bluuebunny/crossref_metadata_2025 huggingface dataset:
Development and Validation of an Evaluation Tool of Consumers’ Knowledge and Confidence to Report Patient Deterioration in Hospitals
Authors: King Lindy , Ullah Shahid , Belan Ingrid , Clark Robyn A. , Young Tom , Grantham Hugh , Peacock Guy , Kidd Michael R.
Published: September 2021

Objectives

Studies have shown that many preventable hospital deaths may be reduced through early reporting of deterioration by patients and their visitors to health professionals. Engagement of patients and families for safer health care was recommended by the World Health Organization. As no validated tool was identified, the objective of the study was to develop and validate a tool to measure the impact of messages contained in self-developed educational materials on consumers’ knowledge and confidence to report patient deterioration.

Methods

A tool was created using consumer-based input. A test-retest methodology was used 2 weeks apart, using 37 participants sourced from consumer groups. Fourteen 5-point Likert scale questionnaire items were categorized into knowledge and confidence components to identify the impact of the materials in both of these areas.

Results

Test-retest reliability confirmed 10 of the 14 proposed questionnaire items (4 knowledge items and 6 confidence) had at least moderate κ agreement ranging from 0.42 to 0.69 and an intraclass correlation coefficient of 0.66. An exploratory factor analysis of the 10 remaining items indicated a 2-factor solution had the best interpretability accounting for 96.9% of variability. The Cronbach α and factor loadings for the factors, knowledge, and confidence suggested an acceptable level of reliability and validity.

Conclusions

The study confirms our tool for assessment of educational materials to be a reliable, context-specific, and validated instrument. The tool is an appropriate instrument to assess the effectiveness of educational materials in public awareness campaigns that focus on consumer reporting of patient deterioration within hospitals.
FDG PET/CT in Isolated Thoracic Vertebral Rosai-Dorfman Disease
Authors: Zhao Qian , Bai Yushu , Dong Aisheng , Zuo Changjing
Published: September 2021

Isolated osseous Rosai-Dorfman disease is rare. We describe FDG PET/CT findings of solitary thoracic vertebral Rosai-Dorfman disease without extraosseous involvement. The vertebral lesion caused osteolytic destruction of the vertebral body and showed intense FDG uptake.
Timing of tracheostomy in acute traumatic spinal cord injury: A systematic review and meta-analysis
Authors: Foran Sarah J. , Taran Shaurya , Singh JM , Kutsogiannis Demetrios James , McCredie Victoria
Published: September 2021

BACKGROUND

Patients with acute traumatic cervical or high thoracic level spinal cord injury (SCI) typically require mechanical ventilation (MV) during their acute admission. Placement of a tracheostomy is preferred when prolonged weaning from MV is anticipated. However, the optimal timing of tracheostomy placement in patients with acute traumatic SCI remains uncertain. We systematically reviewed the literature to determine the effects of early versus late tracheostomy or prolonged intubation in patients with acute traumatic SCI on important clinical outcomes.

METHODS

Six databases were searched from their inception to January 2020. Conference abstracts from relevant proceedings and the gray literature were searched to identify additional studies. Data were obtained by two independent reviewers to ensure accuracy and completeness. The quality of observational studies was evaluated using the Newcastle Ottawa Scale.

RESULTS

Seventeen studies (2,804 patients) met selection criteria, 14 of which were published after 2009. Meta-analysis showed that early tracheostomy was not associated with decreased short-term mortality (risk ratio [RR], 0.84; 95% confidence interval [CI], 0.39–1.79; p = 0.65; n = 2,072), but was associated with a reduction in MV duration (mean difference [MD], 13.1 days; 95% CI, –6.70 to –21.11; p = 0.0002; n = 855), intensive care unit length of stay (MD, –10.20 days; 95% CI, –4.66 to –15.74; p = 0.0003; n = 855), and hospital length of stay (MD, –7.39 days; 95% CI, –3.74 to –11.03; p < 0.0001; n = 423). Early tracheostomy was also associated with a decreased incidence of ventilator-associated pneumonia and tracheostomy-related complications (RR, 0.86; 95% CI, 0.75–0.98; p = 0.02; n = 2,043 and RR, 0.64; 95% CI, 0.48–0.84; p = 0.001; n = 812 respectively). The majority of studies ranked as good methodologic quality on the Newcastle Ottawa Scale.

CONCLUSION

Early tracheostomy in patients with acute traumatic SCI may reduce duration of mechanical entilation, length of intensive care unit stay, and length of hospital stay. Current studies highlight the lack of high-level evidence to guide the optimal timing of tracheostomy in acute traumatic SCI. Future research should seek to understand whether early tracheostomy improves patient comfort, decreases duration of sedation, and improves long-term outcomes.

