bluuebunny/crossref_metadata_2025 huggingface dataset:
Critical success factors for high routine immunization performance: A case study of Senegal
Authors: Sakas Zoe , Hester Kyra A. , Rodriguez Katie , Diatta Saly Amos , Ellis Anna S. , Gueye Daouda Malick , Matapano Dawn , Mboup Pr Souleymane , Ogutu Emily Awino , Yang Chenmua , Bednarczyk Robert A. , Freeman Matthew C. , Sarr Moussa ,   the Vaccine Exemplars Research Consortium
Published: January 2022

BACKGROUND

The essential components of a vaccine delivery system are well-documented, but robust evidence is lacking on how policies and implementation strategies are operationalized to drive catalytic improvements in coverage. To address this gap, we identified success factors that supported improvements in routine immunization coverage in Senegal, especially from 2000 to 2019.

METHODS

We identified Senegal as an exemplar in the delivery of childhood vaccines through analysis of DTP1 and DTP3 coverage data. Through interviews and focus group discussions at the national, regional, district, health facility, and community-level, we investigated factors that contributed to high and sustained vaccination coverage. We conducted a thematic analysis through application of implementation science frameworks to determine critical success factors. We triangulated these findings with quantitative analyses using publicly available data.

RESULTS

The following success factors emerged: 1) Strong political will and prioritization of resources for immunization programming supported urgent allocation of funding and supplies; 2) Collaboration between the Ministry of Health and Social Action and external partners fostered innovation, capacity building, and efficiency; 3) Improved surveillance, monitoring, and evaluation allowed for timely and evidence-based decision making; 4) Community ownership of vaccine service delivery supported tailored programming and quick response to local needs; and 5) Community health workers spearheaded vaccine promotion and demand generation for vaccines.

CONCLUSION

The vaccination program in Senegal was supported by evidence-based decision making at the national-level, alignment of priorities between governmental entities and external partners, and strong community engagement initiatives that fostered local ownership of vaccine delivery and uptake. High routine immunization coverage was likely driven by prioritization of immunization programming, improved surveillance systems, a mature and reliable community health worker program, and tailored strategies for addressing geographical, social, and cultural barriers.
Acceptability and preliminary effectiveness of a remote dementia educational training among healthcare professionals
Authors: Perales-Puchalt Jaime , Townley Ryan , Niedens Michelle , Vidoni Eric D , Greiner K Allen , Zufer Tahira , Schwasinger-Schmidt Tiffany , McGee Jerrihlyn L , Arreaza Hector , Burns Jeffrey M
Published: January 2022

Background

Optimal care for families living with Alzheimer’s disease and related disorders (ADRD) has the potential to improve their lives. However, ADRD care remains under-implemented among healthcare professionals, partly due to professionals’ limited ADRD training and inexperience. Professional training might help, but most training is in person, time-intensive, and does not focus on the potential of early detection, client empowerment, and cultural competency. We aimed to explore the acceptability and preliminary effectiveness of an online ADRD training, The Dementia Update Course, which addressed these issues. We hypothesized that the Dementia Update Course would lead to increased levels of perceived ADRD care competency among healthcare professionals.

Methods

This was a mixed-methods research design using pre-post training assessments. The training included 59 primary care providers (PCPs) and other healthcare professionals (e.g., medical specialists, nurses, social workers). The Dementia Update Course was a remote 6.5-hour training that included didactic lectures, case discussion techniques, and materials on ADRD detection and care. Outcomes included two 5-point Likert scales on acceptability, eleven on perceived dementia care competency, and the three subscales of the General Practitioners Confidence and Attitude Scale for Dementia. We used paired samples t-tests to assess the mean differences in all preliminary effectiveness outcomes.

Results

The training included 18.0% of professionals that self-identified as non-White or Latino and 37.7% of professionals who served in rural areas. Most participants (90.0% and 87.5%) reported a high likelihood to recommend the training and high satisfaction respectively. All preliminary effectiveness outcomes analyzed in the total sample experienced a statistically significant improvement from pre- to post-training averaging 0.7 points in 1-5 scales (p<0.05). Most outcomes improved statistically among PCPs too.

Conclusions

A relatively brief, remote, and inclusive ADRD training led to high levels of acceptability and improved perceived ADRD care competency among PCPs and other healthcare professionals. Future research should include a control group and assess guideline compliance, behavioral outcomes, and health outcomes among people with ADRD and their families.
Clinical experience with paliperidone palmitate in a specialty hospital in the Philippines: A short report
Authors: Alinea Amadeo A. , Antonio Carl Abelardo T. , Bermudez Amiel Nazer C. , Cochon Kim L. , Martinez Maria Fatima V. , Guevarra Jonathan P.
Published: January 2022

Objective

To describe the clinical outcomes related to the introduction of paliperidone palmitate in a specialty hospital in the Philippines

Design

Cross-sectional study among patients seen at the psychiatry service of a specialty hospital catering to veterans who were initiated on paliperidone palmitate. We reviewed and abstracted baseline patient data from the medical record of eligible patients. Outcome of treatment was collected through a one-time objective assessment of the patient by a third-party psychiatrist using the Structured Clinical Interview for Symptoms of Remission (SCI-SR) tool.

