bluuebunny/crossref_metadata_2025 huggingface dataset:
Diversity of the bacterial and viral communities in the tropical horse tick,Dermacentor nitensin Colombia
Authors: Holguin-Rocha Andres F. , Calle-Tobon Arley , Vásquez Gissella M. , Astete Helvio , Fisher Michael L. , Tobon-Castano Alberto , Velez-Tobon Gabriel , Maldonado-Ruiz L. Paulina , Silver Kristopher , Park Yoonseong , Londono-Renteria Berlin
Published: May 2023

Ticks are obligatory hematophagous ectoparasites that transmit pathogens among various vertebrates, including humans. The composition of the microbial and viral communities in addition to the pathogenic microorganisms is highly diverse in ticks, but the factors driving the diversity are not well understood. The tropical horse tick,Dermacentor nitens, is distributed throughout the Americas and it is recognized as a natural vector ofBabesia caballiandTheileria equi, the causal agents of equine piroplasmosis. We characterized the bacterial and viral communities associated with partially-fedD. nitensfemales collected by a passive survey on horses from field sites representing three distinct geographical areas in Colombia (Bolivar, Antioquia, and Cordoba). RNA-seq and sequencing of the V3 and V4 hypervariable regions of the 16S rRNA gene were performed using the Illumina-Miseq platform. A total of 356 operational taxonomic units (OTUs) were identified, in which the presumed endosymbiotic Francisellaceae/Francisellaspp. was predominantly found. Nine contigs corresponding to six different viruses were identified in three viral families: Chuviridae, Rhabdoviridae, and Flaviviridae. Differences in the relative abundance of the microbial composition among the geographical regions were found to be independent of the presence ofFrancisella-Like Endosymbiont (FLE). The most prevalent bacteria found on each region wereCorynebacteriumin Bolivar,Staphylococcusin Antioquia, andPseudomonasin Cordoba.Rickettsia-like endosymbionts, mainly recognized as the etiological agent of rickettsioses in Colombia were detected in the Cordoba samples. Metatranscriptomics revealed 13 contigs containing FLE genes, suggesting a trend of regional differences. These findings suggest regional distinctions among the ticks and their bacterial compositions.
ILC2 cells promote lung cancer and accumulate in tumors concomitantly with immune-suppressive cells in humans and mice
Authors: Bahhar Ilham , Eş Zeynep , Köse Oğuzhan , Turna Akif , Gunluoglu Mehmet Zeki , Çakır Aslı , Duralı Deniz , Magnusson Fay C.
Published: May 2023

It is now clear that group 2 innate lymphoid cells (ILC2) play crucial and sometimes opposing roles in the lung, such as restoring barrier function and integrity after viral infections or, on the contrary, exacerbating inflammation and tissue damage in allergic asthma. However, their role in lung cancer is still unclear. Here, we report that human non-small cell lung cancer patients bear increased frequencies of ILC2s in tumors, normal lung tissue and peripheral blood (PB) as compared to PB from healthy donors (HDs). Frequencies of Foxp3+regulatory T cells were also increased in NSCLC patients, concomitantly with ILC2s. In mice bearing heterotopic lung cancer, adoptive transfer of ILC2s led to increased tumor growth and reduced survival. The frequencies of monocytic myeloid-derived suppressor cells (M-MDSCs) were found to be increased in the tumors of mice that received ILC2s as compared to controls. Overall, our results indicate that ILC2 cells play a pro-tumoral role in lung cancer potentially by recruiting immune-suppressive cells to the tumors.
LowPcritbut no hypoxia tolerance? Hypoxia compensation in the Arctic keystone speciesBoreogadus saida
Authors: Kempf Sarah , Neven Carolin Julie , Mark Felix Christopher
Published: May 2023

Global warming has already caused a loss of almost 50% Arctic sea-ice coverage since the 1980s. Sea-ice loss strengthens summer stratification of the ocean’s water column and, consequently, hypoxic zones in the deep-water layers may form. The present study investigated the response of an Arctic keystone species, the Polar cod,Boreogadus saida, to hypoxia and warming. We measured the respiratory capacity (standard, routine and maximum metabolic rates, SMR, RMR, MMR, aerobic scope, critical oxygen saturation (Pcrit)) and swimming performance of Polar cod under progressive hypoxia at 2.4 °C and after warm acclimation to close to the species’ thermal limit (10.0 °C) via flow-through and swim tunnel respirometry. We observed clear and stable patterns that were similar in both thermal regimes: Polar cod displayed oxygen-regulating behaviour under progressive hypoxia, with SMR never below aerobic baseline metabolism and a very stable AS. Our study revealed that Polar cod can handle exceptionally low oxygen saturations down to aPcritof 5.9 % air saturation at typical habitat temperatures. Closer to critical temperatures (10.0 °C),Pcritrose to 21.6 % air saturation. However, the pertinent question remains whether the observed behaviour can be summarized under classic hypoxia tolerance, as we a) did not observe any metabolic downregulation and b) no anaerobic component of the hypoxia response in Polar cod, which are usually put forward in the definition of hypoxia tolerance. Therefore, we describe the observed metabolic response to hypoxia rather as metabolic hypoxia compensation than hypoxia tolerance as the mechanisms involved here actively seek to improve oxygen supply instead of (anaerobically) tolerating hypoxia through metabolic depression.
Evaluation of three sets of advanced backcrosses of eggplant with wild relatives from different genepools under low N fertilization conditions
Authors: Villanueva Gloria , Plazas Mariola , Gramazio Pietro , Moya Reyes D. , Prohens Jaime , Vilanova Santiago
Published: May 2023