LEVEL OF EVIDENCE

Systematic Review, level III.
Effects of Cognitive Reserve on Cognition in Individuals With Central Nervous System Disease
Authors: Jammula Varna R. , Leeper Heather , Gilbert Mark R. , Cooper Diane , Armstrong Terri S.
Published: September 2021

Cognitive reserve (CR) has been proposed to account for functional outcome differences in brain pathology and its clinical manifestations. The purpose of our paper is to systematically review the effects of CR on cognitive outcomes in individuals with neurodegenerative and structural CNS diseases. We performed a systematic search of PubMed, CINAHL (Cumulative Index to Nursing and Allied Health Literature), and PsychInfo using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Seventeen studies met the predetermined inclusion criteria and were selected for review. Education level was the most commonly used measure for CR, and various neuropsychological tests were used to measure cognitive outcomes. Regardless of the CNS disease of the individuals, almost all of the studies reported a positive association between CR and cognitive outcomes when they were evaluated cross-sectionally. However, when evaluated longitudinally, CR had either no effect on, or a negative association with, cognitive outcomes. Based on studies across a broad spectrum of CNS diseases, our findings suggest that CR may serve as a predictor of cognitive outcomes in individuals with CNS diseases. However, studies to date are limited by a lack of imaging analyses and standardized assessment strategies. The ability to use a standardized measure to assess the longitudinal effects of CR may allow for the development of more targeted treatment methods, resulting in improved disease outcomes for individuals.
Science funding under an authoritarian regime: Portugal's National Education Board and the European ‘academic landscape’ in the interwar period
Authors: Lopes Quintino , Pereira Elisabete J. Santos
Published: September 2021

This article enables an understanding of scientific practice and funding in a peripheral country ruled by a dictatorship in the interwar period, and thus provides the basis for comparison with studies of other non-democratic regimes. We examine the work of Portugal's Junta de Educação Nacional (National Education Board), which administered and provided funding for science from 1929 to 1936. Our findings show that this public body encouraged the participation of the Portuguese academic community in international science networks. This scenario contrasts with the dominant historiographical thesis that between the wars the Portuguese academic community did not play a role in international networks, and that it lacked state support. Also in contrast with the dominant historiography, whose ideological bias meant that a simplified picture was portrayed, whereas the reality is shown to be complex, this study demonstrates that the Portuguese dictatorial state sought to foster scientific progress through the Junta, but that resentment among academics and the resistance of universities to innovation meant that this objective was only partially achieved. Finally, the memory of a number of scientists has been rescued from oblivion, as we show how their political stance during the dictatorship led to their being ignored by historiographers when democracy prevailed.
Rate of infant carrying impacts infant spontaneous motor tempo
Authors: Rocha Sinead , Southgate Victoria , Mareschal Denis
Published: September 2021

Rhythm production is a critical component of human interaction, not least forming the basis of our musicality. Infants demonstrate a spontaneous motor tempo (SMT), or natural rate of rhythmic movement. Here, we ask whether infant SMT is influenced by the rate of locomotion infants experience when being carried. Ten-month-old, non-walking infants were tested using a free drumming procedure before and after 10 min of being carried by an experimenter walking at a slower (98 BPM) or faster (138 BPM) than average tempo. We find that infant SMT is differentially impacted by carrying experience dependent on the tempo at which they were carried: infants in the slow-walked group exhibited a slower SMT from pre-test to post-test, while infants in the fast-walked group showed a faster SMT from pre-test to post-test. Heart rate data suggest that this effect is not due to a general change in the state of arousal. We argue that being carried during caregiver locomotion is a predominant experience for infants throughout the first years of life, and as a source of regular, vestibular, information, may at least partially form the basis of their sense of rhythm.
No evidence for conspecific recruitment for cooperative hunting in lionfishPterois miles
Authors: Sarhan Hanaa , Bshary Redouan
Published: September 2021

Lionfish are common piscivores in the Indo-Pacific and invasive in the Caribbean. A fin flaring pattern, involving a rapid undulation of the caudal fin and sequential turning of both pectoral fins, was described in zebra lionfish as a signal to initiate cooperative hunting, and it was hypothesized that such hunting tactics may also exist in other lionfish species and contribute to their successful invasion in the Caribbean. Here, we investigated one of those invasive species,Pterois miles, in its natural range in the Red Sea. We did not observe evidence for cooperative hunting in the field. We complemented field observations with a laboratory experiment aimed at inducing subjects to recruit partners for cooperative hunts, exposing subjects to inaccessible prey in transparent housing as well as to a potential partner. We regularly observed the fin flaring pattern, but importantly, it was not directed at the partner. Thus, rather than being a signal, the fin flaring movement pattern seems to be a swimming mode in a confined environment. Furthermore, the two lionfish did not aggregate at the prey housing, reinforcing the field results that this species in the Red Sea does not depend on cooperation to hunt fish.
When conflicts get heated, so does the planet: coupled social-climate dynamics under inequality
Authors: Menard Jyler , Bury Thomas M. , Bauch Chris T. , Anand Madhur
Published: September 2021

Climate dynamics are inextricably linked to processes in social systems that are highly unequal. This suggests a need for coupled social-climate models that capture pervasive real-world asymmetries in the population distribution of the consequences of anthropogenic climate change and climate (in)action. Here, we use evolutionary game theory to develop a social-climate model with group structure to investigate how anthropogenic climate change and population heterogeneity coevolve. We find that greater homophily and resource inequality cause an increase in the global peak temperature anomaly by as much as 0.7°C. Also, climate change can structure human populations by driving opinion polarization. Finally, climate mitigation achieved by reducing the cost of mitigation measures paid by individuals tends to be contingent upon socio-economic conditions, whereas policies that achieve communication between different strata of society show climate mitigation benefits across a broad socio-economic regime. We conclude that advancing climate change mitigation efforts can benefit from a social-climate systems perspective.
The impact of emerging Plasmodium knowlesi on accurate diagnosis by light microscopy: a systematic review and modelling analysis
Authors: Huber John H. , Elliott Margaret , Koepfli Cristian , Perkins T. Alex
Published: September 2021