Main Result

A total of 30 patients were recruited for the study from August 2020 and June 2021, the majority of whom were males (80%), residents of the National Capital Region (50%), and single (20%). The median duration from schizophrenia diagnosis to initiation of paliperidone treatment was 19.50 years (IQR: 16.60 – 33.50). In eight patients (22.67%), other antipsychotic drugs were discontinued following initiation of paliperidone treatment; in the remaining 22 participants (73.33%), paliperidone was taken concurrently with other antipsychotic drugs. The median duration from the initiation of paliperidone treatment to follow-up assessment was 27.20 months (IQR: 24.73 – 30.50), with all participants having at least 6 months of treatment. At follow-up assessment, all participants were classified to be in remission.

Conclusion

In this study among patients with schizophrenia seen in a specialty hospital in the Philippines, we found evidence that clinical outcomes with paliperidone palmitate were comparable to those given a combination of oral and long-acting antipsychotics.
A rigorous and versatile statistical test for correlations between time series
Authors: Yuan Alex E. , Shou Wenying
Published: January 2022

In disciplines from biology to climate science, a routine task is to compute a correlation between a pair of time series, and determine whether the correlation is statistically significant (i.e. unlikely under the null hypothesis that the time series are independent). This problem is challenging because time series typically exhibit autocorrelation, which cannot be properly analyzed with the standard iid-oriented statistical tests. Although there are well-known parametric tests for time series, these are designed for linear correlation statistics and thus not suitable for the increasingly popular nonlinear correlation statistics. Among nonparametric tests, the conditions that guarantee correct false positive rates are either restrictive or unclear. Here we describe the truncated time-shift (TTS) test, a nonparametric procedure to test for dependence between two time series. We prove that this test is valid as long as one of the time series is stationary, a minimally restrictive requirement among current tests. The TTS test is versatile because it can be used with any correlation statistic. Using synthetic data, we demonstrate that this test performs correctly even while other tests suffer high false positive rates. In simulation examples, simple guidelines for parameter choices allow high statistical power to be achieved with sufficient data. We apply the test to data sets from climatology, animal behavior and microbiome science, verifying previously discovered dependence relationships and detecting additional relationships.
A universal insect trait tool (ITT, v1.0) for statistical analysis and evaluation of biodiversity research data
Authors: Hörren Thomas , Sorg Martin , Hallmann Caspar A. , Zizka Vera M. A. , Ssymank Axel , Noll Niklas W. , Schäffler Livia , Scherber Christoph
Published: January 2022

We present a unique data set of trait information for 586 insect families in Central Europe, covering the largest known part of described species (over 34,000 species). Life history information and major functional traits were evaluated with fuzzy coding and weighted according to the number of known species in Germany. An overall analysis of the German insect fauna is given and the data set is exemplarily applied to metabarcoding results of malaise trap samples. Due to the high functional and taxonomic diversity in insects, further developments and refinements of traits to be included will be an ongoing process with advancements of upcoming database versions to be subsequently published.
Grandmaternal allergen exposure causes distinct epigenetic trajectories in offspring associated with airway hyperreactivity and inflammation
Authors: Lebold Katie M. , Cook Madeline , Pincus Alexandra B. , Nevonen Kimberly A. , Davis Brett A. , Carbone Lucia , Calco Gina N. , Fryer Allison D. , Jacoby David B. , Drake Matthew G.
Published: January 2022

Maternal asthma increases childhood asthma risk through multiple mechanisms including epigenetic regulation of asthma-associated genes. DNA methylation is one form of epigenetic regulation that is both inherited and modified by environmental exposures throughout life. In this study, we tested whether grandmaternal house dust mite (HDM) allergen exposure altered airway physiology and inflammation, as well as DNA methylation in both airway epithelium and airway sensory neurons of second-generation offspring. Grandmaternal allergen exposure induced a limited number of epigenetic changes in offspring at baseline that were not associated with increased airway reactivity or inflammation. In contrast, grandmaternal allergen exposure significantly altered offspring’s response to HDM sensitization and challenge, inducing airway hyperreactivity to inhaled serotonin, increased airway inflammation, and potentiated DNA methylation. Gene sequences susceptible to methylation after allergen sensitization, and their corresponding biological processes and enriched pathways, were unique in offspring from HDM-exposed founders, indicating that grandmaternal allergen exposure established an epigenetic trajectory in offspring at birth that directed epigenetic and physiologic responses to subsequent allergen sensitization and challenge, contributing to inheritance of asthma risk.

Grandmaternal allergen exposure establishes an intergenerational, tissue-specific epigenetic trajectory in offspring at birth, which uniquely directs responses to allergen sensitization and challenge later in life and contributes to inheritance of asthma risk.
Loss of the intracellular enzyme QPCTL limits chemokine function and reshapes myeloid infiltration to augment tumor immunity
Authors: Barreira da Silva Rosa , Leitão Ricardo , Pechuan Ximo , Werneke Scott , Oeh Jason , Javinal Vincent , Wang Yingyun , Phung Wilson , Everett Christine , Nonomiya Jim , Arnott David , Lu Cheng , Hsiao Yi-Chun , Koerber James T. , Hotzel Isidro , Ziai James , Modrusan Zora , Pillow Thomas , Roose-Girma Meron , Schartner Jill M. , Merchant Mark , Rutz Sascha , Eidenschenk Céline , Mellman Ira , Albert Matthew L.
Published: January 2022

