bluuebunny/crossref_metadata_2025 huggingface dataset:
An Agent-Based Model for COVID-19 in Bangladesh
Authors: Farheen Farhanaz , Shamil Md Salman , Rahman Jony Sheikh Saifur , Ahmad Zafar , Sojib Kawsar Hosain , Chowdhury Anir , Niaz Arifin SM , Sania Ayesha , Rahman M. Sohel
Published: July 2022

Background

The COVID-19 pandemic, that has resulted in millions of deaths and hundreds of millions of cases worldwide, continues to affect the lives, health and economy of various countries including Bangladesh. Despite the high proportion of asymptomatic cases and relatively low mortality, the virus’s spread had been a significant public health problem for densely populated Bangladesh. With the healthcare system at stress, understanding the disease dynamics in the unique Bangladesh context became essential to guide policy decisions.

Methods

With a goal to capture the COVID-19 disease dynamics, we developed two stochastic Agent-Based Models (ABMs) considering the key characteristics of COVID-19 in Bangladesh, which vastly differ from the developed countries. We have implemented our ABMs extending the popular (but often inadequate) SIR model, where the infected population is sub-divided into Asymptomatic, Mild Symptomatic and Severe Symptomatic populations. One crucial issue in Bangladesh is the lack of enough COVID-19 tests as well as unwillingness of people to do the tests resulting in much less number of official positive cases than the actual reality. Although not directly relevant to the epidemiological process, our model attempts to capture this crucial aspect while calibrating against official daily test-positive cases. Our first model, ABM-BD, divides the population into age-groups that interact among themselves based on an aggregated Contact Matrix. Thus ABM-BD considers aggregate agents and avoids direct agent level interactions as the number of agents are prohibitively large in our context. We also implement a scaled down model, ABM-SD, that is capable of simulating agent level interactions.

Results

ABM-BD was quite well-calibrated for Dhaka: the Mean Absolute Percentage Error (MAPE) between official and forecasted cases was 1.845 approximately during the period between April 4, 2020 and March 31, 2021. After an initial model validation, we conducted a number of experiments - including retrospective scenario analysis, and hypothetical future scenario analysis. For example, ABM-BD has demonstrated the trade off between a strict lockdown with low infections and a relaxed lockdown with reduced burden on the economy. Leveraging the true agent level interaction capability of ABD-SD, we have also successfully analyzed the relative severity of different strains thereby (confidently) capturing the effect of different virus mutations.

Conclusions

Our models have adequately captured the COVID-19 disease transmission dynamics in Bangladesh. This is a useful tool to forecast the impact of interventions to assist policymakers in planning appropriate COVID response. Our models will be particularly useful in a resource constrained setting in countries like Bangladesh where the population size is huge.
Genomic epidemiology reveals the dominance of Hennepin County in transmission of SARS-CoV-2 in Minnesota from 2020-2022
Authors: Scotch Matthew , Lauer Kimberly , Wieben Eric D. , Cherukuri Yesesri , Cunningham Julie M , Klee Eric W , Harrington Jonathan J. , Lau Julie S , McDonough Samantha J , Mutawe Mark , O’Horo John C. , Rentmeester Chad E. , Schlicher Nicole R , White Valerie T , Schneider Susan K , Vedell Peter T , Wang Xiong , Yao Joseph D , Pritt Bobbi S , Norgan Andrew P
Published: July 2022

SARS-CoV-2 has had an unprecedented impact on human health and highlights the need for genomic epidemiology studies to increase our understanding of virus evolution and spread, and to inform policy decisions. We sequenced viral genomes from over 22,000 patient samples tested at Mayo Clinic Laboratories between 2020-2022 and use Bayesian phylodynamics to describe county and regional spread in Minnesota.

The earliest introduction into Minnesota was to Hennepin County from a domestic source around January 22, 2020; six weeks before the first confirmed case in the state. This led to the virus spreading to Northern Minnesota, and eventually, the rest of the state. International introductions were most abundant in Hennepin (home to the Minneapolis/St. Paul International (MSP) airport) totaling 45 (out of 107) over the two-year period. Southern Minnesota counties were most common for domestic introductions with 19 (out of 64), potentially driven by bordering states such as Iowa and Wisconsin as well as Illinois which is nearby. Hennepin also was, by far, the most dominant source of in-state transmissions to other Minnesota locations (n=772) over the two-year period.

We also analyzed the diversity of the location source of SARS-CoV-2 viruses in each county and noted the timing of state-wide policies as well as trends in clinical cases. Neither the number of clinical cases or major policy decisions, such as the end of the lockdown period in 2020 or the end of all restrictions in 2021, appeared to have impact on virus diversity across each individual county.

Importance

We analyzed over 22,000 SARS-CoV-2 genomes of patient samples tested at Mayo Clinic Laboratories during a two-year period in the COVID-19 pandemic that included Alpha, Delta, and Omicron VoCs to examine the roles and relationships of Minnesota virus transmission.

