bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploring the mosquito-arbovirus network: a survey of vector competence experiments
Authors: Chen Binqi , Sweeny Amy R. , Wu Velen Yifei , Christofferson Rebecca , Ebel Gregory , Fagre Anna C. , Gallichotte Emily , Kading Rebekah , Ryan Sadie J. , Carlson Colin J.
Published: May 2022

Arboviruses receive heightened research attention during major outbreaks, or when they cause unusual or severe clinical disease, but are otherwise under-characterized. Global change is also accelerating the emergence and spread of arboviral diseases, leading to time sensitive questions about potential interactions between viruses and novel vectors. Vector competence experiments help determine the susceptibility of certain arthropods to a given arbovirus, but these experiments are often conducted in real-time during outbreaks, rather than with preparedness in mind. We conducted a systematic review of reported mosquito-arbovirus competence experiments, screening 570 abstracts to arrive at 265 studies testing in vivo arboviral competence. We found that over 90% of potential mosquito-virus combinations are untested in experimental settings, and that entire regions and their corresponding vectors and viruses are undersampled. These knowledge gaps stymie outbreak response, and limit attempts to both build and validate predictive models of the vector-virus network.
Fetal imidacloprid causes ASD-like impairment of biological motion perception in neonatal chicks
Authors: Matsushima Toshiya , Miura Momoko , Patzke Nina , Toji Noriyuki , Wada Kazuhiro , Ogura Yukiko , Homma Koichi J. , Sgadò Paola , Vallortigara Giorgio
Published: May 2022

Several environmental chemicals are suspected as risk factors for autism spectrum disorder (ASD), including valproic acid (VPA) and pesticides acting on nicotinic acetylcholine receptor (nAChR) if exposed during pregnancy. However, their target processes in fetal neuro-development are unspecified. We report that fetal injection of VPA impaired the imprinting of an artifact object in hatchlings, while the predisposed preference to biological motion (BM) remained intact. Blockade of nAChR acted oppositely, namely, spared imprinting and impaired BM in chicks. Beside ketamine and tubocurarine, significant effects of imidacloprid (a neonicotinoid insecticide) appeared at dose ≤1ppm. Despite the distinct processes, both VPA and nAChR blockade similarly impaired imprinting of biological image composed of point-light animation. Furthermore, both impairments were rescued by post-natal bumetanide treatment, suggesting common pathology underlying the social attachment malformation. Ambient neonicotinoid could hinder adaptive socialization through impaired development of visual perception in early neonates.
Age-specific and Sex-specific Nectar and Pollen Use by a Butterfly Pollinator
Authors: Boggs Carol L. , Iyengar Vikram
Published: May 2022

Age-specific patterns of nectar and pollen use by insect pollinators may reflect behavioral or physiological changes over the insect’s lifespan, and may also influence flower visitation rate. Studying Heliconius charithonia (Lepidoptera: Nymphalidae) and Psiguria umbrosa (Cucurbitaceae), we showed that honey-water (as a nectar substitute) intake increases over the first ten to twelve days of female’s life, while decreasing over the same age period for males, when individuals were fed ad libitum. Intake then remains stable at least through 28 days of age. Mean intake is higher for females than for males, and is not significantly affected by body size. Intake patterns for honey-water and pollen did not change with age in a similar manner. Pollen feeding increased significantly with age for both sexes, with females showing a two week delay in the increase when studied in a free-flying greenhouse population with competition for pollen. Under both ad libitum and pollen competition conditions, females collected more pollen than did males. Body size did not significantly affect the amount of pollen collected for either sex. Within each sex, butterflies with ad libitum pollen collected more pollen than those in a free-flying greenhouse population with more restricted pollen availability. These results suggest that two resources obtained from the same source, pollen and nectar, are not treated identically by the insect pollinator, and that the demography of the insect population may affect flower visitation rates in some cases. Further, foraging patterns for pollen and nectar are likely driven by physiological demand for different resource types.
Novel insights into the pig gut microbiome using metagenome-assembled genomes
Authors: Holman Devin B. , Kommadath Arun , Tingley Jeffrey P. , Abbott D. Wade
Published: May 2022

Pigs are among the most numerous and intensively farmed food-producing animals in the world. The gut microbiome plays an important role in the health and performance of swine and changes rapidly after weaning. Here, fecal samples were collected from pigs at 7 different times points from 7 to 140 days of age. These swine fecal metagenomes were used to assemble 1,150 dereplicated metagenome-assembled genomes (MAGs) that were at least 90% complete and had less than 5% contamination. These MAGs represented 472 archaeal and bacterial species, and the most widely distributed MAGs were the uncultured species Collinsella sp002391315, Sodaliphilus sp004557565, and Prevotella sp000434975. Weaning was associated with a decrease in the relative abundance of 69 MAGs (e.g. Escherichia coli) and an increase in the relative abundance of 140 MAGs (e.g. Clostridium sp000435835, Oliverpabstia intestinalis). Genes encoding for the production of the short-chain fatty acids acetate, butyrate, and propionate were identified in 68.5%, 18.8%, and 8.3% of the MAGs, respectively. Carbohydrate-active enzymes associated with the degradation of arabinose oligosaccharides and mixed-linkage glucans were predicted to be most prevalent among the MAGs. Antimicrobial resistance genes were detected in 327 MAGs, including 59 MAGs with tetracycline resistance genes commonly associated with pigs such as tet(44), tet(Q), and tet(W). Overall, 82% of the MAGs were assigned to species that lack cultured representatives indicating that a large portion of the swine gut microbiome is still poorly characterized. The results here also demonstrate the value of MAGs in adding genomic context to gut microbiomes.

