bluuebunny/crossref_metadata_2025 huggingface dataset:
tinyRNA: precision analysis of small RNA-seq data with user-defined hierarchical selection rules
Authors: Tate Alex J. , Brown Kristen C. , Montgomery Taiowa A.
Published: July 2022

tinyRNA performs precision analysis of small RNAs, including miRNAs, piRNAs, and siRNAs, from high-throughput sequencing experiments. At the core of tinyRNA is a highly flexible counting utility, tiny-count, that allows for hierarchical assignment of small RNA reads to features based on positional information, extent of feature overlap, 5’ nucleotide, length, and strandedness. tinyRNA provides an all-in-one solution for small RNA-seq data analysis, with documentation and statistics generated at each step for accurate, reproducible results.

Availability and Implementation

tinyRNA tools are implemented in Python and R, and the pipeline workflow is coordinated with CWL. tinyRNA is free and open-source software distributed under the GPLv3 license. tinyRNA is available at https://github.com/MontgomeryLab/tinyRNA.

Contact

tai.montgomery@colostate.edu

Supplementary information

Reference data, including genome sequences and features tables, for certain species can be found at https://www.MontgomeryLab.org.
Molecular characteristics of phages located in Carbapenemase-Producing Escherichia coli clinical isolates: New Phage-Like Plasmids
Authors: Lopez-Diaz Maria , Bleriot Ines , Pacios Olga , Fernandez-Garcia Laura , Blasco Lucia , Ambroa Anton , Ortiz-Cartagena Concha , Woodford Neil , Ellington Matthew J. , Tomas Maria
Published: July 2022

Escherichia coli normally inhabits the gastrointestinal tract of humans and animals. Most E. coli bacteria do not cause problems, but the acquisition of different resistance and virulence genes encoded by mobile plasmids or phages by different bacterial isolates has been associated with the appearance of successful high-risk clones of multidrug-resistant (MDR) E. coli such as ST131 or ST405. In the present study, 50 temperate bacteriophages present in 21 clinical isolates of carbapenemase-producing E. coli of sequence types (STs) ST38, ST131, ST167, ST405 and ST410 were analysed. These phages were classified in the three families of the order Caudovirales: 24 within the family Siphoviridae, 23 in Myoviridae and 3 in Podoviridae. The size of the phages studied ranged from 11 to 95 Kb. Phylogenetic analysis of the terminase large subunit allowed us to classify these phages into different groups showing similarity with the phage sequences deposited in the Microbe Versus Phage (MVP) database and which belonged to clusters 229, 604, 2503 and 2725. On the other hand, bioinformatic study revealed that most of the identified proteins exerted a structural function (26.73%) but also functions involved in lysis/lysogeny (6.70%) or regulation (5.20%) among others. In addition, the ParA-ParB partitioning system and the type II toxin-antitoxin Phd-Doc system were also found in two of the phages studied, which could indicate the presence of plasmid-prophages. Host range testing revealed that two isolates were more susceptible to infection than the other isolates.

IMPORTANCE

Escherichia coli is one of the pathogens that causes most problems in human health, as it presents multiple resistances to different antibiotics. The study of bacteriophages located in different isolates of this species is important for the development of new anti-infective therapies. Currently, antibiotic resistance is a major problem, but more and more studies are pointing to experimental treatments with bacteriophages as a possible solution.
Reconstituted depolarization-induced Ca2+release platform for skeletal muscle disease mutation validation and drug discovery
Authors: Murayama Takashi , Kurebayashi Nagomi , Numaga-Tomita Takuro , Kobayashi Takuya , Okazaki Satoru , Yamashiro Kyosuke , Nakada Tsutomu , Mori Shuichi , Ishida Ryosuke , Kagechika Hiroyuki , Yamada Mitsuhiko , Sakurai Takashi
Published: July 2022

In skeletal muscle excitation-contraction (E-C) coupling, depolarization of the plasma membrane triggers Ca2+release from the sarcoplasmic reticulum (SR), referred to as depolarization-induced Ca2+release (DICR). DICR occurs via the type 1 ryanodine receptor (RyR1), which physically interacts with the dihydropyridine receptor Cav1.1 subunit in specific machinery formed with additional essential components including β1a, Stac3 adaptor protein and junctophilins. Exome sequencing has accelerated the discovery of many novel mutations in genes encoding DICR machinery in various skeletal muscle diseases. However, functional validation is time-consuming because it must be performed in a skeletal muscle environment. In this study, we established a platform of the reconstituted DICR in HEK293 cells. The essential components were effectively transduced into HEK293 cells expressing RyR1 using baculovirus vectors, and Ca2+release was quantitatively measured with R-CEPIA1er, a fluorescent ER Ca2+indicator, without contaminant of extracellular Ca2+influx. In these cells, [K+]-dependent Ca2+release was triggered by chemical depolarization with the aid of inward rectifying potassium channel, indicating a successful reconstitution of DICR. Using the platform, we evaluated several Cav1.1 mutations that are implicated in malignant hyperthermia and myopathy. We also tested several RyR1 inhibitors; whereas dantrolene and Cpd1 inhibited DICR, procaine had no effect. Furthermore, twitch potentiators such as perchlorate and thiocyanate shifted the voltage dependence of DICR to more negative potentials without affecting Ca2+-induced Ca2+release. These results well reproduced the findings with the muscle fibers and the cultured myotubes. Since the procedure is simple and reproducible, the reconstituted DICR platform will be highly useful for validation of mutations and drug discovery for skeletal muscle diseases.