We found that Hennepin County, the most populous county, drove the transmission of SARS-CoV-2 viruses in the state after including the formation of earlier clades including 20A, 20C, and 20G, as well as variants of concern Alpha and Delta. We also found that Hennepin County was the source for most of the county-to-county introductions after its initial introduction with the virus in early 2020 from an international source, while other counties acted as transmission “sinks”. In addition, major policies such as the end of the lockdown period in 2020 or the end of all restrictions in 2021, did not appear to have an impact on virus diversity across individual counties.
Adaptive phototaxis ofChlamydomonasand the evolutionary transition to multicellularity in Volvocine green algae
Authors: Leptos Kyriacos C , Chioccioli Maurizio , Furlan Silvano , Pesci Adriana I , Goldstein Raymond E
Published: July 2022

A fundamental issue in biology is the nature of evolutionary transitions from unicellular to multicellular organisms. Volvocine algae are models for this transition, as they span from the unicellular biflagellateChlamydomonasto multicellular species ofVolvoxwith up to 50,000Chlamydomonas-like cells on the surface of a spherical extracellular matrix. The mechanism of phototaxis in these species is of particular interest since they lack a nervous system and intercellular connections; steering is a consequence of the response of individual cells to light. Studies ofVolvoxandGonium, a 16-cell organism with a plate-like structure, have shown that the flagellar response to changing illumination of the cellular photosensor is adaptive, with a recovery time tuned to the rotation period of the colony around its primary axis. Here, combining high-resolution studies of the flagellar photoresponse with 3D tracking of freely-swimming cells, we show that such tuning also underlies phototaxis ofChlamydomonas. A mathematical model is developed based on the rotations around an axis perpendicular to the flagellar beat plane that occur through the adaptive response to oscillating light levels as the organism spins. Exploiting a separation of time scales between the flagellar photoresponse and phototurning, we develop an equation of motion that accurately describes the observed photoalignment. In showing that the adaptive time scale is tuned to the organisms’ rotational period across three orders of magnitude in cell number, our results suggest a unified picture of phototaxis in green algae in which the asymmetry in torques that produce phototurns arise from the individual flagella ofChlamydomonas, the flagellated edges ofGoniumand the flagellated hemispheres ofVolvox.
Drug repurposing for therapeutic discovery against human metapneumovirus infection
Authors: Van Den Bergh Annelies , Guillon Patrice , von Itzstein Mark , Bailly Benjamin , Dirr Larissa
Published: July 2022

Human metapneumovirus (HMPV) is recognised as an important cause of pneumonia in infants, elderly, and immunocompromised individuals worldwide. The absence of an antiviral treatment or vaccine strategy against HMPV infection creates a high burden on the global health care system. Drug repurposing has become increasingly attractive for the treatment of emerging and endemic diseases as it requires less research and development costs than traditional drug discovery. In this study, we developed anin vitromedium-throughput screening assay that allows for the identification of novel anti-HMPV drugs candidates. Out of ∼2400 compounds, we identified eleven candidates with a dose-dependent inhibitory activity against HMPV infection. Additionally, we further described the mode of action of five anti-HMPV candidates with lowin vitrocytotoxicity. Two entry inhibitors, Evans Blue and aurintricarboxylic acid, and three post-entry inhibitors, mycophenolic acid, mycophenolate mofetil, and 2,3,4-trihydroxybenzaldehyde, were identified. Among them, the mycophenolic acid series displayed the highest levels of inhibition, due to the blockade of intracellular guanosine synthesis. Importantly, MPA has significant potential for drug repurposing as inhibitory levels are achieved below the approved human oral dose. Our drug-repurposing strategy proved to be useful for the rapid discovery of novel hit candidates to treat HMPV infection and provide promising novel templates for drug design.

Highlights

There is currently no treatment against acute HMPV infection.

We developed a medium-throughput screening for drug repurposing against HMPV infection.

Evaluation of a large drug library identified 5 candidates with low μM to nM IC50values against HMPV growth.

The approved drug mycophenolic acid (MPA) is a nM inhibitor of HMPVin vitroinfection

Human MPA plasma levels upon oral dosing are 10x higher than MPA IC50against HMPVin vitroinfection.
PERK-ATAD3A interaction protects mitochondrial proteins synthesis during ER stress
Authors: Hughes Daniel T. , Brar Karinder K. , Morris Jordan L. , Subramanian Kelly , Krishna Shivaani , Gao Fei , Rieder Lara-Sophie , Freeman Joshua , Smith Heather L. , Jukes-Jones Rebekkah , Nunnari Jodi , Prudent Julien , Butcher Adrian J. , Mallucci Giovanna R.
Published: July 2022

Widespread repression of protein synthesis rates is a key feature of Endoplasmic Reticulum (ER) stress, mediated by the ER sensor kinase PERK. While select transcripts escape this repression, global translational down-regulation impacts crucial protein levels in all cellular compartments, beyond the ER. How the cell manages this paradox is unclear. PERK has a unique cytoplasmic loop within its kinase domain that binds PERK’s target, eIF2α. We identified the mitochondrial protein, ATAD3A, as a new interactor of the loop, binding to a highly conserved region within it. During ER stress, increased interaction between ATAD3A and PERK attenuates PERK signalling to eIF2α, removing the translational block on several mitochondrial proteins. This occurs at novel context-dependent, mitochondria-ER contact sites. The interaction provides a previously unknown mechanism for fine-tuning translational repression at a local level, mitigating the impact of ER stress on mitochondria. Further, it represents a new target for selective modulation of PERK-eIF2α signalling in diseases from cancer to neurodegeneration.