Importance

Many of the bacterial strains found in the mammalian gut are difficult to culture and isolate due to their various growth and nutrient requirements that are frequently unknown. Here, we assembled strain-level genomes from short metagenomic sequences, so-called metagenome-assembled genomes (MAGs), that were derived from fecal samples collected from pigs at multiple time points. The majority of these MAGs represented bacterial species that have yet to be cultured or described thus underlining the need for cultivation studies that isolate and describe novel bacterial species. The genomic context of a number of antimicrobial resistance genes commonly detected in swine was also determined. In addition, our study connected taxonomy with potential metabolic functions such as carbohydrate degradation and short-chain fatty acid production.
Does directly integrating health information exchange (HIE) data with the electronic health record increase HIE use by clinicians in the emergency department?
Authors: Hosler Heidi , Jang Jeong Hoon , Schaffer Jason T. , Price John , Schleyer Titus K. , Rivera Rebecca L.
Published: May 2022

Objective

Develop and evaluate the effect of a Fast Healthcare Interoperability Resources (FHIR) app, Health Dart, integrating information from Indiana’s community health information exchange (HIE), the Indiana Network for Patient Care (INPC), directly with Cerner, an electronic health record (EHR)

Materials and Methods

Health Dart was implemented in 14 Indiana University Health emergency departments (ED) using a stepped-wedge study design. We analyzed rates of INPC use in 286,175 ED encounters between October 1, 2019 and December 31, 2020. Logistic regression was used to model the probability of INPC use given the implementation context, such as user interface (UI) enhancements and the COVID-19 pandemic.

Results

INPC use increased by 131% across all encounters (from 3.6% to 8.3%; p<0.001) after Health Dart implementation. INPC use increased by144% (from 3.6% to 8.8%; p<0.001) more than two months post-implementation. After UI enhancements, post-implementation INPC use increased 123% (from 3.5% to 7.8%) compared to 181% (from 3.6% to 10.1%; p<0.001) in post-implementation encounters that occurred before UI enhancements. During the pandemic, post-implementation INPC use increased by 135% (from 3.4% to 8.0%; p<0.001) compared to 178% (from 3.6% to 10%; p<0.001) in post-implementation encounters that occurred before the pandemic. Statistical significance was determined using 95% confidence intervals (α=0.05).

Discussion

Direct integration of HIE information into an EHR substantially increased frequency of HIE use, but the effect was weakened by the UI enhancements and pandemic.

Conclusion

HIE information integrated into EHRs in the form of dashboards can potentially make information retrieval more efficient and effective for clinicians.
MSM with HIV: Improving prevalence and risk estimates by a Bayesian small area estimation modelling approach for public health service areas in the Netherlands
Authors: Wang Haoyi , den Daas Chantal , de Coul Eline Op , Jonas Kai J
Published: May 2022

In many countries, HIV infections among MSM (MSMHIV) are closely monitored, and updated epidemiological reports are made available annually, yet the true prevalence of MSMHIV can be masked for areas with small population density or lack of data. Therefore, this study aimed to investigate the feasibility of small area estimation with a Bayesian approach to improve HIV surveillance. Data from the European MSM Internet Survey 2017 (EMIS-2017, Dutch subsample, n=3,459) and the Dutch survey ‘Men & Sexuality-2018’ (SMS-2018, n=5,653) were utilized in this study. We first applied a frequentist calculation to compare the observed relative risk of MSMHIV per Public Health Services (GGD) region in the Netherlands. We then applied a Bayesian spatial analysis and ecological regression to account for variance due to space and determinants associated with HIV among MSM to obtain more robust estimates. Results of the prevalence and risk estimations from EMIS-2017 and SMS-2018 converged with minor differences. Both estimations confirmed that the risk of MSMHIV is heterogenous across the Netherlands with some GGD regions, such as GGD Amsterdam [RR=1.21 (95% credible interval 1.05-1.38) by EMIS-2017; RR=1.39 (1.14-1.68) by SMS-2018], having a higher-than-average risk. Results from our ecological regression modelling revealed significant regional determinants which can impact on the risk for MSMHIV. In sum, our Bayesian approach to assess the risk of HIV among MSM was able to close data gaps and provide more robust prevalence and risk estimations. It is feasible and directly applicable for future HIV surveillance as a statistical adjustment tool.
Meningococcal vaccination in adolescents and adults induces bactericidal activity against hyperinvasive complement-resistant meningococcal isolates
Authors: Ohm Milou , Wolf Janine J. , van Rooijen Debbie M. , Visser Linda J. , Miellet Willem R. , Mariman Rob , Trzciński Krzysztof , Buisman Anne-Marie , van der Klis Fiona R.M. , Berbers Guy A.M. , Knol Mirjam J. , van Sorge Nina M. , den Hartog Gerco
Published: May 2022

Background

Complement-mediated killing is critical in the defense against meningococci. During a recent outbreak of invasive meningococcal serogroup W disease (IMD-W) in the Netherlands, the predominant isolates belonged to clonal complex (cc) 11, which may suggest a role for cc11-assocated traits in complement resistance. We investigated complement resistance of invasive and carriage meningococcal isolates of different serogroups and lineages. In addition, we investigated whether vaccine-induced antibodies can overcome resistance to complement-mediated killing.

