bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of a Novel Care Rehabilitation Pathway for Post-COVID Conditions (Long COVID) in a Provincial Health System in Alberta, Canada
Authors: Manhas Kiran Pohar , O’Connell Petra , Krysa Jacqueline , Henderson Isabel , Ho Chester , Papathanassoglou Elisavet
Published: July 2022

Objective

The purpose of this study was to describe the development and composition of a codesigned, multidisciplinary, integrated, systematic rehabilitation framework for post-COVID conditions (PCC) that spans the care continuum to streamline and standardize rehabilitation services to support persons with PCC in Alberta, Canada.

Methods

A collaborative, consensus-based approach was used involving 2 iterative provincial taskforces in a Canadian provincial health system. The first taskforce (59 multidisciplinary stakeholders) sought to clarify the requisite facets of a sustainable, provincially coordinated rehabilitation approach for post-COVID rehabilitation needs based on available research evidence. The second taskforce (129 multidisciplinary stakeholders) translated that strategy and criteria into an operational framework for provincial implementation. Both taskforces sought to align with operational realities of the provincial health system.

Results

The summation of this collaborative consensus approach resulted in the Provincial Post COVID-19 Rehabilitation Response Framework (PCRF). The PCRF includes 3 care pathways across the care continuum specifically targeting in-hospital care, continuing care, and community-based care with 3 key elements: (1) the use of specific symptom screening and assessment tools to systematically identify PCC symptoms and functional impairments, (2) pathways to determine patients’ rehabilitation trajectory and guide their transition between care settings, and (3) self-management and education resources for patients and providers.

Conclusion

The PCRF aligns with international mandates for novel, codesigned, multidisciplinary approaches to systematically address PCC and its myriad manifestations across the care continuum. The PCRF allows for local adaptation and highlights equity considerations, allowing for further spread and scale provincially, nationally, and internationally.

Impact

The PCRF is a framework for health systems to ensure consistent identification, assessment, and management of the rehabilitation needs of postacute and chronic PCC. Rehabilitation providers and health systems can build from the PCRF for their local communities to reduce unmet needs and advance the standardization of access to rehabilitation services for persons with PCC.
Patient-Centered Goals After Lumbar Spine Surgery: A Secondary Analysis of Cognitive-Behavioral–Based Physical Therapy Outcomes From a Randomized Controlled Trial
Authors: Coronado Rogelio A , Master Hiral , Bley Jordan A , Robinette Payton E , Sterling Emma K , O’Brien Michael T , Henry Abigail L , Pennings Jacquelyn S , Vanston Susan W , Myczkowski Brittany , Skolasky Richard L , Wegener Stephen T , Archer Kristin R
Published: July 2022

Objective

The purpose of this study was to examine the association between goal attainment and patient-reported outcomes in patients who engaged in a 6-session, telephone-based, cognitive-behavioral–based physical therapy (CBPT) intervention after spine surgery.

Methods

In this secondary analysis of a randomized trial, data from 112 participants (mean age = 63.3 [SD = 11.2] years; 57 [51%] women) who attended at least 2 CBPT sessions (median = 6 [range = 2–6]) were examined. At each session, participants set weekly goals and used goal attainment scaling (GAS) to report goal attainment from the previous session. The number and type of goals and percentage of goals met were tracked. An individual GAS t score was computed across sessions. Participants were categorized based on goals met as expected (GAS t score ≥ 50) or goals not met as expected (GAS t score < 50). Six- and 12-month outcomes included disability (Oswestry Disability Index), physical and mental health (12-Item Short-Form Health Survey), physical function (Patient-Reported Outcomes Measurement Information System), pain interference (Patient-Reported Outcomes Measurement Information System), and back and leg pain intensity (numeric rating scale). Outcome differences over time between groups were examined with mixed-effects regression.

Results

Participants set a median of 3 goals (range = 1–6) at each session. The most common goal categories were recreational/physical activity (36%), adopting a CBPT strategy (28%), exercising (11%), and performing activities of daily living (11%). Forty-eight participants (43%) met their goals as expected. Participants who met their goals as expected had greater physical function improvement at 6 months (estimate = 3.7; 95% CI = 1.0 to 6.5) and 12 months (estimate = 2.8; 95% CI = 0.04 to 5.6). No other outcome differences were noted.

Conclusions

Goal attainment within a CBPT program was associated with 6- and 12-month improvements in postoperative physical functioning.

Impact

This study highlights goal attainment as an important rehabilitation component related to physical function recovery after spine surgery.
The Political Economy of Local Governments’ Requests for Permission to Override Central Fiscal Limitations: Insights from Israel
Authors: Kimhi Omer , Beeri Itai , Reingewertz Yaniv
Published: July 2022

Central governments often restrict municipalities’ ability to raise or reduce taxes, but, in many jurisdictions, municipalities can ask the central government’s permission to set aside these limitations. Using an Israeli dataset, we explore this prevalent, yet unexplored, mechanism we call Permission to Override (PtO). We find that in Israel, at least, the central government’s approval and rejection of these permission requests seem to be equitable and non-political. However, despite the central neutrality, municipalities with lower socio-economic status and fewer political connections tend not to submit requests. Municipalities are also reluctant to submit requests before elections and tend to submit them only afterwards. These socio-economic and political biases may create inequalities and hinder a successful use of the PtO mechanism. We discuss the limited use of this mechanism (requests amount to approximately 0.6 percent of the total property tax income) and its shortcomings and draw conclusions from the Israeli case study.
What Is Holding Us Together? David Hume, Edgar Allan Poe and the Problem of Association
Authors: Kronfeld Maya
Published: July 2022