Graphical Abstract
Structural plasticity of axon initial segment in spinal cord neurons underlies inflammatory pain
Authors: Caspi Yaki , Mazar Michael , Kushnir Yishai , Mazor Yoav , Katz Ben , Lev Shaya , Binshtok Alexander M
Published: July 2022

Activity-dependent structural plasticity of axon initial segment (AIS) regulates neuronal excitability, thus fine-tuning neuronal and overall network output. Here using behavioral, immunohistochemical, electrophysiological and computational approaches, we describe the structural plasticity of AIS in rat’s superficial spinal cord dorsal horn (SDH) neurons, which underlies inflammatory pain. We show an inflammation-mediated distal shift of the AIS away from the soma in inhibitory but not excitatory SDH neurons, concomitant with the peak of inflammatory pain. This AIS translocation was accompanied by a decrease in excitability of the inhibitory neurons. Following recovery from inflammatory hyperalgesia, the AIS location and neuronal excitability reversed to baseline levels. The computational model of SDH inhibitory neurons predicts that the distal shift of AIS is sufficient to decrease the intrinsic excitability of these neurons. Our results provide evidence of differential inflammation-mediated AIS plasticity, reducing the excitability of inhibitory but not excitatory SDH neurons and contributing to inflammatory hyperalgesia.
Differential Regulation Analysis Quantifies Mirna Regulatory Roles and Context-Specific Targets
Authors: Ning Boting , Spira Tamar , Beane Jennifer E. , Lenburg Marc E.
Published: July 2022

Rewiring of transcriptional regulatory networks has been implicated in many biological and pathological processes. However, most current methods for detecting rewiring events (differential network connectivity) are not optimized for miRNA-mediated gene regulation and fail to systematically examine predicted target genes in study designs with multiple experimental or phenotypic groups. We developed a novel method to address these shortcomings. The method first estimates miRNA-gene expression correlations with Spatial Quantile Normalization to remove the mean-correlation relationship. Then, for each miRNA, genes are ranked by their correlation strength per experimental group. Enrichment patterns of predicted target genes are compared using the Anderson-Darling test and significance levels are estimated via permutation. Finally, context-specific target genes for each miRNA are identified with target prioritization based on the correlation strength between miRNA and predicted target genes within each group. In miR-155 KO RNA-seq data from four mice immune cell types, our method captures the known cell-specific regulatory differences of miR-155, and prioritized targets are involved in functional pathways with cell-type specificity. Moreover, in TCGA BRCA data, our method identified subtype-specific targets that were uniquely altered by miRNA perturbations in cell lines of the same subtype. Our work provides a new approach to characterize miRNA-mediated gene regulatory network rewiring across multiple groups from transcriptomic profiles. The method may offer novel insights into cell-type and cancer subtype-specific miRNA regulatory roles.
Age-related change in transient gamma band activity during working memory maintenance through adolescence
Authors: McKeon Shane D. , Calabro Finnegan , Thorpe Ryan V. , de la Fuente Alethia , Foran Will , Parr Ashley C. , Jones Stephanie R. , Luna Beatriz
Published: July 2022

Adolescence is a stage of development characterized by neurodevelopmental specialization of cognitive processes. In particular, working memory continues to improve through adolescence, with increases in response accuracy and decreases in response latency continuing well into the twenties. Human electroencephalogram (EEG) studies indicate that gamma oscillations (35-65 Hz) during the working memory delay period support the maintenance of mnemonic information guiding subsequent goal-driven behavior, which decrease in power with development. Importantly, recent electrophysiological studies have shown that gamma events, more so than sustained activity, may underlie working memory maintenance during the delay period. However, developmental differences in gamma events during working memory have not been studied. Here, we used EEG in conjunction with a novel spectral event processing approach to investigate age-related differences in transient gamma band activity during a memory guided saccade (MGS) task in 164 10- to 30-year-olds. Total gamma power was found to significantly decrease through adolescence, replicating prior findings. Results from the spectral event pipeline showed age-related decreases in the mean power of gamma events and trial-by-trial power variability across both the delay period and fixation epochs of the MGS task. In addition, we found that while event number decreased with age during the fixation period, it did not appear to change during the delay period resulting in an increasing difference between the number of events during fixation and delay period with development, suggesting that as working memory develops there is greater specificity for gamma events supporting working memory. While average power of the transient gamma events was found to mediate age-related changes in total gamma power, the number of gamma events was unrelated to total power, suggesting that the power of gamma events may underlie the sustained gamma activity seen in EEG literature while the number of events may directly support age-related improvements in working memory maintenance. Our findings provide compelling new evidence for mechanistic changes in neural processing characterized by refinements in neural function as behavior becomes optimized in adulthood.
Positive indirect effects more than balance negative direct effects of ungulate grazers on population growth of a grassland herb
Authors: Richards Thomas J. , Thomann Michel , Ehrlén Johan , Ågren Jon
Published: July 2022

Herbivores can affect plant population dynamics both directly because of the damage they inflict, and indirectly by moderating conditions for plant recruitment, competition and other biotic interactions. Still, the relative importance of indirect effects of herbivores on plant population dynamics is poorly known.

