bluuebunny/crossref_metadata_2025 huggingface dataset:
Geospatial segmentation of high-resolution photovoltaic production maps for Switzerland
Authors: Ratnaweera N. , Kahl A. , Sharma V.
Published: October 2023

Until last year, most of Switzerland’s photovoltaic (PV) installations were built on roof tops. But the amount added is not enough to reach the country’s energy transition goals. With the adjustments of September 2023, the government incentivizes large-scale, free-standing photovoltaic installations. It is now essential to identify the best installation locations and to accurately estimate their production potential. Past studies have assessed different landcover classes, but much of the efforts have gone into separating out zones that are not suitable for PV plants; for technical, economical and also legislative reasons. All along, the underlying radiation data that was used to compute the local energy yield remained at a spatial resolution > 1 km. Given the complex terrain of the southern half of the country, this resolution is not high enough to capture the local variability in production potential. Our study introduces a new methodology to derive solar irradiance at a very high resolution of 25 m. Satellite data is combined with high resolution terrain information to compute accurate horizons and to account for local shading effects. These base radiation maps are then converted into potential electricity production from a PV panels. A comparison of the production from a typically chosen panel tilt with the production that can be achieved when the tilt is locally optimized based on the high-resolution radiation maps underlines the value of our new method. In a first application, this data set was used to estimate the lumped production potential of two major landcover classes in Switzerland: agricultural land and water surfaces, each of them divided into two subclasses. The geospatial segmentation was based on land use maps and the total available area within each class was calculated. Comparing the results to the production potential from Swiss roofs shows that these newly incentivized installation areas have a much higher production potential than the conventional roofs; both, in an absolute sense of total potential production (roofs: 120 TWh/a, agricultural: 2,250 TWh/a, water: 210 TWh/a), and in a relative sense of energy yield per installed capacity, especially in winter (roofs <50kWh/m2, agricultural >100kWh/m2, water ≈100kWh/m2).
Structure and function of molecular machines involved in deadenylation-dependent 5′-3′ mRNA degradation
Authors: Zhao Qi , Pavanello Lorenzo , Bartlam Mark , Winkler Gerlof Sebastiaan
Published: October 2023

In eukaryotic cells, the synthesis, processing, and degradation of mRNA are important processes required for the accurate execution of gene expression programmes. Fully processed cytoplasmic mRNA is characterised by the presence of a 5′cap structure and 3′poly(A) tail. These elements promote translation and prevent non-specific degradation. Degradation via the deadenylation-dependent 5′-3′ degradation pathway can be induced by trans-acting factors binding the mRNA, such as RNA-binding proteins recognising sequence elements and the miRNA-induced repression complex. These factors recruit the core mRNA degradation machinery that carries out the following steps: i) shortening of the poly(A) tail by the Ccr4-Not and Pan2-Pan3 poly (A)-specific nucleases (deadenylases); ii) removal of the 5′cap structure by the Dcp1-Dcp2 decapping complex that is recruited by the Lsm1-7-Pat1 complex; and iii) degradation of the mRNA body by the 5′-3′ exoribonuclease Xrn1. In this review, the biochemical function of the nucleases and accessory proteins involved in deadenylation-dependent mRNA degradation will be reviewed with a particular focus on structural aspects of the proteins and enzymes involved.
Genomic Variations Explorer (GenVarX): a toolset for annotating promoter and CNV regions using genotypic and phenotypic differences
Authors: Chan Yen On , Biová Jana , Mahmood Anser , Dietz Nicholas , Bilyeu Kristin , Škrabišová Mária , Joshi Trupti
Published: October 2023

The rapid growth of sequencing technology and its increasing popularity in biology-related research over the years has made whole genome re-sequencing (WGRS) data become widely available. A large amount of WGRS data can unlock the knowledge gap between genomics and phenomics through gaining an understanding of the genomic variations that can lead to phenotype changes. These genomic variations are usually comprised of allele and structural changes in DNA, and these changes can affect the regulatory mechanisms causing changes in gene expression and altering the phenotypes of organisms. In this research work, we created the GenVarX toolset, that is backed by transcription factor binding sequence data in promoter regions, the copy number variations data, SNPs and Indels data, and phenotypes data which can potentially provide insights about phenotypic differences and solve compelling questions in plant research. Analytics-wise, we have developed strategies to better utilize the WGRS data and mine the data using efficient data processing scripts, libraries, tools, and frameworks to create the interactive and visualization-enhanced GenVarX toolset that encompasses both promoter regions and copy number variation analysis components. The main capabilities of the GenVarX toolset are to provide easy-to-use interfaces for users to perform queries, visualize data, and interact with the data. Based on different input windows on the user interface, users can provide inputs corresponding to each field and submit the information as a query. The data returned on the results page is usually displayed in a tabular fashion. In addition, interactive figures are also included in the toolset to facilitate the visualization of statistical results or tool outputs. Currently, the GenVarX toolset supports soybean, rice, and Arabidopsis. The researchers can access the soybean GenVarX toolset from SoyKB via https://soykb.org/SoybeanGenVarX/, rice GenVarX toolset, and Arabidopsis GenVarX toolset from KBCommons web portal with links https://kbcommons.org/system/tools/GenVarX/Osativa and https://kbcommons.org/system/tools/GenVarX/Athaliana, respectively.
Adjusting the dose of traditional drugs combined with immunotherapy: reshaping the immune microenvironment in lung cancer
Authors: Wang Linlin , Du Changqi , Jiang Bing , Chen Lin , Wang Zibing
Published: October 2023

