bluuebunny/crossref_metadata_2025 huggingface dataset:
The Investigation of Somatostatin Receptors as a Potential Target in Breast Phyllodes Tumours
Authors: Süer Mickler Hande , Erkan Murat Mert
Published: January 2024

Somatostatin receptors (SSTRs) constitute a family of G protein-coupled receptors that modulate hormonal secretion and regulate cell proliferation and apoptosis upon binding with somatostatin or its synthetic analogues. SSTRs are expressed in most neuroendocrine neoplasms, particularly in gastroenteropancreatic neuroendocrine tumours, and have been utilized as diagnostic markers as well as therapeutic targets. The radioiodinated somatostatin analogue 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-Tyr3-octreotate (DOTATATE) has been employed for SSTR-targeting for either diagnostic or therapeutic purposes depending on the labelling with68Gallium or177Lutetium, respectively.

SSTR expression is reported in a subset of breast adenocarcinoma and breast neuroendocrine carcinomas; however, minimal knowledge exists regarding their expression in fibroepithelial (biphasic) breast lesions such as fibroadenoma and phyllodes tumours. Aggressive ends of the spectrum, i.e. “cystosarcoma phyllodes” may present a management challenge with recurrences and metastases. In this exploratory study, we investigated both gene and protein expression of SSTR in fibroepithelial lesions of the breast. Our findings reveal that both fibroadenoma and phyllodes tumours express SSTRs. Immunohistochemical analyses suggested that this expression is in the stromal, not epithelial, component by demonstrating that SSTR is predominantly expressed in the areas overlapping with α-smooth muscle actin-positive myoepithelial cells around blood vessels and capillary structures. This study is the first in the literature to demonstrate SSTR positivity in mammary fibroepithelial neoplasms., In a patient undergoing a gallium scan, which is widely used in clinical practice, if a positive lesion is discovered in the breast, the possibility of a fibroadenoma or phyllodes tumour needs to be considered. Once validated, these findings may also have significant implications for the management of these tumours.
Characterization of Cancer Stem Cells in Laryngeal Squamous Cell Carcinoma by Single-Cell RNA Sequencing
Authors: Li Yanguo , Lin Chen , Chu Yidian , Wei Zhengyu , Ding Qi , Gu Shanshan , Deng Hongxia , Liao Qi , Shen Zhisen
Published: January 2024

Cancer stem cells (CSCs) constitute a pivotal element within the tumor microenvironment (TME), driving the initiation and progression of cancer. However, the identification of CSCs and their underlying molecular mechanisms in laryngeal squamous cell carcinoma (LSCC) remains a formidable challenge. We employed single-cell RNA sequencing of matched primary tumor tissues, paracancerous tissues, and local lymph nodes from three LSCC patients. Two distinct clusters of stem cells originating from epithelial populations were delineated and verified as CSCs and normal stem cells (NSCs) respectively. CSCs were abundant in the paracancerous tissues compared to the tumor tissues. CSCs showed high expression of stem cell marker genes such asPROM1,ALDH1A1, andSOX4, and increased activity of tumor-related hypoxia, Wnt/β-catenin, and notch signaling pathways. We then explored the intricate crosstalk between CSCs and the TME cells and identified targets within the TME that related with CSCs. We also find eight marker genes of CSCs that correlated significantly with the prognosis of LSCC patients. Furthermore, bioinformatics analyses showed that drugs such as erlotinib, OSI-027, and ibrutinib selectively targeted the CSC-specifically expressed genes. In conclusion, our results represent the first comprehensive characterization of CSCs properties in LSCC at the single-cell level.
iVirP: An integrative, efficient, and user-friendly pipeline to annotate viral contigs from raw reads of metagenome or VLP sequencing
Authors: Li Bowen , Jiao Xianyue , Liang Guanxiang
Published: January 2024

Metagenome sequencing and virus-like particles sequencing make it possible to explore the virome in the humans and other organisms. One way to analyze the sequencing data is to assemble reads into contigs according to the overlapping regions, and then the predicted viral contigs are screened out to conduct deeper dives. iVirP (integrative virome pipeline) is a user-friendly pipeline that includes the whole process of viral contigs discovery from the quality control of raw data to the filter of high quality viral contigs. This pipeline also features a branching function that can estimate the abundance of known eukaryotic viruses in a short period, while reducing host contamination. It is suitable for the rapid diagnosis of pathogens. Throughout iVirP, many details that might affect the experience of users are optimized carefully to reduce the time spent on dealing with usage and errors. iVirP was tested on a published, high-quality VLP sequencing dataset and was able to well reproduce the conclusions of the corresponding research. The benchmark indicates that iVirP could accurately assemble viral contigs from real sequencing data. iVirP is easy to install and currently available athttps://github.com/li-bw18/iVirP.
Exploring the potential of water channels for developing MRI reporters and sensors without the need for exogenous contrast agents
Authors: Chacko Asish N. , Miller Austin D.C. , Dhanabalan Kaamini M. , Mukherjee Arnab
Published: January 2024