Mutations in essential components for depolarization-induced Ca2+release (DICR) are implicated into various skeletal muscle diseases. Murayama et al. establish a reconstituted DICR platform in nonmuscle cells for evaluation of disease-causing mutations and drug discovery.
Scaling pattern of the carnivoran forelimb: Locomotor types, differential scaling and thoughts on a dying similarity
Authors: Gálvez-López Eloy , Casinos Adrià
Published: July 2022

The scaling pattern of the forelimb in Carnivora was determined using a sample of 30 variables measured on the scapula, humerus, radius, ulna, and third metacarpal, of 429 specimens belonging to 137 species of Carnivora. Standardized major axis regressions on body mass were calculated for all variables, using both traditional regression methods and phylogenetically independent contrasts (PIC). In agreement with previous studies on the scaling of the appendicular skeleton, conformity to either the geometric similarity hypothesis or the elastic similarity hypothesis was low. The scaling pattern of several phyletic lines and locomotor types within Carnivora was also determined, and significant deviations from the scaling pattern of the order were found in some of these subsamples. Furthermore, significant evidence for differential scaling was found for several variables, both in the whole sample and in various phylogenetic and locomotor subsamples. Contrary to previous studies, significant differences were found between the allometric exponents obtained with traditional and PIC regression methods, emphasizing the need to take into account phylogenetic relatedness in scaling studies. In light of these and previous results, we conclude that similarity hypotheses are too simplistic to describe scaling patterns in the carnivoran appendicular skeleton, and thus we propose that scaling hypotheses should be built from similarities in the scaling patterns of phylogenetically narrow samples of species with similar locomotor requirements. The present work is a first step in the study of those samples.
A cross-species approach using an in vivo evaluation platform in mice demonstrates that sequence variation in the human RABEP2 gene modulates ischemic stroke outcomes
Authors: Lee Han Kyu , Kwon Do Hoon , Marchuk Douglas A.
Published: July 2022

Ischemic stroke, caused by vessel blockage, results in cerebral infarction; the death of brain tissue. Previously, quantitative trait locus mapping (QTL) of cerebral infarct volume and collateral vessel number identified a single, strong genetic locus regulating both phenotypes. Additional studies identified the causative gene, encoding RAB GTPase Binding Effector Protein 2 (Rabep2). However, there is yet no evidence that variation in the human ortholog of this gene plays any role in ischemic stroke outcomes. We established an in vivo evaluation platform in mice using adeno-associated virus (AAV) gene replacement and verified that both mouse and human RABEP2 rescue the mouse Rabep2 KO ischemic stroke volume and collateral vessel phenotypes. Importantly, this cross-species complementation enabled us to experimentally investigate the functional effects of coding sequence variation in the human RABEP2 gene. We chose four coding variants from the human population that are predicted by multiple in silico algorithms to be damaging to RABEP2 function. In vitro and in vivo analyses verify that all four led to decreased collateral vessel connections and increased infarct volume. Thus, there are naturally occurring loss-of-function alleles. This cross-species approach will expand the number of targets for therapeutics development for ischemic stroke.
A scalable open-source framework for machine learning based image collection, annotation and classification: a case study for automatic fish species identification
Authors: Silva Catarina NS , Dainys Justas , Simmons Sean , Vienožinskis Vincentas , Audzijonyte Asta
Published: July 2022

Citizen science platforms, social media and multiple smart phone applications enable collection of large amounts of georeferenced images. This provides a huge opportunity in biodiversity and ecological research, but also creates challenges for efficient data handling and processing. Recreational and small-scale fisheries is one of the fields that could be revolutionised by efficient, widely accessible and machine learning based processing of georeferenced images. The majority of non-commercial inland and coastal fisheries are considered data poor and are rarely assessed, yet they provide multiple societal benefits and can have large ecological impacts. Given that large quantities of fish observations and images are being collected by fishers every day, artificial intelligence (AI) and computer vision applications offer a great opportunity to improve data collection, automate analyses and inform management. Yet, to date, many AI image analysis applications in fisheries are focused on the commercial sector and are not publicly available for community use. In this study we present an open-source modular framework for large scale image storage, handling, annotation and automatic classification, using cost- and labour-efficient methodologies. The tool is based on TensorFlow Lite Model Maker library and includes data augmentation and transfer learning techniques, applied to different convolutional neural network models. We demonstrate the implementation of this framework in an example case study for automatic fish species identification from images taken through a recreational fishing smartphone application. The framework presented here is highly customisable for further advancement and community based image collection and annotation.
Natural occurrence and analysis of Nosema sp. infection in the adult population of western bean cutworm in Michigan
Authors: Bunn Dakota C. , Miller Nicholas
Published: July 2022

