $\mu$m and a seminal step for the future kilometric infrared fibre-linked interferometer at CHARA.
A hidden active galactic nucleus population: the first radio luminosity functions constructed by physical process
Authors: Morabito Leah K , Kondapally R , Best P N , Yue B -H , de Jong J M G H J , Sweijen F , Bondi Marco , Schwarz Dominik J , Smith D J B , van Weeren R J , Röttgering H J A , Shimwell T W , Prandoni Isabella
Published: November 2024

Both star formation (SF) and active galactic nuclei (AGNs) play an important role in galaxy evolution. Statistically quantifying their relative importance can be done using radio luminosity functions (RLFs). Until now these relied on galaxy classifications, where sources with a mixture of radio emission from SF and AGN are labelled as either a star-forming galaxy or an AGN. This can cause the misestimation of the relevance of AGN. Brightness temperature measurements at 144 MHz with the International LOw Frequency ARray telescope can separate radio emission from AGN and SF. We use the combination of sub-arcsec and arcsec resolution imaging of 7497 sources in the Lockman Hole and ELAIS-N1 fields to identify AGN components in the sub-arcsec resolution images and subtract them from the total flux density, leaving flux density from SF only. We construct, for the first time, RLFs by physical process, either SF or AGN activity, revealing a hidden AGN population at $L_{\textrm {144 MHz}}$$\lt 10^{24}$ W Hz$^{-1}$. This population is 1.56 $\pm$ 0.06 more than expected for $0.5\lt z\lt 2.0$ when comparing to RLFs by galaxy classification. The star-forming population has only 0.90 $\pm$ 0.02 of the expected SF. These ‘hidden’ AGNs can have significant implications for the cosmic SF rate and kinetic luminosity densities.
Alterations in zinc, copper, and iron levels in the retina and brain of Alzheimer's disease patients and the APP/PS1 mouse model
Authors: Hosseinpour Mashkani Seyed Mostafa , Bishop David P , Westerhausen Mika T , Adlard Paul A , Golzan S Mojtaba
Published: November 2024

Transition metals like copper (Cu), iron (Fe), and zinc (Zn) are vital for normal central nervous system function and are also linked to neurodegeneration, particularly in the onset and progression of Alzheimer's disease (AD). Their alterations in AD, identified prior to amyloid plaque aggregation, offer a unique target for staging pre-amyloid AD. However, analysing their levels in the brain is extremely challenging, necessitating the development of alternative approaches. Here, we utilized laser ablation–inductively coupled plasma–mass spectrometry and solution nebulization–inductively coupled plasma–mass spectrometry to quantitatively measure Cu, Fe, and Zn concentrations in the retina and hippocampus samples obtained from human donors (i.e. AD and healthy controls), and in the amyloid precursor protein/presenilin 1 (APP/PS1) mouse model of AD and wild-type (WT) controls, aged 9 and 18 months. Our findings revealed significantly elevated Cu, Fe, and Zn levels in the retina (*P < .05, P < .01, and P < .001) and hippocampus (*P < .05, *P < .05, and *P < .05) of human AD samples compared to healthy controls. Conversely, APP/PS1 mouse models exhibited notably lower metal levels in the same regions compared to WT mice—Cu, Fe, and Zn levels in the retina (**P < .01, *P < .05, and *P < .05) and hippocampus (**P < .01, **P < .01, and *P < .05). The contrasting metal profiles in human and mouse samples, yet similar patterns within each species’ retina and brain, suggest the retina mirrors cerebral metal dyshomoeostasis in AD. Our findings lay the groundwork for staging pre-AD pathophysiology through assessment of transition metal levels in the retina.
Early Mortality and Health Care Costs in Patients Recently Diagnosed With Kaposi Sarcoma at the National Cancer Institute, Mexico City
Authors: Carpio-Guadarrama Daniel , Camiro-Zúñiga Antonio , Pérez-Dorame Renzo , Martin-Onraët Alexandra , García-Escutia Diana , Mendoza-Palacios María José , Volkow-Fernández Patricia
Published: November 2024

Background

Kaposi sarcoma (KS) is a marker of advanced HIV disease; it is still the most frequent AIDS-associated malignancy in Mexico despite universal access to antiretroviral therapy, reflecting a gap in early HIV diagnosis.

Methods

The objectives of the study were to describe people with HIV with KS who died within 30 days of admission at INCan (National Cancer Institute) and to quantify resources and years of life lost (YLL). We collected demographic data, HIV-related variables, all diagnostic and therapeutic procedures, hospitalizations, and estimated YLL and disability-adjusted life years.

Results

Eighteen (6.7%) people with HIV with KS from 270 patients admitted at INCan from 2014 to 2021 were included. The median age was 31 years (IQR 27–36), and the median days from admission to death and from HIV diagnosis to death were 15 (IQR, 6–24) and 73 (IQR, 30–857), respectively. Upon admission, the median HIV viral load was 314 476 copies/mL (IQR, 140 709–695 613); CD4+ T cells, 93 cells/mL (IQR 35–124); and CD4/CD8 ratio, 0.08 (IQR, 0.06–0.12). Coinfections were diagnosed in 14 (77.7%) patients. The average expenditure per patient was US $7685.99 USD, and the total YLL was 737.4 with a median 42 years (IQR, 37.7–47) per patient. The total care cost was US $183 947.48, equivalent to a screening program in key populations, which would have allowed the early detection of 1227 cases and saved 8410 disability-adjusted life years.

