bluuebunny/crossref_metadata_2025 huggingface dataset:
Hospital length of stay in a mixed Omicron and Delta epidemic in New South Wales, Australia
Authors: Tobin Ruarai J , Wood James G , Jayasundara Duleepa , Sara Grant , Walker James , Martin Genevieve E , McCaw James M , Shearer Freya M , Price David J
Published: March 2022

Aim

To estimate the length of stay distributions of hospitalised COVID-19 cases during a mixed Omicron-Delta epidemic in New South Wales, Australia (16 Dec 2021 – 7 Feb 2022), and compare these to estimates produced over a Delta-only epidemic in the same population (1 Jul 2021 – 15 Dec 2022).

Background

The distribution of the duration that clinical cases of COVID-19 occupy hospital beds (the ‘length of stay’) is a key factor in determining how incident caseloads translate into health system burden as measured through ward and ICU occupancy.

Results

Using data on the hospital stays of 19,574 individuals, we performed a competing-risk survival analysis of COVID-19 clinical progression. During the mixed Omicron-Delta epidemic, we found that the mean length of stay for individuals who were discharged directly from ward without an ICU stay was, for age groups 0-39, 40-69 and 70+ respectively, 2.16 (95% CI: 2.12–2.21), 3.93 (95% CI: 3.78–4.07) and 7.61 days (95% CI: 7.31–8.01), compared to 3.60 (95% CI: 3.48–3.81), 5.78 (95% CI: 5.59–5.99) and 12.31 days (95% CI: 11.75–12.95) across the preceding Delta epidemic (15 Jul 2021 – 15 Dec 2021). We also considered data on the stays of individuals within the Hunter New England Local Health District, where it was reported that Omicron was the only circulating variant, and found mean ward-to-discharge length of stays of 2.05 (95% CI: 1.80–2.30), 2.92 (95% CI: 2.50–3.67) and 6.02 days (95% CI: 4.91–7.01) for the same age groups.

Conclusions

Hospital length of stay was substantially reduced across all clinical pathways during a mixed Omicron-Delta epidemic compared to a prior Delta epidemic. These changes in length of stay have contributed to lessened health system burden despite greatly increased infection burden and should be considered in future planning of response to the COVID-19 pandemic in Australia and internationally.
A log-odds system for waning and boosting of COVID-19 vaccine effectiveness
Authors: Blakely Tony , Szanyi Joshua , Wilson Tim , Scott Nick
Published: March 2022

Immunity to SARS-CoV-2 following vaccination wanes over time in a non-linear fashion, making modelling of likely population impacts of COVID-19 policy options challenging. We observed that it was possible to mathematize non-linear waning of vaccine effectiveness (VE) on the percentage scale as linear waning on the log-odds scale, and developed a random effects logistic regression equation based on UK Health Security Agency data to model VE against Omicron following two and three doses of a COVID-19 vaccine. VE on the odds scale reduced by 47% per month for symptomatic infection after two vaccine doses, lessening to 35% per month for hospitalisation. Waning on the odds scale after triple dose vaccines was 35% per month for symptomatic disease and 19% for hospitalisation. This log-odds system for estimating waning and boosting of COVID-19 VE provides a simple solution that may be used to parametrize SARS-CoV-2 immunity over time parsimoniously in epidemiological models.
Gene expression signature of castrate resistant prostate cancer
Authors: Dixcy Jaba Sheeba JM , Hegde Shraddha , Tamboli Ninad , Nadig Namratha , Keshavamurthy Ramaiah , Ranganathan Prathibha
Published: March 2022

Prostate gland is a highly androgen dependent gland and hence the first line of treatment for metastatic prostate cancer happens to be androgen ablation. This is achieved by multiple non-surgical methods. However, most of these cancers although respond well initially, become resistant to androgen ablation sooner or later. These cancers then become extremely aggressive and difficult to treat, thereby drastically affect the patient prognosis. The purpose of this project was to identify a gene expression signature for castrate resistant prostate cancer which may aid in identification of mechanisms responsible for castrate resistance. For this purpose, we have collected patient samples belonging to a. Control group; b. Castrate Sensitive group and c. Castrate resistant group. Gene expression profiling has been done on these samples using RNA-seq and several differentially expressed genes identified between the castrate sensitive and resistant groups. We have also identified some genes which are expressed in the castrate resistant group alone, which is of interest since these may have an implication in evolution of castrate resistance and also prognosis.

We have compared this with data from The Cancer Genome Atlas (TCGA). Using criteria such as overall survival, disease free survival, progression free survival and biochemical recurrence, we have identified genes which may have relevance in progression to castrate resistance and in prognosis. Functional annotation of these genes may give an insight into the mechanism of development of castrate resistance.
Engineering Principles and Algorithmic Design Synthesis for Ultracompact Bio-Hybrid Perfusion Chip
Authors: Erben Amelie , Kellerer Thomas , Lissner Josefine , Eulenkamp Constanze , Hellerer Thomas , Hauke-Clausen-Schaumann  , Sudhop Stefanie , Heymann Michael
Published: March 2022