An understanding of population dynamics and insect biology is important for effective crop management strategies. Biotic factors such as pathogens play a large role on the fitness and dynamics of insect populations. Microsporidia are obligate intracellular parasites that infect more than 150 insect species and range from sublethal and chronic to fast acting and deadly. The western bean cutworm, Striacosta albicosta (Smith) (Lepidoptera: Noctuidae), is a pest of both corn (Zea maize L.) and dry beans (Phaseolus sp L.) that is infected by a microsporidian parasite from the genus Nosema. Unfortunately, little is known about the interactions between the Nosema sp. infecting the western bean cutworm and its prevalence and effects on the host population. This is especially true for the western bean cutworm population that has settled in the Great Lakes region over the last two decades. Using field caught samples and phase contrast microscopy, we found a 100% prevalence of infection in the adult western bean cutworm population in Michigan. No consistent trends in pathogen load were observed over the course of the western bean cutworm flight season. A weak, but statistically significant relationship was observed between male body weight and pathogen load.
Reactive Bergmann glia play a central role in Spinocerebellar ataxia inflammation via the JNK pathway
Authors: Edamakanti Chandrakanth Reddy , Mohan Vishwa , Opal Puneet
Published: July 2022

The spinocerebellar ataxias (SCAs) are devastating neurological diseases characterized by progressive cerebellar incoordination. While neurons bear the brunt of the pathology, a growing body of evidence suggests that glial cells are also affected. It has, however, been difficult to understand the role of glia, given the diversity of subtypes, each with their individual contributions to neuronal health. Using human SCA autopsy samples we have discovered that Bergmann glia—the radial glia of the cerebellum, which form intimate functional connections with cerebellar Purkinje neurons—display inflammatory JNK-dependent c-Jun phosphorylation. This phosphorylation defines a signaling pathway not observed in other activated glial populations, providing an opportunity to specifically isolate the role of Bergmann glia in SCA inflammation. Turning to an SCA1 mouse model as a paradigmatic SCA, we demonstrate that inhibiting the JNK pathway reduces Bergmann glia inflammation accompanied by improvements in the SCA1 phenotype both behaviorally and pathologically. These findings demonstrate the causal role for Bergmann glia inflammation in SCA1 and point to a novel therapeutic strategy that could span several ataxic syndromes where Bergmann glia inflammation is a major feature.

Significance Statement

We have identified a Bergmann-glia specific signaling pathway that contributes to cerebellar degeneration in the spinocerebellar ataxias. This pathway is defined by activation of JNK that phosphorylates the transcription factor c-Jun leading to the release of IL-1β and potentially other cytokines from Bergmann glia. Inhibiting c-Jun phosphorylation with pharmacological JNK inhibition could serve as therapeutic approach to treating cerebellar degeneration.
Life history strategies and niches of soil bacteria emerge from interacting thermodynamic, biophysical, and metabolic traits
Authors: Marschmann Gianna L. , Tang Jinyun , Zhalnina Kateryna , Karaoz Ulas , Cho Heejung , Le Beatrice , Pett-Ridge Jennifer , Brodie Eoin L.
Published: July 2022

Efficient biochemical transformation of belowground carbon by microorganisms plays a critical role in determining the long-term fate of soil carbon. As plants assimilate carbon from the atmosphere, up to 50% is exuded into the area surrounding growing roots, where it may be transformed into microbial biomass and subsequently stabilized through mineral associations. However, due to a hierarchy of interacting microbial traits, it remains elusive how emergent life-history strategies of microorganisms influence the processing of root exudate carbon. Here, by combining theory-based predictions of substrate uptake kinetics for soil bacteria and a new genome-informed trait-based dynamic energy budget model, we predicted life history traits and trade-offs of a broad range of soil bacteria growing on 82 root exudate metabolites. The model captured resource-dependent trade-offs between growth rate (power) and growth efficiency (yield) that are fundamental to microbial fitness in communities. During early phases of plant development, growth rates of bacteria were largely constrained by maximum growth potential, highlighting the predictive power of genomic traits during nutrient-replete soil conditions. In contrast, selection for efficiency was important later in the plant growing season, where the model successfully predicted microbial substrate preferences for aromatic organic acids and plant hormones. The predicted carbon-use efficiencies for growth on organics acids were much higher than typical values observed in soil. These predictions provide mechanistic underpinning for the apparent efficiency of the microbial route to mineral stabilization in the rhizosphere and add an additional layer of complexity to rhizosphere microbial community assembly.
Neutrophils infiltrate sensory ganglia and mediate chronic widespread pain in fibromyalgia
Authors: Caxaria Sara , Bharde Sabah , Fuller Alice M. , Evans Romy , Thomas Bethan , Celik Petek , Dell’Accio Francesco , Yona Simon , Gilroy Derek , Voisin Mathieu-Benoit , Wood John N. , Sikandar Shafaq
Published: July 2022

Fibromyalgia is a debilitating widespread chronic pain syndrome that occurs in 2-4% of the population. The prevailing view that fibromyalgia results from central nervous system dysfunction has recently been challenged with data showing changes in peripheral nervous system activity. Using a mouse model of chronic widespread pain through hyperalgesic priming of muscle, we show that neutrophils invade sensory ganglia and confer mechanical hypersensitivity on recipient mice, whilst adoptive transfer of immunoglobulin, serum, lymphocytes or monocytes have no effect on pain behaviour. Neutrophil depletion abolishes the establishment of chronic widespread pain in mice. Neutrophils from patients with fibromyalgia also confer pain on mice. A link between neutrophil derived mediators and peripheral nerve sensitisation is already established. These observations suggest new approaches for targeting fibromyalgia pain through an understanding of the mechanisms that cause altered neutrophil activity and interactions with sensory neurons.