Conclusions

Reinforcement of early HIV infection detection in key population programs should be prioritized to reduce KS-associated deaths and YLL and for rational use of health budgets.
Evolution in the diagnosis and treatment of carcinoma of unknown primary: a multicenter Canadian analysis
Authors: Wong Boaz , Liu Jessica , Yeo Sarah , Akurang Deborah , Lo Alexandra , Xu Ying Hui , Wang Ying , Welch Stephen , Wheatley-Price Paul
Published: November 2024

Background

Guidelines for the management of patients with cancer of unknown primary (CUP), who have metastatic disease without an identified primary tumor site, have evolved. We sought to describe the diagnostic work-up and outcomes of patients with CUP in Canada over the last decade. We also sought to identify factors associated with improved prognosis in CUP, including primary tumor site identification, identification of “favorable subtypes,” and concordance with published guidelines.

Methods

With ethics board approval, patients with histologically confirmed CUP between 2012 and 2021 in 3 Canadian cancer centers were reviewed and clinicopathological variables retrospectively collected. The primary endpoint was to describe significant trends in CUP diagnosis and management over the decade using linear regression models. Univariable (UVA) and multivariable (MVA) logistic regression analyses identified variables correlated with primary site identification and overall survival (OS). Kaplan–Meier curves with the log-rank test were used to compare OS outcomes.

Results

In total, 907 patients were included, with a median follow-up of 5.1 months. There was an increase in both 5-year survival and identification of primary tumors over the decade. Diagnostic tests including next-generation sequencing were independently associated with primary site identification on UVA. However, primary site identification was not found to be predictive of survival; instead, patients with “favorable subtypes” of CUP had significantly longer OS.

Conclusions

Survival in patients with CUP in Canada has been increasing over the last decade. Identifying the primary site does not influence survival, and efforts should be focused on discovering novel “favorable subtypes” which have superior outcomes.
microRNA858 represses the transcription factor gene SbMYB47 and regulates flavonoid biosynthesis in Scutellaria baicalensis
Authors: Yang Jiaxin , Lu Xiayang , Hu Suying , Yang Xiaozeng , Cao Xiaoyan
Published: November 2024

MicroRNAs (miRNAs) are noncoding endogenous single-stranded RNAs that regulate target gene expression by reducing their transcription and translation. Several miRNAs in plants function in secondary metabolism. The dried root of Scutellaria baicalensis Georgi is a traditional Chinese medicine that contains flavonoids (baicalin, wogonoside, and baicalein) as its main active ingredients. Although the S. baicalensis genome sequence has been published, information regarding its miRNAs is lacking. In this study, 12 small RNA libraries of different S. baicalensis tissues were compiled, including roots, stems, leaves, and flowers. A total of 129 miRNAs were identified, including 99 miRNAs from 27 miRNA families and 30 predicted miRNAs. Furthermore, 46 reliable target genes of 15 miRNA families were revealed using psRNATarget and confirmed by degradome sequencing. It was speculated that the microRNA858 (miR858)–SbMYB47 module might be involved in flavonoid biosynthesis. Transient assays in Nicotiana benthamiana leaves indicated that miR858 targets SbMYB47 and suppresses its expression. Artificial miRNA-mediated knockdown of miR858 and overexpression of SbMYB47 significantly increased the flavonoid content in S. baicalensis hairy roots, while SbMYB47 knockdown inhibited flavonoid accumulation. Yeast one-hybrid and dual-luciferase assays indicated that SbMYB47 directly binds to and activates the S. baicalensis phenylalanine ammonia-lyase 3 (SbPAL-3) and flavone synthase II (SbFNSⅡ-2) promoters. Our findings reveal the link between the miR858–SbMYB47 module and flavonoid biosynthesis, providing a potential strategy for the production of flavonoids with important pharmacological activities through metabolic engineering.
Processes independent of nonphotochemical quenching protect a high-light-tolerant desert alga from oxidative stress
Authors: Levin Guy , Yasmin Michael , Liran Oded , Hanna Rawad , Kleifeld Oded , Horev Guy , Wollman Francis-André , Schuster Gadi , Nawrocki Wojciech J
Published: November 2024

Nonphotochemical quenching (NPQ) mechanisms are crucial for protecting photosynthesis from photoinhibition in plants, algae, and cyanobacteria, and their modulation is a long-standing goal for improving photosynthesis and crop yields. The current work demonstrates that Chlorella ohadii, a green microalga that thrives in the desert under high light intensities that are fatal to many photosynthetic organisms does not perform nor require NPQ to protect photosynthesis under constant high light. Instead of dissipating excess energy, it minimizes its uptake by eliminating the photosynthetic antenna of photosystem II. In addition, it accumulates antioxidants that neutralize harmful reactive oxygen species (ROS) and increases cyclic electron flow around PSI. These NPQ-independent responses proved efficient in preventing ROS accumulation and reducing oxidative damage to proteins in high-light-grown cells.
The Q2 approach for percutaneous peripheral neuromodulation stimulator implantation targeting the C2 dorsal root ganglion at the C2 lamina for treatment of intractable headache: a technical note
Authors: Chen QiLiang , Qian Xiang
Published: November 2024

Objectives

Despite significant medical treatment advancements, interventional treatments for intractable headache disorders are limited. This study’s objective is to detail a novel percutaneous approach (the “Q2 approach”) and its technical considerations for implanting peripheral neuromodulation stimulators (PNS) to the C2 dorsal root ganglion (C2-DRG) at the C2 lamina, a previously unattempted target, as a treatment for intractable headache.