Genetically encoded reporters for magnetic resonance imaging (MRI) offer a valuable technology for making molecular-scale measurements of biological processes within living organisms with high anatomical resolution and whole-organ coverage without relying on ionizing radiation. However, most MRI reporters rely on contrast agents, typically paramagnetic metals and metal complexes, which often need to be supplemented exogenously to create optimal contrast. To eliminate the need for contrast agents, we previously introduced aquaporin-1, a mammalian water channel, as a new reporter gene for the fully autonomous detection of genetically labeled cells using diffusion-weighted MRI. In this study, we aimed to expand the toolbox of diffusion-based genetic reporters by modulating aquaporin membrane trafficking and harnessing the evolutionary diversity of water channels across species. We identified a number of new water channels that functioned as diffusion-weighted reporter genes. In addition, we show that loss-of-function variants of yeast and human aquaporins can be leveraged to design first-in-class diffusion-based sensors for detecting the activity of a model protease within living cells.
CAT Bridge: An Efficient Toolkit for Gene-Metabolite Association Mining from Multi-Omics Data
Authors: Yang Bowen , Meng Tan , Wang Xinrui , Li Jun , Zhao Shuang , Wang Yingheng , Yi Shu , Zhou Yi , Zhang Yi , Li Liang , Guo Li
Published: January 2024

Background

With advancements in sequencing and mass spectrometry technologies, multi-omics data can now be easily acquired for understanding complex biological systems. Nevertheless, substantial challenges remain in determining the association between gene-metabolite pairs due to the non-linear and multifactorial interactions within cellular networks. The complexity arises from the interplay of multiple genes and metabolites, often involving feedback loops and time-dependent regulatory mechanisms that are not easily captured by traditional analysis methods.

Findings

Here, we introduce Compounds And Transcripts Bridge (abbreviated as CAT Bridge, available athttps://catbridge.work), a free user-friendly platform for longitudinal multi-omics analysis to efficiently identify transcripts associated with metabolites using time-series omics data. To evaluate the association of gene-metabolite pairs, CAT Bridge is a pioneering work benchmarking a set of statistical methods spanning causality estimation and correlation coefficient calculation for multi-omics analysis. Additionally, CAT Bridge features an artificial intelligence (AI) agent to assist users interpreting the association results.

Conclusions

We applied CAT Bridge to experimentally obtainedCapsicum chinense(chili pepper) and public human andEscherichia coli(E. coli) time-series transcriptome and metabolome datasets. CAT Bridge successfully identified genes involved in the biosynthesis of capsaicin inC. chinense. Furthermore, case study results showed that the convergent cross mapping (CCM) method outperforms traditional approaches in longitudinal multi-omics analyses. CAT Bridge simplifies access to various established methods for longitudinal multi-omics analysis, and enables researchers to swiftly identify associated gene-metabolite pairs for further validation.
MR-link-2: pleiotropy robustcisMendelian randomization validated in four independent gold-standard datasets of causality
Authors: van der Graaf Adriaan , Warmerdam Robert , Auwerx Chiara ,   eQTLGen Consortium, Võsa Urmo , Borges Maria Carolina , Franke Lude , Kutalik Zoltán
Published: January 2024

Mendelian randomization (MR) can identify causal relationships from observational data but has increased Type 1 error rates (T1E) when genetic instruments are limited to a single associated region, a typical scenario for molecular exposures. To address this, we developed MR-link-2, which uses summary statistics and linkage disequilibrium (LD) information to simultaneously estimate a causal effect and pleiotropy in a single associated region. We extensively compare MR-link-2 to othercisMR methods: i) In realistic simulations, MR-link-2 has calibrated T1E and high power. ii) We replicate causal relationships derived from three metabolic pathway references using four independent metabolite quantitative trait locus studies as input to MR. Compared to other methods, MR-link-2 has a superior area under the receiver operator characteristic curve (AUC) (up to 0.80). iii) Applied to canonical causal relationships between complex traits, MR-link-2 has a lower per-locus T1E rate than competing methods (0.09 vs 0.15, at a nominal 5% level) and has several fold less heterogeneous causal effect estimates. iv) Testing the correct causal direction between blood cell type compositions and gene expression of their marker genes reveals that MR-link has superior AUC 0.90 (best competing: 0.67). Finally, when testing for causality between metabolites that are not connected by canonical reactions, MR-link-2 exclusively identifies a link between glycine and pyrroline-5-carboxylate, corroborating results for hypomyelinating leukodystrophy-10, otherwise only found in model systems. Overall, MR-link-2 is the first method to identify pleiotropy-robust causality from summary statistics in single associated regions, making it ideally suited for applications on molecular phenotypes.
Circulating blood circular RNA in Parkinson’s Disease; a systematic study
Authors: Beric Aleksandra , Sun Yichen , Sanchez Santiago , Martin Charissa , Powell Tyler , Pardo Jose Adrian , Sanford Jessie , Botia Juan A. , Cruchaga Carlos , Ibanez Laura
Published: January 2024

We aimed to identify circRNAs associated with Parkinson’s disease (PD) by leveraging 1,848 participants and 1,789 circRNA from two of the largest publicly available studies with longitudinal clinical and blood transcriptomic data. To comprehensively understand changes in circRNAs we performed a cross-sectional study utilizing the last visit of each participant, and a longitudinal (mix model) analysis that included 1,166 participants with at least two time points. We identified 192 circRNAs differentially expressed in PD participants compared to healthy controls, with effects that were consistent in the mixed models, mutation carriers, and diverse ancestry. Finally, we included the 149 circRNA in a model with a ROC AUC of 0.825, showing that have the potential to aid the diagnosis of PD. Overall, we demonstrated that circRNAs play an important role in PD and can be leveraged as biomarkers.
Agriculturally developed areas reduce genetic connectivity for a keystone neotropical ungulate
Authors: Baptista Mozart Sávio Pires , Keuroghlian Alexine , Tambosi Leandro Reverberi , Côrtes Marina Corrêa , Maciel Fernanda de Góes , Cirino Douglas William , Shmaedecke Gabriela , Biondo Cibele
Published: January 2024