Tumor-associated macrophages are composed of distinct populations arising from monocytes or tissue macrophages, with a poorly understood link to disease pathogenesis. Here, we demonstrate that mouse monocyte migration was supported by glutaminyl-peptide cyclotransferase-like (QPCTL), an enzyme that mediates N-terminal modification of several subtrates, including the monocyte-chemoattractants CCL2 and CCL7, protecting them from proteolytic inactivation. Knockout of Qpctl disrupted monocyte homeostasis, attenuated tumor growth and reshaped myeloid cell infiltration, with loss of monocyte-derived populations with immunosuppressive and pro-angiogenic profiles. Antibody blockade of the receptor CSF1R, which more broadly eliminates tissue macrophages, reversed tumor growth inhibition in Qpctl−/− mice, and prevented lymphocyte infiltration. Modulation of QPCTL synergized with anti-PD-L1 to expand CD8+ T cells and limit tumor growth. QPCTL inhibition constitutes an effective approach for myeloid cell-targeted cancer immunotherapy.
The ALT pathway generates telomere fusions that can be detected in the blood of cancer patients
Authors: Muyas Francesc , Gómez Rodriguez Manuel José , Cortes-Ciriano Isidro , Flores Ignacio
Published: January 2022

Telomere fusions (TFs) can trigger the accumulation of diverse genomic rearrangements and the acquisition of oncogenic alterations leading to malignant transformation and resistance to chemotherapy. Despite their relevance in tumour evolution, our understanding of the patterns and consequences of TFs in human cancer remains limited. Here, we have characterized the rates and spectrum of somatic TFs across >30 cancer types using whole-genome sequencing data. TFs are pervasive in human tumours with rates varying markedly across and within cancer types. In addition to end-to-end fusions, we find novel patterns of TFs that we mechanistically link to the activity of the alternative lengthening of telomeres (ALT) pathway. We show that TFs can be detected in the blood of cancer patients, which enables cancer detection with high specificity and sensitivity even for early-stage tumours and cancer types for which early detection remains a high unmet clinical need, such as pancreatic cancer and brain tumours. Overall, we report a novel genomic footprint that enables characterization of the telomere maintenance mechanism of tumours and liquid biopsy analysis, which has implications for early detection, prognosis, and treatment selection.
Variation and impact of polygenic hematological traits in monogenic sickle cell disease
Authors: Pincez Thomas , Lo Ken Sin , Pham Hung d’Alexandry d’Orengiani Anne-Laure , Garrett Melanie E. , Brugnara Carlo , Ashley-Koch Allison E. , Telen Marilyn J. , Galactéros Frédéric , Joly Philippe , Bartolucci Pablo , Lettre Guillaume
Published: January 2022

Several complications observed in sickle cell disease (SCD) are influenced by variation in hematological traits (HT), such as fetal hemoglobin (HbF) level and neutrophil count. Previous large-scale genome-wide association studies carried out in largely healthy individuals have identified 1000s of variants associated with HT, which have then been used to develop multi-ancestry polygenic trait scores (PTS). Here, we tested if these PTS associate with HT in SCD patients and can improve the prediction of SCD-related complications. In 2,056 SCD patients, we found that the PTS predicted less HT variance than in non-SCD African-ancestry individuals. This was particularly striking at the Duffy/DARC locus, where we observed an epistatic interaction between the SCD genotype and the Duffy null variant (rs2814778) that led to a two-fold weaker effect on neutrophil count. PTS for these routinely measured HT were not associated with complications in SCD. In contrast, we found that a simple PTS for HbF that includes only six variants explained a large fraction of the phenotypic variation (17.1-26.4%), associated with acute chest syndrome and stroke risk, and improved the prediction of vaso-occlusive crises. Using Mendelian randomization, we found that increasing HbF by 4.8% reduces stroke risk by 36% (P = 0.0008). Taken together, our results highlight the importance of validating PTS in large diseased populations before proposing their implementation in the context of precision medicine initiatives.
Mucosal immunity against SARS-CoV-2 variants of concern including Omicron following vaccination
Authors: Tang Jinyi , Zeng Cong , Cox Thomas M. , Li Chaofan , Son Young Min , Cheon In Su , Wu Yue , Behl Supriya , Taylor Justin J. , Chakaraborty Rana , Johnson Aaron J. , Shiavo Dante N , Utz James P. , Reisenauer Janani S. , Midthun David E. , Mullon John J. , Edell Eric S. , Alameh Mohamad G. , Borish Larry , Kaplan Mark H. , Weissman Drew , Kern Ryan , Hu Haitao , Vassallo Robert , Liu Shan-Lu , Sun Jie
Published: January 2022