Methods

In an outpatient setting, under combined ultrasound and fluoroscopic guidance, PNS electrodes were percutaneously implanted at the C2-DRG in patients under moderate sedation. The final electrode position was determined by intraoperative patient feedback to ensure optimal stimulation. Four patients were included to demonstrate technical parameters and feasibility. Follow-ups were conducted on postoperative days 10, 30, 60, and 100–120.

Results

The Q2 approach allows safe C2-DRG PNS implantations in an outpatient setting. Average operative duration was <60 minutes. All 4 patients achieved >50% pain relief during the 60-day implant period, and 3 of 4 demonstrated sustained benefit beyond the implant period. No complications (eg, lead migration, infection) were observed.

Conclusions

The present technical note demonstrates the feasibility of a novel, safe, minimally invasive approach to access the C2-DRG at the C2 lamina for the treatment of intractable headaches. The use of PNS on the C2-DRG fills an important gap in headache management, as it provides an alternative neuromodulation treatment modality to the existing destruction/denervation-based techniques.
The intersectionality of chronic pain stigma and racial discrimination in Black and White adults with chronic low back pain
Authors: Wilson Jenna M , Booker Staja Q , Goodin Burel R , Thomas Pavithra A , Sorge Robert E , Quinn Tammie L , Morris Matthew C , Aroke Edwin N , Meints Samantha M
Published: November 2024

Objective

We examined the intersection between chronic pain stigma and racial discrimination, separately among Black and White US adults with chronic low back pain.

Methods

Participants completed measures of chronic pain stigma, lifetime experiences of racial discrimination, pain severity and interference. A composite variable representing the intersectionality of stigma and discrimination was created, and Black and White participants were separately categorized into 4 groups. Black participants were categorized as: (1) high discrimination/high stigma, (2) high discrimination/low stigma, (3) low discrimination/high stigma, and (4) low discrimination/low stigma. White participants were categorized as: (1) any discrimination/high stigma, (2) any discrimination/low stigma, (3) no discrimination/high stigma, and (4) no discrimination/low stigma.

Results

Black participants reported more frequent experiences of racial discrimination than White participants (P < .05), but there was not a racial difference in chronic pain stigma (P > .05). Among Black participants, those in the high discrimination/high stigma and low discrimination/high stigma groups reported greater pain severity and interference than those in the high discrimination/low stigma and low discrimination/low stigma groups (P < .05). Among White participants, those in the any discrimination/high stigma group reported greater pain severity and interference than those in the no discrimination/low stigma group (P < .05), but there were no differences in pain severity or interference between the any discrimination/no stigma and no discrimination/high stigma groups (P > .05).

Conclusion

Our findings suggest that the relationship of intersectional chronic pain stigma and racial discrimination with pain is nuanced and differs across racial groups.
Quantifying lower extremity blood flow using low-dose CT perfusion: validation in a swine model
Authors: Shojazadeh Alireza , Hadjiabdolhamid Negin , Black Dale J , Antunes Ines , Lee Chaeeun , Li Wenbo , Molloi Sabee
Published: November 2024

Background

Quantitative assessment of blood flow in peripheral extremities in conjunction with simultaneous CT angiography measurements can improve risk assessment and provide a critical decision-making tool for patients across a wide spectrum of vascular disease severity.

Purpose

This study assessed the reproducibility and accuracy of lower extremity blood flow measurements with a low-dose first-pass analysis CT perfusion technique.

Materials and Methods

This prospective study utilized 16 Yorkshire Swine to obtain lower extremity blood flow CT measurements at baseline and under induced femoral stenosis using a vascular occluder. Thirty-three pairs of CT measurements evaluated reproducibility, and 43 CT measurements assessed accuracy against ultrasound flow probe references. Contrast agent and saline chaser were both injected peripherally at a rate of 5 mL/s. Bolus tracking was used, and a pre-contrast and post-contrast helical scan were acquired at the base and approximately the peak of the femoral enhancement (CT angiogram), respectively. The acquired data were then used as analytical inputs into a first-pass analysis model to derive perfusion in mL/min/g. The reproducibility and accuracy of lower extremity perfusion measurements were assessed via Mixed model regression and Bland-Altman analysis.

Results

Calculated CT perfusion measurements derived from first-pass analysis technique (PCT), and the reference standard ultrasound perfusion measurements (Pref) were related by PCT = 1.06 Pref + 0.00 (r2 = 0.90, Root-Mean-Square Error [RMSE] = 0.01 mL/min/g). The first (P1) and second (P2) CT perfusion measurements were related by P2 = 0.98 P1 + 0.02 (r = 0.97, RMSE = 0.11 mL/min/g). The average effective dose of perfusion measurement using first-pass analysis technique was calculated to be only 2.13 mSv.