Poe’s experimental fiction revitalizes Hume’s ambivalent empiricism, the complexities of which were sometimes obscured in the philosopher’s nineteenth-century American reception. Poe’s ‘Murders in the Rue Morgue’ broaches formally the question of how one thought leads to another, while ‘The Man that Was Used Up’ stages the question of what grounds the unity of one’s thoughts. Reading both tales together exposes the scope and limits of an associationist paradigm often traced back to Hume. But reading Hume through Poe’s verbal art reveals that Hume’s ‘mitigated scepticism’ about personal identity is more difficult to grapple with, and potentially more devastating for Western Reason, than the modes of scepticism that more comfortably entered the English canon. In ‘Rue Morgue’, Detective Dupin’s presumption to reconstruct fully the narrator’s train of thought may be the real locus of the tale’s horror. In the ‘Man that Was Used Up’, the heroic General A.B.C. Smith disintegrates on the floor into a talking ‘bundle’ that parodically literalizes Hume’s most famous metaphor in the Treatise. Hume’s bundle thus reappears in Poe as the proto-surrealist ‘terminus’ of a reductive explanation that has become physically real. To say with Hume that the mind is a ‘fiction’ is not to deny the goings-on of mental phenomena, but to attempt a much more challenging claim: that our minds conceptualize themselves out of their own limited nature, but not in a way that necessarily accords with that nature. If Hume brings out the parody in Poe, we might also say that Poe amplifies the irony in Hume.
Lessons from the field: COVID-19 outbreak investigations in Kpone-Katamanso, Greater Accra, Ghana: a Global South approach to disease control and contact tracing
Authors: Danquah Esther P B , Darko Shadrack , Frimpong Adom , Head Michael G , Osei Bright
Published: July 2022

In the Kpone-Katamanso Municipality (Greater Accra, Ghana), as part of the coronavirus disease 2019 (COVID-19) pandemic response, public health teams implemented and carried out enhanced contact tracing and surveillance from March 2020 to March 2021. There were 725 confirmed COVID-19 cases during this time period, most of which were detected as part of the enhanced surveillance. This is resource intensive, but beneficial in the early detection of cases, thus reducing further community transmission and, in effect, stopping larger outbreaks at the source. A proactive approach to case detection can be successful in reducing community transmission and supporting the pandemic response.
Persistence of Trypanosoma cruzi vector-borne transmission among school-age children in the Bolivian Chaco documented by 24-month longitudinal serosurveillance
Authors: Spinicci Michele , Macchioni Fabio , Gamboa Herlan , Poma Veronica , Villagrán Ana Liz , Strohmeyer Marianne , Roselli Mimmo , Vargas Roberto , Bartoloni Alessandro , Gabrielli Simona
Published: July 2022

Background

Chagas disease represents a major public health concern in several Latin American countries, including Bolivia.

Methods

We present a longitudinal serosurvey for Trypanosoma cruzi antibodies among a cohort of 120 school-age children from rural communities in the Bolivian Chaco at three time points between 2017 and 2019. Serum samples extracted from dry blood spots collected on filter paper were tested for T. cruzi antibodies by enzyme-linked immunosorbent assay and rapid diagnostic test.

Results

T. cruzi antibodies were detected in 7/120 (5.8%), 8/120 (6.7%) and 11/120 (9.2%) samples in 2017, 2018 and 2019, respectively. An average incidence of 1.76 per 100 person-years was observed.

Conclusions

Our findings support the persistence of vector-borne T. cruzi transmission in this area, highlighting the need for strengthening multidisciplinary efforts against Chagas disease.
Pathology of T-cell-mediated drug hypersensitivity reactions and impact of tolerance mechanisms on patient susceptibility
Authors: Line James , Thomson Paul , Naisbitt Dean J.
Published: July 2022

Purpose of review

T-cell-mediated drug hypersensitivity is responsible for significant morbidity and mortality, and represents a substantial clinical concern. The purpose of this article is to focus on T-cell reactions and discuss recent advances in disease pathogenesis by exploring the impact of tolerance mechanisms in determining susceptibility in genetically predisposed patients.

Recent findings

Certain drugs preferentially activate pathogenic T cells that have defined pathways of effector function. Thus, a critical question is what extenuating factors influence the direction of immune activation. A large effort has been given towards identifying phenotypic (e.g., infection) or genotypic (e.g., human leukocyte antigen) associations which predispose individuals to drug hypersensitivity. However, many individuals expressing known risk factors safely tolerate drug administration. Thus, mechanistic insight is needed to determine what confers this tolerance. Herein, we discuss recent clinical/mechanistic findings which indicate that the direction in which the immune system is driven relies upon a complex interplay between co-stimulatory/co-regulatory pathways which themselves depend upon environmental inputs from the innate immune system.

It is becoming increasingly apparent that tolerance mechanisms impact on susceptibility to drug hypersensitivity. As the field moves forward it will be interesting to discover whether active tolerance is the primary response to drug exposure, with genetic factors such as HLA acting as a sliding scale, influencing the degree of regulation required to prevent clinical reactions in patients.
Effects of systemic targeted immunosuppressive therapy on ocular surface
Authors: Mukhtar Sabrina , Jhanji Vishal
Published: July 2022

Purpose of review

The purpose of this review is to give an overview of the corneal manifestations of targeted systemic immunotherapies and provide guidelines for management when applicable.