We quantified direct and indirect effects of ungulate grazers on population growth rate of the short-lived perennial herb Primula farinosa, using integral projection models based on demographic data collected over 7 years in exclosures and open control plots at nine grassland sites in southern Sweden. In addition, we explored the mechanisms behind indirect effects with simulations.

Grazers had negative direct effects on P. farinosa population growth rate, but these were more than balanced by positive indirect effects. The positive indirect effects were mainly linked to improved conditions for plant recruitment. Simulations indicated that indirect effects of ungulate grazers on population growth rate via interactions with pollinators, seed predators, and small herbivores were weak in this system.

Synthesis. The results demonstrate that a full understanding of the effects of grazing on plant population dynamics requires that both direct and indirect effects are identified and quantified. Plant species vary considerably in their response to shifts in grazing regime. Our study sets an example for how the causes of such variation can be assessed, and thus providing a better understanding of the variable effects of herbivores on plant fitness, abundance and distribution.
Specific recognition and ubiquitination of slow-moving ribosomes by human CCR4-NOT
Authors: Absmeier Eva , Chandrasekaran Viswanathan , O’Reilly Francis J , Stowell James AW , Rappsilber Juri , Passmore Lori A
Published: July 2022

Eukaryotic messenger RNA (mRNA) decay is generally initiated by removal of the 3’ polyadenosine (poly(A)) tail by the CCR4-NOT complex. Yeast Ccr4-Not binds and ubiquitinates ribosomes stalled on mRNAs with sub-optimal codons to trigger deadenylation and decay of the associated transcript. However, the mammalian ortholog of the E3 ubiquitin ligase subunit, CNOT4, is not a constitutive component of human CCR4-NOT. It therefore remains unclear how the mammalian deadenylation machinery targets stalled ribosomes. Here, we reconstitute translational stalling on non-optimal codons. We find that human CCR4-NOT recognizes translating mammalian ribosomes and is required for stable CNOT4 association. Our cryoEM structure reveals that the CNOT3 subunit detects slow translation and locks the L1 stalk of the ribosome in an open conformation to impede further elongation. Using crosslinking mass spectrometry, we show that CNOT4 and CNOT11 also bind in the vicinity of the E site. Overall, our work defines how CCR4-NOT enforces ribosomal stalling in response to low codon optimality.
Comparisons of the rate of acute myocardial infarction between COVID-19 patients and individuals received COVID-19 vaccines: a population-based study
Authors: Chou Oscar Hou In , Chung Cheuk To , Satti Danish Iltaf , Zhou Jiandong , Lee Teddy Tai Loy , Wai Abraham Ka Chung , Liu Tong , Lee Sharen , Vassiliou Vassilios S , Cheung Bernard Man Yung , Tse Gary
Published: July 2022

Background

Both Coronavirus Disease-2019 (COVID-19) infection and COVID-19 vaccination have been associated with the development of acute myocardial infarction (AMI). This study compared the rates of AMI after COVID-19 infection and among the COVID-19 vaccinated populations in Hong Kong.

Methods

This was a population-based cohort study from Hong Kong, China. Patients with positive real time-polymerase chain reaction (RT-PCR) test for COVID-19 between January 1st, 2020 and June 30th, 2021 were included. The data of the vaccinated and unvaccinated population was obtained from the “Reference Data of Adverse Events in Public Hospitals” published by the local government. The individuals who were vaccinated with COVID-19 vaccination prior the observed period (December 6th, 2021 to January 2nd, 2022) in Hong Kong were also included. The vaccination data of other countries were obtained by searching PubMed using the terms [“COVID-19 vaccine” AND “Myocardial infarction”] from its inception to February 1st, 2022. The main exposures were COVID-19 test positivity or previous COVID-19 vaccination. The primary outcome was the development of AMI within 28 days observed period.

Results

This study included 11441 COVID-19 patients, of whom 25 suffered from AMI within 28 days of exposure (rate per million: 2185; 95% confidence interval [CI]: 1481-3224). The rates of AMI were much higher than those who were not vaccinated by the COVID-19 vaccine before December 6th, 2021 (rate per million: 162; 95% CI: 147-162) with a rate ratio of 13.5 (95% CI: 9.01-20.2). Meanwhile, the rate of AMI was lower amongst the vaccinated population (rate per million: 47; 95% CI: 41.3-53.5) than COVID-19 infection with a rate ratio of 0.02 (0.01, 0.03). Regarding post-vaccination AMI, COVID-19 infection was associated with a significantly higher rate of AMI than post-COVID-19 vaccination AMI in other countries.

Conclusions

COVID-19 infection was associated with a higher rate of AMI than the vaccinated general population, and those immediately after COVID-19 vaccination.
CD3e-immunotoxin spares CD62LloTregs and reshapes organ-specific T-cell composition by preferentially depleting CD3ehiT cells
Authors: Kim Shihyoung , Shukla Rajni Kant , Yu Hannah , Baek Alice , Cressman Sophie G , Golconda Sarah , Lee Ga-Eun , Choi Hyewon , Reneau John C , Wang Zhirui , Huang Christene A. , Liyanage Namal P. M. , Kim Sanggu
Published: July 2022