Significance statement

We used a back-translational model in mice to demonstrate the pro-nociceptive role of neutrophils in fibromyalgia. Adoptive transfer of neutrophils from mice with chronic widespread pain or from patients with fibromyalgia can confer mechanical pain to recipient naïve mice, sensitise evoked action potential firing of spinal cord neurons and produce phenotypic changes in cell surface expression of neutrophil proteins that cause infiltration of neutrophils into dorsal root ganglia. These data provide the framework for an immunological basis of chronic widespread pain in fibromyalgia mediated by polymorphonuclear granulocytes.
The SCN1A Philadelphia variant – a gain-of-function mutation causing an early-onset epileptic encephalopathy
Authors: Clatot Jérôme , Parthasarathy Shridhar , Cohen Stacey , McKee Jillian , Massey Shavonne , Somarowthu Ala , Goldberg Ethan M. , Helbig Ingo
Published: July 2022

Objective

Loss-of-function variants in SCN1A cause Dravet Syndrome, the most common genetic developmental and epileptic encephalopathy (DEE). However, emerging evidence suggests separate entities of SCN1A-related disorders due to gain-of-function variants. Here, we aim to refine the clinical, genetic, and functional electrophysiological features of a recurrent p.R1636Q gain-of-function variant, identified in four individuals at a single center.

Methods

Individuals carrying the recurrent SCN1A p.R1636Q variant were identified through diagnostic testing. Whole-cell voltage-clamp electrophysiological recording in HEK-293T cells was performed to compare the properties of sodium channels containing wild-type Nav1.1 or Nav1.1-R1636Q along with both Navβ1 and Navβ2 subunits, including response to oxcarbazepine. To delineate differences to other SCN1A-related epilepsies, we analyzed electronic medical records.

Results

All four individuals had an early-onset DEE characterized by focal tonic seizures and additional seizure types starting in the first few weeks of life. Electrophysiological analysis showed a mixed gain-of-function effect with normal current density, a leftward (hyperpolarized) shift of steady-state inactivation, and slower inactivation kinetics leading to a prominent late sodium current (INa). The observed functional changes closely paralleled effects of pathogenic variants in SCN3A and SCN8A at corresponding positions. Both wildtype and variant exhibited sensitivity to block by oxcarbazepine, partially correcting electrophysiological abnormalities of the SCN1A p.R1636Q variant. Clinically, a single individual responded to treatment with oxcarbazepine. Across 51 individuals with SCN1A-related epilepsies, those with the recurrent p.R1636Q variants had the earliest ages of onset.

Interpretation

The recurrent SCN1A p.R1636Q variant causes a clinical entity with a wider clinical spectrum than previously reported, characterized by ultra early-onset epilepsy and absence of prominent movement disorder. Functional consequences of this variant lead to mixed loss- and gain-of-function that is partially corrected by oxcarbazepine. The recurrent p.R1636Q variant represents one of the most common causes of early-onset SCN1A-related epilepsies with separate treatment and prognosis implications.

Key Points

Loss-of-function variants in SCN1A cause Dravet syndrome, but gain-of-function variants have an emerging clinical spectrum.

The SCN1A p.R1636Q variant shows similar overall gain-of-function effects to identical missense variants in other voltage-gated sodium channels.

Features of four unreported individuals with SCN1A p.R1636Q from a single center expand the SCN1A gain-of-function phenotype.

Individuals with this variant are recognizable by their ultra early-onset seizures in contrast to Dravet syndrome.
An independent external validation of the QRISK3 cardiovascular risk prediction model applied to UK Biobank participants
Authors: Parsons Ruth E. , Liu Xiaonan , Collister Jennifer A. , Clifton David A. , Cairns Benjamin J. , Clifton Lei
Published: July 2022

Background

The QRISK3 cardiovascular disease (CVD) risk prediction model was derived using primary care data; however, it is frequently used outside of clinical settings. The use of QRISK3 in epidemiological studies without external validation may lead to inaccurate results, however it has been used multiple times on data from UK Biobank. We aimed to externally evaluate the performance of QRISK3 for predicting 10-year risk of cardiovascular events in the UK Biobank cohort.

Methods

We used data from the UK Biobank, a large-scale prospective cohort study of 403,370 participants aged 40-69 years recruited between 2006 and 2010 in the United Kingdom (UK). We included participants with no previous history of CVD or statin treatment and the outcome was the first occurrence of coronary heart disease, ischaemic stroke or transient ischaemic attack, derived from linked hospital episode statistics (HES) and death registration data (DRD).

Results

Our study population included 233,233 females and 170,137 males, with 9295 and 13,028 incident cardiovascular events, respectively. The overall median follow-up time after recruitment was 11.7 years. The discrimination measure of QRISK3 in the overall population was reasonable (Harrell’s C-Index 0.722 in females and 0.697 in males), this was poorer in older participants (<0.62 in all participants aged 65 or older). QRISK3 had systematic over-prediction of CVD risk in UK Biobank, particularly in older participants, by as much as 20%.

