bluuebunny/crossref_metadata_2025 huggingface dataset:
BerEP4-Negative Basal Cell Carcinoma: An Immunophenotype Not to Forget
Authors: Murray Douglas W. , Thiel Robert W. , Phillips Mariana A. , Grider Douglas J.
Published: March 2024

Basal cell carcinoma (BCC) is the most common cancer worldwide. Although not typically metastatic, BCC can be locally destructive. BerEP4 is an antibody against CD326, an epithelial cell adhesion molecule (EpCAM) that is expressed on epithelial progenitor cells and carcinomas. BerEP4 has been reported to have a 100% positive sensitivity in basal cell carcinomas, but a much lower sensitivity for a variety of other carcinomas, including clear cell renal cell carcinoma and metastatic renal cell carcinoma. A 74-year-old woman presented with a BerEP4-negative, but anti–renal cell antibody-positive BCC, and the stark clinical implications of misdiagnosis. This case stresses the importance of considering BerEP4-negative BCC, even when other abnormal features are present.
Predictive utility of remnant cholesterol in atherosclerotic cardiovascular disease
Authors: Proctor Spencer D. , Wang Maggie , Vine Donna F. , Raggi Paolo
Published: March 2024

Purpose of Review

Remnant cholesterol (RC) is the cholesterol carried in lipoproteins derived from the catabolism of chylomicrons and very low-density lipoproteins. Evidence supporting the causal relationship of RC with atherosclerotic cardiovascular disease (ASVD) is accumulating rapidly. The number of impactful contributions to this field are increasing and provide a pathophysiological insight into the current residual cardiovascular risk beyond low-density cholesterol (LDL)-cholesterol (LDL-C). They also raise the question of whether RC should be used in prediction models and become the target of new therapeutic interventions. The intent of this review is to highlight the recent advances on the role of RC in atherogenesis and the validation of RC as a predictor of ASVD.

Recent Findings

Numerous prospective and retrospective cohorts helped validate a significant causal relationship of RC with various forms of ASVD, independent of LDL-C. A recent large Mendelian randomization study reinforced the existence of this relationship and showed that the risk of atherosclerotic events was driven nearly entirely by a direct effect of RC.

Both available and accumulating evidence suggest that a lifelong reduction in RC could translate into a substantial reduction in ASVD risk. The data support a revision of current guidelines to incorporate RC as an independent risk factor for ASVD. We propose that early screening of RC should be implemented and that RC lowering should become the target of future drug developments.
Corneal Transplant Rejection Postvaccination Among Medicare Beneficiaries
Authors: Ali Muhammad , Dun Chen , Yenokyan Gayane , Soiberman Uri , Jeng Bennie H. , Makary Martin A. , Woreta Fasika , Srikumaran Divya
Published: March 2024

Purpose:

The purpose of this study was to describe the incidence of corneal graft rejection after COVID and influenza vaccination.

Methods:

Patients 65 years or older undergoing penetrating keratoplasty or endothelial keratoplasty any time between 2016 and 2021 followed by COVID or influenza vaccination in 2021 among the 100% Medicare Fee-For-Service database were included. Demographic and ocular history characteristics of patients with (cases) and without graft rejection (controls) were compared using the χ2 test.

Results:

After COVID (n = 31,398) and influenza (n = 24,290) vaccination, 0.45% (n = 140) and 0.17% (n = 41) patients developed rejection within 90 days, respectively. There was no difference in the rate of graft rejection within 90 days relative to 90 to 180 days after vaccination after both COVID (90 days: 0.45% vs. 180 days: 0.61%, P = 0.37) and influenza (90 days: 0.17% vs. 180 days: 0.29%, P = 0.11) vaccines. For COVID vaccination, patients who underwent penetrating keratoplasty (n = 51, 0.97%; vs. endothelial keratoplasty = 89; 0.34%, P < 0.001), history of rejection up to 1 year before vaccination (n = 13; 1.30% vs. no history = 127, 0.42%; P < 0.001), and having an ocular comorbidity (n = 110, 0.54% vs. no ocular comorbidity = 30, 0.27%; P = 0.001) had higher rates of graft rejections, and most rejections were after 1 year postkeratoplasty (87.14%, n = 122).

Conclusions:

The incidence of graft rejection postvaccination is low compared with the overall rates of rejection in the published literature. Most post-COVID vaccination graft rejections were after 1 year postkeratoplasty when corticosteroids are expected to have been tapered to lower doses. Surgeons may counsel patients regarding graft rejection symptoms, but overall low rates may not warrant pretreatment in low-risk keratoplasty patients.
Clinical and Economic Burden of Antibiotic Use Among Pediatric Patients With Varicella Infection in the Outpatient Setting: A Retrospective Cohort Analysis of Real-world Data in France
Authors: Kujawski Stephanie A. , Casey Caroline S. , Haas Hervé , Patel Amisha , Diomatari Christina , Holbrook Tim , Pawaskar Manjiri
Published: March 2024

Background:

Varicella infects 90% of children before age 9. Though varicella is self-limiting, its complications may require antibiotics, though how antibiotics are utilized for varicella in France is not well known. This study assessed antibiotic use and costs associated with varicella and its complications in pediatric patients managed in the outpatient setting in France.

Methods:

A retrospective cohort study using the Cegedim Strategic Data-Longitudinal Patient Database, an electronic medical record database from general practitioners and office-based specialists in France, was conducted. Children <18 years old diagnosed with varicella between January 2014 and December 2018 with 3-month follow-up available were included. We used descriptive analysis to assess varicella-related complications, medication use, healthcare resource utilization and costs.