Modified landscapes can restrict the movement of organisms, leading to isolation and reduced population viability, particularly for species with extensive home ranges and long-distance travel, such as white-lipped peccaries (WLPs,Tayassu pecari). Previous studies have indicated that forested areas favor WLP herd movements, but the impact of the non-forested areas on their genetic connectivity is unknown. In this study, we used land cover, the Brazilian Roads Map, and population genetic data to investigate the impact of non-forested matrices on WLP’s genetic connectivity in the Pantanal floodplain and surrounding Cerrado plateau of central-west Brazil. We compared isolation-by-distance (IBD), isolation-by-barrier, and isolation-by-resistance models and tested 39 hypotheses within a modeling framework. Finally, we identified the optimal areas for ecological corridors based on the most effective landscape model. Barrier and landscape resistance were more strongly correlated with genetic relatedness than the IBD model. The model that received the most robust support considered only forest as habitat. All other classes formed a matrix that impeded gene flow, including agriculture, grassland, savannah, and paved and unpaved roads. WLP herds living in landscapes with reduced forest cover are more vulnerable to the effects of genetic isolation. To maintain gene flow, it is essential to establish connections between habitats throughout the landscape. Conservation programs should prioritize strategies that strengthen connections between habitats, including facilitating wildlife road-crossing structures and creating/restoring ecological corridors to link isolated habitat fragments.
The SUbventral-Gland master Regulator (SUGR) of nematode virulence
Authors: Pellegrin Clement , Damm Anika , Sperling Alexis L. , Molloy Beth , Shin Dio S. , Long Jonathan , Brett Paul , Bravo Andrea Díaz-Tendero , Lynch Sarah Jane , Senatori Beatrice , Vieira Paulo , Mejias Joffrey , Kumar Anil , Masonbrink Rick E. , Maier Tom R. , Baum Thomas J. , Eves-van den Akker Sebastian
Published: January 2024

All pathogens must tailor their gene expression to their environment. Therefore, targeting host:parasite biology that regulates these changes in gene expression could open up routes to pathogen control. Here, we show that in the plant-parasitic nematodeHeterodera schachtii,host signals (termed effectostimulins) within plant roots activate the master regulatorsugr1. SUGR1, then, directly binds effector promoters, and orchestrates their production. Effector production, in turn, facilitates host entry, releasing more effectostimulins. These data show that gene expression during the very earliest stages of parasitism is defined by a feed forward loop for host entry. Importantly, we demonstrate that blocking SUGR1 blocks parasitism, underlining the SUGR1 signalling cascade as a valuable target for crop protection. Given that nematodes also parasitise humans and other animals, the potential impact is broad: disrupting effector production could, in principle, be applied to any pathogen that secrets effectors.

Graphical abstract
Cryopreservation of the collector urchin embryo,Tripneustes gratilla
Authors: Westbrook Charley E. , Daly Jonathan , Bowen Brian , Hagedorn Mary
Published: January 2024

The collector urchin,Tripneustes gratilla, is an ecologically important member of the grazing community of Hawaii’s coral reefs. Beyond its ability to maintain balance between native seaweeds and corals,T. gratillahas also been used as a food source and a biocontrol agent against alien invasive algae species. Due to overexploitation, habitat degradation, and other stressors, their populations face local extirpation. However, artificial reproductive techniques, such as cryopreservation, could provide more consistent seedstock throughout the year to supplement aquaculture efforts. Although the sperm and larvae of temperate urchins have been successfully cryopreserved, tropical urchins living on coral reefs have not. Here, we investigated the urchin embryos’ tolerance to various cryoprotectants and cooling rates to develop a cryopreservation protocol forT. gratilla. We found that using 1M Me2SO with a cooling rate of 9.7°C/min on gastrula stage embryos produced the best results with survival rates of up to 85.5% and up to 50.8% maturation to the 4-arm echinopluteus stage, assessed three days after thawing. Continued research could see cryopreservation added to the repertoire of artificial reproductive techniques forT. gratilla, thereby assisting in the preservation of this ecologically important urchin, all while augmenting aquaculture efforts that contribute to coral reef restoration.
High-throughput selection of humande novo-emerged sORFs with high folding potential
Authors: Aubel Margaux , Buchel Filip , Heames Brennen , Jones Alun , Honc Ondrej , Bornberg-Bauer Erich , Hlouchova Klara
Published: January 2024