CD3-epsilon(CD3e) immunotoxins (IT), a promising precision reagent for various clinical conditions requiring effective depletion of T cells, often shows limited treatment efficacy for largely unknown reasons. Tissue-resident T cells that persist in peripheral tissues have been shown to play pivotal roles in local and systemic immunity, as well as transplant rejection, autoimmunity and cancers. The impact of CD3e-IT treatment on these local cells, however, remains poorly understood. Here, using a new murine testing model, we demonstrate a substantial enrichment of tissue-resident Foxp3+ Tregs following CD3e-IT treatment. Differential surface expression of CD3e among T-cell subsets appears to be a main driver of Treg enrichment in CD3e-IT treatment. The surviving Tregs in CD3e-IT-treated mice were mostly the CD3edimCD62Lloeffector phenotype, but the levels of this phenotype markedly varied among different lymphoid and nonlymphoid organs. We also found notable variations in surface CD3e levels among tissue-resident T cells of different organs, and these variations drive CD3e-IT to uniquely reshape T-cell compositions in local organs. The functions of organs and anatomic locations (lymph nodes) also affected the efficacy of CD3e-IT. The multi-organ pharmacodynamics of CD3e-IT and potential treatment resistance mechanisms identified in this study may generate new opportunities to further improve this promising treatment.
Neuronal Activity Alters Neuron to OPC Synapses
Authors: Moura  , Parvathaneni  , Sahagun  , Noguchi  , Brennan  , Tilton  , Brock  , Halladay  , Pleasure  , Cocas
Published: July 2022

The mechanisms that drive the timing and specificity of oligodendrocyte myelination during development, or remyelination after injury or immune attack are not well understood. Recent work has shown that oligodendrocyte progenitors receive synapses from neurons, providing a potential mechanism for neuronal-glial communication. We hypothesize that these connections are important both for correct myelination of neurons during development and for myelination during neuronal plasticity. We utilized chemogenetic tools and viral monosynaptic circuit tracing to analyze these neuroglial connections and to examine OPC proliferation, myelination, synapse formation, and neuronal-glial connectivity after increasing or decreasing neuronal activity in vivo. We found that increasing neuronal activity increased OPC activation, but not proliferation. We also found that altering neuronal activity altered neuronal-glial synaptic connections: while it did not impact the total number of neuronal inputs, or the number of inhibitory neuronal inputs, it did alter the number of excitatory neuron to OPC connections. We also found that increasing or decreasing neuronal activity impacted the ratio of excitatory and inhibitory synapses. Our data show that neuronal activity affects OPC activation, neuronal synapse formation onto OPCs, as well as the types of neuronal inputs to OPCs, indicating that neuronal activity is important for OPC circuit composition and function.
Synonymous polymorphism difference relating to codon degeneracy between co-transcribed genes in the genome ofEscherichia coli
Authors: Beura Pratyush Kumar , Sen Piyali , Aziz Ruksana , Chetia Chayanika , Dash Madhusmita , Satapathy Siddhartha Shankar , Ray Suvendra Kumar
Published: July 2022

The previous findings suggest that replication and transcription are two major reasons behind the different substitution patterns of mutations in genomic DNA. In the current work, we have compared the adjacent co-transcribed gene pairs regarding synonymous polymorphism in five different operons inEscherichia coli. It is interesting that the co-transcribed genes were different from each other regarding the polymorphism spectra. The transition to transversion ratio between gene pairs were different due to their compositional differences regarding two-fold degenerate codon and four-fold degenerate codons. Further, the polymorphism spectra difference between the gene pairs was more prominent in four-fold and six-fold degenerate codons than in the two-fold degenerate codons. In case ofrpoBandrpoC, the major difference was found at UCC, GUA, CCG, GCU, GGC and CGC codons. Similarly, in case of the other four pairs of co-transcribed genes, the difference was more prominent in the higher degenerate codons than the two-fold degenerate codons. It may be that the restriction of two-fold degenerate codons to transition substitutions only regarding synonymous polymorphism is making these codons different from the higher degeneracy codons in this study.
Validation of manifold-based direct control for a brain-to-body neural bypass
Authors: Losanno E. , Badi M. , Roussinova E. , Bogaard A. , Delacombaz M. , Shokur S. , Micera S.
Published: July 2022

Brain-body interfaces (BBIs) are neuroprostheses that can restore the connection between brain activity and body movements. They have emerged as a radical solution for restoring voluntary hand control in people with upper-limb paralysis. The BBI module decoding motor commands to actuate the limb from brain signals should provide the user with intuitive, accurate, and stable control. Here, we present the design and demonstration in a monkey of a novel brain decoding strategy based on the direct coupling between the activity of intrinsic neural ensembles and output variables, meant to achieve ease of learning and long-term robustness. We identified once an intrinsic low-dimensional space (called manifold) capturing the co-variation patterns of the monkey’s neural activity associated to reach-to-grasp movements. We then tested the animal’s ability to directly control a computer cursor using cortical activation along the manifold axes and demonstrated rapid learning and stable high performance over 16 weeks of experiments. Finally, we showed that this brain decoding strategy can be effectively coupled to peripheral nerve stimulation to trigger hand movements. These results provide evidence that manifold-based direct control has promising characteristics for clinical applications of BBIs.
Prophylactic low-dose, bi-weekly benznidazole treatment fails to prevent Trypanosoma cruzi infection in dogs under intense transmission pressure
Authors: Bustamante Juan M. , Padilla Angel M. , White Brooke , Auckland Lisa D. , Busselman Rachel E. , Collins Stephanie , Malcolm Elizabeth L. , Wilson Briana F. , Saunders Ashley B. , Hamer Sarah A. , Tarleton Rick L.
Published: July 2022