Bioinspired 3D microfluidic systems that combine vascularization with extracellular matrix architectures of organotypic geometry, composition and biophysical traits can help advance our understanding of microorgan physiology. Here, two-photon stereolithography is adopted to fabricate freestanding perfusable 3D cell scaffolds with micrometer resolution from gelatin methacryloyl hydrogel derived from extracellular matrix protein. As a proof of concept, we introduce an ultracompact bio-hybrid chip layout to demonstrate perfusion and cell seeding of double-digit μm proteinaceous channels. This perfusion chip consists of a standardized microfluidic interface fabricated from standard resin and a GM10 bioink channel printed atop of this interface. In addition, we demonstrate that algorithmic design synthesis can recapitulate intact alveoli and capillary networks with tunable design parameters to implement vascularized alveolar tissue models. This approach will allow for a systematic investigation of cell-cell and tissue dynamics in response to defined structural, mechanical and bio-molecular cues and is ultimately scalable to fabricate organ-on-a-chip systems.
Projective LDDMM: Spatially Reconstructing a Story of Rostrally-Dominant Tau in Alzheimer’s Disease
Authors: Stouffer Kaitlin , Witter Menno , Chen Claire , Xu Eileen , Albert Marilyn , Mori Susumu , Troncoso Juan , Tward Daniel , Miller Michael
Published: March 2022

Since Braak’s initial histological observations, it has been recognized that Alzheimer’s disease (AD) neurofibrillary tangles (NFTs) appear in the medial temporal lobe (MTL) of the brain very early in the disease course. MRI-based shape diffeomorphometry markers have demonstrated pre-clinical AD changes in the MTL but it has not been possible to confirm that these MRI changes correspond to the presence of NFTs. Here, we present a method termed Projective LDDMM for aligning sparse measurement profiles of AD pathology (i.e., 2D digital histology images) with 3D MRI. We reconstruct measures of 2D NFT density in the dense metric of 3D MRI, using the Mai Paxinos Atlas coordinates for two cases of advanced AD. Analyses reveal the highest levels of NFT density in the rostral third (10-15 mm) of the hippocampus and the adjoining regions of the entorhinal cortex and amygdala. These findings emphasize the selective vulnerability of MTL subregions in AD, and suggest that high resolution MRI methods might benefit from focusing on the rostral MTL to more closely link these MRI images to AD neuropathology.
WNK1-dependent water influx is required for CD4+T cell activation and T cell-dependent antibody responses
Authors: O’May Joshua Biggs , Vanes Lesley , de Boer Leonard L. , Hartweger Harald , Kunzelmann Simone , Hayward Darryl , Llorian Miriam , Lewis David A. , Köchl Robert , Tybulewicz Victor L. J.
Published: March 2022

Signaling from the T cell antigen receptor (TCR) on CD4+T cells plays a critical role in adaptive immune responses by inducing T cell activation, proliferation, and differentiation. We demonstrate that WNK1, a kinase implicated in osmoregulation in the kidney, is required in T cells to support T-dependent antibody responses. WNK1-deficient CD4+T cells are severely impaired in their ability to proliferate and to generate antigen-specific T follicular helper cells in response to immunization with a T-dependent antigen. We show that WNK1 and its downstream OXSR1 and STK39 kinases are required for TCR signaling in CD4+T cells and for entry into cell cycle. Additionally, by preventing ATR activation, this pathway is required for T cells to progress from G2 into M phase of the cell cycle. Unexpectedly, we show that this WNK1 pathway regulates water influx, most likely through AQP3, which is required for TCR-induced signaling and cell cycle entry. Thus, TCR signaling via WNK1, OXSR1, STK39 and AQP3 leads to water entry that is essential for CD4+T cell proliferation and hence T cell-dependent antibody responses. Given the broad expression of WNK1, WNK1-dependent water influx may be a common feature of mitogenic pathways in many cell types, both within the immune system and beyond.

One Sentence Summary

T cell antigen receptor signaling via the WNK1 kinase causes water entry which is essential for CD4+T cell proliferation.
Extracellular matrix guidance determines proteolytic and non-proteolytic cancer cell patterning
Authors: Beunk Lianne , van Helvert Sjoerd , Bekker Bram , Ran Lars , Kang Ross , Paulat Tom , Syga Simon , Deutsch Andreas , Friedl Peter , Wolf Katarina
Published: March 2022

Metastatic tumor cell invasion into interstitial tissue is a mechanochemical process that responds to tissue cues and further involves proteolytic remodeling of the tumor stroma. How matrix density, tissue guidance and the ability of proteolytic tissue remodeling cooperate and determine decision-making of invading tumor cells in complex-structured three-dimensional (3D) tissue remains unclear. We here developed a collagen-based invasion assay containing a guiding interface of low collagen density adjacent to randomly organized 3D fibrillar lattice and examined the invasion of melanoma cells from multicellular spheroids in response to matrix density, guidance cues and collagenolysis. After 48 hours of culture, two invasion niches developed, (i) sheet-like collective migration along the interface and (ii) single cell- and strand-like invasion into randomly organized 3D matrix. High collagen density impeded migration into the random matrix, whereas migration along a high-density collagen interface was increased compared to the low-density matrix assay. In silico analysis predicted that facilitated interface migration in high-density matrix depended on physical guidance without collagen degradation, whereas migration into randomly organized matrix was strongly dependent on collagenolysis. When tested in 3D culture, inhibition of matrix metalloprotease (MMP)-mediated collagen degradation compromised migration into random matrix in dependence of density, whereas interface-guided migration remained effective. In conclusion, with increasing tissue density, matrix cues bordered by dense matrix, but not randomly organized matrix, support effective MMP-independent migration. This identifies the topology of interstitial tissue a primary determinant of switch behaviors between MMP-dependent and MMP-independent cancer cell invasion.
DNA co-methylation has a stable structure and is related to specific aspects of genome regulation
Authors: Watkins Sarah Holmes , Suderman Matthew , Hemani Gibran , Burrows Kimberly , Lawlor Deborah A , West Jane , Willan Kathryn , Timpson Nicholas J , Min Josine , Gaunt Tom R
Published: March 2022