Conclusions

QRISK3 had reasonable overall discrimination for the whole study population, which was best in younger participants. The observed CVD risk in UK Biobank participants was lower than that predicted by QRISK3, particularly for older participants. The UK Biobank cohort is known to be healthier than the general population and therefore it is necessary to recalibrate QRISK3 before using it to predict absolute CVD risk in the UK Biobank cohort.
Low back pain service utilization and costs: association with timing of first-line services for individuals initially contacting a primary care provider. A retrospective cohort study
Authors: Elton David , Zhang Meng
Published: July 2022

Background

Low back pain (LBP) is prevalent, costly, and a common reason for a visit to a primary care provider (PCP). Clinical practice guidelines (CPG) recommend a stepped approach to management.

Objective

For individuals with LBP initially contacting a PCP, examine the association between the incorporation of first-line therapies, use of second- and third-line services and total episode cost.

Design

Retrospective cohort study

Setting/Patients

National sample of individuals with non-surgical LBP occurring in 2017-2019.

Measurements

Independent variables were initial contact with a PCP, and the timing of incorporation of 5 types of first-line therapies. Dependent measures included use of 13 types of health care services and total episode cost.

Results

8.5% of 118,503 PCPs initially contacted by 308,790 individuals with 347,627 episodes of non-surgical LBP were associated with an episode including any first-line service at any time. 17.5% of episodes included any first-line service at any time. Active care (11.6% of episodes), manual therapy (8.0%) and chiropractic manipulative therapy (7.0%) were the most common first-line services. 5.4% of episodes included a first-line service during the first 7 days with these episodes associated with a modest reduction (risk ratio 0.34 to 0.89) in the use of prescription pharmaceuticals. First-line services were associated with an increase in total episode cost with the smallest increase associated with chiropractic and osteopathic manipulation. Younger individuals from ZIP codes with higher adjusted gross income were more likely to receive a first-line service in the first 7 days of an episode.

Limitations

As a retrospective observational analysis of associations there are numerous potential confounders and limitations.

Conclusions

Individuals with non-surgical LBP initially contacting a PCP infrequently receive a first-line service, and if received, it is typically in addition to second- and third-line pharmaceutical, imaging, and interventional services. There is an opportunity to improve concordance with the stepped approach to management described in LBP CPGs.
Increased disparity in routine infant vaccination during COVID-19
Authors: Righolt Christiaan H. , Pabla Gupreet , Mahmud Salaheddin M.
Published: July 2022

Background

COVID-19 restrictions and its impact on healthcare resources have reduced routine infant vaccine uptake, although some report that this effect was short-lived. These prior studies mostly described entire populations, but disparities in uptake may have changed during the pandemic due to differential access to healthcare.

Objectives

We aimed to examine disparities in the reduction in routine infant vaccine uptake during the COVID-19 pandemic in Manitoba, Canada.

Methods

We assessed vaccine uptake for routine infant vaccines for a pre-pandemic and pandemic subcohort. We assessed how the reduction in vaccine uptake differed by gender, neighborhood income quintile and region of residence. For each evaluation age, we limited the pandemic subcohort to children reaching this milestone age on/before November 30, 2021.

Results

Vaccine uptake was about 5-10% lower during the pandemic. The groups most vulnerable to COVID-19 saw the largest reductions in vaccine uptake, with an ongoing downward trend throughout the pandemic. Children in the lowest income neighborhoods saw a 17% reduction in diphtheria, tetanus, and acellular pertussis dose 4 uptake at 24 months, 4.4-fold that of high-income neighborhoods, and an 11% reduction in measles, mumps, rubella (MMR) vaccine uptake at 24 months, 5.6-fold that of high-income neighborhoods. The largest reductions were for low-income Northern residents and smallest for high-income Winnipeg residents, e.g. 16-fold larger for MMR at 24 months (79:94 pre-pandemic to 65:93 during the pandemic).

Conclusions

While privileged children have similar high vaccine uptake as before the pandemic, children in populations hardest hit by COVID-19 continue seeing concerning reductions in routine infant vaccination. It is imperative that infant vaccination rates are increased, especially in communities with lower socioeconomic status, as a failure to do so could lead to persistent rebound epidemics in the most vulnerable populations.

Synopsis

Study question

How did COVID-19 and its restrictions affect routine infant vaccine uptake?

What’s already known

We know that vaccine uptake in infants decreased during the pandemic. We do not know whether this affected everyone equally or whether the pandemic worsened existing disparities in vaccine uptake.

What this study adds

Although vaccine uptake was not affected in wealthy urban neighborhoods, the reduction in uptake was largest, and continued on a downward trend, for groups with the lowest baseline vaccine uptake. Only two-thirds of children, instead of the 4/5th before the pandemic, in the remote, predominantly Indigenous Northern region received a measles vaccine by their second birthday.
Predicting infectious disease for biopreparedness and response: A systematic review of machine learning and deep learning approaches
Authors: Keshavamurthy Ravikiran , Dixon Samuel , Pazdernik Karl T. , Charles Lauren E.
Published: July 2022