Results:

Overall, 48,027 patients were diagnosed with varicella; 15.3% (n = 7369) had ≥1 varicella-related complication. Antibiotics were prescribed in up to 25.1% (n = 12,045/48,027) of cases with greater use in patients with complications (68.1%, n = 5018/7369) compared with those without (17.3%, n = 7027/40,658). Mean medication and outpatient varicella-related costs were €32.82 per patient with medications costing a mean of €5.84 per patient; antibiotics contributed ~23% to total costs annually.

Conclusion:

This study showed high antibiotic use for the management of varicella and its complications. A universal varicella vaccination program could be considered to alleviate complications and associated costs in France.
Acute Compartment Syndrome and Rhabdomyolysis Caused by a Single Electrical Muscle Stimulation in a 46-Year-Old Female Professional Athlete With Fibromyalgia, Chronic Fatigue Syndrome, and Myofascial Disorder: A Case Report
Authors: von Deneen Karen M. , Alemayehu Dereje Gobena , Khosla Ajit
Published: March 2024

Electrical muscle stimulation (EMS) training has been recognized as an effective modality for improving body composition, enhancing body strength, and facilitating injury recovery. However, individuals who are new to EMS training and those with certain chronic diseases should exercise caution due to the increased risk of rhabdomyolysis. This case report describes the occurrence of rhabdomyolysis and gluteal compartment syndrome following a single session of EMS training in a 46-year-old Caucasian female professional athlete. The patient was successfully managed with intensive intravenous fluid therapy and sodium bicarbonate supplementation, along with close monitoring of electrolytes and renal function. Electrical muscle stimulation training poses an increased risk of severe complications in individuals with chronic diseases and myopathy. Therefore, careful subject selection is required for EMS training in individuals with chronic diseases and myopathy to prevent common side effects. For individuals trying EMS training for the first time, it is recommended to avoid high-frequency EMS exercises.
The Use of Portable, Very Low-field (0.064T) MRI to Image Cochlear Implants: Metallic Image Artifact in Comparison to Traditional, Stationary 3T MRI
Authors: Munhall Christopher C. , Roberts Donna R. , Labadie Robert F.
Published: March 2024

Objective:

To assess image artifact when imaging a cochlear implant (CI) with a conventional 3T MRI machine compared with a very low-field (0.064T) MRI.

Patients:

None.

Intervention:

Diagnostic study.

Main Outcome Measure:

Image artifact size associated with the CI affixed to an MRI phantom at very low-field 0.064T MRI versus 3T MRI.

Results:

The longest diameter of the image artifact was 125 mm for the 3T MRI and 86 mm for the 0.064T MRI, representing 45% longer image artifact generated in the 3T MRI. The actual volume of the imaging phantom was 1371 cm3. The volume of the image artifact was measured as 379 cm3 in the 3T MRI, representing a loss of 27.6% of the actual volume of the imaging phantom. The volume of image artifact was measured as 170 cm3 in the 0.064T MRI, representing a loss of 12.4% of the phantom volume.

Conclusions:

3T MRI had better image quality. This result was not surprising given that larger magnetic field strength is known to provide higher resolution. There was 15% less image artifact generated in the very low-field MRI machine compared with a conventional 3T device. And there was also subjectively increased distortion of the imaging phantom at 3T MRI compared with the 0.064T MRI. With minimized safety concerns and a much lower cost than conventional 3T machines, very low-field scanners may find expanded clinical uses. This preclinical study explores the potential utility of very low-field MRI in scanning CI recipients.
Differential Expression of Noncoding RNAs Revealed Enhancer RNA AC016735.2 as a Potential Pathogenic Marker of Congenital Microtia Patients
Authors: Liu Ying , Zhao Yanyong , Lin Lin , Yang Qinghua , Zhang Ling
Published: March 2024

Purpose:

Congenital microtia is a complex maxillofacial malformation with various risk factors. This study aimed to find potential pathogenic noncoding RNAs for congenital microtia patients.

Methods:

We collected 3 pairs of residual ear cartilage samples and corresponding normal ear cartilage samples from nonsyndromic congenital microtia patients for microarray experiments. The differentially expressed RNAs were screened, and enrichment analysis and correlation expression analysis were performed to elucidate the function of the differentially expressed genes (DEGs). We further investigated the most significantly differentially expressed long noncoding RNA (lncRNA), AC016735.2, through follow-up analyses including RT-qPCR and Western blotting, to validate its differential expression in residual ear cartilage compared with normal ear cartilage. SiRNA was designed to study the regulatory role of AC016735.2, and cell proliferation experiments were conducted to explore its impact on residual ear chondrocytes.

Results:

Analysis of the microarray data revealed a total of 1079 differentially expressed RNAs, including 305 mRNAs and x lncRNAs, using a threshold of FC>1.5 and P<0.05 for mRNA, and FC>1.0 and P<0.05 for lncRNA. Enrichment analysis indicated that these genes are mainly involved in extracellular matrix regulation and embryonic development. AC016735.2 showed the highest differential expression among the eRNAs, being upregulated in residual ear cartilage. It acts in cis to regulate the nearby coding gene ZFP36L2, indirectly affecting downstream genes such as BMP4, TWSG1, COL2A1, and COL9A2.