Recent findings

The advent of newer systemic immunosuppressive therapy has resulted in the need for more awareness of potential ocular side effects. Side effects can range from vortex keratopathy as seen with the tyrosine kinase inhibitors, to epithelial microcysts as reported in the use of cytarabine and belantamab mafodotin, spontaneous corneal perforations have been reported with programmed death 1 inhibitors, while eyelid cicatrization has been reported epidermal growth factor inhibitors. Several immunomodulatory therapies result in conjunctivitis which tends to respond to topical lubrication and corticosteroid treatment. Most manifestations listed in the review are limited to the anterior segment; however, some may lead to retinal and optic nerve changes which can be permanently damaging.

Ocular surface and corneal changes secondary to systemic immunosuppression can affect main components of the ocular surface. Although most adverse effects are reversible, few changes can be permanent and therefore close ophthalmologic monitoring is necessary.
Enrichment of breast cancer stem cells following cytotoxic chemotherapy is mediated by hypoxia-inducible factors
Authors: Samanta Debangshu , Gilkes Daniele M. , Xiang Lisha , Chaturvedi Pallavi , Semenza Gregg L.
Published: July 2022

Breast cancers (BCs) that do not express the estrogen or progesterone receptor or human epidermal growth factor receptor 2 are known as triple negative breast cancers (TNBCs). Women with TNBC receive non-targeted chemotherapy with a durable response rate of less than 20%. BC stem cells (BCSCs) are a small subpopulation of BC cells that are characterized by the capacity for infinite self-renewal; are the only BC cells capable of forming a secondary (recurrent or metastatic) BC; and must be eliminated in order to eradicate BC. Hypoxia-inducible factors (HIFs) activate hundreds of genes in TNBCs and HIF-1α expression in the diagnostic tumor biopsy is associated with patient mortality. In this paper, we report that treatment of TNBC cells with cytotoxic chemotherapy increased HIF-1α and HIF-2α protein levels and HIF target gene expression. Chemotherapy also increased the percentage of BCSCs through pathways involving interleukin-6 (IL-6), IL-8, and multidrug resistance 1. HIF inhibitors blocked increased BCSC specification in response to cytotoxic chemotherapy and combination therapy led to tumor eradication. Increased HIF target gene expression in BC biopsies was correlated with increased mortality, especially in those patients treated with chemotherapy alone. Our results suggest that HIF-dependent BCSC enrichment provides a molecular and cellular basis for the high incidence of relapse in women with TNBC.
Identification and characterization of genetic risk shared across 24 chronic pain conditions in the UK Biobank
Authors: Zorina-Lichtenwalter Katerina , Bango Carmen I. , Van Oudenhove Lukas , Čeko Marta , Lindquist Martin A. , Grotzinger Andrew D. , Keller Matthew C. , Friedman Naomi P. , Wager Tor D.
Published: July 2022

Chronic pain is attributable to both local and systemic pathology. To investigate the latter, we focused on genetic risk shared among 24 chronic pain conditions in the UK Biobank. We conducted genome-wide association studies (GWAS) on all conditions and estimated genetic correlations among them, using these to model a factor structure in Genomic SEM. This revealed a general factor explaining most of the shared genetic variance in all conditions and an additional musculoskeletal pain-selective factor. Network analyses revealed a large cluster of highly genetically inter-connected conditions, with arthropathic, back, and neck pain showing the highest centrality. Functional annotation (FUMA) showed organogenesis, metabolism, transcription, and DNA repair as associated pathways, with enrichment for associated genes exclusively in brain tissues. Cross-reference with previous GWAS showed genetic overlap with cognition, mood, and brain structure. In sum, our results identify common genetic risks and suggest neurobiological and psychosocial mechanisms of vulnerability to chronic pain.
Non-invasive quantification of contractile dynamics in cardiac cells, spheroids and organs-on-a-chip using high frequency ultrasound
Authors: Strohm Eric M. , Callaghan Neal , Latifi Neda , Rafatian Naimeh , Funakoshi Shunsuke , Fernandes Ian , Radisic Milica , Keller Gordon , Kolios Michael C. , Simmons Craig A.
Published: July 2022

Cell-based models that mimic in vivo heart physiology are poised to make significant advances in cardiac disease modeling and drug discovery. In these systems, cardiomyocyte (CM) contractility is an important functional metric, but current measurement methods are inaccurate, low-throughput, or require complex set-ups. To address this need, we developed a standalone non-invasive, label-free ultrasound technique operating at 40-200 MHz to measure the beat rate, beat rhythm, and force of contraction of cardiac models, ranging from single adult CMs to 3D microtissue constructs in standard cell culture formats. The high temporal resolution of 1000 fps resolved the beat profile of single mouse CMs paced at up to 9 Hz, revealing limitations of lower speed optical based measurements to resolve beat kinetics or characterize aberrant beats. Coupling of ultrasound with traction force microscopy enabled the measurement of CM longitudinal modulus and facile estimation of adult mouse CM contractile forces of 2.34 ± 1.40 μN, comparable to more complex measurement techniques. Similarly, measurements of beat rate, rhythm, and drug responses of CM spheroid and microtissue models were demonstrated. In conclusion, ultrasound can be used for the rapid characterization of CM contractile function in a wide range of commonly-studied configurations ranging from single cells to 3D tissue constructs using standard well plates, with applications in cardiac drug discovery and cardiotoxicity evaluation.
A new transcriptional metastatic signature predicts survival in clear cell renal cell carcinoma
Authors: Alchahin Adele M. , Mei Shenglin , Tsea Ioanna , Hirz Taghreed , Kfoury Youmna , Dahl Douglas , Wu Chin-Lee , Subtelny Alexander O. , Wu Shulin , Scadden David T. , Shin John H. , Saylor Philip J. , Sykes David B. , Kharchenko Peter V. , Baryawno Ninib
Published: July 2022

Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer in adults. When ccRCC is localized to the kidney, surgical resection or ablation of the tumor is often curative. However, in the metastatic setting, ccRCC remains a highly lethal disease. Here we take advantage of fresh patient samples that include treatment-naive primary tumor tissue, matched adjacent normal kidney tissue, as well as tumor samples collected from patients with bone metastases. Single-cell transcriptomic analysis of tumor cells from the primary tumors revealed a distinct transcriptional signature that was predictive of metastatic potential and patient survival. Analysis of supporting stromal cells within the tumor environment demonstrated vascular remodeling within the endothelial cells and a proliferative signature within the fibroblasts that was associated with poor survival. An in silico cell-to-cell interaction analysis highlighted the CXCL9/CXCL10-CXCR3 axis and the CD70-CD27 axis as potential therapeutic targets. Our findings provide biological insights into the interplay between tumor cells and the ccRCC microenvironment.
Evaluation of EN2 gene as a potential biomarker for bladder cancer
Authors: Aldoghachi Ahmed Faris , Baharudin Aminuddin , Ahmad Umar , Choy Chan Soon , Aik Ong Ting , Yunus Rosna , Razack Azad , Yusoff Khatijah , Veerakumarasivam Abhi
Published: July 2022

Background

Among the most prevalent cancers in the urinary tract is bladder cancer, a caner with a high rate of recurrence and metastasis as compared to other malignancies. To date, there have been many genes reported as potential bladder cancer biomarkers among which is the EN2 gene, a member of the homeobox family containing transcriptional factors. Several studies suggested the overexpression of EN2 to be involved with the development of a number of tumors such as bladder cancer. However, the process of involvement of EN2 in the bladder tumorigenesis remains elusive.

Methods

RT-qPCR was carried out to determine the gene expression of 17 cell lines. The short-term silencing of EN2 expression was then implemented in high-expressing cell lines using siRNAs. Using the scratch assay, the outcome of modulating the in vitro EN2 expression on the bladder cancer migration was determined. Correlation between the IC50 values with the EN2 expression was analyzed by correlating the viability of cells following the Newcastle Disease Virus infection with the fold change. Immunohistochemistry was then performed to determine the expression of the EN2 protein in the bladder cancer tissues.

Results

In the current study, EN2 was differentially expressed in bladder cancer in vitro and upon modulating the expression of EN2, we found a reduction in the migratory effect of bladder cancer in vitro. In addition, following 24 hours post infection, a moderate correlation between EN2 gene expression and NDV-mediated oncolysis was observed. No expression of EN2 in bladder cancer tissues suggesting the need for further studies to investigate the expression of EN2 protein in bladder cancer.

Conclusion

EN2 may be a potential prognostic or diagnostic bladder cancer biomarker, however, further investigations are required to evaluate the EN2 gene as a potential bladder cancer biomarker.
Discovery of a non-canonical GRHL1 binding site using deep convolutional and recurrent neural networks
Authors: Proft Sebastian , Leiz Janna , Heinemann Udo , Seelow Dominik , Schmidt-Ott Kai M. , Rutkiewicz Maria
Published: July 2022

Transcription factors regulate gene expression by binding to transcription factor binding sites (TFBSs). Most models for predicting TFBSs are based on position weight matrices (PWMs), which require a specific motif to be present in the DNA sequence and do not consider interdependencies of nucleotides. Novel approaches such as Transcription Factor Flexible Models or recurrent neural networks consequently provide higher accuracies. However, it is unclear whether such approaches can uncover novel non-canonical, hitherto unexpected TFBSs relevant to human transcriptional regulation. In this study, we trained a convolutional recurrent neural network with HT-SELEX data for GRHL1 binding and applied it to a set of GRHL1 binding sites obtained from ChIP-Seq experiments from human cells. We identified 46 non-canonical GRHL1 binding sites, which were not found by a conventional PWM approach. Unexpectedly, some of the newly predicted binding sequences lacked the CNNG core motif, so far considered obligatory for GRHL1 binding. Using isothermal titration calorimetry, we experimentally confirmed binding between the GRHL1-DNA binding domain and predicted GRHL1 binding sites, including a non-canonical GRHL1 binding site. Mutagenesis of individual nucleotides revealed a correlation between predicted binding strength and experimentally validated binding affinity across representative sequences. This correlation was neither observed with a PWM-based nor another deep learning approach. Our results show that convolutional recurrent neural networks may uncover unanticipated binding sites and facilitate quantitative transcription factor binding predictions.
Graphene Biointerface for Cardiac Arrhythmia Diagnosis and Treatment
Authors: Lin Zexu , Kireev Dmitry , Liu Ning , Gupta Shubham , LaPaino Jessica , Obaid Sofian N. , Chen Zhiyuan , Akinwande Deji , Efimov Igor R.
Published: July 2022