Trypanosoma cruzi naturally infects a wide variety of wild and domesticated mammals, in addition to humans. Depending on the infection dose and other factors, the acute infection can be life-threatening, and in all cases, the risk of chagasic heart disease is high in persistently infected hosts. Domestic, working, and semi-feral dogs in the Americas are at significant risk of T. cruzi and in certain settings in the southern United States, the risk of new infections can exceed 30% per year, even with the use of vector control protocols. In this study, we explored whether intermittent low-dose treatment with the trypanocidal compound benznidazole (BNZ) during the transmission season, could alter the number of new infections in dogs in an area of known, intense transmission pressure. Preliminary studies in mice suggested that twice-weekly administration of BNZ could prevent or truncate infections when parasites were delivered at the mid-point between BNZ doses. Pre-transmission season screening of 126 dogs identified 53 dogs (42.1%) as T. cruzi infection positive, based upon blood PCR and Luminex-based serology. Serial monitoring of the 67 uninfected dogs during the high transmission season (May to October) revealed 15 (22.4%) new infections, 6 in the untreated control group and 9 in the group receiving BNZ prophylaxis, indicating no impact of this prophylaxis regimen on the incidence of new infections. Although these studies suggest that rigorously timed and more potent dosing regimen may be needed to achieve an immediate benefit of prophylaxis, additional studies would be needed to determine if drug prophylaxis reduced disease severity despite this failure to prevent new infections.

Author Summary

Trypanosoma cruzi, the parasite that causes Chagas disease, circulates extensively in the southern U.S. and working dog populations in south-central Texas are at very high risk of infection, and morbidity and early mortality due to this infection. In this study, we used low level administration of an FDA-approved drug during the transmission season to attempt to prevent new infections in these dogs. Although that effort failed, the study revealed new information about the transmission dynamics and generation of antibody responses and immune control of infection in this high-transmission setting.
KSHV infection of endothelial precursor cells with lymphatic characteristics as a novel model for translational Kaposi’s sarcoma studies
Authors: Tuohinto Krista , DiMaio Terri A. , Kiss Elina A. , Laakkonen Pirjo , Saharinen Pipsa , Karnezis Tara , Lagunoff Michael , Ojala Päivi M.
Published: July 2022

Kaposi’s sarcoma herpesvirus (KSHV) is the etiologic agent of Kaposi’s sarcoma (KS), a hyperplasia consisting of enlarged malformed vasculature and spindle-shaped cells, the main proliferative component of KS. While spindle cells express markers of lymphatic and blood endothelium, the origin of spindle cells is unknown. Endothelial precursor cells have been proposed as the source of spindle cells. We previously identified two types of circulating endothelial colony forming cells (ECFCs), ones that expressed markers of blood endothelium and ones that expressed markers of lymphatic endothelium. Here we examined both blood and lymphatic ECFCs infected with KSHV. Lymphatic ECFCs are significantly more susceptible to KSHV infection than the blood ECFCs and maintain the viral episomes during passage in culture while the blood ECFCs lose the viral episome. Only the KSHV-infected lymphatic ECFCs grew to small multicellular colonies in soft agar whereas the infected blood ECFCs and all uninfected ECFCs failed to proliferate. The lymphatic ECFCs express high levels of SOX18, which supported the maintenance of high copy number of KSHV genomes. When implanted subcutaneously into NSG mice, the KSHV-infected lymphatic ECFCs persisted in vivo and recapitulated the phenotype of KS tumor cells with high number of viral genome copies and spindling morphology. These spindle cell hallmarks were significantly reduced when mice were treated with SOX18 inhibitor, SM4. These data suggest that KSHV-infected lymphatic ECFCs can be utilized as a KSHV infection model for in vivo translational studies to test novel inhibitors representing potential treatment modalities for KS.

Author summary

Kaposi’s sarcoma herpesvirus (KSHV) is the etiologic agent of Kaposi’s sarcoma (KS). The main proliferative component of KS, spindle cells, express markers of lymphatic and blood endothelium. Endothelial precursor cells, which are circulating endothelial colony forming cells (ECFCs), have been proposed as the source of spindle cells. Here we examined both blood and lymphatic ECFCs infected with KSHV. Lymphatic ECFCs are readily infected by KSHV, maintain the viral episomes and show minimal transformation of the cells, which the infected blood ECFCs and all uninfected ECFCs failed to show. The lymphatic ECFCs express SOX18, which supported the maintenance of high copy numbers of KSHV genomes. The KSHV-infected lymphatic ECFCs persisted in vivo and recapitulated the phenotype of KS tumor cells such as high number of viral genome copies and spindling morphology. These KS tumor cell hallmarks were significantly reduced by SOX18 chemical inhibition using a small molecule SM4 treatment. These data suggest that KSHV-infected lymphatic ECFCs could be the progenitors of KS spindle cells and are a promising model for the translational studies to develop new therapies for KS.
Poor sensitivity of iPSC-derived neural progenitors and glutamatergic neurons to SARS-CoV-2
Authors: Zivaljic Marija , Hubert Mathieu , Grzelak Ludivine , Sansone Giulia , Maskos Uwe , Schwartz Olivier
Published: July 2022