Methods

We analyzed IMD isolates (n=56) and carriage isolates (n=19) of different serogroups and clonal lineages in the serum bactericidal antibody (SBA) assay using pooled serum from unvaccinated and vaccinated individuals. Furthermore, we determined meningococcal serogroup W geometric mean titers (GMTs) and protection levels with the routinely-used non-cc11 isolate and hyperinvasive cc11 isolates using individual serum samples from adolescents and adults 5 years postvaccination.

Results

The hyperinvasive IMD isolates showed high variation in their resistance to complement-mediated killing when pooled serum from unvaccinated individuals was used (median 96, range 2-1,536). When pooled sera from vaccinated individuals was used, all isolates were killed. The minimum spanning tree revealed moderate clustering of serogroup and cc, while complement resistance did not. While a significantly lower GMT was observed against cc11 meningococcal serogroup W (MenW) compared to a non-cc11 MenW isolate in vaccinated adults but not in adolescents, we found no differences in the proportion protected between these isolates.

Conclusions

These data show that vaccine-induced antibodies are effectively inducing complement-mediated killing of complement-resistant hyperinvasive and carriage meningococcal isolates.

Short summary

Meningococcal isolates of hyperinvasive lineages are resistant to complement-mediated killing but vaccine-induced antibodies effectively kill these invasive isolates.
Neonatal outcomes and indirect consequences following maternal SARS-CoV-2 infection in pregnancy: A systematic review
Authors: Sturrock Sarah , Ali Shohaib , Gale Chris , Battersby Cheryl , Doare Kirsty Le
Published: May 2022

Objectives

Identify the association between maternal SARS-CoV-2 infection in pregnancy and individual neonatal morbidities and outcomes, particularly longer-term outcomes such as neurodevelopment.

Setting

Case-control and cohort studies from any location published after 1st January 2020, including pre-print articles.

Participants

Neonates born to pregnant women diagnosed with a SARS-CoV-2 infection at any stage during pregnancy, including asymptomatic women.

Primary and secondary outcome measures

Neonatal mortality and morbidity, including preterm birth, Caesarean delivery, small for gestational age, admission to neonatal intensive care unit, level of respiratory support required, diagnosis of culture-positive sepsis, evidence of brain injury, necrotising enterocolitis, visual or hearing impairment, neurodevelopmental outcomes, and feeding method. These outcomes were selected according to a Core Outcome Set developed between health professionals, researchers and parents.

Results

The search returned 3234 papers, from which 204 were included with a total of 45,646 infants born to mothers with SARS-CoV-2 infection during pregnancy across 36 countries. We found limited evidence of an increased risk of some neonatal morbidities, including respiratory disease. There was minimal evidence from low-income settings (1 study) and for neonatal outcomes following first trimester infection (17 studies). Neonatal mortality was very rare. Preterm birth, neonatal unit admission and small for gestational age status were more common in infants born following maternal SARS-CoV-2 infection in pregnancy in most larger studies.

Conclusions

There is limited data on neonatal morbidity and mortality following maternal SARS-CoV-2 infection in pregnancy, particularly from low-income countries and following early pregnancy infections. Large, representative studies addressing these outcomes are needed to better understand the consequences for babies born to women with SARS-CoV-2 in pregnancy.

Trial registration

PROSPERO ID: CRD42021249818

Strengths and limitations

Inclusion of studies of both asymptomatic and symptomatic SARS-CoV-2 infections at any point in pregnancy to maximise generalisability of findings

Focus on neonatal outcomes, as opposed to purely obstetric outcomes, to accurately quantify neonatal morbidity

Study is limited by available data; important data gap in low-income settings
Household Air Pollution from Cooking Fuels and its Association with Under-Five Mortality in Bangladesh
Authors: Alam Md. Badsha , Acharjee Supria , Mahmud S. M. Ashique , Tania Jesmin Akter , Ali Khan Md Mostaured , Islam Md. Syful , Khan Md. Nuruzzaman
Published: May 2022

Background

Solid fuel use was found to be associated with under-five mortality in low- and lower-middle income countries (LMICs). However, the current understanding of this association for Bangladesh is absent through around 80% of the total households in Bangladesh used solid fuel and the higher under-five mortality rate is a significant public health burden. We explored the associations of household cooking fuels used and the level of exposure to HAP through cooking fuels used with neonatal, infant, and under-five child mortality in Bangladesh.

Methods

We analysed 4,198 mother-child dyads data extracted from the 2017/18 Bangladesh Demographic and Health Survey data. Type of cooking fuels used (solid fuel, clean fuel) and level of exposure to HAP through cooking fuels used (unexposed, moderately exposed, highly exposed) were considered as exposure variables. Neonatal, infant and under-five mortality were considered as the outcome variables. Relationships between the exposure and outcome variable were explored by using the multilevel mixed-effect logistic regression model adjusting for possible confounders.