Immunotherapy is currently the most promising clinical treatment for lung cancer, not only revolutionizing second-line therapy but now also approved for first-line treatment. However, its clinical efficiency is not high and not all patients benefit from it. Thus, finding the best combination strategy to expand anti-PD-1/PD-L1-based immunotherapy is now a hot research topic. The conventional use of chemotherapeutic drugs and targeted drugs inevitably leads to resistance, toxic side effects and other problems. Recent research, however, suggests that by adjusting the dosage of drugs and blocking the activation of mutational mechanisms that depend on acquired resistance, it is possible to reduce toxic side effects, activate immune cells, and reshape the immune microenvironment of lung cancer. Here, we discuss the effects of different chemotherapeutic drugs and targeted drugs on the immune microenvironment. We explore the effects of adjusting the dosing sequence and timing, and the mechanisms of such responses, and show how the effectiveness and reliability of combined immunotherapy provide improved treatment outcomes.
Exercise sensitizes PD-1/PD-L1 immunotherapy as a hypoxia modulator in the tumor microenvironment of melanoma
Authors: Yan Huiyu , Jiang Aimin , Huang Yinong , Zhang Jun , Yang Wenguang , Zhang Wei , Liu Tianya
Published: October 2023

Introduction

Hypoxia is associated with unfavorable prognoses in melanoma patients, and the limited response rates of patients to PD-1/PD-L1 blockade could be attributed to the immunosuppressive tumor microenvironment induced by hypoxia. Exercise offers numerous benefits in the anti-tumor process and has the potential to alleviate hypoxia; however, the precise mechanisms through which it exerts its anti-tumor effects remain unclear, and the presence of synergistic effects with PD-1/PD-L1 immunotherapy is yet to be definitively established.

Methods

We established a B16F10 homograft malignant melanoma model and implemented two distinct exercise treatments (low/moderate-intensity swim) based on the mice’s exercise status. The specific function manner of exercise-induced anti-tumor effects was determined through RNA sequencing and analysis of changes in the tumor microenvironment. Furthermore, moderate-intensity swim that exhibited superior tumor suppression effects was combined with Anti-PD-1 treatment to evaluate its in vivo efficacy in mouse models.

Results

Exercise intervention yielded a considerable effect in impeding tumor growth and promoting apoptosis. Immunohistochemistry and RNA sequencing revealed improvements in tumor hypoxia and down-regulation of hypoxia-related pathways. Cellular immunofluorescence and ELISA analyses demonstrated a notable increase of cytotoxic T cell amount and a decrease of regulatory T cells, indicating an improvement of tumor immune microenvironment. In comparison to Anti-PD-1 monotherapy, tumor suppressive efficacy of exercise combination therapy was found to be enhanced with improvements in both the hypoxic tumor microenvironment and T cell infiltration.

Conclusion

Exercise has the potential to function as a hypoxia modulator improving the tumor immune microenvironment, resulting in the promotion of anti-tumor efficacy and the facilitation of biologically safe sensitization of PD-1/PD-L1 immunotherapy.
Transcriptome analysis reveals molecular mechanisms of lymphocystis formation caused by lymphocystis disease virus infection in flounder (Paralichthys olivaceus)
Authors: Zhang Honghua , Sheng Xiuzhen , Tang Xiaoqian , Xing Jing , Chi Heng , Zhan Wenbin
Published: October 2023

Lymphocystis disease is frequently prevalent and transmissible in various teleost species worldwide due to lymphocystis disease virus (LCDV) infection, causing unsightly growths of benign lymphocystis nodules in fish and resulting in huge economic losses to aquaculture industry. However, the molecular mechanism of lymphocystis formation is unclear. In this study, LCDV was firstly detected in naturally infected flounder (Paralichthys olivaceus) by PCR, histopathological, and immunological techniques. To further understand lymphocystis formation, transcriptome sequencing of skin nodule tissue was performed by using healthy flounder skin as a control. In total, RNA-seq produced 99.36%-99.71% clean reads of raw reads, of which 91.11%-92.89% reads were successfully matched to the flounder genome. The transcriptome data showed good reproducibility between samples, with 3781 up-regulated and 2280 down-regulated differentially expressed genes. GSEA analysis revealed activation of Wnt signaling pathway, Hedgehog signaling pathway, Cell cycle, and Basal cell carcinoma associated with nodule formation. These pathways were analyzed to interact with multiple viral infection and tumor formation pathways. Heat map and protein interaction analysis revealed that these pathways regulated the expression of cell cycle-related genes such as ccnd1 and ccnd2 through key genes including ctnnb1, lef1, tcf3, gli2, and gli3 to promote cell proliferation. Additionally, cGMP-PKG signaling pathway, Calcium signaling pathway, ECM-receptor interaction, and Cytokine-cytokine receptor interaction associated with nodule formation were significantly down-regulated. Among these pathways, tnfsf12, tnfrsf1a, and tnfrsf19, associated with pro-apoptosis, and vdac2, which promotes viral replication by inhibiting apoptosis, were significantly up-regulated. Visual analysis revealed significant down-regulation of cytc, which expresses the pro-apoptotic protein cytochrome C, as well as phb and phb2, which have anti-tumor activity, however, casp3 was significantly up-regulated. Moreover, bcl9, bcl11a, and bcl-xl, which promote cell proliferation and inhibit apoptosis, were significantly upregulated, as were fgfr1, fgfr2, and fgfr3, which are related to tumor formation. Furthermore, RNA-seq data were validated by qRT-PCR, and LCDV copy numbers and expression patterns of focused genes in various tissues were also investigated. These results clarified the pathways and differentially expressed genes associated with lymphocystis nodule development caused by LCDV infection in flounder for the first time, providing a new breakthrough in molecular mechanisms of lymphocystis formation in fish.
Syntaxin-4 and SNAP23 are involved in neutrophil degranulation, but not in the release of mitochondrial DNA during NET formation
Authors: Gigon Lea , Fettrelet Timothée , Miholic Marta , McLeish Kenneth R. , Yousefi Shida , Stojkov Darko , Simon Hans-Uwe
Published: October 2023