Conclusion:

Significant differences were observed in the expression of lncRNAs and mRNAs between residual ear cartilage and normal auricular cartilage tissues in the same genetic background of congenital microtia. These differentially expressed lncRNAs and mRNAs may play crucial roles in the occurrence and development of microtia through pathways associated with extracellular matrix regulation and gastrulation. Particularly, AC016735.2, an eRNA acting in cis, could serve as a potential pathogenic noncoding gene.
Identifying community safety and policy-based injury prevention opportunities to reduce golf cart injuries
Authors: DeJesus Jana , Chavez Carlos , Zou Jazzalyn , Brahmbhatt Kush , O'Daniel Elizabeth , Schaeffer August , Shah Nikhil R. , Nguyen Hoang , Matson Julie , Radhakrishnan Ravi , Naik-Mathuria Bindi
Published: March 2024

BACKGROUND

In small US communities, golf cart utilization has become increasingly more common. In the past 3 years, the incidence and severity of pediatric golf cart–related trauma evaluated at our trauma center have noticeably increased. Thus, the aim of this study was to analyze trends, identify risk and protective factors, and provide community-level recommendations to improve golf cart safety for children in a coastal community.

METHODS

A retrospective cross-sectional study of our institutional trauma registry was performed. The registry was queried for golf cart injuries between 2012 and 2022. Demographics, accident details, hospital course, and outcomes were reviewed. Data analysis involved quantitative statistics. Incident locations were mapped, including additional data from the County emergency medical service. In addition, customer education at four prominent golf rental shops was observed.

RESULTS

Annual golf cart–related traumas doubled starting in 2020. Of 235 total patients, 105 (46%) were children. Median age was 11.5 years (range, 2–17 years). Fifty-five percent were female, and 67% were non-Hispanic White. Eighty percent were out-of-county residents. The most common injury location was extremity (56%). The median Injury Severity Score was 4, and 3% died. Only 10% of children were restrained. Forty-one percent were ejected, and most (84%) were front-facing passengers. Ejection was associated with more severe injury (odds ratio, 4.13; p = 0.01). Most injuries occurred during 5 to 10 pm (47%), weekends, and summertime. Nighttime injuries were more severe than daytime (p = 0.04). A hotspot of crashes was identified in a zone where golf carts were restricted. Rental stores provided education on seat belt use, car seat use for infants, and off-limit zones. However, rules were not enforced.

CONCLUSION

Our results inform the following golf cart injury prevention opportunities: raising awareness of injury risks to children in high-tourist areas, partnering with rental stores to enforce rules, improving signage, adding protected lanes, and adopting a no nighttime operation policy.

LEVEL OF EVIDENCE

Prognostic and Epidemiological; Level IV.
Ligify: Automated genome mining for ligand-inducible transcription factors
Authors: d’Oelsnitz Simon , Ellington Andrew D. , Ross David J.
Published: March 2024

Abstract Figure

Prokaryotic transcription factors can be repurposed into biosensors for the ligand-inducible control of gene expression, but the landscape of chemical ligands for which biosensors exist is extremely limited. To expand this landscape, we developed Ligify, a web application that leverages information in enzyme reaction databases to predict transcription factors that may be responsive to user-defined chemicals. Candidate transcription factors are then incorporated into automatically generated plasmid sequences that are designed to express GFP in response to the target chemical. Our benchmarking analyses demonstrated that Ligify correctly predicted 31/100 previously validated biosensors, and highlighted strategies for further improvement. We then used Ligify to build a panel of genetic circuits that could induce a 47-fold, 5-fold, 9-fold, and 27-fold change in fluorescence in response to D-ribose, L-sorbose, isoeugenol, and 4-vinylphenol, respectively. Ligify should enhance the ability of researchers to quickly develop biosensors for an expanded range of chemicals, and is publicly available athttps://ligify.streamlit.app.
Genome evolution and between-host transmission of Spiroplasma endosymbiont in wild communities of Morpho butterflies
Authors: Jonathan Filee , Lopez-Villavicencio Manuella , Vincent Debat , Rignault Gabin , Rachel Fourdin , Camilo Salazar , Karina Lucas Silva-Brandao , Patrick Blandin , Andre Victor Lucci Freitas , Carolina Pardo-Diaz , Violaine Llaurens
Published: March 2024

The evolution of endosymbiont genomes is likely influenced by the ecological interactions with their hosts. Here, we studied the evolution of Spiroplasma genomes, as well as their transmission patterns within and between Morpho butterflies sampled in the wild. Spiroplasma was detected in 4 out of 11 Morpho species studied and displayed a 3 times larger genome size as compared to Spiroplasma genomes documented in other hosts. This inflation in genome size is caused by massive and recent expansion of various mobile genetic elements and by the acquisition of new genes stemming from prophages. Interestingly, these new Spiroplasma genomes also revealed a peculiar evolution of toxin genes in plasmids that may enhance host resistance to parasites. Phylogenetic comparisons with Spiroplasma extracted from other plant and insect host suggest multiple independent colonization of Lepidoptera by Spiroplasma, and probable horizontal exchanges among distantly-related butterfly species occurring in South America. In contrast, resequencing data obtained for multiple populations of the two sister-species M. helenor and M. achilles living in sympatry over the majority of their distribution revealed an opposite prevalence (97% in M. achilles and 3% in M. helenor), suggesting low levels of transmission between these sympatric host-species. Reconciliation analysis of the phylogenetic relationships of mitochondrial genomes within M. achilles and Spiroplasma strains furthermore confirms predominant vertical transfers of the endosymbiont within species. Altogether, our results indicate persistent interactions between Spiroplasma symbiont and some Morpho species, as well as contrasted prevalence among sympatric host-species, consistent with an evolution of ecological interactions between the endosymbiont and its different hosts that may modify their genomic evolution
TASOR expression in naive embryonic stem cells safeguards their developmental potential
Authors: Pinzon-Arteaga Carlos A. , O’Hara Ryan , Mazzagati Alice , Ballard Emily , Hu Yingying , Pan Alex , Schmitz Daniel A. , Wei Yulei , Sakurai Masahiro , Ly Peter , Banaszynski Laura , Wu Jun
Published: March 2024