Results

Solid fuels were found to be used in nearly 80% of the total mothers analysed. A higher likelihood of mortality was found among neonates (aOR, 3.78; 95% CI, 1.14-12.51) and infants (aOR, 2.93; 95% CI, 1.60-6.15) of the women who used solid fuels as compared to the mothers who used clean fuel. The association was found strongest when we considered solid fuel used together with place of cooking. The likelihood of neonatal and infant mortality was found 4.33 (95% CI, 1.16-16.23) and 2.05 (95% CI, 1.18-7.23) times higher among mothers who were highly exposed to solid fuel used as compared to the mothers who were unexposed to solid fuel used.

Conclusion

Solid fuel used and its increased exposure increased the occurrence of neonatal and infant mortality. Prioritizing the use of clean fuel use and increasing awareness about the adverse effects of solid fuel use are important.
The negative impact of COVID-19 on working memory revealed using a rapid online quiz
Authors: Baseler Heidi A , Aksoy Murat , Salawu Abayomi , Green Angela , Asghar Aziz UR
Published: May 2022

Although coronavirus disease 2019 (COVID-19) affects the respiratory system, it can also have neurological consequences leading to cognitive deficits such as memory problems. The aim of our study was to assess the impact of COVID-19 on working memory function. We developed and implemented an online anonymous survey with a working memory quiz incorporating aspects of gamification to engage participants. 5428 participants successfully completed the survey and memory quiz between 8th December 2020 and 5th July 2021 (68.6% non-COVID-19 and 31.4% COVID-19). Most participants (93.3%) completed the survey and memory quiz relatively rapidly (mean time of 8.84 minutes). Categorical regression was used to assess the contribution of COVID status, age, time post-COVID (number of months elapsed since having had COVID), symptoms, ongoing symptoms and gender, followed by non-parametric statistics. A principal component analysis explored the relationship between subjective ratings and objective memory scores. The objective memory scores were significantly correlated with participants’ own assessment of their cognitive function. The factors significantly affecting memory scores were COVID status, age, time post-COVID and ongoing symptoms. Our main finding was a significant reduction in memory scores in all COVID groups (self-reported, positive-tested and hospitalised) compared to the non-COVID group. Memory scores for all COVID groups combined were significantly reduced compared to the non-COVID group in every age category 25 years and over, but not for the youngest age category (18-24 years old). We found that memory scores gradually increased over a period of 17 months post-COVID-19. However, those with ongoing COVID-19 symptoms continued to show a reduction in memory scores. Our findings demonstrate that COVID-19 negatively impacts working memory function, but only in adults aged 25 years and over. Moreover, our results suggest that working memory deficits with COVID-19 can recover over time, although impairments may persist in those with ongoing symptoms.
Brain Total Creatine Differs Between Primary Progressive Aphasia (PPA) Subtypes and Correlates with Disease Severity
Authors: Hupfeld Kathleen E. , Zöllner Helge J. , Oeltzschner Georg , Hyatt Hayden W. , Herrmann Olivia , Gallegos Jessica , Hui Steve C. N. , Harris Ashley D. , Edden Richard A. E. , Tsapkini Kyrana
Published: May 2022

Primary progressive aphasia (PPA) is comprised of three subtypes: logopenic (lvPPA), non-fluent (nfvPPA), and semantic (svPPA). We used magnetic resonance spectroscopy (MRS) to measure tissue-corrected metabolite levels in the left inferior frontal gyrus (IFG) and right sensorimotor cortex (SMC) from 61 PPA patients. We aimed to: 1) characterize subtype differences in metabolites; and 2) test for metabolite associations with symptom severity. tCr differed by subtype across the left IFG and right SMC. tCr levels were lowest in lvPPA and highest in svPPA. tCr levels predicted lvPPA versus svPPA diagnosis. Higher IFG tCr and lower Glx correlated with greater disease severity. As tCr is involved in brain energy metabolism, svPPA pathology might involve changes in specific cellular energy processes. Perturbations to cellular energy homeostasis in language areas may contribute to symptoms. Reduced cortical excitatory capacity (i.e., lower Glx) in language regions may also contribute to symptoms. Thus, tCr may be useful for differentiating between PPA subtypes, and both tCr and Glx might have utility in understanding PPA mechanisms and tracking progression.

Highlights

No prior work has examined differences in brain metabolite levels for PPA subtypes.

Total creatine (tCr) levels were lowest in lvPPA and highest in svPPA.

tCr levels differentiated lvPPA from svPPA diagnosis.

Higher tCr and lower Glx in the left IFG correlated with greater disease severity.

Changes in cellular energy and excitatory processes may relate to PPA pathology.
Factors Associated With Regional Differences in Healthcare Quality for Patients With Acute Myocardial Infarction in Japan
Authors: Watanabe Shusuke , Shin Jung-ho , Goto Etsu , Kunisawa Susumu , Imanaka Yuichi
Published: May 2022

Objectives

Regional medical coordination is essential for health-system reform in Japan, and the quality of healthcare at the regional level is of great interest. Regional differences in the quality of healthcare for cardiovascular diseases have been pointed out in previous research, and we aimed to clarify regional factors that influence the quality.