Neutrophils are a specialized subset of white blood cells, which have the ability to store pre-formed mediators in their cytoplasmic granules. Neutrophils are well-known effector cells involved in host protection against pathogens through diverse mechanisms such as phagocytosis, degranulation, extracellular traps, and oxidative burst. In this study, we provide evidence highlighting the significance of the SNARE proteins syntaxin-4 and synaptosomal-associated protein (SNAP) 23 in the release of azurophilic granules, specific granules, and the production of reactive oxygen species in human neutrophils. In contrast, the specific blockade of either syntaxin-4 or SNAP23 did not prevent the release of mitochondrial dsDNA in the process of neutrophil extracellular trap (NET) formation. These findings imply that degranulation and the release of mitochondrial dsDNA involve at least partially distinct molecular pathways in neutrophils.
Deciphering the role of HPV-mediated metabolic regulation in shaping the tumor microenvironment and its implications for immunotherapy in HNSCC
Authors: Gong Xiangjin , Xiong Jingwen , Gong Yu , Zhang Jieying , Zhang Jinhao , Yang Guanhu , Chi Hao , Tian Gang
Published: October 2023

Head and neck squamous cell carcinoma (HNSCC), as a complex and variable malignancy, poses a significant threat to human health. Since the intricate association between HPV and HNSCC emerged, its role within the TME has garnered extensive attention. HPV+HNSCC exhibits distinct immunological characteristics within the TME, intricately intertwined with mechanisms of immune evasion. HPV employs multifaceted pathways to intervene in metabolic regulation within the TME, exerting influence over immune cell functionality and neoplastic cell genesis. Furthermore, the heightened immune reactivity exhibited by HPV+HNSCC within the TME augments responses to immune interventions such as immune checkpoint inhibitors. Therefore, amidst the current limitations of therapeutic approaches, immunotherapy stands as a promising strategy to overcome the conventional confines of treating HNSCC. This article comprehensively outlines the impact of HPV on the inception and progression of HNSCC while discussing the amalgamation of metabolic regulation within the TME and immunotherapeutic strategies. By intervening in the reciprocal interactions between HPV and HNSCC within the TME, the potential to modulate the efficacy of immune-based treatments becomes evident. Concurrently, a synthesis of pertinent biomarker development is summarized. Such endeavors hold paramount significance for personalized therapeutic approaches and the more effective management of HNSCC patients.
Tool use, or not tool use, that is the question: is the necessity hypothesis really inconsequential for the African great apes?
Authors: Masi Shelly
Published: October 2023

Investigating the drivers of tool use in animals has recently received great attention because of its implication in understanding animals’ cognition and the evolution of tool use in hominins. The necessity hypothesis posits tool use as a necessary response to food scarcity, but its role is an ongoing debate. The largest body of literature comparing animal tool use frequencies is with regard to primates, particularly comparisons between the Pan species. This supports the hypothesis that tool use is rarer in wild bonobos because of differential manipulation abilities of chimpanzees rather than different ecological needs. In this article, I aim to enrich the discussion concerning the necessity hypothesis and the ecological drivers of tool use in apes. The higher feeding flexibility of bonobos may be a key aspect to explaining the lower use of feeding tools than that observed in chimpanzees. The diet flexibility of bonobos is similar to that of the lowest level of tool users among the wild great apes: the gorilla. Gorillas can thus help to shed further light on this debate. When fruit is scarce, Western gorillas and bonobos rely more on widely available proteinaceous herbs than chimpanzees, who remain highly frugivorous. Chimpanzees may thus face a greater necessity to search for an alternative to obtain high-quality food: tool-assisted feeding. An indirect piece of evidence for this higher level of herbivory is that the prevalence of gut ciliates in bonobos is double that of chimpanzees. In each animal species, a different combination of necessity, opportunities, predisposition, and learning processes are likely to be at play in the emergence of flexible tool use in animals.
Satellite imagery in evaluating oil spill modelling scenarios for the Syrian oil spill crisis, summer 2021
Authors: Keramea Panagiota , Kokkos Nikolaos , Zodiatis George , Sylaios Georgios , Coppini Giovanni , Peña Juan , Benjumeda Pablo , Sepp Neves Antonio Augusto , Lardner Robin , Liubartseva Svitlana , Soloviev Dmitry , Scuro Matteo , Nikolaidis Andreas , Viola Fabio
Published: October 2023