De novogenes emerge from previously non-coding stretches of the genome. Their en-codedde novoproteins are generally expected to be similar to random sequences and, accordingly, with no stable tertiary fold and high predicted disorder. However, structural properties ofde novoproteins and whether they differ during the stages of emergence and fixation have not been studied in depth and rely heavily on predictions. Here we generated a library of short human putativede novoproteins of varying lengths and ages and sorted the candidates according to their structural compactness and disorder propensity. Using Förster resonance energy transfer (FRET) combined with Fluorescence-activated cell sorting (FACS) we were able to screen the library for most compact protein structures, as well as most elongated and flexible structures. Compactde novoproteins are on average slightly shorter and contain lower predicted disorder than less compact ones. The predicted structures for most and least compactde novoproteins correspond to expectations in that they contain more secondary structure content or higher disorder content, respectively. Our experiments indicate that olderde novoproteins have higher compactness and structural propensity compared to young ones. We discuss possible evolutionary scenarios and their implications underlying the age-dependencies of compactness and structural content of putativede novoproteins.
Autism spectrum disorders: an impaired glycolysis induces an ATP deficiency and a reduced cell respiration
Authors: Féron Francois , Caillol Damien , Fourel Laure , Leimkuhler Silke , Iranzo Olga , Gepner Bruno , Guiraudie-Capraz Gaelle
Published: January 2024

In two previous studies, based on human olfactory ecto-mesenchymal stem cells (OE-MSC) of 11 patients with autism spectrum disorders (ASD) and 11 healthy individuals, we demonstrated that the lower abundance of the enzyme MOCOS (MOlybdenum COfactor Sulfurase) and its associated lower expression of the long non-coding RNA, COSMOC, induces neurotransmission and synaptic defects as well as an exacerbated oxidative stress sensitivity. To move a step further, we assessed whether these defects were associated to a disturbed mitochondrial homeostasis. For that purpose, we used cellular and molecular techniques to quantitfy mitochondrial metabolism and biogenesis, ATP production and cell respiration in OE-MSCs from the 8 ASD patients of the cohort that display the most severe symptoms. We show here that OE-MSCs from ASD patients, when compared to control individuals, display i) a reduced expression/abundance of glycolysis-associated transcripts and metabolites, ii) an overall reduced ATP, mainly due to the impaired glycolysis, iii) a reduced basal cell respiration and iv) a modified mitochondrial network. These results are in accordance with some of our previously published data and may explain some of the symptoms – stress, overarousal, seizures, increased or decreased muscle tone, fatigue - observed in autism spectrum disorders.
Interplay ofMycobacterium abscessusandPseudomonas aeruginosain coinfection: Biofilm Dynamics and Host Immune Response
Authors: Campo-Pérez Víctor , Julián Esther , Torrents Eduard
Published: January 2024

The incidence of infection by nontuberculous mycobacteria, mainlyMycobacterium abscessus, in patients with cystic fibrosis and other chronic pulmonary illnesses is increasing, translating into an acceleration in the decline of lung function. In most cases,M. abscessuscoinfects withPseudomonas aeruginosa, the most common pathogen in these chronic diseases. However, it is unknown how these two bacterial species interact when coinfecting. This study aims to explore the behavior of both species in three relevant pathogenic settings: dual-species biofilm development using a recently developed method to monitor individual species in dual-species biofilms; coinfection in bronchial epithelial cells usingin vitroassays; andin vivocoinfection using theGalleria mellonellamodel. The results demonstrate the capability of both species to form stable mixed biofilms and to reciprocally inhibit single-biofilm progression. Coinfections in bronchial epithelial cells were correlated with significantly decreased cell viability, while inG. mellonella,coinfections induced lower survival rates than individual infections. Outstandingly, the analysis of the immune response triggered by each bacterium in bronchial epithelial cell assays andG. mellonellalarvae revealed thatP. aeruginosainduces the overexpression of proinflammatory and melanization cascade responses, respectively. In contrast,M. abscessusandP. aeruginosacoinfection significantly inhibited the immune response in both models, resulting in worse consequences for the host than those generated by singleP. aeruginosainfection. Overall, the presence ofM. abscessusproduces a decline in the immune responses that worsens the infection and compromises the host.

Importance

The appearance of bacterial infections in the respiratory tract of patients with chronic respiratory diseases suppose a serious and difficult to treat health problem. This complication is exacerbated by the increase resistance against antibiotics generated by pathogenic microorganisms. The most common and virulent pathogenic bacteria reported in the respiratory airway isPseudomonas aeruginosa. It is a Gram-negative, ubiquitous, and intrinsic resistant to antibiotics bacteria. However, the incidence of a rapidly growing, multi-drug resistant mycobacteria;Mycobacterium abscessus, is growing worldwide. The pulmonary coinfection by both pathogens is directly related with higher rates of morbidity and mortality of patients. The significance of our research is characterizing the behavior of these two pathogens when they coinfects together, exploring the immune response triggered by the host and its impact in the survival. The purpose is enhancing the limited understanding we have of this clinically relevant coinfection to favor the development of new effective treatments.
Implementation of the Short-Form 36 (SF-36) in childhood cancer survivors: An analysis on measurement properties across 5 European countries
Authors: Baust Katja , Calaminus Gabriele , Berger Claire , Byrne Julianne , Grabow Desiree , van den Heuvel-Eibrink Marry M. , Kaiser Melanie , Kepak Tomas , Kremer Leontien C.M. , Kruseova Jarmila , Kuonen Rahel , Roser Katharina , Spix Claudia , Maurice-Stam Heleen , Kuehni Claudia E. , Sommer Grit
Published: January 2024

Purpose

The Short Form-36 (SF-36) is widely used in many research contexts and cultures to assess health-related quality of life (HRQOL). We investigated the measurement properties of the SF-36 in a large cohort study among childhood cancer survivors living in 5 European countries.