Conclusion

The low-dose quantitative CT perfusion technique can accurately measure lower extremity perfusion (mL/min/g) using only 2 helical scans. The CT angiogram and perfusion measurements can be used as a comprehensive technique for morphological and physiological assessment of limb ischemia.
Uncovering the relationships among herring-like fossils (Clupei: Teleostei): a phylogenetic analysis
Authors: Kevrekidis Charalampos , Moritz Timo , Cerwenka Alexander F , Bauer Elena , Reichenbacher Bettina
Published: November 2024

Research interest in the diversity and evolutionary history of herring-like fossils (subcohort Clupei) has increased in recent decades. However, little is known about the relationships between fossils assigned to Clupei, particularly those that are demonstrably related to extant herring-like members of the order Clupeiformes. To help bridge this gap, we present a new morphological phylogeny that includes representatives of all major clupeiform lineages. The data matrix consists of 192 characters, drawn from 79 extant and 37 fossil taxa and selected to be readily identifiable in fossils. Most clupeiform families are recovered as monophyletic, and their interrelationships are generally compatible with previous morphological hypotheses. The phylogenetic positions of six fossil clupeiform taxa are resolved, as the results of all analyses (unconstrained/constrained parsimony and Bayesian inference) are consistent. Twenty-one fossil taxa are incertae sedis, including two species of Ellimmichtyiformes, which are recovered as Clupeoidei in the parsimony analyses. The relationships of the rest of the fossils are interpreted with varying degrees of certainty. The evolution of key morphological characters is discussed in light of the new results, and four fossil taxa are proposed as calibration points for future dating studies.
FOXO3 induces TUG1‐mediated miR‐375/GATA3 signaling axis to promote the survival of melanocytes in vitiligo
Authors: Nie Xiaojuan , Chen Lamei , Wang Baihe , Wang Shengnan , Li Yuanyuan
Published: November 2024

Vitiligo is characterized by the depletion of melanocytes due to the activation of CD8+ T cells. Taurine‐upregulated gene 1 (TUG1), a long noncoding RNA, is involved in melanogenesis. This study aimed to explore the role and mechanism of TUG1 in vitiligo. RT‐qPCR and western blot analyses demonstrated decreased TUG1 levels and increased miR‐375 levels in patients with vitiligo. MTT and transwell assays indicated that TUG1 upregulation facilitated melanocyte survival and inhibited CD8+ T cell migration. Dual luciferase reporter and chromatin immunoprecipitation assays verified that Forkhead box O3 (FOXO3) directly interacted with the TUG1 promoter, leading to the positive regulation of TUG1 expression. In addition, FOXO3 promoted melanocyte survival by enhancing the transcription of TUG1. Luciferase reporter assay and RNA immunoprecipitation assay confirmed that TUG1 upregulated GATA binding protein 3 (GATA3) expression by targeting miR‐375. TUG1 facilitated melanocyte survival by regulating the miR‐375/GATA3 axis. In vitiligo, melanocyte survival is promoted by the induction of the TUG1‐mediated miR‐375/GATA3 axis by FOXO3, which offers new therapeutic targets for vitiligo treatment.
Formyl peptide receptors in the microglial activation: New perspectives and therapeutic potential for neuroinflammation
Authors: Gao Juan , Su Gang , Liu Jifei , Shen Minghui , Zhang Zhenchang , Wang Manxia
Published: November 2024

Secondary neurological impairment mediated by neuroinflammation is recognized as a crucial pathological factor in central nervous system (CNS) diseases. Currently, there exists a lack of specific therapies targeting neuroinflammation. Given that microglia constitute the primary immune cells involved in the neuroinflammatory response, a thorough comprehension of their role in CNS diseases is imperative for the development of efficacious treatments. Recent investigations have unveiled the significance of formyl peptide receptors (FPRs) in various neuroinflammatory diseases associated with microglial overactivation. Consequently, FPRs emerge as promising targets for modulating the neuroinflammatory response. This review aims to comprehensively explore the therapeutic potential of targeting FPRs in the management of microglia‐mediated neuroinflammation. It delineates the molecular characteristics and functions of FPRs, elucidates their involvement in the inflammatory response linked to microglial overactivation, and synthesizes therapeutic strategies for regulating microglia‐mediated neuroinflammation via FPR modulation, thereby charting a novel course for the treatment of neuroinflammatory diseases.
Land plant-specific H3K27 methyltransferases ATXR5 and ATXR6 control plant development and stress responses
Authors: Li Xiaoyi , Pan Jie , Zhang Huairen , Li Hui , Liu Qian , Jiang Danhua
Published: November 2024