SARS-CoV-2 mRNA vaccination induces robust humoral and cellular immunity in the circulation; however, it is currently unknown whether it elicits effective immune responses in the respiratory tract, particularly against variants of concern (VOCs), including Omicron. We compared the SARS-CoV-2 S-specific total and neutralizing antibody (Ab) responses, and B and T cell immunity, in the bronchoalveolar lavage fluid (BAL) and blood of COVID-19 vaccinated individuals and hospitalized patients. Vaccinated individuals had significantly lower levels of neutralizing Ab against D614G, Delta and Omicron in the BAL compared to COVID-19 convalescents, despite robust S-specific Ab responses in the blood. Further, mRNA vaccination induced significant circulating S-specific B and T cell immunity, but in contrast to COVID-19 convalescents, these responses were absent in the BAL of vaccinated individuals. Using an animal immunization model, we demonstrate that systemic mRNA vaccination alone induced weak respiratory mucosal neutralizing Ab responses, especially against SARS-CoV-2 Omicron; however, a combination of systemic mRNA vaccination plus mucosal adenovirus-S immunization induced strong neutralizing Ab response, not only against the ancestral virus but also the Omicron variant. Together, our study supports the contention that the current COVID-19 vaccines are highly effective against severe disease development, likely through recruiting circulating B and T cell responses during re-infection, but offer limited protection against breakthrough infection, especially by Omicron. Hence, mucosal booster vaccination is needed to establish robust sterilizing immunity in the respiratory tract against SARS-CoV-2, including infection by Omicron and future variants.
Projected health impact of post-discharge malaria chemoprevention among children with severe malarial anaemia in Africa
Authors: Okell Lucy C , Kwambai Titus K. , Dhabangi Aggrey , Khairallah Carole , Nkosi-Gondwe Thandile , Opoka Robert , Mousa Andria , Kühl Melf-Jakob , Lucas Tim C. D. , Idro Richard , Weiss Daniel J. , Cairns Matthew , ter Kuile Feiko O , Phiri Kamija , Robberstad Bjarne , Mori Amani Thomas
Published: January 2022

Children recovering from severe malarial anaemia (SMA) remain at high risk of readmission and death after discharge from hospital. However, a recent trial found that post-discharge malaria chemoprevention (PDMC) reduces this risk. We developed a mathematical model describing the daily incidence of uncomplicated and severe malaria requiring readmission among 0-5 year-old children after hospitalised SMA. We fitted the model to a multicentre clinical PDMC trial using Bayesian methods. We then modelled the potential impact of PDMC across malaria-endemic African countries. In the 19 highest-burden countries, we estimate that only 2-5 children need to be given PDMC to prevent one hospitalised malaria episode, and less than 100 to prevent one death. If all hospitalised SMA cases access PDMC, 37,000 (range 16,000-84,000) malaria-associated readmissions could be prevented annually, depending on access to hospital care. We estimate that recurrent SMA post-discharge constitutes 18-29% of all SMA episodes in higher transmission settings.
Estimating the Effects of Legalizing Recreational Cannabis on Newly Incident Cannabis Use
Authors: Montgomery Barrett Wallace , Roberts Meaghan H. , Margerison Claire E. , Anthony James C.
Published: January 2022

Liberalized state-level recreational cannabis policies in the United States (US) fostered important policy evaluations with a focus on epidemiological parameters such as proportions [e.g., active cannabis use prevalence; cannabis use disorder (CUD) prevalence]. This cannabis policy evaluation project adds novel evidence on a neglected parameter – namely, estimated occurrence of newly incident cannabis use for underage (<21 years) versus older adults. The project’s study populations were specified to yield nationally representative estimates for all 51 major US jurisdictions, with probability sample totals of 819,543 non-institutionalized US civilian residents between 2008 and 2019. Standardized items to measure cannabis onsets are from audio computer-assisted self-interviews. Policy effect estimates are from event study difference-in-difference (DiD) models that allow for causal inference when policy implementation is staggered. The evidence indicates no policy-associated changes in the occurrence of newly incident cannabis onsets for underage persons, but an increased occurrence of newly onset cannabis use among older adults (i.e., >21 years). We offer a tentative conclusion of public health importance: Legalized cannabis retail sales might be followed by the increased occurrence of cannabis onsets for older adults, but not for underage persons who cannot buy cannabis products in a retail outlet. Cannabis policy research does not yet qualify as a mature science. We argue that modeling newly incident cannabis use might be more informative than the modeling of prevalences when evaluating policy effects and provide evidence of the advantages of the event study model over regression methods that seek to adjust for confounding factors.
Neanderthals did not likely consume Physcomitrium patens – a model moss species
Authors: Haas Fabian B. , Eisenhofer Raphael , Schreiber Mona , Weyrich Laura S. , Rensing Stefan A.
Published: January 2022

This manuscript is discussing the method of Weyrich et al., 2017, “Neanderthal behaviour, diet, and disease inferred from ancient DNA in dental calculus”. When studying the dietary profile of a Neanderthal specimen from El Sidrón cave (Spain) by sequencing ancient DNA present in calcified dental plaque (calculus) the authors identified a wide-range of potential food sources, including woolly rhinoceros, mushrooms, pine nuts, and moss – namely the less-than-abundant model species Physcomitrium patens. We doubted that Neanderthals were actually eating P. patens. By analyzing the ancient DNA reads using different mapping methods, we show likely a misinterpretation based on the previously used methods. The probability of Neanderthals eating P. patens is the same as eating rice or tomato. However, neither crop was grown in Europe at the time Neanderthals thrived.
A chromosome-level, fully phased genome assembly of the oat crown rust fungus Puccinia coronata f. sp. avenae: a resource to enable comparative genomics in the cereal rusts
Authors: Henningsen Eva C. , Hewitt Tim , Dugyala Sheshanka , Nazareno Eric S. , Gilbert Erin , Li Feng , Kianian Shahryar F. , Steffenson Brian J. , Dodds Peter N. , Sperschneider Jana , Figueroa Melania
Published: January 2022