The second-largest oil pollution incident in the Eastern Mediterranean Levantine basin, following the oil pollution crisis in Lebanon in 2006, is considered to be the oil leakage from the Syrian Baniyas power plant (summer 2021), during which 12,000 tons of oil were released. At the operational phase, the everyday predictions of oil drift were provided using the MEDSLIK and MEDSLIK-II models in the framework of an agreement between the Mediterranean Operational Network for Global Ocean Observing System (MONGOOS) and the Regional Marine Pollution Emergency Response Centre for the Mediterranean (REMPEC). In this work, we present a novel post-operational comprehensive model-based analysis, conducting a SAR validation in two model outputs: the MEDSLIK and the OpenDrift models. Each simulation is initiated with the operationally acquired EMSA-CSN and ESA SAR images. Moreover, the high-resolution met-ocean fields (CYCOFOS, SKIRON) are used to force the oil drift and transformation in both models. The spill was developed under the calm-wind conditions that prevailed during the incident. We found that the boundary sea currents developed on the periphery of the Lattakia eddies (anticyclonic and cyclonic) were responsible for the fast westward spreading of the oil spill offshore in the NE Levantine, the north-south pathway bifurcation, and re-landing of oil in the extended coastal area of Lattakia. Model outputs were validated against Synthetic-aperture radar (SAR) images with appropriate performance metrics, used for the first time, to assess the capacity of a reliable representation of oil spill drift. The intercomparison between the two oil spill models indicated that both models produce almost similar results, while their validation against the satellite SAR observations illustrates moderate accuracy.
Effect of tofacitinib therapy on angiotensin converting enzyme activity in rheumatoid arthritis
Authors: Kacsándi Dorottya , Fagyas Miklós , Horváth Ágnes , Végh Edit , Pusztai Anita , Czókolyová Monika , Soós Boglárka , Szabó Attila Ádám , Hamar Attila , Pethő Zsófia , Bodnár Nóra , Kerekes György , Hodosi Katalin , Szamosi Szilvia , Szűcs Gabriella , Papp Zoltán , Szekanecz Zoltán
Published: October 2023

Introduction

The Renin-Angiotensin-Aldosterone system (RAAS) has been implicated in the regulation of the cardiovascular system and linked to rheumatoid arthritis (RA). Little information has become available on the effects of Janus kinase (JAK) inhibition on RAAS. Here we studied the effects of 12-month tofacitinib treatment on angiotensin converting enzyme (ACE), ACE2 production and ACE/ACE2 ratios in RA along with numerous other biomarkers.

Patients and methods

Thirty RA patients were treated with tofacitinib in this prospective study. Serum ACE concentrations were assessed by ELISA. ACE2 activity was determined by a specific quenched fluorescent substrate. ACE/ACE2 ratios were calculated. We also determined common carotid intima-media thickness (ccIMT), brachial artery flow-mediated vasodilation (FMD) and carotid-femoral pulse-wave velocity (cfPWV) by ultrasound. C-reactive protein (CRP), rheumatoid factor (RF) and anti-citrullinated protein autoantibodies (ACPA) were also determined. All measurements were performed at baseline, as well as after 6 and 12 months of tofacitinib treatment.

Results

After the dropout of 4 patients, 26 completed the study. Tofacitinib treatment increased ACE levels after 6 and 12 months, while ACE2 activity only transiently increased at 6 months. The ACE/ACE2 ratio increased after 1 year of therapy (p < 0.05). Logistic regression analyses identified correlations between ACE, ACE2 or ACE/ACE2 ratios and RF at various time points. Baseline disease duration also correlated with erythrocyte sedimentation rate (ESR) (p < 0.05). One-year changes of ACE or ACE2 were determined by tofacitinib treatment plus ACPA or RF, respectively (p < 0.05).

Conclusion

JAK inhibition increases serum ACE and ACE/ACE2 ratio in RA. Baseline inflammation (ESR), disease duration and ACPA, as well as RF levels at various time points can be coupled to the regulation of ACE/ACE2 ratio. The effect of tofacitinib on RAAS provides a plausible explanation for the cardiovascular effects of JAK inhibition in RA.
Predictive risk factors before the onset of familial rheumatoid arthritis: the Tatarstan cohort study
Authors: Arleevskaya Marina I. , Larionova Regina V. , Shagimardanova Elena I. , Gogoleva Natalia E. , Kravtsova Olga A. , Novikov Andrej A. , Kazarian Gevorg G. , Carlé Caroline , Renaudineau Yves
Published: October 2023

Background

A familial history of rheumatoid arthritis (RA) predisposes an individual to develop RA. This study aimed at investigating factors associated with this conversion from the Tatarstan cohort.

Methods

A total of 144 individuals, referred to as pre-RA and at risk for familial RA, were selected 2 years (range: 2–21 years) before conversion to RA and compared to non-converted 328 first-degree relatives (FDR) from RA as assessed after ≥2 years follow-up, and 355 healthy controls were also selected (HC). Preclinical parameters and socio-demographic/individual/HLA genetic factors were analyzed when data were available at the time of enrollment.

Results

As compared to FDR and HC groups, pre-RA individuals were characterized before conversion to RA by the presence of arthralgia, severe morning symptoms, a lower educational level, and rural location. An association with the HLA-DRB1 SE risk factor was also retrieved with symmetrical arthralgia and passive smoking. On the contrary, alcohol consumption and childlessness in women were protective and associated with the HLA-DRB1*07:01 locus.