DNA methylation (DNAm) is influenced by genetic and environmental factors, and can be used to understand interindividual variability in genomic regulation. Co-methylation between DNAm sites is a known phenomenon, but the architecture of relationships between the approximately 450,000 (450k) sites commonly measured in epidemiological studies has not been described. We investigate whether interindividual co-methylation structure amongst the 450k sites changes with age, whether it differs between UK-born White (n=849, 910, 921 and 424) and Pakistani ancestry (n=439) individuals, and how it relates to genome regulation. We find stability between birth and adolescence, across cohorts, and between two ethnic groups. Highly correlated DNAm sites in close proximity are heritable, but these relationships are weakly influenced by nearby genetic variants, and are enriched for transcription factor (TF) binding sites related to regulation of short RNAs transcribed by RNA polymerase III. Highly correlated sites that are distant, or on different chromosomes (in trans), are driven by common and unique environmental factors, with methylation at these sites less likely to be driven by genotype. Trans co-methylated DNAm sites are enriched for multiple TF binding sites and for inter-chromosomal chromatin contact sites, suggesting DNA co-methylation of distant sites may relate to long-range cooperative TF interactions. We conclude that DNA co-methylation has a stable structure from birth to adolescence, and between UK-born White and Pakistani individuals. This stable structure might have implications for future design and interpretation of epigenetic studies. We hypothesise that co-methylation may have roles in genome regulation in humans, including 3D chromatin architecture.
Transcriptomic analysis of the C3-CAM transition in Cistanthe longiscapa, a drought tolerant plant in the Atacama Desert
Authors: Ossa P. G. , Moreno A. A. , Orellana D. , Toro M. , Carrasco-Valenzuela T. , Riveros A. , Meneses C. C. , Nilo-Poyanco R. , Orellana A.
Published: March 2022

One of the most outstanding plant species during the blooming of the Atacama Desert is the annual plantCistanthe longiscapa. This plant can perform CAM photosynthesis, but the ecophysiological and molecular mechanisms that this plant uses to withstand the extreme conditions it inhabits in the field are unknown.

Morphological and ecophysiological traits were studied and leaf samples at dawn/dusk times were collected from three sites distributed across an increasing south to north arid gradient, to evaluate CAM expression and transcriptomic differences, and search for links between photosynthetic path and abiotic response.

Plants from the different sites presented significant differences in nocturnal leaf acid accumulation, isotopic carbon ratio (δ13C), succulence and other four traits that clearly indicated a spectrum of CAM photosynthesis intensity that correlated with aridity intensity. The differential gene expression analysis among Dawn vs Dusk between sampling sites showed higher gene expression in the arid northern site (3991 v/s 2293) with activation of regulatory processes associated with abscisic acid and circadian rhythm.

The analysis highlights clear ecophysiological differences and the requirement of a strong rewiring of the gene expression to allow a transition from a weak into a strong CAM inC. longiscapa.
Analysis of alternative mRNA splicing in vemurafenib-resistant melanoma cells
Authors: Bokharaie Honey , Kolch Walter , Krstic Aleksandar
Published: March 2022

Alternative mRNA splicing is common in cancers. In BRAF V600E mutated malignant melanoma a frequent mechanism of acquired resistance to BRAF inhibitors involves alternative splicing (AS) of BRAF. The resulting shortened BRAF protein constitutively dimerizes and conveys drug resistance. Here, we have analysed AS in SKMEL-239 melanoma cells and a BRAF inhibitor (vemurafenib) resistant derivative that expresses an AS, shortened BRAF V600E transcript. Transcriptome analysis showed differential expression of spliceosome components between the two cell lines. As there is no consensus approach to analysing AS events, we used and compared four common AS softwares based on different principles, DEXSeq, rMATS, ASpli, and LeafCutter. Two of them correctly identified the BRAF V600E AS in the vemurafenib resistant cells. Only 12 AS events were identified by all four softwares. Testing the AS predictions experimentally showed that these overlapping predictions are highly accurate. Interestingly, they identified AS caused alterations in the expression of melanin synthesis and cell migration genes in the vemurafenib resistant cells. This analysis shows that combining different AS analysis approaches produce reliable results and meaningful, biologically testable hypotheses.
GPCR-IFP: A Web Server for Analyzing G-Protein Coupled Receptor-Ligand Fingerprint Interaction from Experimental Structures
Authors: Xu Marc , li Yi , Dong Junlin , Yuan Shuguang
Published: March 2022

G-protein coupled receptors (GPCRs) are interesting targets for a broad range of drugs. The comprehensions of the interaction’s mode between GPCRs and their ligands remains to be resolved. Here, we present GPCR-IFP, a web server which drives to gather experimental information supports a better understanding of ligand-receptor interaction and the chemical space. Despite the vast chemical library used for drug discovery, the structures of ligands for a particular receptor share some common molecular features. Thus, we foraged to collect all experimental structures of GPCRs and analyzed protein-ligand interactions which resulted in important unique patterns for both agonist and antagonist. All those results can be analyzed and visualized in GPCR-IFP, a friendly-used webserver.
Development of visual cortex in human neonates are selectively modified by postnatal experience
Authors: Li Mingyang , Liu Tingting , Xu Xinyi , Wen Qingqing , Zhao Zhiyong , Dang Xixi , Zhang Yi , Wu Dan
Published: March 2022