Advances in sequencing technologies as well as development of algorithms and workflows have made it possible to generate fully phased genome references for organisms with non-haploid genomes such as dikaryotic rust fungi. To enable discovery of pathogen effectors and further our understanding of virulence evolution, we generated a chromosome-scale assembly for each of the two nuclear genomes of the oat crown rust pathogen, Puccinia coronata f. sp. avenae (Pca). This resource complements two previous released partially phased genome references of Pca, which display virulence traits absent in the isolate of historic race 203 (isolate Pca203) which was selected for this genome project. A fully phased, chromosome-level reference for Pca203 was generated using PacBio reads and Hi-C data and a recently developed pipeline named NuclearPhaser for phase assignment of contigs and phase switch correction. With 18 chromosomes in each haplotype and a total size of 208.10 Mbp, Pca203 has the same number of chromosomes as other cereal rust fungi such as Puccinia graminis f. sp. tritici and Puccinia triticina, the causal agents of wheat stem rust and wheat leaf rust, respectively. The Pca203 reference marks the third fully-phased chromosome-level assembly of a cereal rust to date. Here, we demonstrate that the chromosomes of these three Puccinia species are syntenous and that chromosomal size variations are primarily due to differences in repeat element content.
Temporal Optimization of Radiation Therapy to Heterogeneous Tumour Populations and Cancer Stem Cells
Authors: Meaney Cameron , Kohandel Mohammad , Novruzi Arian
Published: January 2022

External beam radiation therapy is a key part of modern cancer treatments which uses high doses of radiation to destroy tumour cells. Despite its widespread usage and extensive study in theoretical, experimental, and clinical works, many questions still remain about how best to administer it. Many mathematical studies have examined optimal scheduling of radiotherapy, and most come to similar conclusions. Importantly though, these studies generally assume intratumoral homogeneity. But in recent years, it has become clear that tumours are not homogeneous masses of cancerous cells, but wildly heterogeneous masses with various subpopulations which grow and respond to treatment differently. One subpopulation of particular importance is cancer stem cells (CSCs) which are known to exhibit higher radioresistence compared with non-CSCs. Knowledge of these differences between cell types could theoretically lead to changes in optimal treatment scheduling. Only a few studies have examined this question, and interestingly, they arrive at apparent conflicting results. However, an understanding of their assumptions reveals a key difference which leads to their differing conclusions.

In this paper, we generalize the problem of temporal optimization of dose distribution of radiation therapy to a two cell type model. We do so by creating a mathematical model and a numerical optimization algorithm to find the distribution of dose which leads to optimal cell kill. We then create a data set of optimization solutions and use data analysis tools to learn the relationships between model parameters and the qualitative behaviour of optimization results. Analysis of the model and discussion of biological importance are provided throughout. We find that the key factor in predicting the behaviour of the optimal distribution of radiation is the ratio between the radiosensitivities of the present cell types. These results can provide guidance for treatment in cases where clinicians have knowledge of tumour heterogeneity and of the abundance of CSCs.
How to use transcriptomic data for game-theoretic modeling of treatment-induced resistance in cancer cells? A case study in patient-derived glioblastoma organoids
Authors: Spekking Louise , Lohk Christer , Jung Weronika , Verduin Maikel , Azimi Sepinoud , Hubert Christopher , Vooijs Marc , Cavill Rachel , Staňková Kateřina
Published: January 2022

Game theory is a powerful tool to model strategic decision making, but also interactions within Darwinian biological systems, such as cancer. As such, in the past decades, game-theoretical models have helped to understand cancer, its response to various treatments, and to design better therapies. However, to fully utilize the potential of game-theoretical modelling in designing better anti-cancer therapies, we need more information on cancer population (ecological) and strategy (evolutionary) dynamics in response to treatment for each patient and their tumors. Here we explore how transcriptomics data can be utilized as an input of game-theoretical models for predicting evolutionary response to irradiation in patient-derived glioblastoma organoids. For that purpose, we utilize both supervised and unsupervised machine learning methods to identify relevant cancer cell types and how their proportions change over time in the organoids. We then fit these proportions to the replicator dynamics, the most common evolutionary game dynamics, to predict both transient evolutionary dynamics and evolutionary stable strategy (ESS) cell proportions. Our predictions in glioblastoma organoids suggest that hypoxia is the most important factor in identifying short-term response to irradiation, while this seems much less relevant for the long-term response corresponding to the ESSs. Further, we conclude that supervised methods are the best way to estimate cancer evolutionary dynamics when therapy resistance is a qualitative evolutionary trait. We believe that our methodology can help in designing better therapies through testing evolutionary responses in patient-derived organoids, while in parallel the ecological response can be tracked through serum biomarkers and imaging in the corresponding patients.
A Statistical Physics Approach for Disease Module Detection
Authors: Wang Xu-Wen , Qiao Dandi , Cho Michael , DeMeo Dawn L. , Silverman Edwin K. , Liu Yang-Yu
Published: January 2022