The development of new cultivars with improved nitrogen use efficiency (NUE) is key for implementing sustainable agriculture practices. Crop wild relatives (CWRs) provide valuable genetic resources for breeding programs aimed at achieving this goal. In this study, three eggplant (Solanum melongena) accessions together with their advanced backcrosses (ABs; BC3 to BC5 generations) with introgressions from the wild relativesS. insanum,S. dasyphyllum, andS. elaeagnifoliumwere evaluated for 22 morpho-agronomic, physiological, and N use efficiency (NUE) traits under low nitrogen fertilization conditions. The threeS. melongenarecurrent parents were also evaluated under control (normal) N fertilization. Reduction of N fertilization in the parents resulted in decreased chlorophyll content-related traits, aerial biomass, stem diameter and yield, and increased NUE, nitrogen uptake efficiency (NUpE), and nitrogen utilization efficiency (NUtE). However, the decrease in yield was moderate, ranging between 62.6% and 72.6%. A high phenotypic variation was observed within each of the three sets of ABs under low nitrogen conditions, with some individuals displaying improved transgressive characteristics over the recurrent parents. Genotyping with the SPET 5k probes platform revealed a high, although variable, degree of recovery of the recurrent parent genome in the ABs and allowed the identification of 16 QTLs. Different allelic effects were observed for the introgressed QTL alleles. Several candidate genes were identified in the QTL regions associated with plant growth, yield, fruit size, and NUE-related parameters. Our results show that eggplant materials with introgressions from CWRs can result in a dramatic impact in eggplant breeding for a more sustainable agriculture.
Nuclear export is a limiting factor in eukaryotic mRNA metabolism
Authors: Müller Jason M. , Moos Katharina , Baar Till , Zumer Kristina , Tresch Achim
Published: May 2023

The eukaryotic mRNA life cycle includes transcription, nuclear mRNA export and degradation. To quantify all these processes simultaneously, we perform thiol-linked alkylation after metabolic labeling of RNA with 4-thiouridine (4sU), followed by sequencing of RNA (SLAM-seq) in the nuclear and cytosolic compartments. We develop a model that reliably quantifies mRNA synthesis, nuclear export, and nuclear and cytosolic degradation rates on a genome-wide scale. We find that nuclear degradation of polyadenylated mRNA is negligible and nuclear mRNA export is slow, while cytosolic mRNA degradation is comparatively fast. Consequently, an mRNA molecule generally spends most of its life in the nucleus. We also observe large differences in the nuclear export rates of different 3’UTR transcript isoforms. Furthermore, we identify genes whose expression is abruptly induced upon metabolic labeling. These transcripts are exported substantially faster than average mRNAs, suggesting the existence of alternative export pathways. Our results highlight nuclear mRNA export as a limiting factor in mRNA metabolism and gene regulation.
Evaluation of a set of eggplant (Solanum melongena) lines with introgressions ofS. incanumunder water stress conditions
Authors: Flores-Saavedra Martín , Gramazio Pietro , Vilanova Santiago , Mircea Diana M. , Ruiz-González Mario X. , Vicente Óscar , Prohens Jaime , Plazas Mariola
Published: May 2023

As access to irrigation water becomes increasingly limited, introgression of relevant genomic regions from drought-tolerant wild genotypes is a promising breeding strategy for crop plants. In this study, nine eggplant (Solanum melongena) introgression lines (ILs) covering altogether 71.6% of the genome of the donor wild relative parentS. incanumwere evaluated for drought tolerance under water stress conditions. Plants at the five true leaves stage were irrigated at either 100% (control) or 30% (water stress) field capacity for 14 days, and growth and biochemical traits were measured. Reduced irrigation resulted in decreased growth and increased levels of stress markers such as proline and malondialdehyde. Most ILs had lower growth and biomass production than the cultivated parent under both conditions. However, the wild alleles for two QTLs related to stem and root dry weight (dwt8anddwr6%) conferred improved tolerance to water stress. In addition, severalS. incanumalleles had a positive effect on important traits that may improve yield under drought conditions, such as leaf water content (lwc12%), water use efficiency (wue1%) and chlorophyll content (chl2andchl8%). Fine-mapping of the QTLs for tolerance and reducing linkage drag with regions affecting growth will be crucial for significantly improving eggplant drought tolerance through introgression breeding.
Drivers of plankton community structure in intermittent and continuous coastal upwelling systems–from microscale in-situ imaging to large scale patterns
Authors: Schmid Moritz S , Sponaugle Su , Sutherland Kelly R , Cowen Robert K
Published: May 2023