Experience-dependent cortical plasticity is a pivotal process of human brain development and essential for the formation of most cognitive functions. Although studies found that early visual experience could influence the endogenous development of visual cortex in animals, little is known about such impact on human infants. Using the multi-modal MRI data from developing human connectome project, we revealed the early structural and functional maps in the ventral visual cortex and their development across the first month of age. Particularly, we found the postnatal experience could modulate both the cortical morphology in ventral visual cortex and the functional circuit between bilateral primary visual cortices. But the cortical myelination and overall functional circuits of ventral cortex, particularly that of the high-order visual cortex, developed without significant influence of postnatal experience in such early period. These experience-dependent cortical properties were further validated in the preterm-born infants who have longer postnatal time but immature cortical development at birth. The results confirmed that the development of cortical thickness was dominated by the postnatal experience but the functional circuit might be determined by the overall maturity of visual cortex. These data suggest in human newborns that early postnatal experience shapes the structural and functional development of the visual cortex in selective and organized pattern.
Enhanced envelope coding following acoustic trauma is detrimental to neural coding of speech in noise
Authors: Parida Satyabrata , Heinz Michael G.
Published: March 2022

People with hearing loss struggle understanding speech in noisy backgrounds. Speech-intelligibility models highlight the importance of slow-varying envelopes of speech and noise; however, the physiological basis of impaired perception remains unclear. We provide neurophysiological evidence that, although acoustic trauma enhances both speech and noise envelopes, disruptions in cochlear tonotopicity preferentially enhance neural responses to noise in noisy speech. These results provide mechanistic insights into everyday-communication challenges created by hearing loss.
Extracting physical characteristics of higher-order chromatin structures from 3D image data
Authors: Lamberti William Franz , Zang Chongzhi
Published: March 2022

Abstract

Higher-order chromatin structures have functional impacts on gene regulation and cell identity determination. Using high-throughput sequencing (HTS)-based methods like Hi-C, active or inactive compartments and open or closed topologically associating domain (TAD) structures can be identified on a cell population level. Recently developed high-resolution three-dimensional (3D) molecular imaging techniques such as 3D electron microscopy with in situ hybridization (3D-EMSIH) and 3D structured illumination microscopy (3D-SIM) enable direct detection of physical representations of chromatin structures in a single cell. However, computational analysis of 3D image data with explainability and interpretability on functional characteristics of chromatin structures is still challenging. We developed Extracting Physical-Characteristics from Images of Chromatin Structures (EPICS), a machine-learning based computational method for processing high-resolution chromatin 3D image data. Using EPICS on images produced by 3D-EMISH or 3D-SIM techniques, we generated more direct 3D representations of higher-order chromatin structures, identified major chromatin domains, and determined the open or closed status of each domain. We identified several high-contributing features from the model as the major physical characteristics that define the open or closed chromatin domains, demonstrating the explainability and interpretability of EPICS. EPICS can be applied to the analysis of other high-resolution 3D molecular imaging data for spatial genomics studies. The R and Python codes of EPICS are available athttps://github.com/zang-lab/epics.
Gene mutations and molecular evolution of the chikungunya virus E1 and E2 from 2014 to 2019
Authors: Li Xiaoxia , Li Xinyue , Liu Jinyue , Liang Song , Chen Hanzong , Ke Changwen , Wan Chengsong
Published: March 2022

Chikungunya virus (CHIKV), a mosquito-borne Alphavirus, is the etiological agent of chikungunya fever. To investigate the prevalence and genetic characteristics of CHIKV in China, we performed a molecular epidemiological study during the 2014–2019 period. Phylogenetic analysis of CHIKV in the 2014-2019 shows that it is currently clustered geographically, which means that CHIKV’s local adaptability is gradually strengthening. Focusing on CHIKV adaptive mutation E1-A226V is not obvious in our study. The CHIKV E1 amino acid non-synonymous mutation results revealed the common mutation site M343I. Most mutation sites belong to the American epidemic strains, and the mutation rate is 2.8%. In 31 sequences, 19 non-synonymous mutations were found in CHIKV E1 (total mutation rate 20/499 = 4%), and 37 non-synonymous mutations in CHIKV E2 (total mutation rate 30/425 = 7%). It is worth noting that the mutation of CHIKV E2 has changed more than that of CHIKV E1 between 2014 and 2019. CHIKV E2 screened out common mutation sites, and the results showed that there are five common mutation sites, namely S119G, L182M, G206D, S300N, and A345T. Eighty-three percent of the CHIKV E2 receptor binding domain mutations in the American strains, namely T3I and N6H, may cause immune escape.

We constructed a new luciferase immunosorbent assay using CHIKV E2 antigen and mutant E2 antigen to test the serum of the CHIKV infected patients, and the detected samples and dilution ratios were different. The T3I, N6H, S119G, L182M, G206D, S300N, and A345T mutations in CHIKV E2 could explain these differences between patients.