The five Plasmodium spp. that cause human malaria appear similar under light microscopy, which raises the possibility that misdiagnosis could routinely occur in clinical settings. Assessing the extent of misdiagnosis is of particular importance for monitoring P. knowlesi, which co-circulates with the other Plasmodium spp. We performed a systematic review and meta-analysis of studies comparing the performance of microscopy and PCR for diagnosing malaria in settings with co-circulation of the five Plasmodium spp. We assessed the extent to which co-circulation of Plasmodium parasites affects diagnostic outcomes. We fit a Bayesian hierarchical latent class model to estimate variation in microscopy sensitivity and specificity. Mean sensitivity of microscopy was low, yet highly variable across Plasmodium spp., ranging from 41.7% (95% CI: 22.8 – 64.1%) for P. falciparum and 40.3% (22.0 – 61.5%) for P. vivax to 0.119% (0.0121 – 0.640%) for P. knowlesi, 7.57% (2.66 – 22.0%) for P. malariae, and 0.180% (0.00491 – 1.21%) for P. ovale. Observed PCR prevalence was positively correlated with estimated microscopic sensitivity and negatively correlated with estimated microscopic specificity, though the strength of the associations varied by species. Our analysis suggests that co-circulation of Plasmodium spp. undermines the accuracy of microscopy. Sensitivity was considerably lower for P. knowlesi, P. malariae, and P. ovale. The negative association between specificity and prevalence imply that less frequently encountered species may be misdiagnosed as more frequently encountered species. Together, these results suggest that the burden of P. knowlesi, P. malariae, and P. ovale may be underappreciated in a clinical setting.
Anticipating racial/ethnic mortality displacement from COVID-19
Authors: Kissler Stephen M. , Grad Yonatan H.
Published: September 2021

In 2020, life expectancy in the United States decreased by an estimated 1.5 years. Due to mortality displacement during the COVID-19 pandemic, life expectancy could soon rebound to above its pre-pandemic baseline. We estimated the size and duration of this anticipated rise in life expectancy through 2030. We found that this rebound could persist for years and will likely be most pronounced in minority populations who suffered the highest rates of mortality during the pandemic. Accounting for this artificial rebound will be critical to avoid funneling resources away from populations that still urgently need them.
Strong experimental support for the hologenome hypothesis revealed from Drosophila melanogaster selection lines
Authors: Kristensen Torsten Nygaard , Schönherz Anna A. , Rohde Palle Duun , Sørensen Jesper Givskov , Loeschcke Volker
Published: September 2021

Recently it has been proposed, that the holobiont, i.e., the host and its associated microbiome, constitute a distinct biological entity, on which selection operates. This is a fascinating idea that so far has limited empirical justification. Here Drosophila melanogaster lines from a large-scale artificial selection experiment, where we selected for stress resistance traits and for longevity, were used to test the hologenome hypothesis. We raised flies from all selection regimes, including a regime where flies were kept at benign standard laboratory condition (control regime) throughout the duration of the experiment, under common garden conditions and sequenced the microbiome of the flies. We found abundant differences in microbial communities between control and selection regimes, but not between replicate lines within the regimes, and microbial diversity was higher in selected relative to control lines. Several major core Drosophila bacterial species were differentially abundant in the different selection regimes despite flies being exposed to similar nutritional and general environmental conditions. Our results support the idea that the host and microbiome genomes have evolved in concert and provide experimental support for the hologenome theory of evolution.
Molecular basis for the R-type anion channel QUAC1 activity in guard cells
Authors: Qin Li , Tang Ling-hui , Xu Jia-shu , Zhang Xian-hui , Zhu Yun , Zhang Chun-rui , Liu Xue-lei , Wang Mei-hua , Li Fei , Sun Fei , Su Min , Zhai Yu-jia , Chen Yu-hang
Published: September 2021

The rapid (R)-type anion channel plays a central role in controlling stomatal closure in plant guard cells, thus regulating the exchange of water and photosynthetic gas (CO2) in response to environmental stimuli. The activity of the R- type anion channel is regulated by malate. However, the molecular basis of the R-type anion channel activity remains elusive. Here, we describe the first cryo-EM structure of the R-type anion channel QUAC1 at 3.5 Å resolution in the presence of malate. The structure reveals that the QUAC1 is a symmetrical dimer, forming a single electropositive T-shaped pore for passing anions across the membrane. The transmembrane and cytoplasmic domains are assembled into a twisted bi-layer architecture, with the associated dimeric interfaces nearly perpendicular. Our structural and functional analyses reveal that QUAC1 functions as an inward rectifying anion channel and suggests a mechanism for malate-mediated channel activation. Altogether, our study uncovers the molecular basis for a novel class of anion channels and provides insights into the gating and modulation of the R-type anion channel.
Not so local: the population genetics of convergent adaptation in maize and teosinte
Authors: Tittes Silas , Lorant Anne , McGinty Sean , Holland James B. , de Jesus Sánchez-González Jose , Seetharam Arun , Tenaillon Maud , Ross-Ibarra Jeffrey
Published: September 2021