Design

Insurance claims database study.

Setting

Patients of acute care in Japan.

Participants

Japanese patients included in the national Diagnosis Procedure Combination (DPC) databases who admitted to hospitals with diagnosis of acute myocardial infarction (AMI) from April 2016 to March 2019.

Main outcome and measures

Using the national DPC databases, risk-adjusted mortality (RAM) in each secondary medical area (SMA) was derived as an indicator for the quality of the healthcare for patients with AMI. Factors associated with RAM were analysed using the partial least squares (PLS) regression model.

Results

There is a wide variation in RAM in the SMAs; the maximum value was 0.593 and the minimum value was 1.445. The PLS regression identified two components positively correlated with RAM. The first component (Component 1) positively correlates with the proportion of the elderly within the population and negatively correlates with the number of medical facilities per area, the population density, and the intra-SMA access to centres with a high volume of emergency percutaneous coronary interventions (ePCI). The second component (Component 2) positively correlates with the number of medical facilities per area and negatively correlates with the number of physicians per person and the intra-SMA access to centres with a high volume of ePCI.

Conclusion

There was wide regional variation in the quality of in-hospital AMI treatments. Results suggested the degree of rurality, the sufficiency of medical resources, the access to high-volume ePCI centres, and coordination of healthcare delivery were associated with healthcare quality for AMI patients.
Social divisions and risk perception can drive divergent epidemic dynamics and large second and third waves
Authors: Harris Mallory J. , Mordecai Erin A.
Published: May 2022

During infectious disease outbreaks, individuals may adopt protective measures like vaccination and physical distancing in response to awareness of disease burden. Prior work showed how feedback between epidemic intensity and awareness-based behavior shapes disease dynamics (e.g., producing plateaus and oscillations). These models often overlook social divisions, where population subgroups may be disproportionately impacted by a disease and more responsive to the effects of disease within their group. We hypothesize that socially divided awareness-based behavior could fundamentally alter epidemic dynamics and shift disease burden between groups.

We develop a compartmental model of disease transmission in a population split into two groups to explore the impacts of awareness separation (relatively greater in-versus out-group awareness of epidemic severity) and mixing separation (relatively greater in-versus out-group contact rates). Protective measures are adopted based on awareness of recent disease-linked mortality. Using simulations, we show that groups that are more separated in awareness have smaller differences in mortality. Fatigue-driven abandonment of protective behavior can drive additional infection waves that can even exceed the size of the initial wave, particularly if uniform awareness drives early protection in one group, leaving that group largely susceptible to future infection. Finally, vaccine or infection-acquired immunity that is more protective against transmission and mortality may indirectly lead to more infections by reducing perceived risk of infection, and thereby reducing vaccine uptake. The dynamics of awareness-driven protective behavior, including relatively greater awareness of epidemic conditions in one’s own group, can dramatically impact protective behavior uptake and the course of epidemics.
Robust alignment of single-cell and spatial transcriptomes with CytoSPACE
Authors: Vahid Milad R. , Brown Erin L. , Steen Chloé B. , Kang Minji , Gentles Andrew J. , Newman Aaron M.
Published: May 2022

Recent studies have emphasized the importance of single-cell spatial biology, yet available assays for spatial transcriptomics have limited gene recovery or low spatial resolution. Here we introduce CytoSPACE, a method for aligning single-cell and spatial transcriptomes via convex linear optimization. Across diverse platforms and tissue types, we show that CytoSPACE outperforms previous methods with respect to noise-tolerance, accuracy, and efficiency, enabling improved analysis of spatial transcriptomics data at single-cell resolution.
Ratiometric NAD+ sensors reveal subcellular NAD+ modulators
Authors: Chen Liuqing , Chen Meiting , Luo Mupeng , Li Yong , Liao Bagen , Hu Min , Yu Qiuliyang
Published: May 2022

Mapping NAD+ dynamics in live cells and human are essential for translating NAD+ interventions into effective therapies. Yet genetically encoded NAD+ sensors with better specificity and pH-resistance are still needed for cost-effective monitoring of subcellular and clinical NAD+. We introduce multicolor, resonance energy transfer-based NAD+ sensors that cover nano- to milli-molar concentration ranges for clinical NAD+ measurement and subcellular NAD+ visualization. The sensors captured the blood NAD+ increase induced by NMN supplementation and revealed the distinct subcellular effects of NAD+ supplements and modulators. Then, the sensors enabled high-throughput screenings for mitochondrial and nucleic NAD+ modulators and identified α-GPC, a cognition-related metabolite, induces NAD+ redistribution from mitochondria to nucleus relative to the total adenine nucleotides, which was confirmed by NAD+ FRET microscopy.
Skin mesenchymal niches maintain and protect AML-initiating stem cells
Authors: Sandhow Lakshmi , Cai Huan , Leonard Elory , Xiao Pingnan , Tomaipitinca Luana , Månsson Alma , Kondo Makoto , Sun Xiaoyan , Johansson Anne-Sofie , Tryggvason Karl , Kasper Maria , Järås Marcus , Qian Hong
Published: May 2022