IMPORTANCE

CHIKV originated in Africa more than 500 years ago, with a common lineage dividing into two distinct branches called West Africa (West African, WA) and East/Central/South Africa (East/Central/South African, ECSA). Moreover, the E1-A226V mutation enhanced the replication and transmission capacity of CHIKV in Aedes albopictus. However, it should be noted that E1-A226V does not explain the CHIKV epidemic that has occurred in the Americas in recent years. We analyzed CHIKV samples in the 2014-2019, and the results showed that the mutation of CHIKV E1 protein occurred was not mainly concentrated in E1-A226V, but concentrated in M343I. This also means that CHIKV constantly mutates in the natural environment and is formed under natural conditions. Analysis of the common mutation sites of CHIKV E2 showed that there were seven common mutation sites S119G/L182M/ G206D /S300N/A345T, and the new mutation of CHIKV E2 may affect serological antibody detection.
Spatially constrained ICA enables robust detection of schizophrenia from very short resting-state fMRI data
Authors: Duda Marlena , Iraji Armin , Ford Judith M. , Lim Kelvin O. , Mathalon Daniel H. , Mueller Bryon A. , Potkin Steven G. , Preda Adrian , Van Erp Theo G.M. , Calhoun Vince D.
Published: March 2022

Resting-state functional network connectivity (rsFNC) has shown utility for identifying characteristic functional brain patterns in individuals with psychiatric and mood disorders, providing a promising avenue for biomarker development. However, several factors have precluded widespread clinical adoption of rsFNC diagnostics, namely a lack of standardized approaches for capturing comparable and reproducible imaging markers across individuals, as well as the disagreement on the amount of data required to robustly detect intrinsic connectivity networks (ICNs) and diagnostically relevant patterns of rsFNC at the individual subject level. Recently, spatially constrained independent component analysis (scICA) has been proposed as an automated method for extracting ICNs standardized to a chosen network template while still preserving individual variation. Leveraging the novel scICA methodology, which solves the former challenge of standardized neuroimaging markers, we investigate the latter challenge of identifying a minimally sufficient data length for clinical applications of resting-state fMRI (rsfMRI). Using a dataset containing individuals with schizophrenia and controls (M = 310) as well as simulated rsfMRI, we evaluate the robustness of ICN and rsFNC estimates at both the subject- and group-level, as well as the performance of diagnostic classification, with respect to the length of the rsfMRI time course. We found individual estimates of ICNs and rsFNC from the full-length (5 minute) reference time course were sufficiently approximated with just 3-3.5 minutes of data (r = 0.85, 0.88, respectively), and significant differences in group-average rsFNC could be sufficiently approximated with even less data, just 2 minutes (r = 0.86). The results from the shorter clinical data were consistent with the results from the longer simulated data, reliably estimating both individual- and group-level metrics from the full-length (30 minute) reference with just 3-4 minutes of data (r = 0.85 - 0.88). Furthermore, we found a model trained on 2 minutes of data retained 97-98% classification accuracy relative to that of the full-length reference model. Our results suggest that clinical rsfMRI scans, when decomposed with scICA, could potentially be shortened to just 2-4 minutes without significant loss of individual rsFNC information or classification performance of longer scan lengths.
Suppression of de novo antibody responses against SARS-CoV2 and the Omicron variant after mRNA vaccination and booster in patients with B cell malignancies undergoing active treatment, but maintenance of pre-existing antibody levels against endemic viruses
Authors: Azar Joseph , Evans John P. , Sikorski Madison , Chakravarthy Karthik , McKenney Selah , Carmody Ian , Zeng Cong , Teodorescu Rachael , Song No Joon , Hamon Jamie , Bucci Donna , Velegraki Maria , Bolyard Chelsea , Weller Kevin P. , Reisinger Sarah , Bhat Seema A. , Maddocks Kami J. , Gumina Richard J. , Vlasova Anastasia N. , Oltz Eugene M. , Saif Linda J. , Chung Dongjun , Woyach Jennifer A. , Shields Peter G. , Liu Shan-Lu , Li Zihai , Rubinstein Mark P.
Published: March 2022

The impact of SARS-CoV2 vaccination in cancer patients remains incompletely understood given the heterogeneity of cancer and cancer therapies. We assessed vaccine-induced antibody response to the SARS-CoV2 Omicron (B.1.1.529) variant in 57 patients with B cell malignancies with and without active B cell-targeted therapy. Ancestral- and Omicron-reactive antibody levels were determined by ELISA and neutralization assays. In over one third of vaccinated patients at the pre-booster timepoint, there were no ELISA-detectable antibodies against either the ancestral strain or Omicron variant. The lack of vaccine-induced antibodies was predominantly in patients receiving active therapy such as anti-CD20 monoclonal antibody (mAb) or Bruton’s tyrosine kinase inhibitors (BTKi). While booster immunization was able to induce detectable antibodies in a small fraction of seronegative patients, the benefit was disproportionately evident in patients not on active therapy. Importantly, in patients with post-booster ELISA-detectable antibodies, there was a positive correlation of antibody levels against the ancestral strain and Omicron variant. Booster immunization increased overall antibody levels, including neutralizing antibody titers against the ancestral strain and Omicron variant; however, predominantly in patients without active therapy. Furthermore, ancestral strain neutralizing antibody titers were about 5-fold higher in comparison with those to Omicron, suggesting that even with booster administration, there may be reduced protection against the Omicron variant. Interestingly, in almost all patients regardless of active therapy, including those unable to generate detectable antibodies against SARS-CoV2 spike, we observed comparable levels of EBV, influenza, and common cold coronavirus reactive antibodies demonstrating that B cell-targeting therapies primarily impair de novo but not pre-existing antibody levels. These findings suggest that patients with B cell malignancies on active therapy may be at disproportionately higher risk to new versus endemic viral infection and suggest utility for vaccination prior to B cell-targeted therapy.
Characteristics of mental health stability during COVID-19: An online survey with people residing in the Liverpool City Region
Authors: Gomez Katalin Ujhelyi , Corcoran Rhiannon , Ring Adele , Hassan Shaima , Abba Katherine , Downing Jennifer , Goodall Mark , Gabbay Mark , Clarke Pam , Moran Paul , Obe Dorcas Akeju , Bennett Kate M
Published: March 2022