Methods

The PanCareLIFE project includes adult survivors of childhood cancer living in the Czech Republic, France, Germany, The Netherlands, and Switzerland. We invited 19,268 survivors aged >18 years, and 10,077 (53%) returned questionnaires. Of these, 9,871 (98%) were included in the analyses. We assessed HRQOL with the SF-36 version 1 (V1) or version 2 (V2) and investigated its performance. We analysed data completeness, floor and ceiling effects, item-internal consistency, item-discriminant validity, reliability, and scaling assumptions focusing on country-and version-specific differences.

Results

Data completeness was high but differed between countries (90% in the Czech Republic to 96% in France). Floor effects were negligible, but ceiling effects in 5 out of 8 SF-36 scales were present (50-70%). V2 had slightly fewer ceiling effects than V1 in 2 scales. Item-internal consistency, item-discriminant validity, and reliability were good. Scaling assumptions were met, with 4 scales representing strong mental health content, and the other 4 representing strong physical health content.

Conclusion

The SF-36 (V1 and V2) provided robust measurement properties among childhood cancer survivors, and differences in study design across the 5 European countries did not affect measurement properties. Researchers need to take into account that ceiling effects exist which might limit sensitivity among participants who fared particularly well.

PLAIN ENGLISH SUMMARY

This study investigated how well the Short Form-36 (SF-36), a commonly used tool for assessing health-related quality of life, performs in childhood cancer survivors from five different European countries. We looked at the amount of survivors answering to all of the SF-36 questions, how many indicated the most positive or the most negative answer category, whether the questions were consistent within the different aspects of the questionnaire and how consistent and dependable it measured quality of life in the survivors. We found that overall, the SF-36 measured health-related quality of life well in all the countries. This is reassuring for researchers considering its use in studies involving multiple centers across Europe.
RMS: A ML-based system for ICU Respiratory Monitoring and Resource Planning
Authors: Hüser Matthias , Lyu Xinrui , Faltys Martin , Pace Alizée , Berger David , Hoche Marine , Hyland Stephanie L , Yèche Hugo , Burger Manuel , Merz Tobias M , Rätsch Gunnar
Published: January 2024

Acute hypoxemic respiratory failure (RF) occurs frequently in critically ill patients and is associated with substantial morbidity, mortality and increased resource use. We used machine learning to create a comprehensive monitoring system to assist intensive care unit (ICU) physicians in managing acute RF. The system encompasses early detection and ongoing monitoring of acute hypoxemic RF, assessment of readiness for tracheal extubation and prediction of the risk of extubation failure. In study patients, the model predicted 80% of RF events at a precision of 45%, with 65% of RF events identified more than 10 hours before RF onset. System predictive performance was significantly higher than standard clinical monitoring based on the patient’s oxygenation index and was successfully validated in an external cohort of ICU patients. We have demonstrated how the estimated risk of extubation failure (EF) could facilitate prevention of both, extubation failure and unnecessarily prolonged mechanical ventilation. Furthermore, we illustrated how machine-learning-based monitoring of RF risk, along with the necessity for mechanical ventilation and extubation readiness on a patient-by-patient basis, can facilitate resource planning for mechanical ventilation in the ICU. Specifically, our model predicted ICU-level ventilator use within 8 to 16 hours into the future, with a mean absolute error of 0.4 ventilators per 10 patients of effective ICU capacity.
Genetic and neurodevelopmental markers in schizophrenia-spectrum disorders: analysis of the combined role of the Cannabinoid Receptor 1 gene (CNR1) and dermatoglyphics
Authors: Guardiola-Ripoll Maria , Sotero-Moreno Alejandro , Chaumette Boris , Kebir Oussama , Hostalet Noemí , Almodóvar-Payá Carmen , Moreira Mónica , Giralt-López Maria , Odile-Krebs Marie , Fatjó-Vilas Mar
Published: January 2024

The aetiology of schizophrenia-spectrum disorders (SSD) involves genetic and environmental factors impacting neurodevelopmental trajectories. Dermatoglyphic pattern deviances have been associated with SSD and considered vulnerability markers for these disorders based on the shared ectodermal origin of the epidermis and the central nervous system. The endocannabinoid system participates in epidermal differentiation, is sensitive to the prenatal environment and is associated with SSD. We assessed whether theCannabinoid receptor 1(CNR1) gene is a common denominator in dermatoglyphic pattern configurations and SSD risk and whether it modulates the dermatoglyphics-SSD association.

In a sample of 112 controls and 97 SSD patients, three dermatoglyphic markers were assessed: the total palmar a-b ridge count (TABRC), the a-b ridge count fluctuating asymmetry (ABRC-FA), and the pattern intensity index (PII). TwoCNR1polymorphisms were genotyped: rs2023239-A/G and rs806379-A/T. We tested theCNR1association with SSD and with the dermatoglyphic variability within diagnostic groups. Secondly, we assessed theCNR1x dermatoglyphic measures interaction on SSD susceptibility.

Both polymorphisms were associated with the risk for SSD, and within controls, rs2023239 and rs806379 modulated the PII and TABRC, respectively. Lastly, our data showed that rs2023239 modulated the relationship between PII and SSD: a high PII score was associated with a lower SSD risk within G-allele-carriers and a higher SSD risk within AA-homozygotes.