Conclusion

Before RA onset, a combination of individual and genetic factors characterized those who are at risk of progressing to RA among those with familial RA relatives.
Serological analysis reveals differential antibody responses between TB patients and latently infected individuals from the TB endemic country of Mozambique
Authors: Tran Andy C. , Boariu Eugenia , García-Bengoa María , Kim Mi-Young , Vergara Emil Joseph , Mussá Tufária , Reljic Rajko
Published: October 2023

Serological antibody profiling of tuberculosis (TB) patients and household contacts with latent TB infection (LTBI) could identify risk indicators of disease progression, and potentially also serve as an easily accessible diagnostic tool to discriminate between these two stages of Mycobacterium tuberculosis (Mtb) infection. Yet, despite significant efforts over many decades, neither application has yet fully materialised, and this is at least in part due to inconsistent and varying antibody profiles from different TB endemic regions. In this study, we conducted a retrospective exploratory analysis of serum antibodies in a cohort of active TB patients (ATB) and their interferon-gamma release assay (IGRA) positive household contacts (LTBI), as well as healthy controls (HC) from Mozambique, a country with a high TB burden from the Sub-Saharan region. Using several Mtb antigens as well as crude preparations of culture filtrate proteins (CFP) from Mtb and Bacille Calmette Guérin (BCG), we report that the most discriminatory response for TB and LTBI was observed for serum IgA antibodies to the MPT64 antigen, followed by IgG antibodies to Ag85B and CFP, with ATB patients having significantly higher levels than LTBI or BCG-vaccinated healthy controls. Conversely, sera from LTBI individuals had higher levels of IgG antibodies to the HBHA antigen than ATB. While our sample size (n = 21 for ATB, 18 for LTBI and 17 for HC) was too small to fully evaluate the diagnostic potential of these differing serological profiles, our study however preliminarily indicated high level of sensitivity (95%) and specificity (97%) of an ELISA MPT64-IgA test for discriminating TB from LTBI and healthy controls, supporting the notion that it alone, or possibly in combination with other antigens such as Ag85B or CFP could lead to development of an easily accessible diagnostic tool for TB.
An assembled bacterial community associated with Artemisia annua L. causes plant protection against a pathogenic fungus
Authors: Wang Yu , Yang Zhan-nan , Luo Shi-qiong
Published: October 2023

The microorganisms associated with a plant influence its growth and fitness. These microorganisms accumulate on the aerial and root surfaces of plants, as well as within the plants, as endophytes, although how the interaction between microorganisms protects the plant from pathogens is still little understood. In the current study, the impact of assembled the bacterial communities against the pathogenic fungus to promote Artemisia annua L. growths was investigated. We established a model of bacterium–fungus–plant system. Eight bacterial strains and a fungal pathogen Globisporangium ultimum (Glo) were isolated from wild A. annua roots and leaves, respectively. We assembled the six-bacteria community (C6: Rhizobium pusense, Paracoccus sp., Flavobacterium sp., Brevundimonas sp., Stenotrophomonas sp., and Bacillus sp.) with inhibition, and eight-bacteria community (C8) composing of C6 plus another two bacteria (Brevibacillus nitrificans and Cupriavidus sp.) without inhibition against Glo in individually dual culture assays. Inoculation of seedlings with C8 significantly reduced impact of Glo. The growth and disease suppression of A. annua seedlings inoculated with C8 + Glo were significantly better than those of seedlings inoculated with only Glo. C8 had more inhibitory effects on Glo, and also enhanced the contents of four metabolites in seedling roots compared to Glo treatment only. Additionally, the inhibitory effects of root extracts from A. annua seedlings showed that Glo was most sensitive, the degree of eight bacteria sensitivity were various with different concentrations. Our findings suggested that the non-inhibitory bacteria played a vital role in the bacterial community composition and that some bacterial taxa were associated with disease suppression. The construction of a defined assembled bacterial community could be used as a biological fungicide, promoting biological disease control of plants.
Modulation of Influenza A virus NS1 expression reveals prioritization of host response antagonism at single-cell resolution
Authors: Yang Qing , Elz Anna E. , Panis Maryline , Liu Ting , Nilsson-Payant Benjamin E. , Blanco-Melo Daniel
Published: October 2023

Influenza A virus (IAV) is an important human respiratory pathogen that causes significant seasonal epidemics and potential devastating pandemics. As part of its life cycle, IAV encodes the multifunctional protein NS1, that, among many roles, prevents immune detection and limits interferon (IFN) production. As distinct host immune pathways exert different selective pressures against IAV, as replication progresses, we expect a prioritization in the host immune antagonism by NS1. In this work, we profiled bulk transcriptomic differences in a primary bronchial epithelial cell model facing IAV infections at distinct NS1 levels. We further demonstrated that, at single cell level, the intracellular amount of NS1 in-part shapes the heterogeneity of the host response. We found that modulation of NS1 levels reveal a ranking in its inhibitory roles: modest NS1 expression is sufficient to inhibit immune detection, and thus the expression of pro-inflammatory cytokines (including IFNs), but higher levels are required to inhibit IFN signaling and ISG expression. Lastly, inhibition of chaperones related to the unfolded protein response requires the highest amount of NS1, often associated with later stages of viral replication. This work demystifies some of the multiple functions ascribed to IAV NS1, highlighting the prioritization of NS1 in antagonizing the different pathways involved in the host response to IAV infection.
Evolution and functional role prediction of the CYP6DE and CYP6DJ subfamilies in Dendroctonus (Curculionidae: Scolytinae) bark beetles
Authors: Quijano-Barraza J. Manuel , Zúñiga Gerardo , Cano-Ramírez Claudia , López María Fernanda , Ramírez-Salinas Gema L. , Becerril Moises
Published: October 2023