What is the genetic architecture of local adaptation and what is the geographic scale over which it operates? We investigated patterns of local and convergent adaptation in five sympatric population pairs of traditionally cultivated maize and its wild relative teosinte (Zea mayssubsp.parviglumis). We found that signatures of local adaptation based on the inference of adaptive fixations and selective sweeps are frequently exclusive to individual populations, more so in teosinte compared to maize. However, for both maize and teosinte, selective sweeps are also frequently shared by several populations, and often between subspecies. We were further able to infer that selective sweeps were shared among populations most often via migration, though sharing via standing variation was also common. Our analyses suggest that teosinte has been a continued source of beneficial alleles for maize, even after domestication, and that maize populations have facilitated adaptation in teosinte by moving beneficial alleles across the landscape. Taken together, our results suggest local adaptation in maize and teosinte has an intermediate geographic scale, one that is larger than individual populations but smaller than the species range.
Microtubule-based perception of mechanical conflicts controls plant organ morphogenesis
Authors: Stöckle Dorothee , Reyes-Hernández Blanca Jazmin , Barro Amaya Vilches , Nenadic Milica , Winter Zsófia , Marc-Martin Sophie , Bald Lotte , Ursache Robertas , Fujita Satoshi , Maizel Alexis , Vermeer Joop EM
Published: September 2021

Precise coordination between cells and tissues is essential for differential growth in plants. During lateral root formation in Arabidopsis thaliana, the endodermis is actively remodeled to allow outgrowth of the new organ. Here, we show that microtubule arrays facing lateral root founder cells display a higher order compared to arrays on the opposite wall of the same cell, and this asymmetry is required for endodermal remodeling and lateral root initiation. We identify that MICROTUBULE ASSOCIATED PROTEIN 70-5 is necessary for the establishment of this spatially defined microtubule organization and endodermis remodeling, and thus contributes to lateral root morphogenesis. We propose that MAP70-5 and cortical microtubule arrays in the endodermis integrate the mechanical signals generated by lateral root outgrowth, facilitating the channeling of organogenesis.
Generation and diversification of recombinant monoclonal antibodies for studying mitosis
Authors: DeLuca Keith F. , Mick Jeanne E. , Hodges Amy L. , Lima Wanessa C. , Sherman Lori , Schaller Kristin L. , Anderson Steven M. , Zhao Ning , Stasevich Timothy J. , Varma Dileep , Gorbsky Gary J. , Nilsson Jakob , DeLuca Jennifer G.
Published: September 2021

Antibodies are indispensable tools used for a large number of applications in both foundational and translational bioscience research; however, there are drawbacks to using traditional antibodies generated in animals. These include a lack of standardization leading to problems with reproducibility, high costs of antibodies purchased from commercial sources, and ethical concerns regarding the large number of animals used to generate antibodies. To address these issues, we have developed practical methodologies and tools for generating low-cost, high-yield preparations of recombinant monoclonal antibodies and antibody fragments directed to protein epitopes from primary sequences. We describe these methods here, as well as approaches to diversify monoclonal antibodies, including customization of antibody species specificity, generation of genetically encoded small antibody fragments, and conversion of single chain antibody fragments (e.g. scFv) into full-length, bivalent antibodies. This study focuses on antibodies directed to epitopes important for mitotic cell division; however, the methods and reagents described here are applicable to antibodies and antibody fragments for use in any field.
Spexin modulates molecular thermogenic profile of adipose tissue and thermoregulatory behaviors
Authors: Sherman Shermel B. , Gupta Niraj , Harberson Mitchell , Powers Riley , Rashleigh Rebecca , Talla Ramya , Thusu Ashima , Hill Jennifer W.
Published: September 2021

Thermoregulation is a physiological process by which a mammal regulates body temperature in response to its environment. Within the human body, thermoregulatory behaviors and metabolism are modulated by circulating metabolic factors. In our study, we tested the ability of the neuropeptide spexin, which shares sequence homology to galanin, to regulate these functions in female mice. Supraphysiological levels of spexin in C57BL/6 mice were insufficient to protect against diet-induced obesity after 50 days of treatment. Behavioral analysis of long-term spexin treatment appeared to modulate anxiety-like behaviors by promoting exploratory behaviors and thermoregulatory behaviors of nest building that ceased when animals were housed at thermoneutral temperatures. Upon examination of the molecular profile of brown and white adipose tissue, treatment disrupted the thermogenic profile of white adipose tissue, in which β3-adrenergic receptor expression was downregulated. Our results reveal novel functions for spexin as a modulator of thermoregulatory behaviors and adipose tissue metabolism.

Highlights

Spexin treatment did not protect against diet-induced obesity in female mice.

Spexin-treatment promoted thermoregulatory behaviors of nest building.

Behaviors normalized when animals were housed in thermoneutral temperatures.

Funding Sources

Not applicable

Disclosure Summary

Nothing to disclose
Role of mitotic diffusion barriers in regulating the asymmetric division of activated CD8 T cells
Authors: Emurla Hulya , Barral Yves , Oxenius Annette
Published: September 2021

Upon their activation, naïve CD8 T cells divide and differentiate into short-lived effector cells, relevant for exerting immune control, and long-lived memory cells, relevant for long-term immunity. The proportion of memory cells generated depends highly on the context of activation and whether the activated cell divides symmetrically or asymmetrically. However, how T cells control the extent of their asymmetry during their first division in response to contextual signals is not known. Using fluorescence loss in photo-bleaching (FLIP) experiments, we show that the metabolic and plasma membrane asymmetry of mitotic T cells depend on the regulated assembly of a lateral diffusion barrier in their endoplasmic reticulum (ER-) membrane. In asymmetrically dividing T cells, the degrees of asymmetry correlated tightly to barrier strength, whereas symmetrically dividing T cells did not establish such a barrier. Direct positive or negative interference with barrier assembly enhanced or abrogated metabolic and plasma membrane asymmetry, respectively, indicating that barrier strength is a direct and decisive determinant of mitotic asymmetry. Thus, together our data identify diffusion barrier-mediated compartmentalization as a mechanism for how asymmetric T cell regulate their long-term response as a function of the activatory context.
Pharmacological perturbation of intracellular dynamics as a SARS-CoV-2 antiviral strategy
Authors: Bakhache William , Partiot Emma , Lucansky Vincent , Bare Yonis , Bonaventure Boris , Goujon Caroline , Bories Cédric , Deffieu Maika S. , Gaudin Raphael
Published: September 2021