The seamless transition through stages of pluripotency relies on a delicate balance between transcription factor networks and epigenetic silencing mechanisms that ensure proper regulation of the developmental program, critical for normal development. Here, we uncover the pivotal role of the transgene activation suppressor (TASOR), a component of the human silencing hub (HUSH) complex, in sustaining cell viability during the transition from naive to primed pluripotency, despite its rapid downregulation during this transition. Loss of TASOR in naive cells triggers replication stress, disrupts H3K9me3 heterochromatin formation, and compromise the transcriptional and post-transcriptional silencing of LINE-1 (L1) transposable elements (TEs), with these effects become more pronounced in primed cells. Remarkably, the survival ofTasor-knockout cells during naive to primed transition can be restored through the inhibition of cysteine-aspartic acid protease (Caspase) or deletion of mitochondrial antiviral signaling protein (MAVS). This suggests that unscheduled L1 expression activates an innate immune response, leading to programmed cell death, specifically in cells exiting naïve pluripotency. Additionally, we propose that HUSH-promoted H3K9me3 in naïve PSCs sets the stage for ensuing DNA methylation in primed cells, establishing long-term silencing during differentiation. Our findings shed insights on the crucial impact of epigenetic programs established in early developmental stages on subsequent phases, underscoring their significance in the developmental process.
Changes of urinary proteome in rats after intragastric administration of calcium gluconate
Authors: Shen Ziyun , Yang Minhui , Wang Haitong , Gao Youhe
Published: March 2024

Abtract

Calcium is an essential element for maintaining the normal physiological function of organisms. In this study, 3225 mg/kg/d calcium gluconate (equivalent to 300 mg/kg/d calcium) was intragastrically administered to rats for 4 days, and the urine proteome of rats was analyzed. Many differential proteins have been reported to be calcium related, such as Regucalcin (2.6 times higher after gavage than before gavage, p = 0.022), transmembrane protein 132A (8.2 times higher after gavage than before gavage, p = 0.009), creatine kinase (17.5 times higher before gavage than after gavage, p = 0.006), and claudin-3 (13.3 times higher before gavage than after gavage, p = 0.037). Differential protein enriched KEGG pathways included calcium signaling pathways, and biological processes and molecular functions also showed correlation with calcium. In this study, from the perspective of urine proteomics to explore the overall impact of calcium on the body, it is helpful to deeply understand the biological function of calcium and broaden the application potential of urine proteomics.
SUN2 mediates calcium-triggered nuclear actin polymerization to cluster active RNA polymerase II
Authors: Ulferts Svenja , Grosse Robert
Published: March 2024

The nucleoskeleton is essential for nuclear architecture as well as genome integrity and gene expression. In addition to lamins, titin or spectrins, dynamic actin filament polymerization has emerged as a potential intranuclear structural element but its functions are less well explored. Here we found that calcium elevations trigger rapid nuclear actin assembly requiring the nuclear membrane protein SUN2 independently of its function as a component of the LINC complex. Instead, SUN2 colocalized and associated with the formin and actin nucleator INF2 in the nuclear envelope in a calcium-regulated manner. Moreover, SUN2 is required for active RNA polymerase II (RNA Pol II) clustering in response to calcium elevations. Thus, our data uncover a SUN2-formin module linking the nuclear envelope to intranuclear actin assembly to promote signal-dependent spatial reorganization of active RNA Pol II.
Role of van der Waals, electrostatic, and hydrogen-bond interactions for the relative stability of cellulose Iβ and II crystals
Authors: Kullmann Richard , Delbianco Martina , Roth Christian , Weikl Thomas R.
Published: March 2024

Naturally occuring cellulose Iβ with its characteristic parallel orientation of cellulose chains is less stable than cellulose II, in which neighbouring pairs of chains are oriented antiparallel to each other. While the distinct hydrogen-bond patterns of these two cellulose crystal forms are well established, the energetic role of the hydrogen bonds for crystal stability, in comparison to the van der Waals and overall electrostatic interactions in the crystals, is a matter of current debate. In this article, we investigate the relative stability of cellulose Iβ and II in energy minimizations with classical force fields. We find that the larger stability of cellulose II results from clearly stronger electrostatic interchain energies that are only partially compensated by stronger van der Waals interchain energies in cellulose Iβ. In addition, we show that a multipole description of hydrogen bonds that includes the whole COH groups of donor and acceptor oxygen atoms leads to consistent interchain hydrogen-bond energies that account for roughly 70% and 75% of the interchain electrostatics in cellulose Iβ and II, respectively.
Eukaryotic initiation factor 3F (eIF3F) regulates the IRES-mediated translation of Bcl-xL via its interaction with programmed cell death 4 (PDCD4) protein
Authors: Hegde Veda , Sharma Divya K. , Patel Harshil , Narasimha Pavan , Luddu Jason , Holcik Martin , Thakor Nehal
Published: March 2024