Leukemia cutis or leukemic cell infiltration in skin is one of the common extramedullary manifestations of acute myeloid leukemia (AML) and signifies a poorer prognosis. However, its pathogenesis and maintenance remain understudied. Here, we report massive AML cell infiltration in the skin in a transplantation-induced MLL-AF9 AML mouse model. These AML cells could regenerate AML post-transplantation. Prospective niche characterization revealed that skin harbored mesenchymal progenitor cells (MPCs) with a similar phenotype as BM mesenchymal stem cells. These skin MPCs protected AML-initiating stem cells (LSCs) from chemotherapyin vitropartially via mitochondrial transfer. Furthermore,Lama4deletion in skin MPCs promoted AML LSC proliferation and chemoresistance. Importantly, more chemoresistant AML LSCs appeared to be retained inLama4-/-mouse skin post-cytarabine treatment. Our study reveals the characteristics and previously unrecognized roles of skin mesenchymal niches in maintaining and protecting AML LSCs during chemotherapy, meriting future exploration of their impact on AML relapse.

A 40-word summary

Sandhow et al have in transplantation-induced AML mouse models demonstrated the leukemia-regenerating capacity of AML cells infiltrated in the skin and the role of skin mesenchymal niches in maintaining/protecting AML cells, providing new insight into the pathology of leukemia cutis.
Divergent projections from Locus Coeruleus to the cortico-basal ganglia system and ventral tegmental area of the zebra finch
Authors: Singh Alvarado Jonnathan , Hatfield Jordan , Mooney Richard
Published: May 2022

The locus coeruleus (LC) is a small brainstem nucleus that is the primary source of noradrenaline (NA) throughout the vertebrate brain. Understanding the anatomical organization of the LC is important because NA plays a central role in regulating arousal, attention, and performance. In the mammalian brain, individual LC neurons make highly divergent axonal projections to different brain regions, which are distinguished in part by which NA receptor subtypes they express. Here we sought to determine whether similar organizational features - divergent LC projections acting regionally through different receptor subtypes - characterize cortico-basal ganglia (CBG) circuitry important to birdsong learning and performance. Single and dual retrograde tracer injections reveal that single LC-NA neurons make divergent projections to both cortical and basal ganglia components of this circuit, as well as to dopaminergic nuclei that innervate this circuit. Moreover, in situ hybridization revealed that differential expression of the α2A and α2C adrenoreceptor distinguish LC-recipient song nuclei. Therefore, LC - NA signaling in the songbird CBG circuit could employ a similar strategy as in mammals, which allows a relatively small number of LC neurons to exert widespread yet distinct effects across multiple brain regions.

Key Points

The locus coeruleus projects to most of the song system (HVC, RA, LMAN, Area X, DLM).

Noradrenergic receptors are regionally specialized in BG despite divergent connectivity of LC neurons.

Noradrenergic projections to dopaminergic nuclei could influence vocal variability and learning.
A Novel Strategy for Dynamic Modelling of Genome-Scale Interaction Networks
Authors: Borzou Pooya , Ghaisari Jafar , Izadi Iman , Eshraghi Yasin , Gheisari Yousof
Published: May 2022

Background

Modern medicine is equipped with huge amounts of big biological datasets and a wide range of computational methods to understand the molecular events underlying complex disorders. The recent availability of omics data allows a holistic view towards the interactions of various biomolecule types. However, the constructed maps are static, ignoring the dynamicity of molecular processes. On the other hand, the dynamic models of biological systems are commonly generated in small scales. Hence, the construction of large scale dynamic models that can quantitatively predict the time-course cellular behaviors is a big challenge. This study was aimed at developing a pipeline for automatic construction of such models from time-course experimental data.

Results

Information of interactions between input genes is retrieved from SIGNORE 2.0 database and an interaction network is constructed which then is translated to biochemistry language and converted to a biochemical reactions network. In the next step, a large-scale ODE system is constructed by generating the ODE equivalent of each biochemical reaction. To estimate the kinetics parameters of the ODE model, a novel large-scale parameter approximation method is proposed. This method gives an estimation of system parameters by fitting model outputs to time-course experimental measurements. The total pipeline is provided as a MATLAB toolbox called SPADAN, standing for Systematic Protein Association Dynamic ANalyzer. Using multilayer time-series experimental data, the performance of the pipeline was checked by modeling 4379 regulatory interactions between 768 molecules in colon cancer cells exposed to chemotherapy agents.

Conclusion

Starting from time-series experimental data, SPADAN automatically constructs map of interactions, generates an ODE system, and performs a parameter approximation procedure. It constructs genome-scale dynamic models, filling the gap between large-scale static and small-scale dynamic modeling strategies. This simulation approach allows for holistic quantitative predictions which is critical for the simulation of therapeutic interventions in precision medicine.
CRISPR-Cas provides limited phage immunity to a prevalent gut bacterium in gnotobiotic mice
Authors: Rasmussen Torben Sølbeck , Koefoed Anna Kirstine , Deng Ling , Muhammed Musemma K. , Rousseau Geneviève M. , Kot Witold , Sprotte Sabrina , Neve Horst , Franz Charles M.A.P. , Hansen Axel Kornerup , Vogensen Finn Kvist , Moineau Sylvain , Nielsen Dennis Sandris
Published: May 2022