Heart rhythm disorders, known as arrhythmias, cause significant morbidity and are one of the leading causes of mortality. Cardiac arrhythmias are primarily treated by implantable devices, such as pacemakers and defibrillators, or by ablation therapy guided by electroanatomical mapping. Pharmacological treatments are mostly ineffective. Both implantable and ablation therapies require sophisticated biointerfaces for electrophysiological measurements of electrograms and delivery of therapeutic stimulation or ablation energy. In this work, we report for the first time on graphene biointerface forin vivocardiac electrophysiology. Leveraging sub-micrometer thick tissue-conformable graphene arrays, we demonstrate sensing and stimulation of the open mammalian heart bothin vitroandin vivo.Furthermore, we demonstrate graphene pacemaker treatment of a pharmacologically-induced arrhythmia, AV block. The arrays show effective electrochemical properties, namely interface impedance down to 40 Ohm×cm2at 1kHz, charge storage capacity up to 63.7 mC/cm2, and charge injection capacity up to 704 μC/cm2. Transparency of the graphene structures allows for simultaneous optical mapping of cardiac action potentials and optogenetic stimulation while performing electrical measurements and stimulation. Our report presents evidence of the significant potential of graphene biointerfaces for the future clinical device- and catheter-based cardiac arrhythmias therapies.
Driving Osteocytogenesis from Mesenchymal Stem Cells in Osteon-like Biomimetic Nanofibrous Scaffolds
Authors: Soheilmoghaddam Farhad , Hezaveh Hadi , Rumble Madeleine , Cooper-White Justin J.
Published: July 2022

The repair of critical-sized bone defects, resulting from tumor resection, skeletal trauma or infection, remains a significant clinical problem. A potential solution is a tissue-engineered approach that utilises the combination of human mesenchymal stem cells (hMSCs) with synthetic biomaterial scaffolds, mimicking many of the biochemical and biophysical cues present within the native bone. Unfortunately, osteocyte cells, the orchestrators of bone maturation and homeostasis, are rarely produced within such MSC-seeded scaffolds, limiting the formation of true mature cortical bone from these synthetic implants. In this contribution, a bone morphogenic protein-6 (BMP6)-presenting osteon-like scaffolds based on electrospun poly(lactic-co-glycolic acid) (PLGA) fibrous scaffolds and poly(ethylene glycol) (PEG) based-hydrogels is reported. BMP6 peptide is shown to drive higher levels of SMAD signalling than the full-length protein counterpart. Osteon-mimetic scaffolds promoted the formation of osteocyte-like cells displaying multi-dendritic morphology and osteocyte-specific marker, E11/gp38 (E11), along with significant production of dentin matrix protein 1 (DMP1), confirming maturation of the ososteocyte-like cells. These results demonstrate that osteon-like scaffolds presenting chemo-topographical cues can drive the formation of mature osteocyte-like cells from hMSCs,withoutthe need for osteogenic factor media supplements, providing a novel ex vivo production platform for osteocyte-like cells from human MSCs in cortical bone mimics.
Q-SHINE: a versatile sensor for glutamine measurement via ligand-induced dimerization
Authors: Seo Moon-Hyeong , Lim Yun , Kim Ji Yul , Jung Youn Hee , Lee Jae Hoon , Baek Min Seok , Jung Je Hyeong , Kim Ho-Youn , Lee Wookbin , Park Keunwan
Published: July 2022

Studies on glutamine (Gln) metabolism have illuminated the vital role of Gln in cellular functions and its potential as a biomarker for disease detection. Despite the increasing interest in Gln metabolism, in-depth evaluations are challenging owing to limitations of conventional Gln-measuring methods. Thus, we developed a ligand-induced dimerization-based sensor for Gln, termed Q-SHINE, by splitting a glutamine binding protein into two separate domains. Q-SHINE enables highly accurate and convenient measurement of Gln concentration in bio-fluid samples, and the detection range is optimal for physiological Gln levels. Genetically encoded Q-SHINE sensors could also visualize intracellular Gln levels and quantify cytoplasmic and mitochondrial Gln change in living cells, which enabled detection of various cell responses to extracellular Gln supplement.
A Chromosome-level Assembly of the Japanese Eel Genome, Insights into Gene Duplication and Chromosomal Reorganization
Authors: Wang Hongbo , Wan Hin Ting , Wu Bin , Jian Jianbo , Ng Alice HM , Chung Claire Yik-Lok , Chow Eugene Yui-Ching , Zhang Jizhou , Wong Anderson OL , Lai Keng Po , Chan Ting Fung , Zhang Eric Lu , Wong Chris Kong-Chu
Published: July 2022

Abstract

Japanese eels (Anguilla japonica) are commercially important species that have been harvested extensively for foods. Currently, this and related species (American and European eels) are difficult to breed on a commercial basis. Wild stock is used for aquaculture. Due to pollution, overfishing, and international trafficking, eel populations are declining. The International Union for Conservation of Nature lists Japanese eels as critically endangered and on its red list. Here we presented a high-quality genome assembly for Japanese eels and demonstrated that large chromosome reorganizations occurred in the events of third-round whole-genome duplications (3R-WRD). Following multiple chromosomal fusion and fission rearrangement, the Anguilla lineage has reduced the haploid chromosomal number of 19 from the ancestral proto-chromosomal number of 25. Phylogenetic analysis of expanded gene families showed the gene families of olfactory receptors and voltage-gated Ca2+-channel expanded significantly. The expansion of olfactory receptors (group δ and ζ genes) and voltage-gated Ca2+-channel gene families are important for olfaction and neurophysiological functions. Following 3R-WGD, additional tandem (TD) and proximal (PD) duplications occurred to acquire immune-related genes for adaptation. The Japanese eel assembly presented here can be used to study other Anguilla species that are related to evolution and conservation.
Strandings of loggerhead sea turtles south of the Po River delta: insights from a highly impacted area
Authors: Marisaldi Luca , Torresan Andrea , Ferrari Andrea
Published: July 2022