Dendroctonus-bark beetles are natural components and key ecological agents of coniferous forests. They spend most of their lives under the bark, where they are exposed to highly toxic terpenes present in the oleoresin. Cytochrome P450 (CYP) is a multigene family involved in the detoxification of these compounds. It has been demonstrated that CYP6DE and CYP6DJ subfamilies hydroxylate monoterpenes, whose derivatives can act as pheromone synergist compounds or be pheromones themselves in these insects. Given the diversity and functional role of CYPs, we investigated whether these cytochromes have retained their function throughout the evolution of these insects. To test this hypothesis, we performed a Bayesian phylogenetic analysis to determine phylogenetic subgroups of cytochromes in these subfamilies. Subgroups were mapped and reconciled with the Dendroctonus phylogeny. Molecular docking analyses were performed with the cytochromes of each subgroup and enantiomers of α-pinene and β-pinene, (+)-3-carene, β-myrcene and R-(+)-limonene. In addition, functional divergence analysis was performed to identify critical amino acid sites that influence changes in catalytic site conformation and/or protein folding. Three and two phylogenetic subgroups were recovered for the CYP6DE and CYP6DJ subfamilies, respectively. Mapping and reconciliation analysis showed different gain and loss patterns for cytochromes of each subgroup. Functional predictions indicated that the cytochromes analyzed are able to hydroxylate all monoterpenes; however, they showed preferential affinities to different monoterpenes. Functional divergence analyses indicated that the CYP6DE subfamily has experimented type I and II divergence, whereas the CYP6DJ subfamily has evolved under strong functional constraints. Results suggest cytochromes of the CYP6DE subfamily evolve to reinforce their detoxifying capacity hydroxylating mainly α- and β-pinene to (+) and (−)-trans-verbenol, being the negative enantiomer used as a pheromone by several Dendroctonus species; whereas cytochromes of the CYP6DJ subfamily appear to retain their original function related to the detoxification of these compounds.
Brain-derived neurotrophic factor gene polymorphism affects cognitive function and neurofilament light chain level in patients with subcortical ischaemic vascular dementia
Authors: Yao Xiaojuan , Yang Guotao , Fang Tingting , Tian Zhuo , Lu Yunyao , Chen Feifan , Che Ping , Chen Jingshan , Zhang Nan
Published: October 2023

Objective

To investigate the effects of brain-derived neurotrophic factor (BDNF) gene polymorphism on cognitive function, neuroimaging and blood biological markers in patients with subcortical ischaemic vascular dementia (SIVD).

Methods

A total of 81 patients with SIVD were included. According to their BDNF gene polymorphism, the participants were divided into the Val/Val (n = 26), Val/Met (n = 35), and Met/Met (n = 20) groups. A comprehensive neuropsychological evaluation and multimodal brain MRI scan were performed. MRI markers for small vessel disease were visually rated or quantitatively analysed. Moreover, 52 patients were further evaluated with blood marker assays, including amyloid beta (Aβ), phosphorylated tau at threonine-181 (P-tau181), glial fibrillary acidic protein (GFAP), total tau (T-tau) and neurofilament light chain (NfL).

Results

There were no significant differences in demographics, disease duration or MRI markers of small vessel disease between the three groups. Compared with the Val/Val and Val/Met groups, the Met/Met group showed worse performance in the verbal fluency test and higher levels of plasma NfL.

Conclusion

The rs6265 polymorphism of the BDNF gene is associated with semantic language fluency in patients with SIVD. The Met genotype may be a risk factor for cognitive impairment and neuronal injury.
Association between platelet-lymphocyte ratio and 90-day mortality in patients with intracerebral hemorrhage: data from the MIMIC-III database
Authors: Yuan Min , Xiao Zhilong , Zhou Huangyan , Fu Anxia , Pei Zhimin
Published: October 2023

Background

Recent evidence suggested that platelet-lymphocyte ratio (PLR) may play a role in the pathophysiology of intracerebral hemorrhage (ICH), but the results are controversial. This study aimed to explore the relationship between PLR and mortality in patients with ICH.

Methods

All data were extracted from the Medical Information Mart for Intensive Care (MIMIC) III database. The study outcome was 90-day mortality. Multivariable Cox regression analyses were used to calculate the adjusted hazard ratio (HR) with a 95% confidence interval (CI), and curve-fitting (restricted cubic spline) was used to assess the non-linear relationship.

Results

Of 1,442 patients, 1,043 patients with ICH were included. The overall 90-day mortality was 29.8% (311/1,043). When PLR was assessed in quartiles, the risk of 90-day mortality for ICH was lowest for quartile 2 (120.9 to <189.8: adjusted HR, 0.67; 95% CI: 0.48–0.93; P = 0.016), compared with those in quartile 1 (<120.9). Consistently in the threshold analysis, for every 1 unit increase in PLR, there was a 0.6% decrease in the risk of 90-day mortality for ICH (adjusted HR, 0.994; 95% CI: 0.988–0.999) in those with PLR <145.54, and a 0.2% increase in 90-day mortality (adjusted HR, 1.002; 95% CI: 1.000–1.003) in participants with PLR ≥145.54.

Conclusion

There was a non-linear relationship between PLR and 90-day mortality for patients with ICH, with an inflection point at 145.54 and a minimal risk at 120.9 to <189.8 of PLR.
Truncated DNM1 variant underlines developmental delay and epileptic encephalopathy
Authors: Afsar Tayyaba , Huang Xiaoyun , Shah Abid Ali , Abbas Safdar , Bano Shazia , Mahmood Arif , Hu Junjian , Razak Suhail , Umair Muhammad
Published: October 2023

Background

Developmental and epileptic encephalopathies (DEEs) signify a group of heterogeneous neurodevelopmental disorder associated with early-onset seizures accompanied by developmental delay, hypotonia, mild to severe intellectual disability, and developmental regression. Variants in the DNM1 gene have been associated with autosomal dominant DEE type 31A and autosomal recessive DEE type 31B.