Programmed cell death 4 (PDCD4) protein is a well-characterized tumor suppressor protein. PDCD4 inhibits mRNA translation by inhibiting the activity of an RNA helicase, eukaryotic initiation factor 4A (eIF4A). We have previously reported that PDCD4 interacts with the internal ribosome entry site (IRES) element that is found within the 5’ untranslated region (UTR) of mRNA encoding B-cell lymphoma extra-large (Bcl-xL) protein. PDCD4’s interaction with the Bcl-xL IRES element inhibits the IRES-mediated translation initiation on Bcl-xL mRNA. However, S6 kinase (S6K)-mediated phosphorylation of PDCD4 activates its degradation by proteasomal degradation pathway and derepress IRES-mediated translation initiation of Bcl-xL mRNA. Interestingly, eIF3F (one of the 13 subunits of eIF3) was reported to recruit S6K to phosphorylate eIF3. Therefore, we were intrigued by the possibility of co-regulation of PDCD4 and eIF3F by S6K and the regulation of IRES-mediated translation initiation by PDCD4-eIF3F. To this end, using co-immunoprecipitation (co-IP), we demonstrated that PDCD4 interacts with several subunits of eIF3. Reciprocal co-IP, endogenous IP, andin vitropull-down assays demonstrated that eIF3F directly interacts with PDCD4 in an RNA-independent manner. In order to functionally characterize the PDCD4-eIF3F complex, we depleted PDCD4 from the glioblastoma (GBM) cells, which resulted in decreased levels of eIF3F. Also, depletion of eIF3F from GBM cells reduced the levels of PDCD4 protein. However, this was not observed in non-cancer cells. Overexpression of PDCD4 resulted in enhanced levels of eIF3F, andvice versa. We further confirmed that the interaction of eIF3F and PDCD4 proteins prevents each other’s proteasomal degradation. By performing RNA-IP, we showed that PDCD4 and eIF3F interact with Bcl-xL RNA independently. Moreover, our IRES-bi-cistronic reporter assay and polysome profiling experiments demonstrated that eIF3F regulates IRES-mediated translation of Bcl-xL mRNA, likely via its interaction with PDCD4.

Significance

This study uncovers the fundamental mechanism of the internal ribosome entry site (IRES)- mediated translation regulation of B-cell lymphoma extra-large (Bcl-xL) mRNA by programmed cell death 4 (PDCD4) protein, and the eukaryotic initiation factor 3F (eIF3F). Our results show that PDCD4 and eIF3F interact with each other directly and they also interact with Bcl-xL mRNA independently. We show that PDCD4 works via eIF3F to regulate Bcl-xL levels. We also show that the PDCD4-eIF3F-dependent mechanism of Bcl-xL mRNA translation is implicated in glioblastoma (GBM) cells, including the primary brain tumor stem cells (BTSCs), and would likely affect the GBM pathophysiology.
Flame-forged divergence? Ancient human fires and the evolution of diurnal and nocturnal lineages in Mediterranean geckos
Authors: Fulgione Domenico , Russo Danilo , Rivieccio Eleonora , Maselli Valeria , Avallone Bice , Mondanaro Alessandro , Giurato Giorgio , Buglione Maria
Published: March 2024

Human influence has historically exerted a major driving in creating novel ecological niches. Although the controlled use of fire by ancient humans probably played a significant role by attracting positive phototactic prey and favour foraging by insectivorous vertebrates, no study has ever explored this possibility. Using a multidisciplinary approach, we explore whether human-controlled fire has historically affected the temporal niche partitioning in two lineages of Moorish geckosTarentola mauritanica, a diurnal- dark form and a nocturnal-pale form. We showed that the nocturnal-pale variant possesses lower skin melanin for fewer and smaller melanosomes and experiences lower α-MSH plasmatic levels than its diurnal-dark counterpart. Additionally, the analysis of the full mitochondrial genome established that our pale-nocturnal lineage emerged around 40,000 years ago, i.e., 20,000 years before the dark-diurnal lineage. Both variants arose when modern humans expanded into Europe, coinciding with the widespread use of fire, which likely facilitated the availability of arthropod prey for pale geckos, opening a previously untapped niche. Our modelling exercises corroborated a highly probable human-geckos coexistence during the emergence of these lineages. Furthermore, we experimentally demonstrated that fire near a rock surface significantly increases the abundance of arthropod prey, attracting preferred prey for the pale variant during nocturnal foraging. We suggest that ancient fires likely provided a novel foraging niche for pale geckos, yet it remains unclear whether the two lineages originated from diurnal or nocturnal ancestors. We present two alternative interpretations: the “out of the dark” scenario proposes a nocturnal ancestor leading to a diurnal descendant, while the “into the dark” scenario suggests a dark-diurnal ancestor evolving into a pale-nocturnal lineage. Phenotypic plasticity emerges as a critical factor in both scenarios, facilitating adaptation to new environments. We underscore the ongoing impact of artificial lighting on nocturnal behaviour, offering parallels to the potential origins of the gecko’s nocturnal lineage.
Epstein-Barr Virus Orchestrates Spatial Reorganization and Immunomodulation within the Classic Hodgkin Lymphoma Tumor Microenvironment
Authors: Yeo Yao Yu , Qiu Huaying , Bai Yunhao , Zhu Bokai , Chang Yuzhou , Yeung Jason , Michel Hendrik A. , Wright Kyle , Shaban Muhammad , Sadigh Sam , Nkosi Dingani , Shanmugam Vignesh , Rock Philip , Tung Yiu Stephanie Pei , Cramer Precious , Paczkowska Julia , Stephan Pierre , Liao Guanrui , Huang Amy Y. , Wang Hongbo , Chen Han , Frauenfeld Leonie , Mitra Bidisha , Gewurz Benjamin E. , Schürch Christian M. , Zhao Bo , Nolan Garry P. , Zhang Baochun , Shalek Alex K. , Angelo Michael , Mahmood Faisal , Ma Qin , Burack W. Richard , Shipp Margaret A. , Rodig Scott J. , Jiang Sizun
Published: March 2024