COVID-19 is a respiratory disease affecting multiple organs including the central nervous system (CNS), with a characteristic loss of smell and taste. Although frequently reported, the neurological symptoms remain enigmatic. There is no consensus on the extent of CNS infection. Here, we derived human induced pluripotent stem cells (hiPSC) into neural progenitor cells (NPCs) and cortical excitatory neurons to study their permissiveness to SARS-CoV-2 infection. Flow cytometry and western blot analysis indicated that NPCs and neurons do not express detectable levels of the SARS-CoV-2 receptor ACE2. We thus generated cells expressing ACE2 by lentiviral transduction to analyze in a controlled manner the properties of SARS-CoV-2 infection relative to ACE2 expression. Sensitivity of parental and ACE2 expressing cells was assessed with GFP- or luciferase-carrying pseudoviruses and with authentic SARS-CoV-2 Wuhan, D614G, Alpha or Delta variants. SARS-CoV-2 replication was assessed by microscopy, RT-qPCR and infectivity assays. Pseudoviruses infected only cells overexpressing ACE2. Neurons and NPCs were unable to efficiently replicate SARS-CoV-2, whereas ACE2 overexpressing neurons were highly sensitive to productive infection. Altogether, our results indicate that primary NPCs and cortical neurons remain poorly permissive to SARS-CoV-2 across the variants’ spectrum, in the absence of ACE2 expression.
Brainstem fMRI signaling of surprise across different types of deviant stimuli
Authors: Mazancieux Audrey , Mauconduit Franck , Amadon Alexis , de Gee Jan Willem , Donner Tobias , Meyniel Florent
Published: July 2022

The detection of deviant stimuli is crucial to orient and adapt our behavior. Previous work showed that infrequent (hence deviant) stimuli elicit phasic activation of the brainstem locus coeruleus (LC), which releases noradrenaline and controls central arousal. However, it is unclear whether the detection of behaviorally-relevant deviant events selectively trigger LC responses, or also other neuromodulatory systems related to dopamine, acetylcholine, and serotonin. Here, we combined human fMRI recordings optimized for brainstem imaging with pupillometry (a peripheral marker of central arousal) to perform a mapping of deviant-related responses in subcortical structures. Participants had to detect deviant items in a “local-global” paradigm that distinguishes between deviance based on the stimulus probability and the sequence structure. fMRI responses to deviant stimuli were quite distributed, detected in the LC but also other subcortical nuclei and many cortical areas. Both types of deviance elicited responses in the pupil, LC and other neuromodulatory systems. Our results reveal that the detection of task-relevant deviant items recruits the same multiple subcortical systems across computationally different types of deviance.
Efficient generation of marmoset primordial germ cell-like cells using induced pluripotent stem cells
Authors: Seita Yasunari , Cheng Keren , McCarrey John R. , Yadu Nomesh , Cheeseman Ian , Bagwell Alec , Ross Corinna N. , Santana-Toro Isamar , Yen Li-Hua , Vargas Sean , Navara Christopher S. , Hermann Brian P. , Sasaki Kotaro
Published: July 2022

Reconstitution of germ cell fate from pluripotent stem cells provides an opportunity to understand the molecular underpinnings of germ cell development. Here, we established robust methods for pluripotent stem cells (iPSCs) culture in the common marmoset (Callithrix jacchus, cj), which stably propagate in an undifferentiated state. Notably, iPSCs cultured on a feeder layer in the presence of a WNT signaling inhibitor upregulated genes related to ubiquitin-dependent protein catabolic processes and enter a permissive state that enables differentiation into primordial germ cell-like cells (PGCLCs) bearing immunophenotypic and transcriptomic similarities to pre-migratory cjPGCsin vivo. Induction of cjPGCLCs is accompanied by transient upregulation of mesodermal genes culminating in the establishment of a primate specific germline transcriptional network. Moreover, cjPGCLCs can be expanded in monolayer while retaining the germline state. Upon co-culture with mouse testicular somatic cells, these cells acquire an early prospermatogonia-like phenotype. Our findings provide a framework for understanding and reconstituting marmoset germ cell development in vitro, thus providing a comparative tool and foundation for a preclinical modeling of human in vitro gametogenesis.
Robustness of the neuro-muscular octopaminergic system in the face of cold stress
Authors: Kaya-Zeeb Sinan , Delac Saskia , Wolf Lena , Marante Ana Luiza , Scherf-Clavel Oliver , Thamm Markus
Published: July 2022

In recent decades, our planet has undergone dramatic environmental changes resulting in the loss of numerous species. This contrasts with species that can adapt quickly to rapidly changing ambient conditions, which require physiological plasticity and must occur rapidly. The Western honeybee (Apis mellifera) apparently meets this challenge with remarkable success, as this species is adapted to numerous climates, resulting in an almost worldwide distribution. Here, coordinated individual thermoregulatory activities ensure survival at the colony level and thus the transmission of genetic material. Recently, we showed that shivering thermogenesis, which is critical for honeybee thermoregulation, depends on octopamine signaling. In this study, we tested the hypothesis that the thoracic neuro-muscular octopaminergic system strives for a steady-state equilibrium under cold stress to maintain endogenous thermogenesis. We can show that this applies for both, octopamine provision by flight muscle innervating neurons and octopamine receptor expression in the flight muscles. Additionally, we discovered alternative splicing forAmOARβ2and our results suggest that at least one isoform is needed to survive cold stress conditions. We assume that the thoracic neuro-muscular octopaminergic system is finely tuned in order to contribute decisively to survival in a changing environment.
The evolutionary dynamics that retain long neutral genomic sequences in face of indel deletion bias: a model and its application to human introns
Authors: Loewenthal Gil , Wygoda Elya , Nagar Natan , Glick Lior , Mayrose Itay , Pupko Tal
Published: July 2022