Background and aim

Despite the significant mental health challenges the COVID-19 pandemic and its associated government measures have presented, research have shown that the majority of people have adapted and coped well. The aim of this study was i) to determine the proportion of people with mental stability and volatility during the pandemic in a North West urban environment sample and ii) to establish group differences in psychosocial variables. Mental stability and volatility refer to the extent to which individuals reported change in levels of common mental health symptoms over the course of 12 weeks.

Method

a two-wave-online survey (N = 163) was used to explore the psychological and social impact of the pandemic on relatively disadvantaged neighbourhoods within the Liverpool City Region over 12 weeks. Kruskal-Wallis with post-hoc tests were used to determine how people with mental stability and volatility differed on factors categorised within an ecological framework of resilience (individual, community, societal, and COVID-19 specific).

Results

Individuals categorised as ‘stable’ in terms of mental health symptoms (63.6%) had better mental and physical health; were more tolerant of uncertainty; reported higher levels of resilience and wellbeing compared to ‘very volatile’ people (19.8%). These individuals also reported feeling less socially isolated, experienced a greater sense of belonging to their community which was more likely to fulfil their needs, and were more likely to have access to green space nearby for their recommended daily exercise. ‘Stable’ individuals did not report worrying any more during the pandemic than usual and tolerated uncertainty better compared to those in the ‘volatile’ group.

Implications

The majority of participants in this sample were mentally stable and coping well with the challenges presented by the pandemic. The resilience of these individuals was related to key place-based factors such as a strong sense of community and useable local assets. The data showcase the role of place-based social determinants in supporting resilience and thereby highlight key preventative measures for public mental health during times of international crisis.
Protection of prior natural infection compared to mRNA vaccination against SARS-CoV-2 infection and severe COVID-19 in Qatar
Authors: Chemaitelly Hiam , Ayoub Houssein H. , AlMukdad Sawsan , Coyle Peter , Tang Patrick , Yassine Hadi M. , Al-Khatib Hebah A. , Smatti Maria K. , Hasan Mohammad R. , Al-Kanaani Zaina , Al-Kuwari Einas , Jeremijenko Andrew , Kaleeckal Anvar Hassan , Latif Ali Nizar , Shaik Riyazuddin Mohammad , Abdul-Rahim Hanan F. , Nasrallah Gheyath K. , Al-Kuwari Mohamed Ghaith , Butt Adeel A. , Al-Romaihi Hamad Eid , Al-Thani Mohamed H. , Al-Khal Abdullatif , Bertollini Roberto , Abu-Raddad Laith J.
Published: March 2022

BACKGROUND

Protection conferred by natural SARS-CoV-2 infection versus COVID-19 vaccination has not been investigated in rigorously controlled studies. We compared head-to-head protection conferred by natural infection to that from the BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) vaccines in Qatar, between February 28, 2020 and March 6, 2022.

METHODS

Two national matched retrospective target-trial cohort studies were conducted to compare incidence of SARS-CoV-2 infection and COVID-19 hospitalization and death among those with a documented primary infection to incidence among those with a two-dose primary-series vaccination. Associations were estimated using Cox proportional-hazards regression models.

RESULTS

The overall adjusted hazard ratio (AHR) for infection was 0.46 (95% CI: 0.45-0.48) comparing those with a prior infection to those vaccinated with BNT162b2, and 0.51 (95% CI: 0.48-0.53) comparing those with a prior infection to those vaccinated with mRNA-1273. For BNT162b2, the AHR decreased gradually from 0.55 (95% CI: 0.46-0.65) in the fourth month after primary infection/vaccination to 0.31 (95% CI: 0.27-0.37) in the eighth month, while for mRNA-1273, it decreased from 0.80 (95% CI: 0.59-1.07) to 0.35 (95% CI: 0.29-0.41) over the same time period. During the Omicron wave, the AHR was ∼0.50 for BNT162b2 and ∼0.60 for mRNA-1273. The overall AHR for any severe, critical, or fatal COVID-19 (against all variants) was 0.32 (95% CI: 0.10-1.00) for BNT162b2, and 0.58 (95% CI: 0.14-2.43) for mRNA-1273.