Eastern Boundary Systems support major fisheries whose early life stages depend on upwelling production. Upwelling can be highly variable at the regional scale, with substantial repercussions for new productivity and microbial loop activity. A holistic assessment of plankton community structure is challenging due to the range in body forms and sizes of the taxa. Thus, studies that integrate the classic trophic web based on new production with the microbial loop are rare. Underwater imaging can overcome this limitation, and together with machine learning, enables fine resolution studies spanning large spatial scales. We used the In-situ Ichthyoplankton Imaging System (ISIIS) to investigate the drivers of plankton community structure in the northern California Current, sampled along the Newport Hydrographic (NH) and Trinidad Head (TR) lines, in OR and CA, respectively. The non-invasive imaging of particles and plankton (250μm –15cm) over 1644km (30 transects) in the winters and summers of 2018 and 2019 yielded 1.194 billion classified plankton images. The imaged plankton community ranged from protists, crustaceans, and gelatinous taxa to larval fishes. To assess community structure, >2000 single-taxon distribution profiles were analyzed using high resolution spatial correlations. Co-occurrences on the NH line were consistently significantly higher off-shelf while those at TR tended to be highest on-shelf. Taxa co-occurrences at TR increased significantly with upwelling strength and in 2019 TR summer co-occurrences were similar to those on the NH line. Random Forests models identified the concentrations of microbial loop taxa such as protists,Oithonacopepods, and appendicularians as important drivers of co-occurrences at NH line, while at TR, cumulative upwelling and chlorophyll a were of the highest importance. Our results indicate that the microbial loop is actively driving plankton community structure in intermittent upwelling systems such as the NH line and may induce temporal stability. Where upwelling is more continuous such as at TR, primary production may dominate patterns of community structure, obscuring the underlying role of the microbial loop. Future changes in upwelling strength are likely to disproportionately affect plankton community structure in continuous upwelling regions, while high microbial loop activity enhances community structure resilience.
Draft genome sequence of Stenotrophomonas goyisp. nov., a novel bacterium associated with the algaChlamydomonas reinhardtii
Authors: Torres María Jesus , Fakhimi Neda , Dubini Alexandra , González-Ballester David
Published: May 2023

Stenotrophomonas goyisp. nov. has been isolated from a contaminated algal culture (Chlamydomonas reinhardtii). Its genome has been fully sequenced (4,487,389 base pairs) and a tentative annotation is provided (4,147 genes). The genome information suggests thatS. goyisp. nov. is unable to use sulfate and nitrate as sulfur and nitrogen sources, respectively. Growth tests have confirmed the dependence of the sulfur-containing amino acids methionine and cysteine. The potential biotechnological interest of this bacteria is discussed here and in a related research paper (Fakhimi et al., 2023b).
Legionellarelative abundance in shower hose biofilms is associated with specific microbiome members
Authors: Cavallaro Alessio , Rhoads William J. , Sylvestre Émile , Marti Thierry , Walser Jean-Claude , Hammes Frederik
Published: May 2023

Legionellaare natural inhabitants of building plumbing biofilms, where interactions with other microorganisms influence their survival, proliferation, and death. Here, we investigated the associations ofLegionellawith prokaryotic and eukaryotic microbiomes in biofilm samples extracted from 85 shower hoses of a multiunit residential building.Legionellaspp. relative abundance in the biofilms ranged between 0 - 7.8%, of which only 0 - 0.46% wasL. pneumophila. Our data suggest that some microbiome members were associated with high (e.g.,Chthonomonas,Vrihiamoeba) or low (e.g.,Aquabacterium,Vannella)Legionellarelative abundance. The correlations of the differentLegionellavariants (30 Zero-Radius OTUs detected) showed distinct patterns, suggesting separate ecological niches occupied by differentLegionellaspecies. This study provides insights into the ecology ofLegionellawith respect to: 1) the colonization of a high number of real shower hoses biofilm samples; 2) the ecological meaning of associations betweenLegionellaand co-occurring prokaryotic/eukaryotic organisms; 3) critical points and future directions of microbial-interaction-based-ecological-investigations.
TLR priming licenses NAIP inflammasome activation by immunoevasive ligands
Authors: Grayczyk James P. , Egan Marisa S. , Liu Luying , Aunins Emily , Wynosky-Dolfi Meghan A. , Canna Scott , Minn Andy J. , Shin Sunny , Brodsky Igor E.
Published: May 2023

NLR family, apoptosis inhibitory proteins (NAIPs) detect bacterial flagellin and structurally related components of bacterial type III secretion systems (T3SS), and recruit NLR family, CARD domain containing protein 4 (NLRC4) and caspase-1 into an inflammasome complex that induces pyroptosis. NAIP/NLRC4 inflammasome assembly is initiated by the binding of a single NAIP to its cognate ligand, but a subset of bacterial flagellins or T3SS structural proteins are thought to evade NAIP/NLRC4 inflammasome sensing by not binding to their cognate NAIPs. Unlike other inflammasome components such as NLRP3, AIM2, or some NAIPs, NLRC4 is constitutively present in resting macrophages, and not thought to be regulated by inflammatory signals. Here, we demonstrate that Toll-like receptor (TLR) stimulation upregulates NLRC4 transcription and protein expression in murine macrophages, which licenses NAIP detection of evasive ligands. TLR-induced NLRC4 upregulation and NAIP detection of evasive ligands required p38 MAPK signaling. In contrast, TLR priming in human macrophages did not upregulate NLRC4 expression, and human macrophages remained unable to detect NAIP-evasive ligands even following priming. Critically, ectopic expression of either murine or human NLRC4 was sufficient to induce pyroptosis in response to immunoevasive NAIP ligands, indicating that increased levels of NLRC4 enable the NAIP/NLRC4 inflammasome to detect these normally evasive ligands. Altogether, our data reveal that TLR priming tunes the threshold for NAIP/NLRC4 inflammasome activation and enables inflammasome responses against immunoevasive or suboptimal NAIP ligands.