Insertions and deletions (indels) of short DNA segments are common evolutionary events. Numerous studies showed that deletions occur more often than insertions in both prokaryotes and eukaryotes. It raises the question why neutral sequences are not eradicated from the genome. We suggest that this is due to a phenomenon we termborder-induced selection. Accordingly, a neutral sequence is bordered between conserved regions. Deletions occurring near the borders occasionally protrude to the conserved region and are thereby subject to strong purifying selection. Thus, for short neutral sequences, an insertion bias is expected. Here, we develop a set of increasingly complex models of indel-dynamics that incorporate border-induced selection. Furthermore, we show that short conserved sequences within the neutrally evolving sequence help explain: (1) the presence of very long sequences; (2) the high variance of sequence lengths; (3) the possible emergence of multimodality in sequence length distributions. Finally, we fitted our models to the human intron length distribution, as introns are thought to be mostly neutral and bordered by conserved exons. We show that when accounting for the occurrence of short conserved sequences within introns, we reproduce the main features, including the presence of long introns and the multimodality of intron distribution.
Challenges for lean construction adoption in the Brazilian industry: a study in construction companies, universities and class organizations
Authors: Silva Edson Neves da , Brasil de Brito Mello Luiz Carlos , Pinto Gustavo Oliveira
Published: July 2022

Purpose

This paper aims to evaluate the current level of knowledge about lean construction (LC) practices in construction companies, universities and class organizations in Brazil and identify the barriers to implementing LC in the Brazilian construction industry and prioritize them through comparison with global challenges.

Design/methodology/approach

This multiple case study was carried out through a questionnaire answered by 56 construction companies, 15 universities and 10 professional associations. The questionnaire evaluation allowed the authors to determine the level of knowledge about the LC, its adoption and barriers to its adoption in the Brazilian industry. The results were statistically analyzed using the weighted average (MIS) of results using the Kruskal–Wallis test, which compares sample distribution among groups, and Cronbach’s alpha test to measure the questionnaire reliability.

Findings

This study points to universities as the main ones responsible for the low adoption of LC in Brazil and points to the need for an integrated action among construction companies, universities and class organizations to overcome the traditional project management culture and raise the level of knowledge about LC.

Originality/value

This study evaluated the current LC situation in an emerging country, Brazil, and compared it with the principal international challenges observed in studies of other developing countries – China, India, Morocco, Saudi Arabia and Singapore – least developed countries – Bangladesh and Nigeria – and developed country – UK. These studies evaluated construction companies located in the listed countries. Based on that, 22 international challenges were established for the LC adoption. Additionally, this research also evaluated universities and working-class organizations in addition to construction companies. This addition can contribute to a better result understanding that can be explored by Brazil and other countries.
“Live within the messiness”: how a digitally mediated inquiry community supported ELA teachers in cultivating adaptive repertoires
Authors: Monea Bethany , Burrows-Stone Katie , Dunbar Jennifer Griffith , Freed Jennifer , Stornaiuolo Amy , Griffin Autumn A.
Published: July 2022

Purpose

Adaptivity has long been recognized as a key aspect of teaching and shown to be particularly important for English Language Arts (ELA) teachers leading discussions about texts. Teachers' abilities to make such adjustments are especially important when facilitating discussions in digital contexts, as was made clear with the shift to virtual teaching caused by the COVID-19 pandemic. The purpose of this paper is to explore how the structure and process of teacher inquiry supported ELA teachers in enacting and cultivating adaptive repertoires for facilitating discussion in online contexts during the disruptions of the 2020–2021 school year.

Design/methodology/approach

As an inquiry team comprising teacher-researchers from secondary and university-based contexts, the authors used practitioner inquiry methods in the context of a multi-year, multi-sited study involving, design-based and teacher-research methodologies.

Findings

This paper shows how teachers’ engagement in digital teacher inquiry groups supported their willingness to be playful and adapt their practices in response to one another, creating conditions for powerful teacher learning through relational inquiry online. This paper identified three specific relational practices that were critical for cultivating adaptive repertories in teachers’ learning with and from each other: cultivating empathy; attuning to silences and actively listening; and decentering authority across multiple platforms and modalities. The authors discuss how teachers carried these practices to and from their digital discussions with their students and with each other, demonstrating how this recursive cycle of inquiry and practice deepened their learning, relationships and adaptive repertoires.

Originality/value

The authors discuss the implications of these practices for equity-oriented and dialogic teacher learning that can transform classroom practice, illustrating the power of online teacher inquiry groups for developing ELA teachers’ adaptive expertise – something urgently important for teaching in digitally mediated contexts and through unsettled times.