Classic Hodgkin Lymphoma (cHL) is a tumor composed of rare malignant Hodgkin and Reed-Sternberg (HRS) cells nested within a T-cell rich inflammatory immune infiltrate. cHL is associated with Epstein-Barr Virus (EBV) in 25% of cases. The specific contributions of EBV to the pathogenesis of cHL remain largely unknown, in part due to technical barriers in dissecting the tumor microenvironment (TME) in high detail. Herein, we applied multiplexed ion beam imaging (MIBI) spatial pro-teomics on 6 EBV-positive and 14 EBV-negative cHL samples. We identify key TME features that distinguish between EBV-positive and EBV-negative cHL, including the relative predominance of memory CD8 T cells and increased T-cell dysfunction as a function of spatial proximity to HRS cells. Building upon a larger multi-institutional cohort of 22 EBV-positive and 24 EBV-negative cHL samples, we orthogonally validated our findings through a spatial multi-omics approach, coupling whole transcriptome capture with antibody-defined cell types for tu-mor and T-cell populations within the cHL TME. We delineate contrasting transcriptomic immunological signatures between EBV-positive and EBV-negative cases that differently impact HRS cell proliferation, tumor-immune interactions, and mecha-nisms of T-cell dysregulation and dysfunction. Our multi-modal framework enabled a comprehensive dissection of EBV-linked reorganization and immune evasion within the cHL TME, and highlighted the need to elucidate the cellular and molecular fac-tors of virus-associated tumors, with potential for targeted therapeutic strategies.
Comparative efficacy and acceptability of treatment strategies for antipsychotic-induced akathisia: a systematic review and network meta-analysis
Authors: Furukawa Yuki , Imai Kota , Takahashi Yusuke , Efthimiou Orestis , Leucht Stefan
Published: March 2024

Background

Antipsychotics are the treatment of choice for schizophrenia, but they often induce akathisia. However, comparative efficacy of treatment strategies for akathisia remains unclear.

Design

We performed a systematic review and network meta-analyses (PROSPERO CRD42023450720). We searched multiple databases on 24th July 2023. We included randomized clinical trials comparing one or more treatment strategies for antipsychotic-induced akathisia against each other or control conditions. We included adults with schizophrenia or other psychiatric disorders treated with antipsychotics. The primary outcome was akathisia severity at posttreatment. Secondary outcomes included akathisia response, all-cause dropout, psychotic symptoms, and long-term akathisia severity. We synthesized data in random effects frequentist network meta-analyses and assessed confidence in the evidence using CINeMA.

Results

We identified 19 trials with 661 randomized participants (mean age 35.9 [standard deviation 12.0]; 36.7 % [195 of 532] women). No trials examined dose-reduction or switching of antipsychotics. Findings suggested 5-HT2A antagonists (k=6, n=108; standardized mean difference [SMD] -1.07 [95% confidence interval, -1.42; -0.71]) and beta-blockers (k=8, n=105; SMD -0.46 [-0.85; -0.07]) may improve akathisia severity, but confidence in the evidence was deemed low. We also found that benzodiazepines (k=2, n=13; SMD -1.62 [-2.64; -0.59]) and vitamin B6 (k=3, n=67; SMD -0.99 [-1.49; -0.50]) might also be beneficial, but confidence in the evidence was very low. Analyses of secondary outcomes did not provide additional insights.

Conclusions

Our findings suggest that 5-HT2A antagonists, beta blockers, and with a lesser certainty, benzodiazepines and vitamin B6 might improve akathisia. These conclusions are extremely preliminary and further trials are needed.
The concurrent development of psychological distress, heavy episodic drinking, and daily smoking from adolescence to midlife in two cohorts
Authors: Berg Noora , Piirtola Maarit , Marttunen Mauri , Latvala Antti , Kiviruusu Olli
Published: March 2024

Background

Heavy substance use, such as alcohol and tobacco use, is more prevalent among people with poor mental health. Despite the well-established correlation between substance use and mental health, the development of this association over time is unclear. The aim of this study was to examine the development and co-occurrence of psychological distress (mainly depressive and anxiety symptoms), heavy episodic drinking (HED) and daily smoking from adolescence to adulthood.

Methods

Two prospective longitudinal studies, the Stress, Development and Mental Health Study (TAM, N=2194) and the FinnTwin16 Study (N=5563), have followed participants from adolescence to adulthood (TAM ages 16-52, FinnTwin16 ages 16-35) using survey questionnaires. Latent class analysis was used to obtain joint trajectories of distress, HED and daily smoking.

Results

This study identified several different patterns of how HED, daily smoking and psychological distress cluster across time from adolescence to adulthood. In both examined cohorts, distinct groups of i) low levels of all three examined health concerns, ii) high levels of all three concerns, and iii) high distress and low-to-moderate substance use were found. In the older TAM cohort with longer follow-up time, a group indicating iv) increasing HED and a group indicating v) all on average level, with a peak in smoking, were also found.

Conclusions

Found variations set requirements for substance use and mental health services to target interventions for different groups to address all three major public health problems.
The impact of different antimicrobial exposures on the gut microbiome in the ARMORD observational study
Authors: Peto Leon , Fawcett Nicola , Kamfose Musaiwale M , Scarborough Claire , Peniket Andy , Danby Robert , Peto Tim EA , Crook Derrick W , Llewelyn Martin J , Sarah Walker A
Published: March 2024

Background

Better metrics to compare the impact of different antimicrobials on the gut microbiome would aid efforts to control antimicrobial resistance (AMR).