These novel results highlight the endocannabinoid system’s role in the development and variability of dermatoglyphic patterns. The identified interaction encourages combining genetic and dermatoglyphics to assess neurodevelopmental alterations predisposing to SSD.
Patients with end-stage kidney disease and COVID-19 are commonly hospitalized early during COVID-19 illness: an opportunity for early intervention
Authors: Seethapathy Rituvanthikaa , Wang Qiyu , Katz-Agranov Nurit , Strohbehn Ian , Moreno Daiana , Harden Destiny , Bhattacharyya Roby P. , Sise Meghan E.
Published: January 2024

Antiviral medications such as remdesivir, molnupiravir, and nirmatrelvir/ritonavir are most effective when used early in the course of coronavirus disease 2019 (COVID-19). These medications are mainly authorized for outpatient use in high risk populations. End-stage kidney disease (ESKD) is among the strongest risk factors for mortality from COVID-19, however, therapeutic options have been lacking in this patient population given exclusion of ESKD in the registrational trials of antiviral therapy leading to limited FDA approval. In our retrospective study of patients with ESKD on dialysis admitted for symptomatic COVID-19 from March 2020 to January 2020, we found that majority of patients (>80%) were admitted to the hospital early during their disease course (within 5 days of symptom onset). Despite this pattern of early admission, there was a high risk of respiratory failure within 90 days since admission (30%) among this population. We argue that this unique pattern of early presentation and high risk of progression to respiratory failure of the ESKD patients suggests an opportunity for further research to determine if outpatient antiviral therapies should be expanded to patients with ESKD to address the huge unmet need of therapeutic intervention in this vulnerable population.
Estimating effects of serum vitamin B12 levels on psychiatric disorders and cognitive impairment: a Mendelian randomization study
Authors: Lu Tianyuan , Paterson Andrew D.
Published: January 2024

Abstract

Vitamin B12 deficiency can lead to pernicious anemia, various neuropsychiatric diseases, and cognitive decline. However, it is unclear whether increasing vitamin B12 levels can help to prevent the onset of psychiatric disorders and cognitive impairment in the general population. Leveraging large-scale genome-wide association studies (GWASs), we conducted Mendelian randomization (MR) analyses to estimate the potential effects of serum vitamin B12 levels on eight psychiatric disorders, as well as educational attainment and cognitive performance. We performed sensitivity analyses by excluding genetic instruments that demonstrated potential horizontal pleiotropy. We conducted additional MR analyses utilizing within-sibship studies for depressive symptoms, educational attainment, and cognitive performance to mitigate bias due to potential residual confounding in GWASs. As a positive control, we confirmed that a one standard deviation increase in genetically increased vitamin B12 levels was strongly associated with a decreased odds of developing pernicious anemia (odds ratio, OR = 0.24; 95% confidence interval, CI: 0.15-0.40; p-value = 2.1x10-8). In contrast, MR estimates of vitamin B12 effects on all eight psychiatric disorders, educational attainment and cognitive performance largely overlapped with the null. In particular, based on the three most well-powered GWASs, a one standard deviation increase in genetically predicted vitamin B12 levels was associated with an OR of 1.01 for depression (95% CI: 0.97-1.04; p-value = 0.74), a 7.7x10-3standard deviation increase in educational attainment (95% CI: -1.0x10-2-2.5x10-2; p-value = 0.39) and a 1.3x10-2standard deviation increase in cognitive performance (95% CI: -8.8x10-3-3.5x10-2; p-value = 0.24). No significant associations between genetically predicted vitamin B12 levels and any of the outcomes were identified in sensitivity analyses excluding pleiotropic genetic instruments or MR analyses based on within-sibship studies. In summary, our findings suggest that increasing serum vitamin B12 levels may not protect against the investigated psychiatric disorders or cognitive impairment in the general population.
Evolution of glucuronoxylan side chain variability in vascular plants and the counter-adaptation of pathogenic cell-wall-degrading hydrolases
Authors: Yu Li , Wilson Louis F.L. , Terrett Oliver M. , Wurman-Rodrich Joel , Lyczakowski Jan J. , Yu Xiaolan , Krogh Kristian B.R.M. , Dupree Paul
Published: January 2024

• Polysaccharide structural complexity not only influences cell wall strength and extensibility, but also hinders pathogenic and biotechnological attempts to saccharify the wall. In certain species and tissues, glucuronic acid side chains on xylan exhibit arabinopyranose or galactose decorations whose genetic and evolutionary basis is completely unknown, impeding efforts to understand their function and engineer wall digestibility.

• Genetics and polysaccharide profiling were used to identify the responsible loci in Arabidopsis and Eucalyptus from proposed candidates, while phylogenies uncovered a shared evolutionary origin. GH30-familyendo-glucuronoxylanase activities were analysed by electrophoresis and their differing specificities were rationalised by phylogeny and structural analysis.

• The newly identified xylan arabinopyranosyltransferases comprise an overlooked subfamily in the GT47-A family of Golgi glycosyltransferases, previously assumed to comprise mainly xyloglucan galactosyltransferases, highlighting an unanticipated adaptation of both donor and acceptor specificities. Further neofunctionalisation has produced a Myrtaceae-specific xylan galactosyltransferase. Simultaneously, GH30 endo-glucuronoxylanases have convergently adapted to overcome these decorations, suggesting a role for these structures in defence. The differential expression of glucuronoxylan-modifying genes across Eucalyptus tissues, however, hints at further functions.