SARS-CoV-2 (CoV2) is the viral agent responsible for the pandemic of the coronavirus disease 2019 (COVID-19). Vaccines are being deployed all over the world with good efficacy, but there is no approved antiviral treatment to date. This is particularly needed since the emergence of variants and the potential immune escape may prolong pandemic spreading of the infection for much longer than anticipated. Here, we developed a series of small molecules and identified RG10 as a potent antiviral compound against SARS-CoV-2 in cell lines and human airway epithelia (HAE). RG10 localizes to endoplasmic reticulum (ER) membranes, perturbing ER morphology and inducing ER stress. Yet, RG10 does not associate with SARS-CoV-2 replication sites although preventing virus replication. To further investigate the antiviral properties of our compound, we developed fluorescent SARS-CoV-2 viral particles allowing us to track virus arrival to ER membranes. Live cell imaging of replication-competent virus infection revealed that RG10 stalls the intracellular virus-ER dynamics. Finally, we synthesized RG10b, a stable version of RG10, that showed increased potencyin vitroand in HAE with a pharmacokinetic half-life greater than 2 h. Together, our work reports on a novel fluorescent virus model and innovative antiviral strategy consisting of the perturbation of ER/virus dynamics, highlighting the promising antiviral properties of RG10 and RG10b.
Subclonal evolution and expansion of spatially distinct THY1-positive cells is associated with recurrence in glioblastoma
Authors: Al-Holou Wajd N. , Wang Hanxiao , Ravikumar Visweswaran , Oneka Morgan , Verhaak Roel GW , Kim Hoon , Pratt Drew , Camelo-Piragua Sandra , Speers Corey , Wahl Daniel R , Shankar Sunita , Hollon Todd , Sagher Oren , Heth Jason A , Muraszko Karin M. , Lawrence Theodore S. , de Carvalho Ana C , Mikkelsen Tom , Rao Arvind , Rehemtulla Alnawaz
Published: September 2021

Purpose

Glioblastoma (GBM) is a lethal disease characterized by inevitable recurrence. Here we investigate the molecular pathways mediating resistance, with the goal of identifying therapeutic opportunities to target this tumor.

Experimental Design

We developed a longitudinal in vivo recurrence model utilizing patient-derived explants to produce paired specimens (pre- and post-recurrence) following temozolomide(TMZ) and radiation(IR). These specimens were evaluated for treatment response and to identify gene expression pathways driving treatment resistance. Findings were clinically validated using spatial transcriptomics of human GBMs.

Results

These studies reveal in replicate cohorts, a gene expression profile characterized by upregulation of mesenchymal and stem-like genes at recurrence. Analyses of clinical databases revealed increased expression of this transcriptional profile to be significantly associated with worse median overall survival (248 days vs 430 days, p=0.0004), and upregulation of this profile at recurrence. Most notably, we identified upregulation of TGFβ signaling, and more than one-hundred-fold increase in THY1 levels at recurrence. Utilizing cell sorting, we observed that THY1-positive cells represented <10% of cells in the treatment-naïve tumors and 75-96% in the recurrent tumors. We then isolated THY1-positive cells from treatment-naïve patient samples and determined that they were inherently resistant to chemoradiation in orthotopic models. Additionally, using image-guided biopsies from treatment-naïve human GBM, we conducted spatial transcriptomic analyses. This revealed rare THY1+ regions characterized by mesenchymal/stem-like gene expression, analogous to our recurrent mouse model samples, which co-localized with macrophages within the perivascular niche. Since TGFβ signaling contributes to a mesenchymal/stem-like phenotype, we inhibited TGFβRI activity in vivo which resulted in decreased mesenchymal/stem-like protein levels, including THY1, and restored sensitivity to TMZ/IR in recurrent tumors.

Conclusions

These findings reveal that GBM recurrence may result from tumor repopulation by pre-existing, therapy-resistant, THY1-positive, mesenchymal/stem-like cells within the perivascular niche. Furthermore, our data demonstrate the promise of targeting upregulated pathways in resistant subclones as a novel mechanism to achieve therapeutic response, and specifically that THY1 expression may represent a biomarker of response to TGFβ inhibition.
The Role of the Ventrolateral Anterior Temporal Lobes in Social Cognition
Authors: Balgova Eva , Diveica Veronica , Walbrin Jon , Binney Richard J.
Published: September 2021