Methods

The Antibiotic Resistance in the Microbiome – Oxford (ARMORD) study recruited inpatients, outpatients and healthy volunteers in Oxfordshire, UK, who provided stool samples for metagenomic sequencing. Data on previous antimicrobial use and potential confounders were recorded. Exposures to each antimicrobial were considered as factors in a multivariable linear regression, also adjusted for demographics, with separate analyses for those contributing samples cross-sectionally or longitudinally. Outcomes were Shannon diversity and relative abundance of specific bacterial taxa (Enterobacteriaceae,Enterococcus, and major anaerobic groups) and antimicrobial resistance genes (targeting beta-lactams, tetracyclines, aminoglycosides, macrolides, and glycopeptides).

Results

225 adults were included in the cross-sectional analysis, and a subset of 79 patients undergoing haematopoietic stem cell transplant provided serial samples for longitudinal analysis. Results were largely consistent between the two sampling frames. Recent use of piperacillin-tazobactam, meropenem, intravenous co-amoxiclav and clindamycin were associated with large reductions in microbiome diversity and reduced abundance of anaerobes. Exposure to piperacillin-tazobactam and meropenem were associated with a decreased abundance ofEnterobacteriaceae, and an increased abundance ofEnterococcusand major AMR genes, but there was no evidence that these antibiotics had a greater impact on microbiome diversity than iv co-amoxiclav or oral clindamycin. In contrast, co-trimoxazole, doxycycline, antifungals and antivirals had less impact on microbiome diversity and selection of AMR genes.

Conclusion

Simultaneous estimation of the impact of over 20 antimicrobials on the gut microbiome and AMR gene abundance highlighted important differences between individual drugs. Some drugs in the WHO Access group (co-amoxiclav, clindamycin) had similar magnitude impact on microbiome diversity to those in the Watch group (meropenem, piperacillin-tazobactam) with potential implications for acquisition of resistant organisms. Metagenomic sequencing can be used to compare the impact of different antimicrobial agents and treatment strategies on the commensal flora.
Comprehensive knowledge and positive attitudes regarding HIV/AIDS among reproductive-aged women in Bangladesh and their associated factors: a cross-sectional study using the Multiple Indicator Cluster Survey 2019
Authors: Billah Md Arif , Yusof Raba’Aton Adawiah Mohd , Khan Md. Nuruzzaman , Min Ruhani Mat
Published: March 2024

Background

HIV/AIDS remains a global health concern and understanding the knowledge and attitudes of at-risk populations is crucial for effective prevention and management. This study examines the knowledge and attitudes related to HIV/AIDS among reproductive-aged women in Bangladesh and explores associated factors.

Methods

The study analyzed data from a total of 39,066 reproductive women, obtained from the nationally representative 2019 Multiple Indicator Cluster Survey. The outcome variables assessed were the level of HIV/AIDS-related knowledge (highvslow) and attitudes regarding HIV/AIDS (goodvspoor). These variables were derived by calculating the median values of scores obtained from nine and six questions in the survey that assessed knowledge and attitudes toward HIV/AIDS, respectively. The explanatory variables included sociodemographic factors and variables related to media exposure. A multivariate logistic regression model was employed to investigate the associations between the outcome and explanatory variables.

Results

Over half of the total respondents (51.6%) reported a lower level of knowledge, and a significant majority (54.2%) exhibited poor attitudes regarding HIV/AIDS, with notable variations observed across districts. Women in comparatively higher age groups, those with higher levels of education, hailing from more affluent families, residing in urban areas, and having exposure to newspapers, the internet, computers, and mobile phones displayed higher levels of knowledge regarding HIV/AIDS. Conversely, women with higher education levels, residing in rural areas, and having exposure to mobile phones and the internet exhibited good attitudes regarding HIV/AIDS. Unmarried respondents reported lower likelihoods of good attitude towards HIV/AIDS.

Conclusion

The findings underscores the urgent need for policies and programs designed to improve HIV/AIDS-related knowledge and attitudes, with a focus on district-level requirements. Effective strategies may include mass media campaigns and the incorporation of HIV/AIDS- related topics into the national curriculum.
TheEIF4EBP1gene encoding 4EBP1 is transcriptionally upregulated by MYC and linked to shorter survival in medulloblastoma
Authors: Hruby Laura , Scharov Katerina , Delaidelli Alberto , Picard Daniel , Dunham Christopher , Lewandowska Oksana , Reiff Tobias , Larcher Magalie , Pouponnot Celio , Sorensen Poul HB , Rotblat Barak , Reifenberger Guido , Remke Marc , Leprivier Gabriel
Published: March 2024

Medulloblastoma (MB) is the most common malignant brain tumor in childhood and is stratified into four molecular groups ‒ WNT, SHH, Group 3 and Group 4. Group 3 MB patients exhibit the poorest prognosis, with a 5-year overall survival of <60%, followed by Group 4 MB patients. Apart fromMYCamplification in a subset of Group 3 MBs, the molecular pathomechanisms driving aggressiveness of these tumors remain incompletely characterized. The gene encoding the mTOR substrate and mRNA translation inhibitor eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1) represents a possible MYC target gene whose corresponding protein, 4EBP1, was shown to be more active in Group 3 versus Group 4 MBs. However, the prognostic role of 4EBP1 in MB and the mechanisms supporting 4EBP1 overexpression in Group 3 MB are still elusive. We analyzedEIF4EBP1mRNA expression in publicly available data sets and found an upregulation in MB as compared to non-neoblastic brain.EIF4EBP1mRNA expression levels were higher in Group 3 compared to Group 4 MBs.EIF4EBP1mRNA expression was correlated withMYCexpression, most prominently in Group 3 MBs. Survival analyses highlighted that highEIF4EBP1mRNA expression was associated with reduced overall and event-free survival across all MB patients and in Group 3/Group 4 MB patients. Immunohistochemical evaluation of 4EBP1 protein expression in MB tissues confirmed that high levels of 4EBP1 are associated with poor outcome. Functional analyses revealed that MYC directly regulatesEIF4EBP1promoter activity, providing a mechanism for increasedEIF4EBP1mRNA levels in Group 3 MBs. Finally, we observed that 4EBP1 may support colony formation ofin vitrocultured MB cells. Our data highlight that transcriptional upregulation ofEIF4EBP1by MYC promotesin vitrotumorigenicity of MB cells and associates with shorter survival of MB patients.
Growing up in poverty, growing old in frailty: The life course shaping of health in America, Britain, and Europe – a prospective and retrospective study
Authors: Tampubolon Gindo
Published: March 2024