Many prokaryotes harbor the adaptive CRISPR-Cas system, which stores small nucleotide fragments from previous invasions of nucleic acids via viruses or plasmids. This molecular archive blocks further invaders carrying identical or similar nucleotide sequences. However, very few of these systems have been experimentally confirmed to be active in gut bacteria. Here, we experimentally demonstrate that the type I-C CRISPR-Cas system of the prevalent gut bacterium Eggerthella lenta can specifically target and cleave foreign DNA in vitro by using a plasmid transformation assay. We also show that the CRISPR-Cas system acquires new immunities (spacers) from the genome of a virulent E. lenta phage using traditional phage-assays in vitro but also in vivo using gnotobiotic (GB) mice. An increased number of spacer acquisition events were observed when E. lenta was exposed to a low multiplicity of infection in vitro, and three phage genes were found to contain protospacer hotspots. Interestingly, much less new spacer acquisitions were detected in vivo than in vitro. Longitudinal analysis of phage-bacteria interactions showed sustained coexistence in the gut of GB mice, with phage abundance being approximately one log higher than the bacteria. Our findings show that while the type I-C CRISPR-Cas system is active in vitro and in vivo, a highly virulent phage in vitro was still able co-exist with its bacterial host in vivo. Taken altogether, our results suggest that the CRISPR-Cas defense system of E. lenta provides only partial immunity in the gut.
Succinylated lysine residue prediction revisited
Authors: Ahmed Shehab Sarar , Rifat Zaara Tasnim , Rahman Mohammad Saifur , Rahman M. Sohel
Published: May 2022

Motivation

Lysine succinylation is a kind of post-translational modification (PTM) which plays a crucial role in regulating the cellular processes. Aberrant succinylation may cause inflammation, cancers, metabolism diseases and nervous system diseases. The experimental methods to detect succinylation sites are time-consuming and costly. This thus calls for computational models with high efficacy and attention has been given in the literature for developing such models, albeit with only moderate success in the context of different evaluation metrics. One important aspect in this context is the biochemical and physicochemical properties of amino acids, which appear to be useful as features for such computational predictors. However, some of the existing computational models did not use the biochemical and physicochemical properties of amino acids, while some others used them without considering the inter-dependency among the properties.

Results

The combinations of biochemical and physicochemical properties derived through our optimization process achieve better results than the results achieved by the combination of all the properties. We propose three deep learning architectures, CNN+Bi-LSTM (CBL), Bi-LSTM+CNN (BLC) and their combination (CBL_BLC). We find that CBL_BLC is outperforming the other two. Ensembling of different models successfully improves the results. Notably, tuning the threshold of the ensemble classifiers further improves the results. Upon comparing our work with other existing works on two datasets, we find that we successfully achieve better sensitivity and specificity through varying the threshold value.

Availability

https://github.com/Dariwala/Succinylation-with-biophysico-and-deep-learning

Contact

msrahman@cse.buet.ac.bd
Reduced sphingolipid biosynthesis modulates proteostasis networks to enhance longevity
Authors: Hepowit Nathaniel L. , Blalock Eric , Lee Sangderk , MacGurn Jason A. , Dickson Robert C.
Published: May 2022

As the elderly population increases, chronic, age-associated diseases are challenging healthcare systems around the world. Nutrient limitation is well known to slow the aging process and improve health. Regrettably, practicing nutrient restriction to improve health is unachievable for most people. Alternatively, pharmacological strategies are being pursued including myriocin which increases lifespan in budding yeast. Myriocin impairs sphingolipid synthesis, resulting in lowered amino acid pools which promote entry into a quiescent, long-lived state. Here we present transcriptomic data during the first 6 hours of drug treatment that improves our mechanistic understanding of the cellular response to myriocin and reveals a new role for ubiquitin in longevity. Previously we found that the methionine transporter Mup1 traffics to the plasma membrane normally in myriocin-treated cells but is not active and undergoes endocytic clearance. We now show that UBI4, a gene encoding stressed-induced ubiquitin, is vital for myriocin-enhanced lifespan. Furthermore, we show that Mup1 fused to a deubiquitinase domain impairs myriocin-enhanced longevity. Broader effects of myriocin treatment on ubiquitination are indicated by our finding of a significant increase in K63-linked ubiquitin polymers following myriocin treatment. Although proteostasis is broadly accepted as a pillar of aging, our finding that ubiquitination of an amino acid transporter promotes longevity in myriocin-treated cells is novel. Addressing the role of ubiquitination/deubiquitination in longevity has the potential to reveal new strategies and targets for promoting healthy aging.
Hematopoietic stem cells are a reservoir for trained immunity in autoimmune disease
Authors: Mills Taylor S. , Kain Bailee , Burchill Matt A. , Danis Etienne , Culp-Hill Rachel , Goodspeed Andrew , Ferrara Sarah , Roede James R. , D’Alessandro Angelo , King Katherine Y. , Pietras Eric M.
Published: May 2022