The northern Adriatic Sea is an important foraging ground for the loggerhead sea turtle Caretta caretta (Linnaeus, 1758) within the Mediterranean Sea. Here, spatial-temporal patterns of loggerhead sea turtles strandings along a short portion (∼18 km) of the coast south of the Po River delta (Italy) during a three-year period (2019-2021) were investigated. A total of 244 records (alive, n=7; dead, n=237) were analysed and the curved carapace lengths (CCL, notch to tip, cm) mainly reflected sub-adults (average CCL=55.2 cm; 95% CI= 53.3-57). The month of July was identified as the critical month with the highest number of strandings, mirroring migratory processes toward this area during warmer months. Interaction with the trawl fishery was hypothesized as the main cause of mortality and a small fraction of deaths (6%; n=16) could be linked to boat strikes and net entanglement. The number of stranded turtles•km-1 as well as the absolute number of strandings along the short portion of monitored coast confirmed this area as the most impacted in Italy and perhaps in the whole Mediterranean Sea. This study provides valuable information to improve conservation efforts for this species and highlight that, with all due caution, monitoring stranding events can offer useful insights into the geographic ranges, seasonal distribution, and life history of marine species of conservation interest such as the loggerhead sea turtle.
Differential co-expression network analysis with DCoNA reveals isomiR targeting aberrations in prostate cancer
Authors: Zhiyanov Anton , Engibaryan Narek , Nersisya Stepan , Shkurnikov Maxim , Tonevitsky Alexander
Published: July 2022

We developed DCoNA – a statistical tool that allows one to identify pair interactions, which correlation significantly changes between two conditions. Comparing DCoNA with the state-of-the-art analog, we showed that DCoNA is a faster, more accurate, and less memory-consuming tool. We applied DCoNA to prostate mRNA/miRNA-seq data collected from The Cancer Genome Atlas (TCGA) and compared predicted regulatory interactions of miRNA isoforms (isomiRs) and their target mRNAs between normal and cancer samples. As a result, almost all highly expressed isomiRs lost negative correlation with their targets in prostate cancer samples compared to ones without the pathology. One exception to this trend was the canonical isomiR of hsa-miR-93-5p acquiring cancerspecific targets. Further analysis showed that cancer aggresiveness increased with the expression of this isomiR in both TCGA primary tumor samples and 153 blood plasma samples of own patients’ cohort analyzed by miRNA microarrays.
Analysis of nucleus and cytoplasm-specific RNA fractions demonstrates that a significant proportion of the genetic regulation of gene expression across the human brain occurs post-transcriptionally
Authors: D’Sa Karishma , Guelfi Sebastian , Vandrovcova Jana , Reynolds Regina H. , Zhang David , Hardy John , Botía Juan A. , Weale Michael E. , Gagliano Taliun Sarah A. , Small Kerrin S. , Ryten Mina
Published: July 2022

Gaining insight into the genetic regulation of gene expression in human brain is key to the interpretation of genome-wide association studies for major neurological and neuropsychiatric diseases. Expression quantitative trait loci (eQTL) analyses have largely been used to achieve this, providing valuable insights into the genetic regulation of steady-state RNA in human brain, but not distinguishing between molecular processes regulating transcription and stability. RNA quantification within cellular fractions can disentangle these processes in cell types and tissues which are challenging to model in vitro. We investigated the underlying molecular processes driving the genetic regulation of gene expression specific to a cellular fraction using allele-specific expression (ASE). Applying ASE analysis to genomic and transcriptomic data from paired nuclear and cytoplasmic fractions of anterior prefrontal cortex, cerebellar cortex and putamen tissues from 4 post-mortem neuropathologically-confirmed control human brains, we demonstrate that a significant proportion of genetic regulation of gene expression occurs post-transcriptionally in the cytoplasm, with genes undergoing this form of regulation more likely to be synaptic. These findings have implications for understanding the structure of gene expression regulation in human brain, and importantly the interpretation of rapidly growing single-nucleus brain RNA-sequencing and eQTL datasets, where cytoplasm-specific regulatory events could be missed.
Deficit in observational learning in experimental epilepsy
Authors: Doublet Thomas , Ghestem Antoine , Bernard Christophe
Published: July 2022

Individuals use the observation of a conspecific to learn new behaviors and skills in many species. Whether observational learning is affected in epilepsy is not known. Using the pilocarpine rat model of epilepsy, we assessed learning by observation in a spatial task.

The task involves a naïve animal observing a demonstrator animal seeking a reward at a specific spatial location. After five observational sessions, the observer is allowed to explore the rewarded space and look for the reward.

Although control observer rats succeed in finding the reward when allowed to explore the rewarded space, epileptic animals fail. However, epileptic animals are able to successfully learn the location of the reward through their own experience after several trial sessions.