Background

Childhood poverty is directly associated with many health outcomes in late life irrespective of youth health and of variation in health systems. The childhood poor in America, Britain and Europe have reported worse cognitive, muscle and mental functions in their fifties to nineties. But it is not known whether they have higher probabilities of experiencing frailty as their childhood recollections are likely to be erroneous.

Materials and methods

Some 79428 adults aged 50 and older retrospectively recalled their childhood conditions at ten and underwent prospective examinations to construct their Fried’s frailty phenotype. Childhood conditions in ELSA and SHARE include number of books, number of rooms, number of people, presence of running hot or cold water, fixed bath, indoor lavatory and central heating. Across in America, these are mostly replaced with financial hardship indicators including having to move because of family debt. Childhood poverty is a latent construct of error-laced recollection and its distal fully adjusted association with frailty phenotype is estimated with fixed effects probit model.

Results

Childhood poverty associates with higher probabilities of being frail (0.1097 ± 0.0169, p < 0.001) in 29 countries of America, Britain and Europe. Furthermore, women have higher probabilities of being frail (0.3051 ± 0.0152, p < 0.001). Age, education, wealth, marital status and youth illness exert influences on the probabilities of being frail. Sensitivity analyses were conducted using random effects model and by stratifying on sex.

Discussion

Evidence is mounting that childhood can last a life time, affecting cognitive and muscle function, mental health and now frailty. This evidence calls for urgent actions to eliminate child poverty on account of its lifelong rewards. (271 + 4476 words)
Tracking Persistent Symptoms in Scotland (TraPSS): A Longitudinal Prospective Cohort Study of COVID-19 Recovery After Mild Acute Infection
Authors: Sculthorpe Nicholas F , Mclaughlin Marie , Cerexhe Luke , Macdonald Eilidh , Dello Iacono Antonio , Sanal-Hayes Nilihan EM , Ingram Joanne , Meach Rachel , Carless David , Ormerod Jane , Hayes Lawrence D
Published: March 2024

Background

COVID-19 disease results in disparate responses between individuals and has led to the emergence of Long-COVID, characterized by persistent and cyclical symptomology. To understand the complexity of Long-COVID, the importance of symptom surveillance and prospective longitudinal studies is evident.

Methods

A 9-month longitudinal prospective cohort study was conducted within Scotland (n=287), using a mobile app to determine the proportion of recovered individuals, those with persistent symptoms, common symptoms, and associations with gender and age.

Results

3.1% of participants experienced symptoms at month 9, meeting the criteria for Long-COVID, as defined by the NICE terminology. Fatigue, cough, and muscle pain were the most common symptoms at baseline, with fatigue persisting the longest, while symptoms like cough improved rapidly. Older age increased the likelihood of reporting pain and cognitive impairment. Female gender increased the likelihood of headaches and post-exertional malaise (PEM), and increased recovery time from fatigue and PEM.

Conclusions

The majority of people fully recover from acute COVID-19, albeit often slowly. Age and gender play a role in symptom burden and recovery rates, emphasizing the need for tailored approaches to Long-COVID management. Further analysis is required to determine the characteristics of the individuals still reporting ongoing symptoms months after initial infection to identify risk factors and potential predictors for the development of Long-COVID.
Nuclear RNAi Modulates Influenza A Virus Infectivity By Downregulating Type-I Interferon Response
Authors: Huang Hsiang-Chi , Nowak Iwona , Lobo Vivian , Besavilla Danica F. , Schön Karin , Westholm Jakub O. , Fernandez Carola , Patel Angana A.H. , Wiel Clotilde , Sayin Volkan I. , Anastasakis Dimitrios G. , Angeletti Davide , Sarshad Aishe A.
Published: March 2024

The role of Argonaute (AGO) proteins and the RNA interference (RNAi) machinery in mammalian antiviral response has been debated. Therefore, we set out to investigate how mammalian RNAi impacts influenza A virus (IAV) infection. We reveal that IAV infection triggers nuclear accumulation of AGO2, which is directly facilitated by p53 activation. Mechanistically, we show that IAV induces nuclear AGO2 targeting of TRIM71, a proposed AGO2 E3 ligase, and type-I interferon-pathway genes for silencing. Accordingly,Tp53-/-mice do not accumulate nuclear AGO2 and demonstrate decreased susceptibility to IAV infection. Hence, the RNAi machinery is highjacked by the virus to evade the immune system and support viral replication. Furthermore, the FDA approved drug arsenic trioxide, which prevents p53 tetramerization and nuclear translocation, increases interferon response and decreases viral replicationin vitroand in a mouse modelin vivo. Our data indicates that targeting the AGO2:p53-mediated silencing of innate immunity may offer a promising strategy to mitigate viral infections.