Trained immunity (TI) has been speculated to serve as a contributor to autoimmune disease (AD) pathogenesis via generation of hyper-inflammatory myeloid cells. Using a mouse model of systemic lupus erythematosus (SLE), we show that hematopoietic stem cells (HSC) constitute a transplantable, long-term reservoir for macrophages that exhibit features of TI, including increased Mycobacterium avium killing, inflammatory cytokine production, and augmented capacity to co-stimulate naive T cells. Strikingly, hematopoietic progenitor cells derived from these HSC exhibit unique molecular features characterized by reduced chromatin accessibility and transcription of metabolic genes, accompanied by reduced glycolysis and central carbon metabolism. Altogether, our data identify HSC as a functional unit of TI in chronic AD, establish increased T-cell costimulatory activity as a potentially pathogenic feature of TI in this setting, and show that macrophages inherit reduced metabolic activity from AD-exposed HSC, suggesting metabolic activation and TI can be decoupled. Our findings thus implicate HSC as a long-term reservoir for TI that could contribute to AD.
DNAscope: High accuracy small variant calling using machine learning
Authors: Freed Donald , Pan Renke , Chen Haodong , Li Zhipan , Hu Jinnan , Aldana Rafael
Published: May 2022

We present DNAscope, an accurate and efficient germline small-variant caller. DNAscope combines the robust and well-established preprocessing and assembly mathematics of the GATK’s HaplotypeCaller with a machine-learned genotyping model. Benchmarks of DNAscope and DNAseq (Sentieon’s GATK-matching germline variant calling pipeline) demonstrate that DNAscope achieves superior SNP and insertion/deletion accuracy with reduced computational cost.
Artificial Alzheimer’s – visualizing the process of memory decay, confusion and death in a simple Neural Network Model of Associative Memory
Authors: Gustafsson Lennart
Published: May 2022

This paper analyzes the behaviour of Alzheimer’s disease simulation in artificial neural networks and thereby suggests a new possible diagnosis for Alzheimer. Alzheimer’s disease is one of the most common diseases, increasing severity over time. Despite its high prevalence and thousands of yearly publications in this area, no cure has been found to date and early detection is one of the most important factor towards fighting the disease and possibly finding a cure. This paper analyses the behaviour of simulated Alzheimer in Hopfield memories and observes that the main factor influenced by the loss of connections is the time needed to recognize distorted symbols - while the recognition performance stays surprisingly high for a long time. Hence, I suggest a new early diagnosis approach which is based on slightly distorted elements (e.g., characters) and measures the time needed to perform the task, instead of just focusing on the subject’s recognition performance. This insight could have a large impact to future diagnose setups, once being validated in a clinical study.
Rab11 regulates autophagy at dendritic spines in an mTOR- and NMDA-dependent manner
Authors: Janusz-Kamińska Aleksandra , Brzozowska Agnieszka , Tempes Aleksandra , Urbanska Malgorzata , Blazejczyk Magdalena , Miłek Jacek , Zeng Juan , Kisielewska Katarzyna , Jaworski Jacek
Published: May 2022

Synaptic plasticity is a process that shapes neuronal connections during neurodevelopment, learning, and memory. Autophagy is a mechanism that allows cells to degrade their unnecessary or dysfunctional components. Autophagosomes appear at dendritic spines in response to plasticity-inducing stimuli. Autophagy defects contribute to altered dendritic spine development, autistic-like behavior in mice, and neurological disease. While several studies explored the involvement of autophagy in synaptic plasticity, the steps preceding autophagosome emergence at the postsynapse remain unknown. Here we show a postsynaptic association of autophagy-related protein 9A (Atg9A), known to be involved in the initial stages of autophagosome formation, with Rab11, a small GTPase that regulates endosomal trafficking. Rab11 activity is necessary for the maintenance of Atg9A-positive structures at dendritic spines. Inhibition of mTOR increased Rab11 and Atg9A interaction and increased the emergence of autophagosomes in dendritic spines when coupled to NMDA receptor stimulation. Dendritic spines with newly formed autophagosomes were more resistant to NMDA-induced morphologic change. These results collectively suggest that autophagy initiation in dendritic spines depends on an activity-dependent Rab11a-Atg9A interaction regulated by mTOR.
Design of a mucin-selective protease for targeted degradation of cancer-associated mucins
Authors: Pedram Kayvon , Shon D. Judy , Tender Gabrielle S. , Mantuano Natalia R. , Northey Jason J. , Metcalf Kevin J. , Wisnovsky Simon P. , Riley Nicholas M. , Forcina Giovanni C. , Malaker Stacy A. , Kuo Angel , George Benson M. , Miller Caitlyn L. , Casey Kerriann M. , Vilches-Moure José G. , Weaver Valerie M. , Laübli Heinz , Bertozzi Carolyn R.
Published: May 2022

Targeted protein degradation is an emerging strategy for the elimination of classically undruggable proteins. Here, to expand the landscape of substrates that can be selectively degraded, we designed degraders which are dependent on both peptide sequence and glycosylation status of the target protein. We applied this approach to mucins, O-glycosylated proteins that drive cancer progression through biophysical and immunological mechanisms. Engineering of a bacterial mucin-selective protease yielded a variant for fusion to a cancer antigen-binding nanobody. The resulting conjugate selectively degraded mucins on cancer cells, promoted cell death in culture models of mucin-driven growth and survival, and reduced tumor growth in murine models of breast cancer progression. This work establishes a blueprint for the development of biologics which degrade specific glycoforms of cell surface proteins.