The colonization of land by plants relies on numerous evolutionary innovations crucial for terrestrial adaptation. These include advances in sexual reproduction and the ability to properly respond to various environmental stresses, which involve precise control of their regulatory genes. A notable genetic innovation in land plants is the emergence of histone lysine methyltransferases ATXR5/6, which specifically catalyse the repressive histone H3 lysine 27 monomethylation (H3K27me1). However, the significance of the evolution of these enzymes in land plants remains unclear. In this study, we investigate the importance of ATXR5/6 by generating strongatxr5;atxr6double mutants inArabidopsis. Our results show that ATXR5/6 are essential for plant reproductive development and play a critical role in supporting normal plant growth by repressing the transcription of stress responsive genes. In addition, ATXR5/6 are necessary for maintaining H3K27 trimethylation (H3K27me3), likely by providing H3K27me1 as a substrate for further methylation. We also demonstrate that the function of ATXR5/6 in regulating reproductive development and responsive genes is conserved in the monocot rice. We propose that land plants may have evolved ATXR5/6 to assist in the transcriptional regulation necessary for terrestrial adaptation.
Comparison of Tooth Wear Among Young Sports Persons Involved in Individual and Team Sports- A Cross-Sectional Study
Authors: RamyaDurga Rangasamy , SriChinthu KenniyanKumar , Prasad Harikrishnan , Rajmohan Muthusamy , Perumal Prema , Yoithapprabhunath Thuckanickenpalayam Ragunathan , Shanmuganathan S.
Published: November 2024

BACKGROUND

Tooth wear has multifactorial etiology & defined as non-self-reparable loss of hard tissue in the absence of dental caries or trauma. One of the valid aetiologies for pathological tooth wear is stress. During sports activity, athletes tend to clench their teeth involuntarily which results in tooth wear, especially in young sportspersons. Hence, we designed a study to evaluate and compare tooth wear among young sportspersons involved in individual and team sports.

METHODS

The study population comprised 300 subjects and were divided into two groups, group 1 (150 individuals involved in individual sports activity) & group 2 (150 individuals involved in team sport activity) The Tooth wear index was assessed based on Smith & Knight scoring criteria (1984).

RESULTS

88.6% of study participants showed tooth wear in individual sports & 84% in team sports. Tooth wear was highest in the mandibular & maxillary central incisor of both individual & team sports individuals.

CONCLUSION

We found that both individual and team sports players showed tooth wear, especially in the incisal surface of mandibular & maxillary incisors, which might reflect the underlying stress or anxiety. This study is the first of its kind to evaluate and compare tooth wear among young sportspersons involved in individual and team sports in India.
Role of the gut microbiome in frequent gut colonization with extended-spectrum β-lactamase-producing Enterobacterales among Peruvian children
Authors: Nadimpalli Maya L. , Sehgal Neha , Rojas-Salvatierra Luismarcelo , Gilman Robert H. , Earl Ashlee M. , Worby Colin J. , Schwab Madison , Pickering Amy J. , Pajuelo Monica J.
Published: November 2024

We investigated whether differences in gut microbiome development could underlie differential susceptibility to gut colonization with extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E) over time among children in peri-urban Lima. Weekly stool and daily surveys were collected from 345 children <3 years old during a 2016-19 study of enteric infections. A subset of children (n=12) were rarely gut-colonized with ESBL-E from 1-16 months of age. We performed short-read metagenomic sequencing of stool collected at 3, 6, 7, 9, 12, and 16 months from these children and a random subset of 42 frequently colonized children, and characterized differences in antibiotic use, sociodemographic characteristics, and the gut microbiome over time. No gut microbiome differences were identified, but rarely colonized children were more likely to live in households of lower socioeconomic status and consumed fewer antibiotics. Differences in exposures, rather than gut microbiome development, might underlie patterns of ESBL-E gut colonization among children in peri-urban Lima.
Deciphering the Transcriptomic Landscape of Type 2 Diabetes: Insights from Bulk RNA Sequencing and Single-Cell Analysis
Authors: Tkachenko A.A. , Tonyan Z.N. , Nasykhova Y.A. , Barbitoff Y.A. , Renev I.N. , Danilova M.M. , Mikhailova A.A. , Glavnova O.B. , Chepanov S.V. , Selkov S.A. , Golovkin N.V. , Vlasova M.E. , Glotov A.S.
Published: November 2024

Type 2 diabetes (T2D) is a chronic metabolic disorder marked by insulin resistance and relative insulin deficiency, affecting over 422 million people globally and projected to increase, making it a major public health concern. This condition is associated with severe complications such as retinopathy, nephropathy, cardiovascular diseases, and neuropathy, highlighting the need for a deeper understanding of its mechanisms to develop more effective prevention and treatment strategies. Transcriptomic analysis, particularly through RNA-seq, has provided valuable insights into the gene expression patterns in T2D, highlighting pathways involved in insulin signaling, metabolic regulation, and inflammation. This approach, including single-cell RNA sequencing, helps overcome the challenges of immune cell population heterogeneity, enabling the identification of distinct cell types and their specific roles in T2D progression. In this paper, we present a dataset of single-cell and bulk RNA sequencing results comparing expression patterns in blood cells between diabetes and healthy samples and describe some preliminary analysis of the dataset, highlighting differences in both gene expression and cell type composition and putting them in the context of existing research of T2D.
Short Report: Investigating Oropouche as a possible etiology for fevers of unknown origin in a clinical cohort from Colombia, 2013-2015
Authors: Walsh Christine S. , Cardenas Jenny C. , Gutierréz-Silva Lady Y. , González Maria U. , Mores Christopher N. , Londono-Renteria Berlin , Christofferson Rebecca C.
Published: November 2024