• Our results demonstrate the rapid adaptability of biosynthetic and degradative carbohydrate-active enzyme activities, providing insight into a plant-pathogen arms race and facilitating plant cell wall biotechnological utilisation.
Genome data artifacts and functional studies of deletion repair in the BA.1 SARS-CoV-2 spike protein
Authors: Álvarez-Herrera Miguel , Ruiz-Rodriguez Paula , Navarro-Domínguez Beatriz , Zulaica Joao , Grau Brayan , Bracho María Alma , Guerreiro Manuel , Aguilar-Gallardo Cristóbal , González-Candelas Fernando , Comas Iñaki , Geller Ron , Coscollá Mireia
Published: January 2024

Mutations within the N-terminal domain (NTD) of the spike (S) protein are critical for the emergence of successful SARS-CoV-2 viral lineages. The NTD has been repeatedly impacted by deletions, often exhibiting complex and dynamic patterns, such as the recurrent emergence and disappearance of deletions in dominant variants. This study investigates the influence of repair of NTD lineage-defining deletions found in the BA.1 lineage (Omicron variant) on viral success. We performed comparative genomic analyses of more than 10 million SARS-CoV-2 genomes from GISAID to decipher the transmission success of viruses lacking S:ΔH69/V70, S:ΔV143/Y145, or both. These findings were contrasted against a screening of publicly available raw sequencing data, revealing substantial discrepancies between data repositories, suggesting that spurious deletion repair observations in GISAID may result from systematic artifacts. Specifically, deletion repair events were approximately an order of magnitude less frequent in the read-run survey. Our results suggest that deletion repair events are rare, isolated events with limited direct influence on SARS-CoV-2 evolution or transmission. Nevertheless, such events could facilitate the emergence of fitness-enhancing mutations. To explore potential drivers of NTD deletion repair patterns, we characterized the viral phenotype of such markers in a surrogatein vitrosystem. Repair of the S:ΔH69/V70 deletion reduced viral infectivity, while simultaneous repair with S:ΔV143/Y145 led to lower fusogenicity. In contrast, individual S:ΔV143/Y145 repair enhanced both fusogenicity and susceptibility to neutralization by sera from vaccinated individuals. This work underscores the complex genotype-phenotype landscape of the spike NTD in SARS-CoV-2, which impacts viral biology, transmission efficiency, and immune escape potential, offering insights with direct relevance to public health, viral surveillance, and the adaptive mechanisms driving emerging variants.
Novel sensor-integrated proteome on chip (SPOC) platform with thousands of folded proteins on a 1.5 sq-cm biosensor chip to enable high-throughput real-time label-free screening for kinetic analysis
Authors: Agu Chidozie Victor , Cook Rebecca L , Martelly William , Gushgari Lydia R , Mohan Mukilan , Takulapalli Bharath
Published: January 2024

An automated proteomic platform for producing and screening an array of functional proteins on biosensor surfaces was developed to address the challenges of measuring proteomic interaction kinetics in high throughput (HTP). This technology is termed Sensor-Integrated Proteome On Chip (SPOC®) which involvesin-situcell-free protein expression in nano-liter volume wells (nanowells) directly from rapidly customizable arrays of plasmid DNA, facilitating simultaneous capture-purification of up to 2400 unique full-length folded proteins onto a 1.5 sq-cm surface of a single gold biosensor chip. Arrayed SPOC sensors can then be screened by real-time label-free analysis, including surface plasmon resonance (SPR) to generate kinetic affinity, avidity data. Fluorescent and SPR assays were used to demonstrate zero crosstalk between protein spots. The functionality of the SPOC protein array was validated by antibody binding assay, post-translational modification, mutation-mediated differential binding kinetics, and catalytic activity screening on model SPOC protein arrays containing p53, Src, Jun, Fos, HIST1H3A, and SARS-CoV-2 receptor binding domain (RBD) protein variants of interest, among others. Monoclonal antibodies were found to selectively bind their target proteins on the SPOC array. A commercial anti-RBD antibody was used to demonstrate discriminatory binding to numerous SARS-CoV-2 RBD variants of concern with comprehensive kinetic information. With advantages of HTP, flexibility, low-cost, quick turnaround time, and real-time kinetic affinity profiling, the SPOC proteomic platform addresses the challenges of interrogating protein interactions at scale and can be deployed in various research and clinical applications.
Regulatory T cells and IFN-γ-producing Th1 cells play a critical role in the pathogenesis of Sjögren’s Syndrome
Authors: Wang Yin-Hu , Li Wenyi , McDermott Maxwell , Son Ga-Yeon , Maiti George , Zhou Fang , Tao Anthony , Raphael Dimitrius , Moreira Andre L. , Shen Boheng , Vaeth Martin , Nadorp Bettina , Chakravarti Shukti , Lacruz Rodrigo S. , Feske Stefan
Published: January 2024

Objectives

Sjögren’s Disease (SjD) is an autoimmune disorder characterized by progressive dysfunction, inflammation and destruction of salivary and lacrimal glands, and by extraglandular manifestations. Its etiology and pathophysiology remain incompletely understood, though a role for autoreactive B cells has been considered key. Here, we investigated the role of effector and regulatory T cells in the pathogenesis of SjD.