Significance Statement

Cytosolic receptors in the neuronal apoptosis inhibitor protein (NAIP) family detect bacterial flagellin and components of the type III secretion system (T3SS). NAIP binding to its cognate ligand engages the adaptor molecule NLRC4 to form NAIP/NLRC4 inflammasomes culminating in inflammatory cell death. However, some bacterial pathogens evade NAIP/NLRC4 inflammasome detection, thus bypassing a crucial barrier of the immune system. Here, we find that, in murine macrophages, TLR-dependent p38 MAPK signaling increases NLRC4 expression, thereby lowering the threshold for NAIP/NLRC4 inflammasome activation in response to immunoevasive NAIP ligands. Human macrophages were unable to undergo priming-induced upregulation of NLRC4 and could not detect immunoevasive NAIP ligands. These findings provide a new insight into species-specific regulation of the NAIP/NLRC4 inflammasome.
Histone H3 serotonylation dynamics in dorsal raphe nucleus contribute to stress- and antidepressant-mediated gene expression and behavior
Authors: Al-Kachak Amni , Fulton Sasha L. , Di Salvo Giuseppina , Chan Jennifer C , Farrelly Lorna A. , Lepack Ashley E. , Bastle Ryan M. , Kong Lingchun , Cathomas Flurin , Newman Emily L. , Menard Caroline , Ramakrishnan Aarthi , Safovich Polina , Lyu Yang , Covington Herbert E. , Shen Li , Gleason Kelly , Tamminga Carol A. , Russo Scott J. , Maze Ian
Published: May 2023

Background

Major depressive disorder (MDD), along with related mood disorders, is a debilitating illness that affects millions of individuals worldwide. While chronic stress increases incidence levels of mood disorders, stress-mediated disruptions in brain function that precipitate these illnesses remain elusive. Serotonin-associated antidepressants (ADs) remain the first line of therapy for many with depressive symptoms, yet low remission rates and delays between treatment and symptomatic alleviation have prompted skepticism regarding precise roles for serotonin in the precipitation of mood disorders. Our group recently demonstrated that serotonin epigenetically modifies histone proteins (H3K4me3Q5ser) to regulate transcriptional permissiveness in brain. However, this phenomenon has not yet been explored following stress and/or AD exposures.

Methods

We employed a combination of genome-wide and biochemical analyses in dorsal raphe nucleus (DRN) of male and female mice exposed to chronic social defeat stress to examine the impact of stress exposures on H3K4me3Q5ser dynamics, as well as associations between the mark and stress-induced gene expression. We additionally assessed stress-induced regulation of H3K4me3Q5ser following AD exposures, and employed viral-mediated gene therapy to reduce H3K4me3Q5ser levels in DRN and examine the impact on stress-associated gene expression and behavior.

Results

We found that H3K4me3Q5ser plays important roles in stress-mediated transcriptional plasticity. Chronically stressed mice displayed dysregulated H3K4me3Q5ser dynamics in DRN, with both AD- and viral-mediated disruption of these dynamics proving sufficient to rescue stress-mediated gene expression and behavior.

Conclusions

These findings establish a neurotransmission-independent role for serotonin in stress-/AD-associated transcriptional and behavioral plasticity in DRN.
CTCF-mediated insulation and chromatin environment modulateCar5bescape from X inactivation
Authors: Fang He , Tronco Ana R. , Bonora Giancarlo , Nguyen Truong , Thakur Jitendra , Berletch Joel B. , Filippova Galina N. , Henikoff Steven , Shendure Jay , Noble William S. , Disteche Christine M. , Deng Xinxian
Published: May 2023

Background

The number and escape levels of genes that escape X chromosome inactivation (XCI) in female somatic cells vary among tissues and cell types, potentially contributing to specific sex differences. Here we investigate the role of CTCF, a master chromatin conformation regulator, in regulating escape from XCI. CTCF binding profiles and epigenetic features were systematically examined at constitutive and facultative escape genes using mouse allelic systems to distinguish the inactive X (Xi) and active X (Xa) chromosomes.

Results

We found that escape genes are located inside domains flanked by convergent arrays of CTCF binding sites, consistent with the formation of loops. In addition, strong and divergent CTCF binding sites often located at the boundaries between escape genes and adjacent neighbors subject to XCI would help insulate domains. Facultative escapees show clear differences in CTCF binding dependent on their XCI status in specific cell types/tissues. Concordantly, deletion but not inversion of a CTCF binding site at the boundary between the facultative escape geneCar5band its silent neighborSiah1bresulted in loss ofCar5bescape. Reduced CTCF binding and enrichment of a repressive mark overCar5bin cells with a boundary deletion indicated loss of looping and insulation. In mutant lines in which either the Xi-specific compact structure or its H3K27me3 enrichment was disrupted, escape genes showed an increase in gene expression and associated active marks, supporting the roles of the 3D Xi structure and heterochromatic marks in constraining levels of escape.

Conclusion

Our findings indicate that escape from XCI is modulated both by looping and insulation of chromatin via convergent arrays of CTCF binding sites and by compaction and epigenetic features of the surrounding heterochromatin.
Coordination of actin plus-end dynamics by IQGAP1, formin, and capping protein
Authors: Pimm Morgan L. , Haarer Brian K. , Nobles Alexander D. , Haney Laura M. , Marcin Alexandra G. , Eligio Marcela Alcaide , Henty-Ridilla Jessica L.
Published: May 2023