Despite the complex and unpredictable nature of pathogen occurrence, substantial efforts have been made to better predict infectious diseases (IDs). Following PRISMA guidelines, we conducted a systematic review to investigate the advances in ID prediction capabilities for human and animal diseases, focusing on Machine Learning (ML) and Deep Learning (DL) techniques. Between January 2001 and May 2021, the number of relevant articles published steadily increased with a significantly influx after January 2019. Among the 237 articles included, a variety of IDs and locations were modeled, with the most common being COVID-19 (37.1%) followed by Influenza/influenza-like illnesses (8.9%) and Eastern Asia (32.5%) followed by North America (17.7%), respectively. Tree-based ML models (38.4%) and feed-forward DL neural networks (26.6%) were the most frequent approaches taking advantage of a wide variety of input features. Most articles contained models predicting temporal incidence (66.7%) followed by disease risk (38.0%) and spatial movement (31.2%). Less than 10% of studies addressed the concepts of uncertainty quantification, computational efficiency, and missing data, which are essential to operational use and deployment. Our study summarizes the broad aspects and current status of ID prediction capabilities and provides guidelines for future works to better support biopreparedness and response.
A photopolymerizable hydrogel enhances intramyocardial vascular cell delivery and promotes post-myocardial infarction healing by polarizing pro-regenerative neutrophils
Authors: Hong Xuechong , Luo Allen Chilun , Doulamis Ilias , Oh Nicholas , Im Gwang-Bum , del Nido Pedro J. , Melero-Martin Juan M. , Lin Ruei-Zeng
Published: July 2022

The success of vascular progenitor cell transplantation to treat myocardial infarction (MI) is primarily limited by the low engraftment of delivered cells due to a washout effect during myocardium contraction. A clinically applicable biomaterial to improve cell retention is arguably needed to enable optimization of intramyocardial cell delivery. Here, we developed a novel therapeutic cell delivery method for MI treatment based on a photocrosslinkable gelatin methacryloyl (GelMA) hydrogel. A combination of human vascular progenitor cells (endothelial progenitors and mesenchymal stem cells) with the capacity to form functional vasculatures after transplantation, were injected with a rapid in-situ photopolymerization approach into the infarcted zone of mouse hearts. Our approach significantly improved acute cell retention and achieved a long-term beneficial post-MI cardiac healing, including stabilizing cardiac functions, preserving viable myocardium, and preventing cardiac fibrosis. Furthermore, the engrafted vascular cells polarized recruited bone marrow-derived neutrophils toward a non-inflammatory phenotype via TGFβ signaling, establishing a pro-regenerative microenvironment. Depletion of neutrophils canceled the therapeutic benefits produced by cell delivery in the ischemic hearts, indicating that the non-inflammatory, pro-regenerative neutrophils were indispensable mediators of cardiac remodeling. In summary, our novel GelMA hydrogel-based intramyocardial vascular cell delivery approach has the potential to improve the treatment of acute MI.
Discovery of two novel Torque Teno viruses in Callithrix penicillata provides insights on Anelloviridae diversification dynamics
Authors: Cosentino Matheus Augusto Calvano , D’arc Mirela , Moreira Filipe Romero Rebello , Cavalcante Liliane Tavares de Faria , Mouta Ricardo , Coimbra Amanda , Schiffler Francine Bittencourt , Miranda Thamiris dos Santos , Viana Gabriel Medeiros , Dias Cecilia A , Souza Antonizete R , Tavares Maria Clotilde Henriques , Tanuri Amilcar , Soares Marcelo Alves , dos Santos André Felipe Andrade
Published: July 2022

1.

The development of high throughput sequencing (HTS) technologies and metagenomics protocols deeply impacted the discovery of viral diversity. Moreover, the comprehension of evolution and immunology of the Neotropical primates (NP) and their susceptibility to infectious diseases are central for the characterization of the scope of etiological agents that may impact global health, due to their evolutionary proximity to Old World primates, including humans. In the present work, novel anelloviruses were detected and characterized through HTS protocols in the NP Callithrix penicillata, the common black-tufted marmoset. De novo assembly of generated sequences was carried out and a total of 15 contigs were identified with complete Anelloviridae ORF1 gene, two of them including a flanking GC-rich region, confirming the presence of two whole novel genomes of ~3kb. The identified viruses were monophyletic within the Epsilontorquevirus genus, a lineage harboring previously reported anelloviruses infecting hosts from the Cebidae family. The genetic divergence found in the new viruses characterized two novel species, named Epsilontorquevirus callithrichensis I and II. The phylogenetic pattern inferred for the Epsilontorquevirus genus was consistent with the topology of their host species tree, echoing a virus-host diversification model observed in other viral groups. This study expands the host span of Anelloviridae and provides insights into their diversification dynamics, highlighting the importance of sampling animal viral genomes to obtain a clearer depiction of their long-term evolutionary processes.
Healthy and diseased placenta barrier on-a-chip models suitable for high-throughput studies
Authors: Rabussier Gwenaёlle , Bünter Ivan , Bouwhuis Josse , Soragni Camilla , Ng Chee Ping , Dormansky Karel , de Windt Leon J. , Vulto Paul , Murdoch Colin E. , Bircsak Kristin M. , Lanz Henriёtte L.
Published: July 2022