Methods

Histological analysis, RNA-sequencing and flow cytometry were conducted on glands, lungs, eyes and lymphoid tissues of mice with regulatory T cell-specific deletion of stromal interaction proteins (STIM) 1 and 2 (Stim1/2Foxp3), which play key roles in calcium signaling and T cell function. The pathogenicity of T cells fromStim1/2Foxp3mice was investigated through adoptively transfer into lymphopenic host mice. Additionally, single-cell transcriptomic analysis was performed on peripheral blood mononuclear cells (PBMCs) of patients with SjD and control subjects.

Results

Stim1/2Foxp3mice develop a severe SjD-like disorder including salivary gland (SG) and lacrimal gland (LG) inflammation and dysfunction, autoantibodies and extraglandular symptoms. SG inflammation inStim1/2Foxp3mice is characterized by T and B cell infiltration, and transcriptionally by a Th1 immune response that correlates strongly with the dysregulation observed in patients with SjD. Adoptive transfer of effector T cells fromStim1/2Foxp3mice demonstrates that the SjD-like disease is driven by interferon (IFN)-γ producing autoreactive CD4+T cells independently of B cells and autoantiboodies. scRNA-seq analysis identifies increased Th1 responses and attenuated memory Treg function in PBMCs of patients with SjD.

Conclusions

We report a more accurate mouse model of SjD while providing evidence for a critical role of Treg cells and IFN-γ producing Th1 cells in the pathogenesis of SjD, which may be effective targets for therapy.
Self-inspired learning to denoise for live-cell super-resolution microscopy
Authors: Qu Liying , Zhao Shiqun , Huang Yuanyuan , Ye Xianxin , Wang Kunhao , Liu Yuzhen , Liu Xianming , Mao Heng , Hu Guangwei , Chen Wei , Guo Changliang , He Jiaye , Tan Jiubin , Li Haoyu , Chen Liangyi , Zhao Weisong
Published: January 2024

Every collected photon is precious in live-cell super-resolution (SR) fluorescence microscopy for contributing to breaking the diffraction limit with the preservation of temporal resolvability. Here, to maximize the utilization of accumulated photons, we propose SN2N, aSelf-inspiredNoise2Noise engine with self-supervised data generation and self-constrained learning process, which is an effective and data-efficient learning-based denoising solution for high-quality SR imaging in general. Through simulations and experiments, we show that the SN2N’s performance is fully competitive to the supervised learning methods but circumventing the need for large training-set and clean ground-truth, in which a single noisy frame is feasible for training. By one-to-two orders of magnitude increased photon efficiency, the direct applications on various confocal-based SR systems highlight the versatility of SN2N for allowing fast and gentle 5D SR imaging. We also integrated SN2N into the prevailing SR reconstructions for artifacts removal, enabling efficient reconstructions from limited photons. Together, we anticipate our SN2N and its integrations could inspire further advances in the rapidly developing field of fluorescence imaging and benefit subsequent precise structure segmentation irrespective of noise conditions.
High response diversity and conspecific density-dependence, not species interactions, drive dynamics of coral reef fish communities
Authors: Ruiz-Moreno Alfonso , Emslie Michael J. , Connolly Sean R.
Published: January 2024

Species-to-species and species-to-environment interactions are key drivers of community dynamics. Disentangling these drivers in species-rich assemblages is challenging due to the high number of potentially interacting species (the “curse of dimensionality”). We develop a process-based model that quantifies how intraspecific and interspecific interactions, and species’ covarying responses to environmental fluctuations, jointly drive community dynamics. We fit the model to reef fish abundance time series from 41 reefs of Australia’s Great Barrier Reef. We found that fluctuating relative abundances are driven by species’ heterogenous responses to environmental fluctuations, whereas interspecific interactions are negligible. Species differences in long-term average abundances are driven by interspecific variation in the magnitudes of both conspecific density-dependence and density-independent growth rates. This study introduces a novel approach to overcoming the curse of dimensionality, which reveals highly individualistic dynamics in coral reef fish communities that imply a high level of niche structure.
Alterations of genomic imprinting appear during the reprogramming of adult neural stem cells
Authors: Montalbán-Loro Raquel , Lozano-Ureña Anna , Lázaro-Carot Laura , Jiménez-Villalba Esteban , Planells Jordi , Lleches-Padilla Adela , Ito Mitsu , Radford Elisabeth J. , Ferrón Sacri R.
Published: January 2024

Genomic imprinting is an epigenetic mechanism that causes monoallelic expression of genes depending on their parental origin. Loss of imprinting (LOI) is associated with cancer progression and human imprinting disorders (IDs), impacting foetal development, metabolism and cognition. Imprinted genes, organized in clusters, rely on methylation at imprint control regions (ICRs), which are differentially methylated regions (DMRs) on both parental chromosomes. Somatic cell reprogramming into induced pluripotent stem cells (iPSCs) is a valuable tool to understand the mechanisms associated with pluripotency and holds promise for generating patient-specific stem cells for therapeutical applications to treat different pathologies such as IDs. Here, we conduct genome-wide RNA-seq and MeDIP-seq analysis on mouse iPSCs derived from adult neural stem cells (NSCs). Our findings reveal a comprehensive alteration in iPSCs transcriptome profile, aligning with DNA hypomethylation. This correlation is pivotal in discerning which modifications in genomic imprinting during the reprogramming process represent undesirable epigenetic abnormalities that could compromiise the quality of iPSCs. Simultaneously, it helps identify genuine epigenetic modifications that are inherently linked to pluripotency, thus ensuring a clearer understanding of the factors influencing iPSC quality and pluripotent potential.