Cell processes require precise regulation of actin polymerization that is mediated by plus-end regulatory proteins. Detailed mechanisms that explain plus-end dynamics involve regulators with opposing roles, including factors that enhance assembly, e.g., the formin mDia1, and others that stop growth (Capping Protein, CPz). We explore IQGAP1’s roles regulating actin filament plus-ends and the consequences of perturbing its activity in cells. We confirm that IQGAP1 pauses elongation and interacts with plus ends through two residues (C756 and C781). We directly visualize the dynamic interplay between IQGAP1 and mDia1, revealing that IQGAP1 displaces the formin to influence actin assembly. Using four-color TIRF we show that IQ-GAP1’s displacement activity extends to formin-CPz ‘decision complexes’, promoting end-binding protein turnover at plusends. Loss of IQGAP1 or its plus-end activities disrupts morphology and migration, emphasizing its essential role. These results reveal a new role for IQGAP1 in promoting protein turnover on filament ends and provide new insights into how plus-end actin assembly is regulated in cells.
Non-pathogenic leaf-colonising bacteria elicit pathogen-like responses in a colonisation density-dependent manner
Authors: Miebach Moritz , Faivre Léa , Schubert Daniel , Jameson Paula , Remus-Emsermann Mitja
Published: May 2023

Leaves are colonised by a complex mix of microbes, termed the leaf microbiota. Even though the leaf microbiota is increasingly recognised as an integral part of plant life and health, our understanding of its interactions with the plant host is still limited. Here, mature, axenically grownArabidopsis thalianaplants were spray-inoculated with six diverse leaf-colonising bacteria. The transcriptomic changes in leaves were tracked over time and significant changes in ethylene marker (ARL2) expression were observed only two to four days after spray-inoculation. Whole transcriptome sequencing revealed that four days after inoculation, leaf transcriptional changes to colonisation by non-pathogenic and pathogenic bacteria differed in strength but not in the type of response. Inoculation of plants with different densities of the non-pathogenic bacteriumWilliamsiasp. Leaf354 showed that high bacterial titers caused disease phenotypes and led to severe transcriptional reprogramming with a strong focus on plant defence. Anin silicoepigenetic analysis of the data was congruent with the transcriptomic analysis. These findings suggest (1) that plant responses are not rapid after spray-inoculation, (2) that plant responses only differ in strength and (3) that plants respond to high titers of non-pathogenic bacteria with pathogen-like responses.

Plain Language Summary

Plants are colonised by diverse bacteria affecting many aspects of plant life. Here we show that plants do not differentiate between different bacteria but measure their quantities to keep bacterial numbers in check.
Primary series and booster COVID-19 vaccine effectiveness in a cohort of healthcare workers in Albania during a BA.1 and BA.2 variant period, January – May 2022
Authors: Finci Iris , Rojas Castro Madelyn Yiseth , Hasibra Iris , Sulo Jonilda , Fico Albana , Daja Rovena , Vasili Adela , Kota Majlinda , Preza Iria , Mühlemann Barbara , Drosten Christian , Pebody Richard , Lafond Kathryn E. , Kissling Esther , Katz Mark A. , Bino Silvia
Published: May 2023

Background

Healthcare workers (HCWs) have experienced high rates of COVID-19 morbidity and mortality. We estimated COVID-19 two-dose primary series and monovalent booster vaccine effectiveness (VE) against symptomatic SARS-CoV-2 Omicron (BA.1 and BA.2) infection among HCWs in three Albanian hospitals during January–May 2022.

Methods

Study participants completed weekly symptom questionnaires, underwent PCR testing when symptomatic, and provided quarterly blood samples for serology. We estimated VE using Cox regression models (1-hazard ratio), with vaccination status as the time-varying exposure and unvaccinated HCWs as the reference group, adjusting for potential confounders: age, sex, prior SARS-CoV-2 infection (detected by PCR, rapid-antigen test or serology), and household size.

Results

At the start of the analysis period, 76% of 1,462 HCWs had received a primary series, 10% had received a booster dose, and 9% were unvaccinated; 1,307 (89%) HCWs had evidence of prior infection. Overall, 86% of primary series and 98% of booster doses received were BNT162b2. The median time interval from the second dose and the booster dose to the start of the analysis period was 289 days (IQR:210– 292) and 30 days (IQR:22–46), respectively. VE against symptomatic PCR-confirmed infection was 34% (95%CI: -36;68) for the primary series and 88% (95%CI: 38;98) for the booster.

Conclusions

Among Albanian HCWs, most of whom had been previously infected, COVID-19 booster dose offered improved VE during a period of Omicron BA.1 and BA.2 circulation. Our findings support promoting booster dose uptake among Albanian HCWs, which, as of January 2023, was only 20%.
Transcriptomics Analyses of ALS Post-mortem Motor Cortex highlight alteration and potential biomarkers in the Neuropeptide Signalling pathway
Authors: Kabiljo Renata , Marriott Heather , Hunt Guy P , Pfaff Abigail L , Al Khleifat Ahmad , Adey Brett , Jones Ashley , Troakes Claire , Quinn John P , Dobson Richard J B , Koks Sulev , Al-Chalabi Ammar , Iacoangeli Alfredo
Published: May 2023

Background

Amyotrophic lateral sclerosis (ALS) is a fatal heterogeneous neurodegenerative disease that typically leads to death from respiratory failure within two to five years. Despite the identification of several genetic risk factors, the biological processes involved in ALS pathogenesis remain poorly understood. The motor cortex is an ideal region to study dysregulated pathological processes in ALS as it is affected from the earliest stages of the disease. In this study, we investigated motor-cortex gene expression of cases and controls to gain new insight into the molecular footprint of ALS.

Methods

We performed a large case-control differential expression analysis of two independent post-mortem motor cortex bulk RNA-sequencing (RNAseq) datasets from the King’s College London BrainBank (N = 171) and TargetALS (N = 132). Differentially expressed genes from both datasets were subjected to gene and pathway enrichment analysis. Genes common to both datasets were also reviewed for their involvement with known mechanisms of ALS pathogenesis to identify potential candidate genes. Finally, we performed a correlation analysis of genes implicated in pathways enriched in both datasets with clinical outcomes such as the age of onset and survival.