Currently, the largest outbreak of Oropouche virus (OROV) in Latin America and the Caribbean, has also spread across the globe to Italy, Spain, and Germany, bringing this virus into the public domain. With over 8,000 cases and counting in Brazil, there have been two deaths in young women with no known comorbidities, and infection with Oropouche was associated with a late term stillbirth. While OROV has been sporadically detected in Colombia since 2017, with a handful of cases in Cúcuta and Leticia, the distribution of OROV prior to that remains unknown. Therefore, we undertook to test a clinical cohort of febrile patients from Colombia to determine if OROV was circulating within the human population earlier than previously determined. We screened 631 serum samples collected in 2014-2015 from three municipalities: Cúcuta, Los Patio, and Ocaña. We found evidence of OROV infection in three patients from Ocaña, though live virus was not recoverable from patient sera. These data suggest that OROV circulation, while sporadically detected in Colombia, has circulated earlier than previously thought. With the emergence and expansion of new or neglected viruses, there is a need to expand screening of febrile patients both retro- and prospectively to describe and better understand the distribution of arbovirus circulation in human populations. Surveillance for OROV across South America is necessary going forward, especially as the outbreak in Brazil continues.
Strong family- and guild-specific responses of arbuscular mycorrhizal fungi to long-term deficiencies and imbalances of N, P and K
Authors: Jenab Kian , Alteio Lauren , Guseva Ksenia , Gorka Stefan , Darcy Sean , Fuchslueger Lucia , Canarini Alberto , Martin Victoria Sophie , Wiesenbauer Julia , Spiegel Felix , Imai Bruna , Schmidt Hannes , Hage-Ahmed Karin , Poetsch Erich , Richter Andreas , Jansa Jan , Kaiser Christina
Published: November 2024

Many agroecosystems face nitrogen (N), phosphorus (P) or potassium (K) deficiencies due to imbalanced or insufficient nutrient replenishment after plant biomass harvest. How this affects the symbiosis between plants and arbuscular mycorrhizal fungi (AMF), and the abundance of exploration-based AMF guilds (i.e., rhizophilic, edaphophilic, ancestral) remains largely unknown. We studied a 70-year nutrient-deficiency experiment in a managed grassland in central Austria, where aboveground biomass was harvested three times annually. Nitrogen, phosphorus and potassium were fully, partially, or not replenished, causing strong nutrient deficiencies and imbalances. We analysed AMF communities in soil and roots by DNA/RNA amplicon sequencing and fatty-acid biomarkers, alongside soil and plant community changes. Soil AMF communities were primarily affected by N and P deficiencies, while root AMF communities were most susceptible to K deficiency, with a 50% reduction in root AMF biomass. We observed distinct, guild- and family-specific responses: edaphophilic AMF declined with nitrogen deficiency, while rhizophilic fungi decreased with phosphorus and potassium deficiencies. Families within each guild, particularly ancestral ones, exhibited differential responses, indicating complementary nutrient specializations at the family level. Our findings underscore the previously unrecognized role of K deficiency in AMF symbiosis, and suggest the existence of nutrient-related functional subgroups within exploration-based AMF guilds.
The Infectious Diseases Clinical Research Program Acute Respiratory Infection Repository Protocol: Opportunities to Understand Current and Future Epidemics
Authors: Pollett Simon D. , Colombo Rhonda E. , Richard Stephanie A. , Lalani Tahaniyat , Barton Brianne M. , Malloy Allison , Fries Anthony , Parmelee Edward , Merritt Scott , Fritschlanski Mark , Mitre Edward E. , Laing Eric D. , Pratt Kathleen , Garges Eric C. , Mende Katrin , Simons Mark , Agan Brian , Tribble David , O' Connell Robert , Burgess Timothy H.
Published: November 2024

Background: Acute respiratory infections (ARI) are a major cause of morbidity and lost workdays in both military and non-military populations. To better understand these infections and their outcomes, the Infectious Diseases Clinical Research Program has enabled nine major ARI clinical research protocols in the last decade, including observational studies and trials, spanning emerging and reemerging ARI threats including SARS-CoV-2, influenza, adenovirus, entero/rhinovirus, human metapneumovirus, respiratory syncytial virus, and other pathogens. These protocols have resulted in epidemiological, clinical and laboratory data and biospecimens from over 26,000 participants, most of whom were beneficiaries of a geographically distributed Military Health System. Methods: The Acute Respiratory Infection Repository Protocol establishes a unique Department of Defense (DoD) research resource through the pooling of data and specimens from nine ARI protocols into a master, standardized database with a linked specimen repository. This will enable further targeted scientific questions in participant-level pooled meta-analyses and will serve as an on-demand repository for rapid assay development, sample size estimations for prospective studies, and observational study/clinical trial design (including as part of future rapid pandemic research response). Accordingly, the objectives and study design of this protocol are broad. This protocol will allow analyses on outcomes including: (i) short-term ARI outcomes such as hospitalization, work days lost, symptom severity and duration ; (ii) post-acute ARI outcomes, including persistence of symptoms, return-to-health, post-ARI medical encounters; (iii) vaccine effectiveness for COVID-19, influenza, and adenovirus vaccines; (iv) ARI infection and vaccination elicited immune responses (humoral, T-cell, other); (v) therapeutic effectiveness of COVID-19 and influenza antivirals (acute symptoms, hospitalization, post-acute sequelae); (vi) effectiveness of non-pharmaceutical interventions (e.g., masking) against infection; (vii) prognostic and mechanistic host viral biomarkers which correlate with the above outcomes; (viii) ARI diagnostic assay validity and performance. This repository protocol is inherently broad in scope; the collation of standardized data and phenotype-linked specimens is a fundamental, primary objective.
Exploring the Molecular Pathways of Intracranial Aneurysm Formation in Autosomal Dominant Polycystic Kidney Disease Using Proteomic Analysis
Authors: Kim Jin-Myung , Ahn Hee-Sung , Kim Mi Joung , Kwon Hye Eun , Ko Youngmin , Jung Joo Hee , Kwon Hyunwook , Kim Young Hoon , Yu Jiyoung , Kim Kyunggon , Shin Sung
Published: November 2024