Methods

In the current study, a consanguineous Pakistani family consisting of a proband (IV-2) was clinically evaluated and genetically analyzed manifesting in severe neurodevelopmental phenotypes. WES followed by Sanger sequencing was performed to identify the disease-causing variant. Furthermore, 3D protein modeling and dynamic simulation of wild-type and mutant proteins along with reverse transcriptase (RT)–based mRNA expression were checked using standard methods.

Results

Data analysis of WES revealed a novel homozygous non-sense variant (c.1402G>T; p. Glu468*) in exon 11 of the DNM1 gene that was predicted as pathogenic class I. Variants in the DNM1 gene have been associated with DEE types 31A and B. Different bioinformatics prediction tools and American College of Medical Genetics guidelines were used to verify the identified variant. Sanger sequencing was used to validate the disease-causing variant. Our approach validated the pathogenesis of the variant as a cause of heterogeneous neurodevelopmental disorders. In addition, 3D protein modeling showed that the mutant protein would lose most of the amino acids and might not perform the proper function if the surveillance non-sense-mediated decay mechanism was skipped. Molecular dynamics analysis showed varied trajectories of wild-type and mutant DNM1 proteins in terms of root mean square deviation, root mean square fluctuation and radius of gyration. Similarly, RT-qPCR revealed a substantial reduction of the DNM1 gene in the index patient.

Conclusion

Our finding further confirms the association of homozygous, loss-of-function variants in DNM1 associated with DEE type 31B. The study expands the genotypic and phenotypic spectrum of pathogenic DNM1 variants related to DNM1-associated pathogenesis.
Hematological characteristics and hepatobiliary complications of hereditary spherocytosis in a tertiary care pediatric center: optimizing diagnosis and care through local and international networks
Authors: Boaro Maria Paola , Reggiani Giulia , D’Agnolo Mirco , Munaretto Vania , Pozzebon Francesco , Trapanese Roberta , Martella Maddalena , Colombatti Raffaella
Published: October 2023

Background

Hereditary Spherocytosis (HS) is a rare, congenital red blood cell disorder presenting with variable clinical manifestations ranging from mild hemolytic anemia to severe anemia with hypersplenism and hepatobiliary complications.

Methods

The objectives of the study were to evaluate the diagnostic pathway of HS, the presence and management of hepatobiliary complications in pediatric patients with HS followed in a tertiary care center. The demographic, clinical, hematological information were retrieved from medical records of patients having at least 1 hematology visit between 2010 and 2020.

Results

Forty-two patients were enrolled, 23 M. Mean age at onset of symptoms was 2.8 years, at diagnosis was 3.5 years. Anemia was the first manifestation in 73%; suspect of HS arose for all patients in first or second level outpatient clinics. Only 64% of patients performed two confirmation tests in the reference center. 28/42 had familiarity for HS; of the 13/42 who did not, only 47% performed further analysis. Sixteen patients developed gallbladder stones (40%), visible at the first ultrasound (5.6 years). Hemolytic crises and parvovirus infections were more frequent in patients with stones (53.6% vs. 26.1% and 63.6% vs. 28.6%, respectively). 10/16 (62.5%) underwent elective cholecystectomy: 8 had concomitant splenectomy.

Conclusions

our study highlights the need to optimize the diagnostic pathway in networks of care involving general and specialized centers in order to reduce time to diagnosis and ensure that all patients receive confirmatory tests. A high frequency of hepatobiliary complications since young age was observed suggesting that screening with ultrasound should begin earlier
Effects of public reporting of prescription indicators on patient choices: evidence from propensity scores matching
Authors: Chen Manli , Zhang Xinping , Liu Chaojie , Chen Haihong , Wang Dan , Liu Chenxi
Published: October 2023

Background: Public reporting on health providers’ performance (PRHPP) is increasingly used for empowering patients. This study aimed to test the effect of PRHPP using the theory of the consumer choice model.

Methods: The study was conducted in 10 primary care institutions in Hubei province, China. Information related to the percentage of prescriptions requiring antibiotics, the percentage of prescriptions requiring injections, and average costs per prescription for each prescriber was calculated, ranked and displayed in a public place on a monthly basis. A questionnaire survey was undertaken on 302 patients 10 months after the initiation of the PRHPP, tapping into patient awareness, understanding, perceived value and use of the information in line with the theory of the consumer choice model. The fitness of data with the model was tested using structural equation modelling. The patients who were aware of the PRHPP were compared with those who were unaware of the PRHPP. The propensity score method (considering differences between the two groups of patients in age, gender, education, health and income) was used for estimating the effects of the PRHPP.

Results: About 22% of respondents were aware of the PRHPP. Overall, the patients showed limited understanding, perceived value and use of the disclosed information. The data fit well into the consumer choice model. Awareness of the PRHPP was found to be associated with increased understanding of the antibiotic (p = 0.028) and injection prescribing indictors (p = 0.030). However, no significant differences in perceived value and use of the information (p > 0.097) were found between those who were aware and those who were unaware of the PRHPP.