Results

Differential expression analysis identified 2,290 and 402 differentially expressed genes in KCL BrainBank and TargetALS cases, respectively. Enrichment analysis revealed significant synapse-related processes in the KCL BrainBank dataset, while the TargetALS dataset carried an immune system-related signature. There were 44 differentially expressed genes which were common to both datasets, which represented previously recognised mechanisms of ALS pathogenesis, such as lipid metabolism, mitochondrial energy homeostasis and neurovascular unit dysfunction. Differentially expressed genes in both datasets were significantly enriched for the neuropeptide signalling pathway. By looking at the relationship between the expression of neuropeptides and their receptors with clinical measures, we found that in both datasetsNPBWR1, TAC3andSSTR1correlated with age of onset, andGNRH1, TACR1with survival. We provide access to gene-level expression results to the broader research community through a publicly available web application (https://alsgeexplorer.er.kcl.ac.uk).

Conclusion

This study identified motor-cortex specific pathways altered in ALS patients, potential molecular targets for therapeutic disease intervention and a set of neuropeptides and receptors for investigation as potential biomarkers.
Constructing cancer-specific patient similarity network with clinical significance
Authors: Zhang Rukui , Liu Zhaorui , Zhu Chaoyu , Cai Hui , Yin Kai , Zhong Fan , Liu Lei
Published: May 2023

Clinical molecular genetic testing and molecular imaging dramatically increase the quantity of clinical data. Combined with the extensive application of electronic health records, medical data ecosystem is forming, which summons big-data-based medicine model. We tried to use big data analytics to search for similar patients in a cancer cohort and to promote personalized patient management. In order to overcome the weaknesses of most data processing algorithms that rely on expert labelling and annotation, we uniformly adopted one-hot encoding for all types of clinical data, calculating Euclidean distance to measure patient similarity, and subgrouping via unsupervised learning model. Overall survival was investigated to assess the clinical validity and clinical relevance of the model. Thereafter, we built a high-dimensional network cPSN (clinical patient similarity network). When performing overall survival analysis, we found Cluster_2 had the longest survival rates while Cluster_5 had the worst prognosis among all subgroups. Because patients in the same subgroup share some clinical characteristics, clinical feature analysis found that Cluster_2 harbored more lower distal GCs than upper proximal GCs, shedding light on the debates. Overall, we constructed a cancer-specific cPSN with excellent interpretability and clinical significance, which would recapitulate patient similarity in the real-world. The constructed cPSN model is scalable, generalizable, and performs well for various data types. The constructed cPSN could be used to accurately “locate” interested patients, classify the patient into a disease subtype, support medical decision making, and predict clinical outcomes.
Evaluation of plasma biomarkers for causal association with peripheral artery disease
Authors: Sharma Pranav , Levin Michael G. , Klarin Derek , Voight Benjamin F. , Tsao Philip S. , Damrauer Scott M.
Published: May 2023

Background

Hundreds of biomarkers for Peripheral artery disease (PAD) have been reported in the literature, however, the observational nature these studies limit robust causal inference due to the potential of reverse causality and confounding. We aimed to perform a systematic review of plasma biomarkers associated with PAD followed by Mendelian Randomization (MR) to systematically address residual confounding and better understand the causal pathophysiology of PAD. Combining a systematic review with MR facilitates cross-domain verification of observational and experimental results.

Methods

We performed a systematic literature review for terms related to PAD and/or biomarkers using Pubmed, Cochrane, and Embase, followed by manual review to extract biomarkers and their direction of effect. To evaluate evidence for causality, we employed Two-sample Mendelian randomization (MR). We developed genetic instruments for the biomarkers by mapping them to genome wide association studies (GWAS) of circulating biomolecules aggregated by the IEU Open GWAS and deCODE projects. We tested the association of the genetic instruments with PAD using summary statistics from a GWAS of 31,307 individuals with and 211,753 individuals without PAD in the VA Million Veteran Program. We employed Wald ratio or inverse-variance weighted MR; weighted median and weighted mode methods were applied as sensitivity analyses.

Results

We identified a total of 1,993 unique papers related to PAD and biomarkers using extant genetic instruments, and MeSH terms across PubMed, Embase, and Cochrane. After filtering and manual review, 170 unique papers remained, mentioning 204 unique biomarkers. Genetic instruments based on publicly available data were developed for 175 biomarkers. After accounting for multiple testing by controlling the false discovery rate (q < 0.05), 19/175 (10.9%) biomarkers had significant associations with PAD. Of the 19 significant associations, only 13/19 (58.3%) had concordant directions of effects with published reports. These 19 biomarkers represented broad categories including plasma lipid regulation (HDL-C, LPA, Triglycerides, APOA1, EPA, APOB, APOA5, and SHBG), coagulation-inflammatory response (CD36, IL6-sRa, VWF, IL18BP, and CD163), and endothelial damage/dysfunction (HLA-G, NPPA, VCAM-1, CDH5, MMP1, and INS).