Introduction

Intracranial aneurysm (IA) frequently coincides with autosomal dominant polycystic kidney disease (ADPKD), exhibiting incidence rates nearly 10 times higher than the general population. However, the exact mechanism of how these two conditions is related remains unclear. This study aims to identify mechanisms behind IA occurrence in ADPKD patients using proteomics and to discover potential protein biomarkers for early diagnosis.

Method

Pre-kidney transplantation ADPKD patients underwent cranial CT and/or MR angiography, with findings dictating assignment to either a control group (ADPKD without IA, n=20) or IA group (ADPKD with IA, n=9). During transplantation, bilateral nephrectomy was performed and native renal arteries were sampled for proteomic analysis via a liquid chromatography-tandem mass spectrometry. Differentially expressed proteins were subjected to bioinformatic analysis and a protein-protein interaction network analysis.

Results

Eight proteins showed significant variation between IA and control groups, with four proteins upregulated (DIS3, RAB6A, MMS19, EXOC8) and four downregulated (CLUH, SYNC, MEF2D, WDR36) in IA group (Log2fold change (FC) >2 and false discovery rate (FDR] q-value <0.05) compared to the control group. These proteins correlated with pathways implicated in IA development, such as ciliopathy, exocytosis, inflammation, extracellular matrix remodelling, and apoptosis. These proteins were quantitatively validated using Western blot analysis and found to be consistent with proteomic data. Moreover, a connection was observed between protein expression and clinical metrics (bilirubin, prothrombin time, platelet count), indicating their potential as early diagnostic markers.

Conclusion

This study is the first to employ renal artery samples to study underlying mechanisms for IA in ADPKD patients by proteomics. We identified and validated novel candidate markers that are either upregulated or downregulated in the IA group compared to the control group. This research’s finding opens new avenues for understanding and diagnosing IA in ADPKD, potentially leading to earlier diagnosis and targeted treatments.
A Phase Ib/II multi-arm, dose finding and expansion study of a novel thymidylate synthase inhibitor with immune modulating properties, NUC-3373, in combination with pembrolizumab or docetaxel in patients with advanced solid tumors (NuTide:303)
Authors: Middleton Gary , Spicer James , Aktas Burak , Dinizulu Habana , Wilson Richard H , Harrison David J , Oelmann Elisabeth , Bloss Jeff , Thistlethwaite Fiona
Published: November 2024

Background

NUC-3373 is a novel thymidylate synthase (TS) inhibitor designed to directly deliver the active anti-cancer metabolite fluorodeoxyuridine-monophosphate (FUDR-MP or FdUMP) intracellularly. In addition to being a potent TS inhibitor, NUC-3373 has also been shown to cause DNA damage and promote the release of damage-associated molecular patterns. These diverse mechanisms position NUC-3373 as a potentially effective combination partner for several other anti-cancer agents.

Methods

NuTide:303 is a Phase Ib/II open label, multi-arm, parallel cohort dose-finding and expansion study designed to evaluate optimal combination partners for NUC-3373. Module 1 planned to enroll up to 12 evaluable patients with advanced/metastatic solid tumors to determine the recommended dose for NUC-3373 in combination with leucovorin (LV) and pembrolizumab. Module 2 planned to enroll approximately 6-12 evaluable patients with advanced/metastatic non-small cell lung cancer (of any histology) or pleural mesothelioma to determine the recommended dose for NUC-3373 in combination with LV and docetaxel. A 3+3 dose escalation design was used in both modules, with safety parameters continually assessed and tumor assessments conducted at screening and every 8 weeks from C1D1 until progression.

Results

Thirteen patients were enrolled in Module 1, with 9 evaluable for response. No DLTs were observed in these heavily pre-treated PD-(L)1 experienced patients with a variety of different tumor types. Four patients remained on treatment for >3 months and 3 patients were ongoing at the time of data cut-off. An objective response rate of 22% and a disease control rate of 67% were reported. NUC-3373 + LV + pembrolizumab was well tolerated, the most common treatment-related adverse events (AEs) were nausea, vomiting, and diarrhea and the majority of events were Grade 1 (100%) or 2 (85%). Four patients were enrolled in Module 2, with 3 evaluable for response. Two patients treated at the first dose level achieved stable disease and completed >6 months of treatment The most common treatment-related AEs were fatigue (n=4) and diarrhea (n=3) and the majority of events were Grade 1 (100%) or 2 (100%).