CONCLUSIONS

Natural infection was associated with stronger and more durable protection against infection, regardless of the variant, than mRNA primary-series vaccination. Nonetheless, vaccination remains the safest and optimal tool of protection against infection and COVID-19 hospitalization and death.
Ubiquitous lognormal distribution of neuron densities in mammalian cerebral cortex
Authors: Morales-Gregorio Aitor , van Meegen Alexander , van Albada Sacha J.
Published: March 2022

Numbers of neurons and their spatial variation are fundamental organizational features of the brain. Despite the large corpus of cytoarchitectonic data available in the literature, the statistical distributions of neuron densities within and across brain areas remain largely uncharacterized. Here, we show that neuron densities are compatible with a lognormal distribution across cortical areas in several mammalian species, and find that this also holds true within cortical areas. A minimal model of noisy cell division, in combination with distributed proliferation times, can account for the coexistence of lognormal distributions within and across cortical areas. Our findings uncover a new organizational principle of cortical cytoarchitecture: the ubiquitous lognormal distribution of neuron densities, which adds to a long list of lognormal variables in the brain.
Gene Co-expression Connectivity Predicts Gene Targets Underlying High Ionic Liquid Tolerance in Yarrowia lipolytica
Authors: Walker Caleb , Ryu Seunghyun , Garcia Sergio , Dooley David , Mendoza Brian , Trinh Cong T.
Published: March 2022

Microbial tolerance to organic solvents such as ionic liquids (ILs) is a robust phenotype beneficial for novel biotransformation. While most microbes become inhibited in 1%-5% (v/v) IL (e.g., 1-ethyl-3-methylimidazolium acetate), we engineered a robust Yarrowia lipolytica (YlCW001) that tolerates a record high of 18% (v/v) IL via adaptive laboratory evolution. Yet, genotypes conferring high IL tolerance in YlCW001 remain to be discovered. Using dynamic RNA-Seq data, we shed light on the underlying cellular processes that Y. lipolytica responds to IL. We introduced Gene Co-expression Connectivity (GeCCo) to discover genotypes conferring desirable phenotypes that might not be found by the conventional differential expression (DE) approaches. GeCCo selects genes based on their number of co-expressed genes in a sub-network of upregulated genes by the target phenotype. We experimentally validated GeCCo by reversely engineering high IL-tolerant phenotype in wildtype Y. lipolytica. We found that gene targets selected by both DE and GeCCo exhibited the best statistical chance at increasing IL tolerance when individually overexpressed. Remarkably, the best combination of dual-overexpressed genes were genes selected by GeCCo alone. This non-intuitive combination of genes, BRN1 and OYE2, are involved in guiding/regulating mitotic cell division, chromatin segregation/condensation, microtubule and cytoskeletal organization, and Golgi vesicle transport.
Spatial transcriptomics reveal markers of histopathological changes in Duchenne muscular dystrophy mouse models
Authors: Heezen L.G.M. , Abdelaal T. , van Putten M. , Aartsma-Rus A. , Mahfouz A. , Spitali P.
Published: March 2022

Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, leading to lack of dystrophin. Chronic muscle damage eventually leads to histological alterations in skeletal muscles. The identification of genes and cell types driving tissue remodeling is a key step to develop effective therapies. Here we use spatial transcriptomics in two DMD mouse models differing in disease severity to identify gene expression signatures underlying skeletal muscle pathologies and directly link this to the muscle histology. Deconvolution analysis allowed the identification of cell types contributing to histological alterations. We show how the expression of specific genes is enriched in areas of muscle regeneration (Myl4, Sparc, Hspg2), fibrosis (Vim, Fn1, Thbs4) and calcification (Bgn, Ctsk, Spp1). Finally, our analysis of differentiation dynamics in the severely affected D2-mdx muscle shows a subset of the muscle fibers are predicted to become affected in its future state. Genes associated with tissue remodeling could enable to design new diagnostic and therapeutic strategies for DMD.
Stability of asymmetric cell division under confinement: A deformable cell model of cytokinesis applied to C. elegans development
Authors: Cuvelier Maxim , Thiels Wim , Jelier Rob , Smeets Bart
Published: March 2022

Cell division during early embryogenesis has been linked to key morphogenic events such as embryo symmetry breaking and tissue patterning. It is thought that boundary conditions together with cell intrinsic cues act as a mechanical “mold”, guiding cell division to ensure these events are more robust. We present a novel computational mechanical model of cytokinesis, the final phase of cell division, to investigate how cell division is affected by mechanical and geometrical boundary conditions. The model reproduces experimentally observed furrow dynamics and predicts the volume ratio of daughter cells in asymmetric cell divisions based on the position and orientation of the mitotic spindle. We show that the orientation of confinement relative to the division axis modulates the volume ratio in asymmetric cell division and quantified the mechanical contribution of cortex mechanics, relative to the mechanical properties of the furrow ring. We apply this model to early C. elegans development, which proceeds within the confines of an eggshell, and simulate the formation of the three body axes via sequential (a)symmetric divisions up until the six cell stage. We demonstrate that spindle position and orientation alone can be used to predict the volume ratio of daughter cells during the cleavage phase of development. However, for compression perturbed egg geometries, the model predicts that the change in confinement alone is insufficient to explain experimentally observed differences in cell volume, inferring an unmodeled underlying spindle positioning mechanism. Finally, the model predicts that confinement stabilizes asymmetric cell divisions against bubble-instabilities, which can arise due to elevated mitotic cortical tension.