Conclusion

This systematic review paired with Mendelian randomization elucidates biomarkers with genetic evidence for causality relevant to PAD, and highlights discrepancies between published reports and human genetic findings. Conventional studies have previously highlighted biomarkers that have correlation to PAD but have not emphasized the causal pathobiology of this disease. Expansion of genetic datasets to increase the power of these analyses will be crucial to further understand the causal role of plasma biomarkers and highlighting key biological pathways in PAD.
The bladder microbiome of chronic kidney disease with associations to demographics, renal function, and serum cytokines
Authors: Liu Fengping , Du Jingjie , Lin Hao , Xu Zhenyi , Sun Yifan , Yan Feng , Gu Yifeng , Wang Yang , Guo Wei , Zhai Qixiao , Hu Jialin , Tian Yu , Hu Lei , Jiang Peng , Wei Shichao , Gu Chaoqun , Sheng Jiayi , Chen Wei , Wolfe Alan J. , Feng Ninghan
Published: May 2023

Background

High throughput 16S rRNA gene sequencing and enhanced culture methods (e.g., expanded quantitative urine culture, EQUC) have established the existence of the human bladder microbiome. We aim to test the hypothesis that the bladder environment of patients with chronic kidney disease (CKD) differs from that of unaffected controls with associated consequences for the composition of the bladder microbiome.

Methods and Materials

Females (n=66) and males (n=66) diagnosed with CKD and age-BMI-matched healthy control (HC) females (n=22) and males (n=22) were recruited. Transurethral catheterized urine was collected for 16S rRNA gene sequencing and Expanded Quantitative Urine Culture (EQUC). Fecal samples also were sequenced. Urinary analysis, kidney function and serum cytokines were examined.

Results

Bladder microbiomes of CKD females and males versus HC females and males differed (FDR<0.05); however, the difference was more obvious in females. In CKD females, sequencing revealed depletion of 5 genera, includingLactobacillus, and enrichment of 14 genera, includingEscherichia/Shigella, Bifidobacterium, and several clostridial genera (FDR<0.05), while EQUC detected increasedEscherichiaand decreasedLactobacillusCKDB(P<0.05).Escherichia-Shigellawas positively, whereasLactobacilluswas negatively, associated with CKDB-female serum creatinine (r=0.285, P=0.020; r=-0.337, P=0.006, respectively).Lactobacilluswas positively associated with eGFR (r=0.251, P=0.042). Some CKD-related serum cytokines were negatively associated with clostridial genera. In contrast, the fecal microbiomes of CKD and HC females and males did not significantly differ in bacterial diversity or composition. However, bladder and fecal microbiomes of CKD females resembled each other more than those of controls, as assessed by the Bray-Curtis Dissimilarity Index (FDR<0.05).

Conclusions

CKD bladder microbiomes were dysbiotic, which was more obvious in females. This dysbiosis was associated with kidney damage severity and dysregulation of serum cytokines. The increased similarity between bladder and fecal microbiomes of CKD females suggests possible “gut-leakage.”
Mode Connections For Clinical Incremental Learning: Lessons From The COVID-19 Pandemic
Authors: Thakur Anshul , Wang Chenyang , Ceritli Taha , Clifton David , Eyre David
Published: May 2023

Abstract

Dynamic distribution shifts caused by evolving diseases and demographic changes require domain-incremental adaptation of clinical deep learning models. However, this process of adaptation is often accompanied bycatastrophic forgetting, and even the most sophisticated methods are not good enough for clinical applications. This paper studies incremental learning from the perspective ofmode connections, that is, the low-loss paths connecting the minimisers of neural architectures (modes or trained weights) in the parameter space. The paper argues for learning the low-loss paths originating from an existing mode and exploring the learned paths to find an acceptable mode for the new domain. The learned paths, and hence the new domain mode, are afunctionof the existing mode. As a result, unlike traditional incremental learning, the proposed approach is able to exploit information from a deployed model without changing its weights. Pre-COVID and COVID-19 data collected in Oxford University hospitals are used as a case study to demonstrate the need for domain-incremental learning and the advantages of the proposed approach.
Evidence for a reproductive sharing continuum in cooperatively breeding mammals and birds: consequences for comparative research
Authors: Ben Mocha Yitzchak , Dahan Tal , Zou Yuqi , Griesser Michael , Markman Shai
Published: May 2023

Extreme reproductive skew occurs when a dominant female/male monopolises reproduction within a group of multiple sexually mature females/males. It is sometimes considered an additional, restrictive criterion in the definition of cooperative breeding (i.e., when conspecifics provide parental care to other group members’ offspring). However, datasets that use this restrictive definition to classify species as cooperative breeders have two critical shortcomings. First, reproductive skew is systematically overestimated by including groups with a single sexually mature female/male when calculating the reproductive output of “dominant” females/males. Second, a lack of reporting on which species are classified based on limited data prevents accounting for uncertainty in classification. Considering these shortcomings, we show that extreme reproductive skew in multi-female and multi-male groups only occurs rarely in species previously classified as cooperative breeders using restrictive definitions (11 mammal species, 12 bird species). We further provide updated datasets on reproductive sharing in multi-female/male groups of cooperatively breeding mammals and birds that allow accounting for classification uncertainty. Our results demonstrate a reproductive sharing continuum even among those cooperatively breeding species argued to exhibit extreme reproductive skew. At the practical level, these findings call for significant changes in datasets that classify species by social systems. At the conceptual level, we suggest that reproductive skew should not be a defining criterion of cooperative breeding.
Necrosulfonamide causes oxidation of PCM1 and impairs ciliogenesis and autophagy
Authors: Renaud Clotilde C.N. , Alves Nicolau Carolina , Maghe Clément , Trillet Kilian , Jardine Jane , Escot Sophie , David Nicolas , Gavard Julie , Bidère Nicolas
Published: May 2023