Thus, epileptic animals show a clear deficit in learning by observation. This result may be clinically relevant, in particular in children who strongly rely on observational learning.
Losartan controls immune checkpoint blocker-induced edema and improves survival in glioblastoma
Authors: Datta Meenal , Chatterjee Sampurna , Perez Elizabeth M. , Gritsch Simon , Roberge Sylvie , Duquette Mark , Chen Ivy X. , Naxerova Kamila , Kumar Ashwin S. , Ghosh Mitrajit , Emblem Kyrre E. , Ng Mei R. , Ho William W. , Kumar Pragya , Krishnan Shanmugarajan , Dong Xinyue , Speranza Maria C. , Neagu Martha R. , Reardon David A. , Sharpe Arlene H. , Freeman Gordon J. , Suvà Mario L. , Xu Lei , Jain Rakesh K.
Published: July 2022

Immune checkpoint blockers (ICBs) have failed in all Phase III glioblastoma trials. Here, we found that ICBs induce cerebral edema in some patients and mice with glioblastoma. Through single-cell RNA sequencing, intravital imaging, and T cell blocking studies in mice, we demonstrated that this edema results from an inflammatory response following anti-PD1 antibody treatment that disrupts the blood-tumor-barrier. Used in lieu of immunosuppressive corticosteroids, the angiotensin receptor blocker losartan prevented this ICB-induced edema and reprogrammed the tumor microenvironment, curing 20% of mice which increased to 40% in combination with standard of care treatment. Using a bihemispheric tumor model, we identified a “hot” tumor immune signature prior to losartan+anti-PD1 therapy that predicted long-term survival. Our findings provide the rationale and associated biomarkers to test losartan with ICBs in glioblastoma patients.

One-Sentence Summary

Losartan prevents immunotherapy-associated edema and enhances the outcome of immunotherapy in glioblastoma.
Regulatory divergence as a mechanism for X-autosome incompatibilities in Caenorhabditis nematodes
Authors: Viswanath Athmaja , Cutter Asher D.
Published: July 2022

The world’s astounding biodiversity results from speciation, the process of formation of distinct species. Hybrids between species often have reduced fitness due to negative epistatic interactions between divergent genetic factors, as each lineage accumulated substitutions independently in their evolutionary history. Such negative genetic interactions can manifest as gene misexpression due to divergence in gene regulatory controls from mutations in cis-regulatory elements and trans-acting factors. Gene misexpression due to differences in regulatory controls can ultimately contribute to incompatibility within hybrids through developmental defects such as sterility and inviability. We sought to quantify the contributions of regulatory divergence to post-zygotic reproductive isolation using sterile interspecies hybrids of two Caenorhabditis nematodes: C. briggsae and C. nigoni. We analysed previous transcriptome profiles for two introgression lines with distinct homozygous X-linked fragments from C. briggsae in a C. nigoni genomic background that confers male sterility, owing to defects in spermatogenesis (Li et al. 2016). Our analysis identified hundreds of genes that show distinct classes of non-additive expression inheritance and regulatory divergence. We find that these non-overlapping introgressions affect many of the same genes in the same way and demonstrate that the preponderance of transgressive gene expression is due to regulatory divergence involving compensatory and joint effects of cis- and trans-acting factors. The similar transcriptomic responses to non-overlapping genetic perturbations of the X-chromosome implicate multiway incompatibilities as an important feature contributing to hybrid male sterility in this system.

Significance statement

The genetic causes of intrinsic post-zygotic reproductive isolation can arise from hybrids experiencing negative gene regulatory interactions. In Caenorhabditis nematodes, hybrid male sterility involves X-autosome incompatibilities that affect small-RNA regulatory pathways. We sought to understand the role of gene regulatory divergence as a related contributor to hybrid misexpression by analyzing transcriptomes of sterile males from two hybrid introgression lines, each containing distinct X-linked fragments from C. briggsae in a C. nigoni genomic background. We show that gene misexpression occurs due to extensive joint divergence of cis- and trans-acting regulatory factors and provide evidence for multiway incompatibilities as an important feature of this system.
IL-15 superagonist N-803 enhances IFNγ production and alters the trafficking of MAIT cells in SIV+ macaques
Authors: Ellis-Connell Amy L. , Balgeman Alexis J. , Kannal Nadean M. , Chaimson Karigynn Hansen , Batchenkova Anna , Safrit Jeffrey T. , O’Connor Shelby L.
Published: July 2022

Mucosal Associated Invariant T cells (MAIT cells) are innate T cells that recognize bacterial metabolites and secrete cytokines and cytolytic enzymes to destroy infected target cells. This makes MAIT cells promising targets for immunotherapy to combat bacterial infections. Here, we analyzed the effects of an immunotherapeutic agent, the IL-15 superagonist N-803, on MAIT cell activation, trafficking, and cytolytic function in macaques. We found that N-803 could activate MAIT cells in vitro and increase their ability to produce IFNγ in response to bacterial stimulation. To expand upon this, we examined the phenotypes and function of MAIT cells present in samples collected from PBMC, airways (BAL), and lymph nodes (LN) from rhesus macaques that were treated in vivo with N-803. N-803 treatment led to a transient 6-7 fold decrease in the total number of MAIT cells in the peripheral blood relative to pre N-803 timepoints. Concurrent with the decrease in cells in the peripheral blood, we observed a rapid decline in the frequency of CXCR3+CCR6+ MAITs. This corresponded with an increase in the frequency of CCR6+ MAITs in BAL, and higher frequencies of ki-67+ and granzyme B+ MAITs in blood, LN, and BAL. Finally, N-803 improved the ability of MAIT cells collected from PBMC and airways to produce IFNγ in response to bacterial stimulation. Overall, N-803 shows the potential to transiently alter the trafficking and enhance the antibacterial activity of MAIT cells which could be combined with other strategies to combat bacterial infections.
Accountable Prediction of Drug ADMET Properties with Molecular Descriptors
Authors: Boral Nilavo , Ghosh Promita , Goswami Adhish , Bhattacharyya Malay
Published: July 2022