Extensive evidence indicates that the pathobiological processes of a complex disease are associated with perturbation within specific disease neighborhoods of the human protein-protein interaction (PPI) network (a.k.a. the interactome), often referred to as the disease module. Many computational methods have been developed to integrate the interactome and omics profiles to extract context-dependent disease modules. Yet, existing methods all have fundamental limitations in terms of rigor and/or efficiency. Here, we developed a statistical physics approach based on the random-field Ising model (RFIM) for disease module detection, which is both mathematically rigorous and computationally efficient. We applied our RFIM approach with genome-wide association studies (GWAS) of six complex diseases to examine its performance for disease module detection. We found that our RFIM approach outperforms existing methods in terms of computational efficiency, connectivity of disease modules, and robustness to the interactome incompleteness.
Role of RIGI, MDA5 and interferon alpha of duck in Duck Plague infection – a novel report
Authors: Pal Subhomoy , Banerjee Samiddha , Pal Abantika , Kalita Dhruba Jyoti , Batabyal Subhasis , Debnath Manti , Chakraborty Argha , Mondal Gourhari , Roy Barun , Chatterjee Paresh Nath , Chatterjee Jayanta Kumar , Pal Aruna
Published: January 2022

Duck Plague (DP) or Duck viral enteritis is an acute contagious and highly fatal disease in water fowl commonly caused by Anatidalphavirus-1 belonging from Herpesviridae family and contains double stranded DNA as genetic material. Pathogen associated molecular pattern (PAMP)s when identified by Pathogen Recognition Receptor (PRR)s acts as effective immunity system action against the pathogen. Melanoma Differentiation-Associated protein 5 (MDA5) and Retionic Acid Inducible Gene I (RIG1) are protein sensor commonly sense for viral double stranded RNA and helps for pro-inflammatory cytokine expression. Gut Associated Lymphoid Tissue (GALT)s have important role in immune response. The current study depicts the important role of three important immune response genes as RIGI, MDA5 and INFalpha in duck plague infestation for the first time. In silico studies followed by differential mRNA expression of RIG1, MDA5 and INFalpha was employed to detect effectiveness of gut associated immune responsiveness in liver, where kupfer cells are the major immune response cells. This was further confirmed through histological section of liver, kupfer cell and immunohistochemistry. This will be helpful to identify molecular mechanism of host innate immunity through duck plague virus infection in indigenous duck. This information may be helful for production of duck with the inherent resistance against duck plague virus infection through suitable biotechnological approaches as gene editing.Due to this inherent nature of better immunity in terms of resistance to other common avian diseases, duck will evolve as one of the major sustainable poultry species.The current study explores the scope to study host immunity against herpes virus in animal model.
Serum proteomics identifies immune pathways and candidate biomarkers of coronavirus infection in wild vampire bats
Authors: Becker Daniel J. , Lei Guang-Sheng , Janech Michael G. , Brand Alison M. , Fenton M. Brock , Simmons Nancy B. , Relich Ryan F. , Neely Benjamin A.
Published: January 2022

The apparent ability of bats to harbor many virulent viruses without showing disease is likely driven by distinct immune responses that coevolved with mammalian flight and the exceptional longevity of this order. Yet our understanding of the immune mechanisms of viral tolerance is restricted to a small number of bat–virus relationships and remains poor for coronaviruses (CoVs), despite their relevance to human health. Proteomics holds particular promise for illuminating the immune factors involved in bat responses to infection, because it can accommodate especially low sample volumes (e.g., sera) and thus can be applied to both large and small bat species as well as in longitudinal studies where lethal sampling is necessarily limited. Further, as the serum proteome includes proteins secreted from not only blood cells but also proximal organs, it provides a more general characterization of immune proteins. Here, we expand our recent work on the serum proteome of wild vampire bats (Desmodus rotundus) to better understand CoV pathogenesis. Across 19 bats sampled in 2019 in northern Belize with available sera, we detected CoVs in oral or rectal swabs from four individuals (21.1% positivity). Phylogenetic analyses identified all vampire bat sequences as novel α-CoVs most closely related to known human CoVs. Across 586 identified serum proteins, we found no strong differences in protein composition nor abundance between uninfected and infected bats. However, receiver operating characteristic curve analyses identified seven to 32 candidate biomarkers of CoV infection, including AHSG, C4A, F12, GPI, DSG2, GSTO1, and RNH1. Enrichment analyses using these protein classifiers identified downregulation of complement, regulation of proteolysis, immune effector processes, and humoral immunity in CoV-infected bats alongside upregulation of neutrophil immunity, overall granulocyte activation, myeloid cell responses, and glutathione processes. Such results denote a mostly cellular immune response of vampire bats to CoV infection and identify putative biomarkers that could provide new insights into CoV pathogenesis in wild and experimental populations. More broadly, applying a similar proteomic approach across diverse bat species and to distinct life history stages in target species could improve our understanding of the immune mechanisms by which wild bats tolerate viruses.
Functional and evolutionary significance of unknown genes from uncultivated taxa
Authors: Rodríguez del Río Álvaro , Giner-Lamia Joaquín , Cantalapiedra Carlos P. , Botas Jorge , Deng Ziqi , Hernández-Plaza Ana , Paoli Lucas , Schmidt Thomas S.B. , Sunagawa Shinichi , Bork Peer , Coelho Luis Pedro , Huerta-Cepas Jaime
Published: January 2022