Author summary

A crucial morphogenic step during early embryonic development is symmetry breaking in the embryo. For C. elegans the formation of the three body axes can be traced back to the six cell stage, where tissue-topology is the result of symmetric and asymmetric divisions. How cell mechanical boundary conditions and cell intrinsic cues influence this process of symmetry breaking is still an open question, as currently, a quantitative mechanical description of cytokinesis in complex architectures is lacking. We developed a simple mechanical model of cell division, incorporated in an existing mechanical cortex model, to simulate cytokinesis in geometrically confined environments. Our approach was able to both capture furrow ring dynamics and predict the volume ratio of daughter cells accurately. By simulating early C. elegans development with different geometrical boundary conditions, we were able to trace back the origin of volume discrepancies between the experimental setups to a quantifiable shift in spindle positioning during cytokinesis. Finally, we showed how embryo confinement partially stabilizes bubble-instabilities that arise during asymmetric cell division during the early cleavage phase.
The combination of Hebbian and predictive plasticity learns invariant object representations in deep sensory networks
Authors: Halvagal Manu Srinath , Zenke Friedemann
Published: March 2022

Discriminating distinct objects and concepts from sensory stimuli is essential for survival. Our brains accomplish this feat by forming disentangled internal representations in deep sensory networks shaped through experience-dependent synaptic plasticity. To elucidate the principles that underlie sensory representation learning, we derive a local plasticity model that shapes latent representations to predict future activity. This Latent Predictive Learning (LPL) rule conceptually extends Bienenstock-Cooper-Munro (BCM) theory by unifying Hebbian plasticity with predictive learning. We show that deep neural networks equipped with LPL develop disentangled object representations without supervision. The same rule accurately captures neuronal selectivity changes observed in the primate inferotemporal cortex in response to altered visual experience. Finally, our model generalizes to spiking neural networks and naturally accounts for several experimentally observed properties of synaptic plasticity, including metaplasticity and spike-timing-dependent plasticity (STDP). We thus provide a plausible normative theory of representation learning in the brain while making concrete testable predictions.
Inducible depletion of Scleraxis-lineage cells during tendon healing impairs multi-scale restoration of tendon structure
Authors: Korcari Antonion , Muscat Samantha , Buckley Mark R. , Loiselle Alayna E.
Published: March 2022

Tendons are composed of a heterogeneous cell environment, with Scleraxis-lineage (ScxLin) cells being the predominant population. Although ScxLin cells are required for maintenance of tendon homeostasis, their functions during tendon healing are unknown. To this end, we first characterized the spatiotemporal dynamics of ScxLin cells during tendon healing, and identified that the overall ScxLin pool continuously expands up to early remodeling healing phase. To better define the function of ScxLin cells during the late proliferative phase of healing, we inducibly depleted ScxLin cells from day 14-18 post-surgery using the Scx-Cre; Rosa-DTR mouse model, with local administration of diphtheria toxin inducing apoptosis of ScxLin cells in the healing tendon. At D28 post-surgery, ScxLin cell depleted tendons (DTR) had substantial impairments in structure and function, relative to WT, demonstrating the importance of ScxLin cells during tendon healing. Next, bulk RNAseq was utilized to identify the underlying mechanisms that were impaired with depletion and revealed that ScxLin depletion induced molecular and morphological stagnation of the healing process at D28. However, this stagnation was transient, such that by D56 tendon mechanics in DTR were not significantly different than wildtype repairs. Collectively, these data offer fundamental knowledge on the dynamics and roles of ScxLin cells during tendon healing.
Prefrontal PV interneurons facilitate attention and are linked to attentional dysfunction in a mouse model of absence epilepsy
Authors: Ferguson Brielle R. , Huguenard John R.
Published: March 2022

Absence seizures are characterized by brief periods of unconsciousness accompanied by a lapse in motor function that can occur hundreds of times throughout the day. Outside of these frequent moments of unconsciousness, approximately a third of patients experience treatment-resistant attention impairments. Convergent evidence suggests prefrontal cortex (PFC) dysfunction may underlie attention impairments in affected patients. To test this, we use a combination of slice physiology, fiber photometry, electrocorticography (ECoG), optogenetics, and behavior in theScn8a+/−mouse model of absence epilepsy. In these mice, we find decreased parvalbumin interneuron (PVIN) recruitment in the medial PFC (mPFC)in vitroand hypoactivity during cue presentationin vivothat is linked to attention dysfunction. Further, we find that low levels of mPFC PVIN activity are predictive of poorer performance in WT littermates. This highlights cue-evoked PVIN activity as an important mechanism for attention and suggests PVINs may represent a therapeutic target for cognitive comorbidities in absence epilepsy.
Computational Study of Ion Permeation Through Claudin-4 Paracellular Channels
Authors: Berselli Alessandro , Alberini Giulio , Benfenati Fabio , Maragliano Luca
Published: March 2022

Claudins (Cldns) form a large family of protein homologs that are essential for the assembly of paracellular tight junctions (TJs), where they form channels or barriers with tissue-specific selectivity for permeants. In contrast to several family members whose physiological role has been identified, the function of claudin 4 (Cldn4) remains elusive, despite experimental evidence suggesting that it can form anion-selective TJ channels in the renal epithelium. Computational approaches have recently been employed to elucidate the molecular basis of Cldns’ function, and hence could help in clarifying Cldn4 role. In this work, we use structural modeling and all-atom molecular dynamics simulations to transfer two previously introduced structural models of Cldn-based paracellular complexes to Cldn4, in order to reproduce a paracellular anion channel. Free energy (FE) calculations for ionic transport through the pores allow us to establish the thermodynamic properties driving the ion-selectivity of the structures. While one model shows a cavity permeable to chloride and repulsive to cations, the other forms barrier to the passage of all the major physiological ions. Furthermore, our results confirm the charge selectivity role of the residue Lys65 in the first extracellular loop of the protein, rationalizing Cldn4 control of paracellular permeability.