A key challenge for neurobiological models of social cognition is to elucidate whether brain regions are specialised for that domain. In recent years, discussion surrounding the role of anterior temporal regions epitomises such debates; some argue the anterior temporal lobe (ATL) is part of a domain-specific network for social processing, while others claim it comprises a domain-general hub for semantic representation. In the present study, we used ATL-optimised fMRI to map the contribution of different ATL structures to a variety of paradigms frequently used to probe a crucial social ability, namely ‘theory of mind’ (ToM). Using multiple tasks enables a clearer attribution of activation to ToM as opposed to idiosyncratic features of stimuli. Further, we directly explored whether these same structures are also activated by a non-social task probing semantic representations. We revealed that common to all of the tasks was activation of a key ventrolateral ATL region that is often invisible to standard fMRI. This constitutes novel evidence in support of the view that the ventrolateral ATL contributes to social cognition via a domain-general role in semantic processing, and against claims of a specialised social function.
Comparative genomic analysis of skin and soft tissue Streptococcus pyogenes isolates from low- and high-income settings
Authors: Bah Saikou Y. , Keeley Alexander J. , Armitage Edwin P. , Khalid Henna , Chaudhuri Roy R. , Senghore Elina , Manneh Jarra , Tilley Lisa , Marks Michael , Darboe Saffiatou , Sesay Abdul K. , de Silva Thushan I , Turner Claire E.
Published: September 2021

Streptococcus pyogenes is a leading cause of human morbidity and mortality, especially in resource limited settings. The World Health Organisation has recently made a vaccine for S. pyogenes a global health priority to reduce the burden of the post-infection rheumatic heart disease. For a vaccine to be active against all relevant strains in each region, molecular characterisation of circulating S. pyogenes isolates is needed. We performed extensive comparative whole genome analyses of S. pyogenes isolates from skin and soft tissue infections in The Gambia, West Africa, where there is a high burden of such infections. To act as a comparator to this low-income country (LIC) collection of isolates, we performed genome sequencing of isolates from skin infections in Sheffield, UK, as representative high-income country (HIC) isolates. LIC isolates from The Gambia were genetically more diverse (46 emm-types in 107 isolates) compared to HIC isolates from Sheffield (23 emm-types in 142 isolates), with only 7 overlapping emm-types and with diverse genetic backgrounds. Characterisation of other molecular markers indicated some shared features, including a high prevalence of the skin infection-associated emm-pattern D and the variable fibronectin-collagen-T antigen (FCT) types FCT-3 and FCT-4. A previously unidentified FCT (FCT-10) was identified in the LIC isolates, belonging to two different emm-types. A high proportion (79/107; 73.8%) of LIC isolates carried genes for tetracycline resistance, compared to 53/142 (37.3%) HIC isolates. There was also evidence of different circulating prophages, as very few prophage-associated DNases and lower numbers of superantigens were detected in LIC isolates. Our study provides much needed insight into the genetics of circulating isolates in a LIC (The Gambia), and how they differ from those circulating in HICs (Sheffield, UK). Common molecular features may act as bacterial drivers for specific infection types, regardless of the diverse genetic background.
CAMOIP: A Web Server for Comprehensive Analysis on Multi-Omics of Immunotherapy in Pan-cancer
Authors: Lin Anqi , Wei Ting , Liang Junyi , Qi Chang , Li Mengyao , Luo Peng , Zhang Jian
Published: September 2021

Immune checkpoint inhibitors (ICIs) have completely changed the therapeutic approach for tumor patients. Immunotherapy has also produced much needed data about mutation, expression, and prognosis, providing an unprecedented opportunity for discovering candidate drug targets and screening for immunotherapy-relevant biomarkers. Although existing web tools enable biologists to analyze the expression, mutation, and prognosis data on tumors, they are currently not able to carry out data mining and mechanism analyses related to immune checkpoint therapy. Thus, we developed our own web-based tool called Comprehensive Analysis on Multi-Omics of Immunotherapy in Pan-cancer (CAMOIP), in which we can screen prognostic markers and analyze the mechanisms involved with markers and immunotherapy (more than 4000 patients). The analyses include survival analysis, expression analysis, drug sensitivity analysis, mutational landscape, immune checkpoint analysis, immune related signature analysis, immune cell analysis, immune gene analysis, immunogenicity analysis and gene sets enrichment analysis (GSEA). This comprehensive analysis of biomarkers for immunotherapy can be carried out by a click of CAMOIP, and the software should greatly encourage the further development of immunotherapy. CAMOIP fills the gap between the big data of cancer genomics based on immunotherapy and providing comprehensive information to users, helping to release the value of current ICI-treated data resources. CAMOIP can be found inhttps://www.camoip.net.
Unique features of transcription termination and initiation at closely spaced tandem human genes
Authors: Nissani Noa , Ulitsky Igor
Published: September 2021

The synthesis of RNA Polymerase II (Pol2) products, which include messenger RNAs or long noncoding RNAs, culminates in transcription termination. How the transcriptional termination of a gene impacts the activity of promoters found immediately downstream of it, and which can be subject to potential transcriptional interference, remains largely unknown. We examined in an unbiased manner features of the intergenic region of pairs of tandem and closely spaced (<2kb) genes found on the same strand. Intergenic regions separating tandem genes are enriched with Guanines and are characterized by binding of several proteins, including AGO1 and AGO2 of the RNA interference pathway. Additionally, we found that Pol2 with a specific modification pattern is particularly enriched in this region, and it is lost upon perturbations affecting splicing or transcriptional elongation. Perturbations of genes involved in Pol2 pausing and R loop biology preferentially affect expression of downstream genes in tandem gene pairs. Overall, we find that features associated with potential Pol2 recycling rather than those associated with avoidance of transcriptional interference are the predominant driving force shaping these regions.
Deep Learning identifies new morphological patterns of Homologous Recombination Deficiency in luminal breast cancers from whole slide images
Authors: Lazard Tristan , Bataillon Guillaume , Naylor Peter , Popova Tatiana , Bidard François-Clément , Stoppa-Lyonnet Dominique , Stern Marc-Henri , Decencière Etienne , Walter Thomas , Salomon Anne Vincent
Published: September 2021