Conclusions

Preliminary results from Module 1 show signals of anti-cancer activity and tolerability, providing support for further exploration of this combination in the Phase II part of the study. Preliminary results from Module 2 suggest that the probability of being able to escalate to typical efficacious doses of docetaxel used in combination is low due to overlapping toxicity. Further modifications to include the use of a different taxane in this combination are currently being considered.
Adjuvant Recombinant SARS-CoV-2 Spike Protein Vaccine Immunogenicity After Prior mRNA Vaccine Doses
Authors: Adelglass Jeffrey M. , Bradley Paul , Cai Miranda R. , Chau Gordon , Kalkeri Raj , Cloney-Clark Shane , Zhu Mingzhu , Cai Zhaohui , Eickhoff Mark , Plested Joyce S. , Mallory Raburn M. , Dunkle Lisa M.
Published: November 2024

Background

To support heterologous vaccine regimens, periodic SARS-CoV-2 revaccination required immunogenicity and safety data for adjuvanted protein-based vaccines following prior mRNA doses.

Methods

This phase 3, open-label study (2019nCoV-312/NCT05875701) enrolled participants who received one dose of ancestral SARS-CoV-2 protein-based vaccine (NVX-CoV2373) in an earlier study (2019nCoV-307/NCT05463068) after a primary series and possibly one additional dose of mRNA vaccine. In the current study, participants received an additional dose of protein-based vaccine (ancestral [n=104] or Omicron BA.5 [n=40]) at least 180 days after their previous study dose. The primary objective was demonstration of noninferiority of neutralizing antibody (nAb) titers induced by the dose in this study versus the first dose of NVX-CoV-2373 in the earlier study. Safety was also evaluated.

Results

A total of 144 participants were enrolled. The ratio of anti-Wuhan nAbs (GMT, IU/mL [95% CI]) at Day 28 after this study dose (ancestral 393.2 [318.0–468.2]) versus previous study dose (396.6 [328.7–478.6]) was 1.0 (0.8, 1.2), meeting noninferiority. The seroresponse rate difference between doses was 7.4% (95% CI = −1.2%–16.5%), also meeting noninferiority. Omicron BA.5 nAb titers suggest cross-protection against emerging variants. The nAb ratio at Day 28 between Omicron dose in this study (835.0 [597.1–1167.6]) versus previous study ancestral dose (436.0 [305.6–622.2]) was 1.9 (1.5–2.5), exceeding superiority criterion. Local and systemic reactions were similar between doses and strains in both studies.

Conclusions

A heterologous regimen of two adjuvanted recombinant spike protein-based vaccine doses after mRNA vaccination produced robust immune responses, exhibiting cross-reactivity to newer variants.
Factors associated with lower COVID-19 vaccine uptake among populations with a migration background in the Netherlands
Authors: Smagge Bente , Labuschagne Lisanne , Pijpers Joyce , van Roon Annika , van den Hof Susan , Hahné Susan , de Melker Hester
Published: November 2024

Background

In high income countries, the incidence of severe COVID-19 has been disproportionally high among persons with a migration background. We examined determinants of being unvaccinated against COVID-19 in the Netherlands among four large populations of non-Dutch origin with below average vaccination coverage.

Methods

A nationwide study of determinants of being unvaccinated in the 2021 primary COVID-19 vaccination round in adults and 2022 autumn booster in those ≥60 years was performed within the Netherlands’ populations of Dutch-Caribbean, Moroccan, Surinamese and Turkish origin. Using vaccination registry and individual and household level sociodemographic and socioeconomic data, we examined the association between each potential determinant and being unvaccinated using multivariable logistic regression. In addition, we computed population attributable fractions (PAFs).

Results

Among these populations of non-Dutch origin, the odds of being unvaccinated in both the primary vaccination round and the 2022 booster round were higher among younger persons, migrants with two foreign-born parents, inhabitants of highly or extremely urban areas and persons with low medical risk, lower income and lower education level. The higher odds of non-uptake for migrants with two foreign-born parents (reference: Netherlands-born child with one foreign-born parent) weakened but persisted after adjusting for socioeconomic variables in the populations of Dutch-Caribbean, Moroccan and Surinamese origin (Dutch-Caribbean: aORprimary=3.39 vs. 2.51, aORbooster=2.51 vs. 1.99, Moroccan: aORprimary=2.16 vs. 1.80, Surinamese: aORprimary=1.21 vs. 1.09, aORbooster=2.22 vs. 1.99), and inversed in the population of Turkish origin (aORprimary=1.10 vs. 0.93), while adjusting for additional variables had little effect on the estimate. Similarly to the aORs, the PAFs of young age, being a migrant with two foreign-born parents and having low income, low education level and low medical risk were highest.

Conclusion

Age, urbanisation level, medical risk, income, education level and migration background were associated with COVID-19 vaccination status among populations of non-Dutch origin. Socioeconomic status only partially mediated the effect of migration background. Although these findings provide some guidance to target vaccination programmes, qualitative and survey-based research is needed to further understand reasons behind lower vaccine uptake and design (community-based) interventions to improve health equity.