Preeclampsia is one of the leading causes of maternal and perinatal morbidity in the world. Its fundamental mechanisms are yet poorly understood due to a lack of good experimental models. Here we report an in vitro model of the placental barrier, based on co-culture of trophoblasts and endothelial cells against a collagen extracellular matrix in a microfluidic platform. The model yielded a functional syncytium with barrier properties, polarization, secretion of relevant extracellular membrane components, thinning of the materno-fetal space, hormone secretion, and transporter function. The model was exposed to low oxygen conditions and perfusion flow was modulated to induce preeclamptic characteristics, resulting in reduced barrier function, hormone secretion, and microvilli as well as increased nuclei count. The model was implemented in a titer plate microfluidic platform fully amenable to high-throughput screening. We thus believe this model could aid mechanistic understanding of preeclampsia as well as support future development of effective therapies through target and compound screening campaigns.
Ion-channel degeneracy and heterogeneities in the emergence of complex spike bursts in CA3 pyramidal neurons
Authors: Roy Rituparna , Narayanan Rishikesh
Published: July 2022

Complex spike bursting (CSB) is a characteristic electrophysiological signature exhibited by several neurons and has been implicated in neural plasticity, learning, perception, anesthesia, and active sensing. Here, we address the question of how pronounced intrinsic and synaptic heterogeneities affect CSB, with hippocampal CA3 pyramidal neurons (CA3PN) as a substrate where CSB emergence and heterogeneities are well-characterized. We randomly generated 12,000 unique models and found 236 valid models that satisfied 11 characteristic CA3PN measurements. These morphologically and biophysically realistic valid models accounted for gating kinetics and somato-dendritic expression profiles of 10 active ion channels. This heterogeneous population of valid models was endowed with broad distributions of underlying parameters showing weak pair-wise correlations. We found two functional subclasses of valid models, intrinsically bursting and regular spiking, with significant differences in the expression of calcium and calcium-activated potassium conductances. We triggered CSB in all 236 models through different intrinsic or synaptic protocols and observed considerable heterogeneity in CSB propensity and properties spanning models and protocols. Finally, we employed virtual knockout analyses and showed that synergistic interactions between intrinsic and synaptic mechanisms regulated CSB emergence and dynamics. Specifically, although there was a dominance of calcium and calcium-activated potassium channels in the emergence of CSB, individual deletion of none of the several ion channels or N-methyl-D-aspartate receptors resulted in the complete elimination of CSB across all models. Together, our analyses critically implicate ion-channel degeneracy in the robust emergence of CSB and other characteristic signatures of CA3PNs, despite pronounced heterogeneities in underlying intrinsic and synaptic properties.
Constitutive Activation and Oncogenicity Are Mediated by Loss of Helical Structure at the Cytosolic Boundary of the Thrombopoietin Receptor
Authors: Defour Jean-Philippe , Leroy Emilie , Dass Sharmila , Balligand Thomas , Levy Gabriel , Mouton Céline , Genet Lidvine , Pecquet Christian , Smith Steven O. , Constantinescu Stefan N.
Published: July 2022

Dimerization of the thrombopoietin receptor (TpoR) is necessary for receptor activation and downstream signaling through activated Janus kinase 2. We have shown previously that different orientations of the transmembrane (TM) helices within a receptor dimer can lead to different signaling outputs. Here we addressed the structural basis of activation for receptor mutations S505N and W515K that induce myeloproliferative neoplasms. We show using in vivo bone marrow reconstitution experiments that ligand-independent activation of TpoR by TM asparagine (Asn) substitutions is proportional to the proximity of the mutation to the intracellular membrane surface. Solid-state NMR experiments on TM peptides indicate a progressive loss of helical structure in the juxtamembrane (JM) R/KWQFP motif with either proximity of Asn substitutions to the cytosolic boundary or mutation of W515 in the motif. Mutational studies in the TpoR cytosolic JM region show that the helical loss by itself can induce activation, but is localized to a maximum of 6 amino acids downstream of W515, the rest of the region until Box 1 requiring helicity for receptor function. The constitutive activation of TpoR mutants S505N and W515K can be inhibited by rotation of TM helices within the TpoR dimer, which also restores helicity around W515. Together these data allow us to develop a general model for activation and to explain the critical role of the JM W515 residue in the regulation of receptor activity.

(Total manuscript without References and Figure Legends 6507 words, main text (without methods and materials):)
Quantifying the movement, behavior, and environmental context of group-living animals using drones and computer vision
Authors: Koger Benjamin , Deshpande Adwait , Kerby Jeffrey T. , Graving Jacob M. , Costelloe Blair R. , Couzin Iain D.
Published: July 2022

Methods for collecting animal behavior data in natural environments, such as direct observation and bio-logging, are typically limited in spatiotemporal resolution, the number of animals that can be observed, and information about animals’ social and physical environments.

Video imagery can capture rich information about animals and their environments, but image-based approaches are often impractical due to the challenges of processing large and complex multi-image datasets and transforming resulting data, such as animals’ locations, into geographic coordinates.

We demonstrate a new system for studying behavior in the wild that uses drone-recorded videos and computer vision approaches to automatically track the location and body posture of free-roaming animals in georeferenced coordinates with high spatiotemporal resolution embedded in contemporaneous 3D landscape models of the surrounding area.

We provide two worked examples in which we apply this approach to videos of gelada monkeys and multiple species of group-living African ungulates. We demonstrate how to track multiple animals simultaneously, classify individuals by species and age-sex class, estimate individuals’ body postures (poses), and extract environmental features, including topography of the landscape and animal trails.