Drugs are chemical substances of low molecular weights that require to travel from the site of administration to the site of action. For safety and effective permeability, drugs are required to exhibit ideal absorption, distribution, metabolism, excretion and toxicity (ADMET) properties. Given the Simplified Molecular Input Line Entry System (SMILES) representation of drugs, we aim to predict their ADMET properties. By feeding molecular descriptors (as global features) to traditional machine learning models, we show that ADMET properties of drug molecules can be predicted with an accuracy competitive with the state-of-the-art deep learning models. We demonstrate that the proposed approach with only 31 molecular descriptors beats the state-of-the-art for 3 datasets. Moreover, it stands the second best for 2 other datasets, where none of the best provides a statistically significant improvement. We also demonstrate that two-dimensional descriptors can better represent absorption, distribution and excretion properties than the fingerprints widely used in the literature. However, they fail to distinguish metabolism and toxicity properties.
Annotation of Phage Genomes with Multiple Genetic Codes
Authors: Pfennig Aaron , Lomsadze Alexandre , Borodovsky Mark
Published: July 2022

Some of recently discovered in human gut microbiome highly divergent crAssphages were reported to use multiple genetic codes. Opal or amber stop codon reassignments were present in parts of the genomes, while the standard genetic code was used in the remaining genome sections. Essentially, the phage genomes were divided into distinct blocks where one or another code was used. We have developed a tool, Mgcod, that identifies blocks with specific genetic codes and annotates protein-coding regions. We used Mgcod to scan a large set of human metagenomic contigs. As a result, we identified hundreds of contigs of viral origin with the standard genetic code used in some parts while genetic codes with opal or amber stop codon reassignments were used in others. Many of these contigs originated from known crAssphages. Further investigation revealed that while the genes in one genomic block could be translated by a distinct genetic code, translation of genes by either of the two genetic codes genes in an adjacent block would produce proteins with little difference from each other. The dual-coded genes were enriched with early-stage phage genes, while a single code was used for the late-stage genes. The code-block structure expands the phage’s ability to infect bacteria whose genomes employ the standard genetic code. The new tool provides means for accurate annotation of unusual genomes of these phages.
Paracrine signaling by pancreatic δ cells determines the glycemic set point in mice
Authors: Huang Jessica L , Lee Sharon , Pourhosseinzadeh Mohammad S , Krämer Niels , Guillen Jaresley V , Cinque Naomi H , Aniceto Paola A , Koike Shinichiro , Huising Mark O
Published: July 2022

Pancreatic islets contain several endocrine cell types that coordinate to maintain blood glucose homeostasis. While β and α cells are thought to be the main drivers of glucose homeostasis through insulin and glucagon secretion respectively, the contribution of δ cells and somatostatin (SST) secretion to establishing the glycemic set point remains unresolved. Here we remove local SST signaling from δ cells within the pancreatic islet to investigate their contribution to the glycemic set point. Our data demonstrate that ablating δ cells or SST leads to a sustained decrease in the glycemic set point. This coincides with a decreased glucose threshold for insulin response from β cells, leading to increased insulin secretion to the same glucose challenge. In contrast, α cell ablation had no effect on glycemic set point. Collectively, these data establish the physiological role of δ cells in determining the glycemic set point through their interaction with β cells.
Presynaptic Rac1 controls synaptic strength through the regulation of synaptic vesicle priming
Authors: Keine Christian , Al-Yaari Mohammed , Radulovic Tamara , Thomas Connon I. , Ramos Paula Valino , Guerrero-Given Debbie , Ranjan Mrinalini , Taschenberger Holger , Kamasawa Naomi , Young Samuel M.
Published: July 2022

Synapses contain a limited number of synaptic vesicles (SVs) that are released in response to action potentials (APs). Therefore, sustaining synaptic transmission over a wide range of AP firing rates and timescales depends on SV release and replenishment. Although actin dynamics impact synaptic transmission, how presynaptic regulators of actin signaling cascades control SV release and replenishment remains unresolved. Rac1, a Rho GTPase, regulates actin signaling cascades that control synaptogenesis, neuronal development, and postsynaptic function. However, the presynaptic role of Rac1 in regulating synaptic transmission is unclear. To unravel Rac1’s roles in controlling transmitter release, we performed selective presynaptic ablation of Rac1 at the mature mouse calyx of Held synapse. Loss of Rac1 increased synaptic strength, accelerated EPSC recovery after conditioning stimulus trains, and augmented spontaneous SV release with no change in presynaptic morphology or AZ ultrastructure. Analyses with constrained short-term plasticity models revealed faster SV priming kinetics and, depending on model assumptions, elevated SV release probability or higher abundance of tightly docked fusion-competent SVs in Rac1-deficient synapses. We conclude that presynaptic Rac1 is a key regulator of synaptic transmission and plasticity mainly by regulating the dynamics of SV priming and potentially SV release probability.