Centriolar satellites are high-order assemblies, scaffolded by the protein PCM1, that gravitate as particles around the centrosome and play pivotal roles in fundamental cellular processes notably ciliogenesis and autophagy. Despite stringent control mechanisms involving phosphorylation and ubiquitination, the landscape of post-translational modifications shaping these structures remains elusive. Here, we report that necrosulfonamide (NSA), a small molecule known for binding and inactivating the pivotal effector of cell death by necroptosis MLKL, intersects with centriolar satellites, ciliogenesis, and autophagy independently of MLKL. NSA functions as a potent redox cycler and triggers the oxidation and aggregation of PCM1 alongside select partners, while minimally impacting the overall distribution of centriolar satellites. Additionally, NSA-mediated ROS production disrupts ciliogenesis and leads to the accumulation of autophagy markers, partially alleviated by PCM1 deletion. Together, these results identify PCM1 as a redox sensor protein and provide new insights into the interplay between centriolar satellites and autophagy.
Pathogen protein modularity enables elaborate mimicry of a host phosphatase
Authors: Li Hui , Wang Jinlong , Kuan Tung Ariel , Tang Bozeng , Feng Li , Wang Jiuyu , Cheng Zhi , Skłenar Jan , Derbyshire Paul , Hulin Michelle , Li Yufei , Zhai Yi , Hou Yingnan , Menke Frank L.H. , Wang Yanli , Ma Wenbo
Published: May 2023

Pathogens produce diverse effector proteins to manipulate host cellular processes. However, how functional diversity is generated in an effector repertoire is poorly understood. Many effectors in the devastating plant pathogenPhytophthoracontain tandem repeats of the “(L)WY” motif, which are structurally conserved but variable in sequences. Here, we discovered a functional module formed by a specific (L)WY-LWY combination in multiplePhytophthoraeffectors, which efficiently recruit the Serine/Threonine protein phosphatase 2A (PP2A) core enzyme in plant hosts. Crystal structure of an effector-PP2A complex shows that the (L)WY-LWY module enables hijacking of the host PP2A core enzyme to form functional holoenzymes. While sharing the PP2A-interacting module at the amino terminus, these effectors possess divergent C-terminal LWY units and regulate distinct sets of phosphoproteins in the host. Our results highlight the appropriation of an essential host phosphatase through molecular mimicry by pathogens and diversification promoted by protein modularity in an effector repertoire.
Regional patterns of human cortex development correlate with underlying neurobiology
Authors: Lotter Leon D. , Saberi Amin , Hansen Justine Y. , Misic Bratislav , Paquola Casey , Barker Gareth J. , Bokde Arun L.W. , Desrivieres Sylvane , Flor Herta , Grigis Antoine , Garavan Hugh , Gowland Penny , Heinz Andreas , Bruehl Ruediger , Martinot Jean-Luc , Paillere Marie-Laure , Artiges Eric , Papadopoulos Orfanos Dimitri , Paus Tomas , Poustka Luise , Hohmann Sarah , Froehner Juliane H. , Smolka Michael N. , Vaidya Nilakshi , Walter Henrik , Whelan Robert , Schumann Gunter ,   IMAGEN Consortium, Nees Frauke , Banaschewski Tobias , Eickhoff Simon B. , Dukart Juergen
Published: May 2023

Human brain morphology undergoes complex changes over the lifespan. Despite recent progress in tracking brain development via normative models, current knowledge of underlying biological mechanisms is highly limited. We demonstrate that human cortical thickness development and aging trajectories unfold along patterns of molecular and cellular brain organization, traceable from population-level to individual developmental trajectories. During childhood and adolescence, cortex-wide spatial distributions of dopaminergic receptors, inhibitory neurons, glial cell populations, and brain-metabolic features explain up to 50% of variance associated with a lifespan model of regional cortical thickness trajectories. In contrast, modeled cortical thickness change patterns during adulthood are best explained by cholinergic and glutamatergic neurotransmitter receptor and transporter distributions. These relationships are supported by developmental gene expression trajectories and translate to individual longitudinal data from over 8,000 adolescents, explaining up to 59% of developmental change at cohort- and 18% at single-subject level. Integrating neurobiological brain atlases with normative modeling and population neuroimaging provides a biologically meaningful path to understand brain development and aging in living humans.
Oct4 is a gatekeeper of epithelial identity by regulating cytoskeletal organization in skin keratinocytes
Authors: Christofidou Elena D. , Tomazou Marios , Voutouri Chrysovalantis , Michael Christina , Stylianopoulos Triantafyllos , Spyrou George M. , Strati Katerina
Published: May 2023

Oct4 is a pioneer transcription factor regulating pluripotency. However, it is poorly known whether Oct4 has an impact on epidermal cells. We generatedOCT4knockout clonal cell lines using immortalized human skin keratinocytes to identify a functional role for the protein. Here we report that Oct4-deficient cells transitioned into a mesenchymal-like phenotype with enlarged size and shape, exhibited accelerated migratory behavior, decreased adhesion and appeared arrested at G2/M cell cycle checkpoint. Oct4 absence had a profound impact on cortical actin organization, with loss of microfilaments from cell membrane, increased puncta deposition in the cytoplasm and stress fiber formation. E-cadherin, β-catenin and ZO1 were almost absent from cell-cell contacts while fibronectin deposition was markedly increased in ECM. Mapping of the transcriptional and chromatin profiles of Oct4-deficient cells revealed that Oct4 controls the levels of cytoskeletal, ECM and differentiation related genes, whereas epithelial identity is preserved through transcriptional and non-transcriptional mechanisms.