By quantifying animal movement and posture, while simultaneously reconstructing a detailed 3D model of the landscape, our approach opens the door to studying the sensory ecology and decision-making of animals within their natural physical and social environments.
CircRNA-regulated immune response of Asian honey bee workers to microsporidian infection
Authors: Zhu Zhiwei , Wang Jie , Fan Xiaoxue , Long Qi , Chen Huazhi , Ye Yaping , Zhang Kaiyao , Ren Zhongmin , Zhang Yang , Niu Qingsheng , Chen Dafu , Guo Rui
Published: July 2022

Nosema ceranae is a widespread fungal parasite for honey bees, causing bee nosemosis. Based on deep sequencing and bioinformatics, identification of circular RNAs (circRNAs) in Apis cerana cerana workers’ midguts and circRNA-regulated immune response of host to N. ceranae invasion were conducted in this current work, followed by molecular verification of back-splicing sites and expression trends of circRNAs. Here, 10185 and 7405 circRNAs were identified in the midguts of workers at 7 d (AcT1) and 10 d (AcT2) post inoculation (dpi) with N. ceranae. PCR amplification result verified the back-splicing sites in three specific circRNAs (novel_circ_005123, novel_circ_007177, and novel_circ_015140) expressed in N. ceranae-inoculated midgut. In combination with transcriptome data from corresponding un-inoculated midguts (AcCK1 and AcCK2), 2266 circRNAs were found to be shared by the aforementioned four groups, whereas the numbers of specific ones were 2618, 1917, 5691 and 3723 respectively. Further, 83 (52) differentially expressed circRNAs (DEcircRNAs) were identified in AcCK1 vs AcT1 (AcCK2 vs AcT2) comparison group. Source genes of DEcircRNAs in workers’ midgut at 7 dpi were involved in two cellular immune-related pathways such as endocytosis and ubiquitin mediated proteolysis. Additionally, competing endogenous RNA network analysis showed that 23 (13) DEcircRNAs in AcCK1 vs AcT1 (AcCK2 vs AcT2) can target 18 (14) miRNAs and further link to 1111 (1093) mRNAs. These target mRNAs were annotated to six cellular immunity pathways including endocytosis, lysosome, phagosome, ubiquitin mediated proteolysis, metabolism of xenobiotics by cytochrome P450, and insect hormone biosynthesis. Moreover, 284 (164) IRES and 54 (26) ORF were identified from DEcircRNAs in AcCK1 vs AcT1 (AcCK2 vs AcT2) comparison group; additionally, ORFs in DEcircRNAs in midgut at 7 dpi with N. ceranae were associated with several crucial pathways including endocytosis and ubiquitin-mediated proteolysis. Finally, RT-qPCR results showed that the expression trends of six DEcircRNAs were consistent with those in transcriptome data. These results demonstrated that N. ceranae altered the expression pattern of circRNAs in A. c. cerana workers’ midguts, and DEcircRNAs were likely to regulate host cellular and humoral immune response to microsporidian infection. Our findings lay a foundation for clarifying the mechanism underlying host immune response to N. ceranae infection and provide a new insight into interaction between Asian honey bee and microsporidian.
Tyrosine kinase inhibitor independent gene expression signature in CML offers new targets for LSPC eradication therapy
Authors: Gómez-Castañeda Eduardo , Rogers Simon , Munje Chinmay , Bittencourt-Silvestre Joana , Copland Mhairi , Vetrie David , Holyoake Tessa , Hopcroft Lisa , Jørgensen Heather
Published: July 2022

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Tyrosine kinase inhibitors (TKI) have revolutionised the treatment of CML. However, TKI do not eliminate the leukaemia stem cells (LSC), which can reinitiate the disease. Thus, finding new therapeutic targets in CML LSC is key to finding a curative treatment. Using microarray datasets, we defined a list of 227 genes which were differentially expressed in CML LSC compared to healthy controls but were not affected by TKIin vitro. Two of them,CD33andPPIF, are targeted by gemtuzumab-ozogamicin and cyclosporin A, respectively. We treated CML and control CD34+cells with either drug with or without imatinib to investigate the therapeutic potential of the TKI-independent gene expression programme. Cyclosporine A in combination with imatinib reduced the number of CML CFC compared with non-CML controls, but only at supra-therapeutic concentrations. Gemtuzumab-ozogamicin showed a EC50of 146ng/mL, below the plasma peak concentration of 630ng/mL observed in AML patients and below the EC50of 3247ng/mL observed in non-CML cells. Interestingly, gemtuzumab-ozogamicin seems to promote cell cycle progression in CML CD34+cells and demonstrated activation of the RUNX1 pathway in a RNAseq experiment. This suggests that targeting the TKI-independent genes in CML LSC could be exploited for the development of new therapies in CML.

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Simple summary

Chronic myeloid leukaemia (CML) is initiated by a group of cancer cells called leukaemia stem cells (LSC). These LSC can survive current tyrosine kinase inhibitor (TKI) treatments and upon treatment withdrawal, are able to re-initiate the disease. Thus, eradicating the LSC would likely cure CML. In this study, we have identified a number of genes which expression is different between LSC and their healthy counterparts (haematopoietic stem cells) but are not affected by TKI treatment. We hypothesised that these genes may be potential therapeutic targets against LSC and used two different drugs, gemtuzumab-ozogamicin and cyclosporine A, to treat CMLin vitro. We found that both drugs have a stronger effect on CML cells than in healthy cells. Therefore, we propose that the list of genes we identified could represent a novel source of therapeutic targets against CML.