Conclusion: Although PRHPP may improve patient understanding of the prescribing performance indicators, its impacts on patient choices are limited due to low levels of perceived value and use of information from patients. Additional support is needed to enable patients to make informed choices using the PRHPP.
Impact of domiciliary administration of NSAIDs on COVID-19 hospital outcomes: an unCoVer analysis
Authors: Salvador Elena , Mazzi Cristina , De Santis Nicoletta , Bertoli Giulia , Jonjić Antonija , Coklo Miran , Majdan Marek , Peñalvo José L. , Buonfrate Dora
Published: October 2023

Background: Effective domiciliary treatment can be useful in the early phase of COVID-19 to limit disease progression, and pressure on hospitals. There are discrepant data on the use of non-steroidal anti-inflammatory drugs (NSAIDs). Aim of this study is to evaluate whether the clinical outcome of patients who were hospitalized for COVID-19 is influenced by domiciliary treatment with NSAIDs. Secondary objective was to explore the association between other patient characteristics/therapies and outcome.

Methods: A large dataset of COVID-19 patients was created in the context of a European Union-funded project (unCoVer). The primary outcome was explored using a study level random effects meta-analysis for binary (multivariate logistic regression models) outcomes adjusted for selected factors, including demographics and other comorbidities.

Results: 218 out of 1,144 patients reported use of NSAIDs before admission. No association between NSAIDs use and clinical outcome was found (unadj. OR: 0.96, 95%CI: 0.68-1.38). The model showed an independent upward risk of death with increasing age (OR 1.06; 95% CI 1.05-1.07) and male sex (1.36; 95% CI 1.04-1.76).

Conclusion: In our study, the domiciliary use of NSAIDs did not show association with clinical outcome in patients hospitalized with COVID-19. Older ages and male sex were associated to an increased risk of death.
Harnessing mechanical cues in the cellular microenvironment for bone regeneration
Authors: Josephson Timothy O. , Morgan Elise F.
Published: October 2023

At the macroscale, bones experience a variety of compressive and tensile loads, and these loads cause deformations of the cortical and trabecular microstructure. These deformations produce a variety of stimuli in the cellular microenvironment that can influence the differentiation of marrow stromal cells (MSCs) and the activity of cells of the MSC lineage, including osteoblasts, osteocytes, and chondrocytes. Mechanotransduction, or conversion of mechanical stimuli to biochemical and biological signals, is thus part of a multiscale mechanobiological process that drives bone modeling, remodeling, fracture healing, and implant osseointegration. Despite strong evidence of the influence of a variety of mechanical cues, and multiple paradigms proposed to explain the influence of these cues on tissue growth and differentiation, even a working understanding of how skeletal cells respond to the complex combinations of stimuli in their microenvironments remains elusive. This review covers the current understanding of what types of microenvironmental mechanical cues MSCs respond to and what is known about how they respond in the presence of multiple such cues. We argue that in order to realize the vast potential for harnessing the cellular microenvironment for the enhancement of bone regeneration, additional investigations of how combinations of mechanical cues influence bone regeneration are needed.
Hip thrust and back squat training elicit similar gluteus muscle hypertrophy and transfer similarly to the deadlift
Authors: Plotkin Daniel L. , Rodas Merlina A. , Vigotsky Andrew D. , McIntosh Mason C. , Breeze Emma , Ubrik Rachel , Robitzsch Cole , Agyin-Birikorang Anthony , Mattingly Madison L. , Michel J. Max , Kontos Nicholas J. , Lennon Sarah , Frugé Andrew D. , Wilburn Christopher M. , Weimar Wendi H. , Bashir Adil , Beyers Ronald J. , Henselmans Menno , Contreras Bret M. , Roberts Michael D.
Published: October 2023

We examined how set-volume equated resistance training using either the back squat (SQ) or hip thrust (HT) affected hypertrophy and various strength outcomes. Untrained college-aged participants were randomized into HT (n = 18) or SQ (n = 16) groups. Surface electromyograms (sEMG) from the right gluteus maximus and medius muscles were obtained during the first training session. Participants completed 9 weeks of supervised training (15–17 sessions), before and after which gluteus and leg muscle cross-sectional area (mCSA) was assessed via magnetic resonance imaging. Strength was also assessed prior to and after the training intervention via three-repetition maximum (3RM) testing and an isometric wall push test. Gluteus mCSA increases were similar across both groups. Specifically, estimates [(−) favors HT (+) favors SQ] modestly favored the HT versus SQ for lower [effect ±SE, −1.6 ± 2.1 cm2; CI95% (−6.1, 2.0)], mid [−0.5 ± 1.7 cm2; CI95% (−4.0, 2.6)], and upper [−0.5 ± 2.6 cm2; CI95% (−5.8, 4.1)] gluteal mCSAs but with appreciable variance. Gluteus medius + minimus [−1.8 ± 1.5 cm2; CI95% (−4.6, 1.4)] and hamstrings [0.1 ± 0.6 cm2; CI95% (−0.9, 1.4)] mCSA demonstrated little to no growth with small differences between groups. mCSA changes were greater in SQ for the quadriceps [3.6 ± 1.5 cm2; CI95% (0.7, 6.4)] and adductors [2.5 ± 0.7 cm2; CI95% (1.2, 3.9)]. Squat 3RM increases favored SQ [14 ± 2 kg; CI95% (9, 18),] and hip thrust 3RM favored HT [−26 ± 5 kg; CI95% (−34, −16)]. 3RM deadlift [0 ± 2 kg; CI95% (−4, 3)] and wall push strength [−7 ± 12N; CI95% (−32, 17)] similarly improved. All measured gluteal sites showed greater mean sEMG amplitudes during the first bout hip thrust versus squat set, but this did not consistently predict gluteal hypertrophy outcomes. Squat and hip thrust training elicited similar gluteal hypertrophy, greater thigh hypertrophy in SQ, strength increases that favored exercise allocation, and similar deadlift and wall push strength increases.