Most microbes on our planet remain uncultured and poorly studied. Recent efforts to catalog their genetic diversity have revealed that a significant fraction of the observed microbial genes are functional and evolutionary untraceable, lacking homologs in reference databases. Despite their potential biological value, these apparently unrelated orphan genes from uncultivated taxa have been routinely discarded in metagenomics surveys. Here, we analyzed a global multi-habitat dataset covering 151,697 medium and high-quality metagenome assembled genomes (MAGs), 5,969 single-amplified genomes (SAGs), and 19,642 reference genomes, and identified 413,335 highly curated novel protein families under strong purifying selection out of previously considered orphan genes. These new protein families, representing a three-fold increase over the total number of prokaryotic orthologous groups described to date, spread out across the prokaryote phylogeny, can span multiple habitats, and are notably overrepresented in recently discovered taxa. By genomic context analysis, we pinpointed thousands of unknown protein families to phylogenetically conserved operons linked to energy production, xenobiotic metabolism and microbial resistance. Most remarkably, we found 980 previously neglected protein families that can accurately distinguish entire uncultivated phyla, classes, and orders, likely representing synapomorphic traits that fostered their divergence. The systematic curation and evolutionary analysis of the unique genetic repertoire of uncultivated taxa opens new avenues for understanding the biology and ecological roles of poorly explored lineages at a global scale.
A catalogue of resistance gene homologs and a chromosome-scale reference sequence support resistance gene mapping in winter wheat
Authors: Kale Sandip M. , Schulthess Albert W. , Padmarasu Sudharsan , Boeven Philipp H. G. , Schacht Johannes , Himmelbach Axel , Steuernagel Burkhard , Wulff Brande B. H. , Reif Jochen C. , Stein Nils , Mascher Martin
Published: January 2022

A resistance gene atlas is an integral component of the breeder’s arsenal in the fight against evolving pathogens. Thanks to high-throughput sequencing, catalogues of resistance genes can be assembled even in crop species with large and polyploid genomes. Here, we report on capture sequencing and assembly of resistance gene homologs in a diversity panel of 907 winter wheat genotypes comprising ex situ genebank accessions and current elite cultivars. In addition, we use accurate long-read sequencing and chromosome conformation capture sequencing to construct a chromosome-scale genome sequence assembly of cv. Attraktion, an elite variety representative of European winter wheat. We illustrate the value of our resource for breeders and geneticists by (i) comparing the resistance gene complements in plant genetic resources and elite varieties and (ii) conducting genome-wide associations scans (GWAS) for the fungal diseases yellow rust and leaf rust using reference-based and reference-free GWAS approaches. The gene content under GWAS peaks was scrutinized in the assembly of cv. Attraktion.
Robust and reproducible neuronal differentiation of human embryonic stem cells for neurotoxicology
Authors: Samara Athina , Falck Martin , Spildrejorde Mari , Leithaug Magnus , Acharya Ganesh , Lyle Robert , Eskeland Ragnhild
Published: January 2022

Neuronal differentiation from pluripotent cells is commonly used to recapitulate events in early brain development. Neuronal precursors and developing neurons cultured in vivo, rely on attachment, density and cell-to-cell communication, and cell-passaging steps should be minimised to avert disruption of network cross-connectivity. This is crucial both for viability and maturation, and the former also applies to human embryonic stem cells (hESCs). Neuronal differentiation protocols from hESCs for neurotoxicology assessment studies should therefore provide standardized cell density requirements, and optimised coating matrix conditions. The effect of drug treatments may be masked by compound instability and degradation in cell culture medium but performing daily media changes can circumvent these issues. Here, we describe a robust neuronal differentiation protocol using dual SMAD/WNT signalling inhibitors LDN193189, SB431542 and XAV939 (LSX) for neural induction of hESCs, followed by self-patterning and cell maturation stages, for the generation of ventral telencephalic progenitors and neurons. We provide critical information on the optimized cell culture parameters and standardized methods of stage-specific validation. Using cell counts, immunofluorescence, qRT-PCR, and a proof of principle treatment with valproic acid to showcase issues with drug-induced cell toxicity, we facilitate reproducibility of the protocol.

Graphical abstract
The CIC-ERF co-deletion underlies fusion independent activation of ETS family member, ETV1, to drive prostate cancer progression
Authors: Gupta Nehal , Song Hanbing , Wu Wei , Ponce Rovingaile Kriska , Lin Yone Kawe , Kim Ji Won , Small Eric J , Feng Felix Y. , Huang Franklin W. , Okimoto Ross A.
Published: January 2022

The dysregulation of ETS family transcription factors drives human prostate cancer. The majority of prostate cancer is the result of chromosomal rearrangements that lead to aberrant ETS gene expression. The mechanisms that lead to fusion independent ETS factor upregulation and prostate oncogenesis remain unknown. Here, we show that two neighboring transcription factors, Capicua (CIC) and ETS2 repressor factor (ERF), which are co-deleted in human prostate tumors can drive prostate oncogenesis. Concurrent CIC and ERF loss commonly occurs through focal genomic deletions at chromosome 19q13.2. Mechanistically, CIC and ERF co-bind the proximal regulatory element and mutually repress the ETS transcription factor, ETV1. Targeting ETV1 in CIC and ERF deficient prostate cancer limits tumor growth. Thus, we have uncovered a fusion independent mode of ETS transcriptional activation defined by concurrent loss of CIC and ERF.
Mindin is essential for cutaneous fibrogenesis in a new mouse model of systemic sclerosis
Authors: Rana Isha , Kataria Sunny , Tan Tuan Lin , Hajam Edries Yousaf , Kashyap Deepak Kumar , Saha Dyuti , Ajnabi Johan , Paul Sayan , Jayappa Shashank , Ananthan Akhil SHP , Kumar Pankaj , Zaarour Rania F. , J Haarshaadri , Samuel Rekha , George Renu , Danda Debashish , Jacob Paul Mazhuvanchary , Dey Rakesh , Dhandapany Perundurai S , He You-Wen , Varga John , Varghese Shyni , Jamora Colin
Published: January 2022