Homologous Recombination DNA-repair deficiency (HRD) is a well-recognized marker of platinum-salt and PARP inhibitor chemotherapies in ovarian and breast cancers (BC). Causing high genomic instability, HRD is currently determined by BRCA1/2 sequencing or by genomic signatures, but its morphological manifestation is not well understood. Deep Learning (DL) is a powerful machine learning technique that has been recently shown to be capable of predicting genomic signatures from stained tissue slides. However, DL is known to be sensitive to dataset biases and lacks interpretability. Here, we present and evaluate a strategy to control for biases in retrospective cohorts. We train a deep-learning model to predict the HRD in a controlled cohort with unprecedented accuracy (AUC: 0.86) and we develop a new visualization technique that allows for automatic extraction of new morphological features related to HRD. We analyze in detail the extracted morphological patterns that open new hypotheses on the phenotypic impact of HRD.
Clinical grade ACE2 as a universal agent to block SARS-CoV-2 variants
Authors: Wirnsberger Gerald , Monteil Vanessa , Eaton Brett , Postnikova Elena , Murphy Michael , Braunsfeld Benedict , Crozier Ian , Kricek Franz , Niederhöfer Janine , Schwarzböck Alice , Breid Helene , Sanchez Jimenez Anna , Bugajska-Schretter Agnes , Dohnal Alexander , Ruf Christine , Gugenberger Romana , Hagelkruys Astrid , Montserrat Nuria , Holbrook Michael R. , Oostenbrink Chris , Shoemaker Robert H. , Mirazimi Ali , Penninger Josef M.
Published: September 2021

The recent emergence of multiple SARS-CoV-2 variants has caused considerable concern due to reduced vaccine efficacy and escape from neutralizing antibody therapeutics. It is therefore paramount to develop therapeutic strategies that inhibit all known and future SARS-CoV-2 variants. Here we report that all SARS-CoV-2 variants analyzed, including variants of concern (VOC) Alpha, Beta, Gamma, and Delta, exhibit enhanced binding affinity to clinical grade and phase 2 tested recombinant human soluble ACE2 (APN01). Importantly, soluble ACE2 neutralized infection of VeroE6 cells and human lung epithelial cells by multiple VOC strains with markedly enhanced potency when compared to reference SARS-CoV-2 isolates. Effective inhibition of infections with SARS-CoV-2 variants was validated and confirmed in two independent laboratories. These data show that SARS-CoV-2 variants that have emerged around the world, including current VOC and several variants of interest, can be inhibited by soluble ACE2, providing proof of principle of a pan-SARS-CoV-2 therapeutic.
Human-specific enrichment of schizophrenia risk-genes in callosal neurons of the developing neocortex
Authors: Zuccaro Emanuela , Murek Vanessa , Kim Kwanho , Chen Hsu-Hsin , Mancinelli Sara , Oyler-Castrillo Paul , Jiménez-Barrón Laura T. , Gerhardinger Chiara , Brown Juliana R. , Byrnes Andrea , Neale Benjamin M. , Levin Joshua Z. , Ziller Michael J. , Lodato Simona , Arlotta Paola
Published: September 2021

Human genetic studies have provided a wealth of information on genetic risk factors associated with neuropsychiatric diseases. However, whether different brain cell types are differentially affected in disease states and when in their development and maturation alterations occur is still poorly understood. Here we generated a longitudinal transcriptional map of excitatory projection neuron (PN) and inhibitory interneuron (IN) subtypes of the cerebral cortex, across a timeline of mouse embryonic and postnatal development, as well as fetal human cortex and human cortical organoids. We found that three types of gene signatures uniquely defined each cortical neuronal subtype: dynamic (developmental), adult (terminal), and constitutive (stable), with individual neuronal subtypes varying in the degree of similarity of their signatures between species. In particular, human callosal projection neurons (CPN) displayed the greatest species divergence, with molecular signatures highly enriched for non-coding, human-specific RNAs. Evaluating the association of neuronal class-specific signatures with neuropsychiatric disease risk genes using linkage disequilibrium score regression showed that schizophrenia risk genes were enriched in CPN identity signatures from human but not mouse cortex. Human cortical organoids confirmed the association with excitatory projection neurons. The data indicate that risk gene enrichment is both species- and cell type-specific. Our study reveals molecular determinants of cortical neuron diversification and identifies human callosal projection neurons as the most species-divergent population and a potentially vulnerable neuronal class in schizophrenia.
Intranasal administration of a VLP-based vaccine against COVID-19 induces neutralizing antibodies against SARS-CoV-2 and Variants of Concerns
Authors: Rothen Dominik A. , Krenger Pascal S. , Nonic Aleksandra , Balke Ina , Vogt Anne-Cathrine S. , Chang Xinyue , Manenti Alessandro , Vedovi Fabio , Resevica Gunta , Walton Senta M. , Zeltins Andris , Montomoli Emanuele , Vogel Monique , Bachmann Martin F. , Mohsen Mona O.
Published: September 2021

Background

The highly contagious SARS-CoV-2 is mainly transmitted by respiratory droplets and aerosols. Consequently, people are required to wear masks and maintain a social distance to avoid spreading of the virus. Despite the success of the commercially available vaccines, the virus is still uncontained globally. Given the tropism of SARS-CoV-2, a mucosal immune reaction would help to reduce viral shedding and transmission locally. Only seven out of hundreds of ongoing clinical trials are testing the intranasal delivery of COVID-19 vaccines.

Methods

In the current study, we tested in murine model the immunogenicity of a conventional vaccine platform based on virus-like particles (VLPs) displaying RBD of SARS-CoV-2 for intranasal vaccination. The candidate vaccine, CuMVTT-RBD, has been immunologically optimized to incorporate tetanus-toxin and is self-adjuvanted with TLR7/8 ligands.

Results

CuMVTT-RBD elicited strong RBD- and spike- specific systemic IgG and IgA antibody responses of high avidity. Local immune responses were assessed and results demonstrate strong mucosal antibody and plasma cell production in lung tissue. The induced systemic antibodies could efficiently recognize and neutralize different Variants of Concerns of mutated SARS-CoV-2 RBDs.

Conclusion

In summary, intranasal vaccination with CuMVTT-RBD shows high immunogenicity and induces protective systemic and local specific antibody response against SARS-CoV-2 and its variants.

One sentence summary

Evaluation of an intransal administrated conventional VLP-based vaccine against COVID-19 in a murine model.
Kv1.3 induced hyperpolarisation and Cav3.2-mediated calcium entry are required for efficient Kaposi’s sarcoma-associated herpesvirus lytic replication
Authors: Carden Holli , Dallas Mark L. , Hughes David J. , Lippiat Jonathan D. , Mankouri Jamel , Whitehouse Adrian
Published: September 2021

Understanding the host factors critical for Kaposi’s sarcoma-associated herpesvirus (KSHV) lytic replication can identify new targets for therapeutic intervention. Using pharmacological and genetic silencing approaches, we reveal for the first time that KSHV requires a B cell expressed voltage-gated K+channel, Kv1.3, to enhance lytic replication. We show that the KSHV replication and transcription activator (RTA) protein upregulates Kv1.3 expression, leading to enhanced K+channel activity and hyperpolarisation of the B cell membrane. Enhanced Kv1.3 activity then promotes intracellular Ca2+influx through Cav3.2, a T-type Ca2+channel, leading to the Ca2+driven nuclear localisation of NFAT and the subsequent NFAT1-responsive gene expression. Importantly, KSHV lytic replication and infectious virion production could be inhibited by both Kv1.3 and Cav3.2 blockers or through Kv1.3 silencing. These findings provide new mechanistic insight into the essential role of host ion channels during KSHV infection and highlight Kv1.3 and Cav3.2 as new druggable host factors that are key to the successful completion of KSHV lytic replication.
SILAC phosphoproteomics reveals unique signaling circuits in CAR-T cells and the inhibition of B cell-activating phosphorylation in target cells
Authors: Griffith Alijah A. , Callahan Kenneth P. , King Nathan Gordo , Xiao Qian , Su Xiaolei , Salomon Arthur R.
Published: September 2021

Chimeric antigen receptor (CAR) is a single-pass transmembrane receptor designed to specifically target and eliminate cancers. While CARs prove highly efficacious against B cell malignancies, the intracellular signaling events which promote CAR T cell activity remain elusive. To gain further insight into both CAR T cell signaling and the potential signaling response of cells targeted by CAR, we analyzed phosphopeptides captured by two separate phopshoenrichment strategies from third generation CD19-CAR T cells cocultured with SILAC labeled Raji B cells by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Here, we report that CD19-CAR T cells upregulated several key phosphorylation events also observed in canonical T cell receptor (TCR) signaling while Raji B cells exhibited a significant decrease in B cell receptor-signaling related phosphorylation events in response to coculture. Our data suggest that CD19-CAR stimulation activates a mixture of unique CD19-CAR-specific signaling pathways and canonical TCR signaling while global phosphorylation in Raji B cells is reduced after association with the CD19-CAR T cells.
An inactivated multivalent influenza A virus vaccine is broadly protective in mice and ferrets
Authors: Park Jaekeun , Fong Sharon , Schwartzman Louis M. , Sheng Zhong-Mei , Freeman Ashley , Matthews Lex , Xiao Yongli , Ramuta Mitchell D. , Batchenkova Natalia A. , Qi Li , Rosas Luz Angela , Williams Stephanie , Scherler Kelsey , Gouzoulis Monica , Bellayr Ian , Morens David M. , Walters Kathie-Anne , Memoli Matthew J. , Kash John C. , Taubenberger Jeffery K.
Published: September 2021

Influenza A viruses (IAVs) present major public health threats from annual seasonal epidemics, from pandemics caused by novel virus subtypes, and from viruses adapted to a variety of animals including poultry, pigs and horses. Vaccines that broadly protect against all such IAVs, so-called “universal” influenza vaccines, do not currently exist, but are urgently needed. This study demonstrates that an inactivated, multivalent whole virus vaccine, delivered intramuscularly or intranasally, is broadly protective against challenges with multiple IAV HA/NA subtypes in both mice and ferrets, including challenges with IAV subtypes not contained in the vaccine. This vaccine approach indicates the feasibility of eliciting broad “universal” IAV protection, and identifies a promising candidate for influenza vaccine clinical development.

One-Sentence Summary

An inactivated, whole avian influenza virus vaccine delivered intramuscularly or intranasally provides extremely broad protection against antigenically divergent viral challenge and is a promising candidate for a “universal” influenza virus vaccine.