Fibrosis is a result of chronically activated fibroblasts leading to the overproduction of extracellular matrix (ECM), causing tissue hardening and loss of organ function. Systemic sclerosis (SSc) is a fibrotic skin disease marked by inflammation, autoimmunity and vasculopathy along with progressive fibrosis of the skin and internal organs. A major bottleneck in understanding the etiology of SSc has been the lack of a holistic animal model that can mimic the human SSc disease. We found that the transcription factor Snail is overexpressed in the epidermis of SSc patients and a transgenic mouse recapitulating this expression pattern is sufficient to induce hallmark clinical features of the human disease. Using this mouse model as a discovery platform, we have uncovered a critical role for the matricellular protein Mindin in fibrogenesis. Mindin is produced by Snail transgenic skin keratinocytes and aids fibrogenesis by inducing inflammatory cytokine and collagen production in resident dermal fibroblasts. Given the dispensability of Mindin in normal tissue physiology, targeting this protein holds promise as an effective therapy for fibrosis.
Existence of blood circulating immune-cell clusters (CICs) comprising antigen-presenting cells and B cells
Authors: Bae Sangwook , Lee Yonghee , Kang MyeongHo , Noh Jinsung , Seo Dongyup , Seo Hanna , Lee Sumin , Kwon Sunghoon
Published: January 2022

Cell-to-cell physical interactions are involved in almost every physiological processes in multicellular organisms. Although the dynamics of these interactions could be highly diverse and complex in many circumstances, certain cell-to-cell interactions among immune cells have been well studied due importance in understanding disease pathogenesis and immune therapy development1. Dendritic cells (DCs) and B cells are directly involved in adaptive immune response against pathogens. Interaction mechanism between these two celltypes is well-known to occur in germinal centers either indirectly via helper T (Th) cells or directly via cell contact. However, there are animalin vitroandin vivoevidence that such direct DC-to-B cell contact can occur outside germinal centers like in peripheral blood or collagen matrix and display antiviral immune-related activity2,3. Here, we provide evidence that certain types of antigen presenting cells (APCs) can form robust cell clusters with B cells and circulate in blood. From healthy human blood immune single cell RNA-seq datasets, we detected APC subpopulations (0.34±0.19% of total PBMCs) that were also enriched with well-known naïve B cell markers. We visually observed DC:B doublets and multiplets (∼0.69% of total live PBMCs) in wildtype mouse blood using flow cytometry and microscopic imaging, thus proving the existence of circulating immune-cell clusters (CICs) composed of APCs and B cells. BCR repertoire of these healthy mouse CICs were similar to circulating B cells. Noticeably, frequency of these APC:B CICs were higher COVID-19 patients than healthy donors and their B cell subtype composition (e.g. naïve, plasmablast, IgM+, IgG+) varied with disease severity.
In silico transcriptomics identifies FDA-approved drugs and biological pathways for protection against cisplatin-induced hearing loss
Authors: Salehi Pezhman , Zallocchi Marisa , Vijayakumar Sarath , Urbanek Madeleine , Giffen Kimberlee P. , Li Yuju , Hati Santanu , Zuo Jian
Published: January 2022

Acquired hearing loss is a major health problem that affects 5-10% of the world population. However, there are no FDA-approved drugs for the treatment or prevention of hearing loss. Employing the Connectivity Map (CMap) that contains >54,000 compounds, we performed an unbiased in silico screen using the transcriptomic profiles of cisplatin-resistant and -sensitive cancer cell lines. Pathway enrichment analysis identified gene-drug targets for which 30 candidate drugs were selected with potential to confer protection against cisplatin-induced ototoxicity. In parallel, transcriptomic analysis of a cisplatin-treated cochlear-derived cell line identified common enriched pathway targets. We subsequently tested these top 30 candidate compounds, 15 (50%) of which are FDA-approved for other indications, and 26 (87%) of which were validated for their protective effects in either a cochlear-derived cell line or zebrafish lateral line neuromasts, thus confirming our in silico transcriptomic approach. Among these top compounds, niclosamide, a salicyanilide drug approved by the FDA for treating tapeworm infections for decades, protected from cisplatin- and noise-induced hearing loss in mice. Finally, niclosamide and ezetimibe (an Nrf2 agonist) exerted synergistic protection against cisplatin-ototoxicity in zebrafish, validating the Nrf2 pathway as part of niclosamide’s mechanism of action. Taken together, employing the CMap, we identified multiple pathways and drugs against cisplatin ototoxicity and confirmed that niclosamide can effectively be repurposed as an otoprotectant for future clinical trials against cisplatin- and noise-induced hearing loss.

Significant Statement

Employing the Connectivity Map as our in silico transcriptomic screening strategy we identified FDA-approved drugs and biological pathways for protection against cisplatin-induced hearing loss.