bluuebunny/crossref_metadata_2025 huggingface dataset:
A Review of Legal, Ethical, and Governance Issues for Team Doctors
Authors: Orchard Jessica J. , Maddocks David , Carneiro Eva , Orchard John W.
Published: November 2021

Objective:

To provide a review and discussion of a range of legal and ethical issues commonly faced by team physicians, with reference to high-profile international integrity crises in sport that have involved doctors. The article also presents some recommendations and guidance for team doctors and sporting organizations.

Data Sources:

Media reports, legal cases, and journal articles describing recent sporting integrity crises that have involved medical issues and governance reforms which are emerging in response.

Main Results:

Many of the modern “integrity crises” in sport have a medical aspect (eg, doping cases, catastrophic injuries and illnesses, “Bloodgate” and other “medical cheating,” sexual contact between doctors and athletes, harassment/bullying of doctors, concussion mismanagement, and management of the coronavirus pandemic in sport). A key issue is that while doctors bear ultimate responsibility for any perceived medical negligence, they do not always have ultimate power in decision-making. This is common in the traditional governance structure where the coach/manager “outranks” the doctor and can overrule medical decisions. There can be a blurring of the traditional doctor–patient relationship, especially on tour, and conflicts of interests occur when the needs of the employer/sporting organization differ from the player (patient). Further issues can arise in treating other staff members and players' family members.

Conclusions:

Doctors must be aware of range of important legal and ethical issues that arise in the team setting. Medical integrity crises have inspired governance reforms, such as policy development, appointment of chief medical officers, medical staff reporting to integrity departments, and sanctions of teams that breach medical integrity requirements. Sporting organizations must continue to implement and strengthen frameworks reinforcing doctors' seniority in the medical area.
Work-related musculoskeletal pain in prosthetists and orthotists: a comparison between Australia and other countries
Authors: Anderson Sarah , Weale Victoria , Stuckey Rwth , Oakman Jodi
Published: November 2021

Background:

Musculoskeletal pain (MSP) is a substantial societal and personal burden resulting in loss of employment and reduced productivity. Prosthetics and orthotics professionals working in Australia have previously reported a high prevalence of MSP; however, little is known about the prosthetic and orthotic communities in other countries.

Objectives:

To explore the prevalence and range of workplace exposures associated with MSP in a convenience sample of the international prosthetic and orthotic profession.

Study design:

A cross-sectional study using a convenience sample was conducted with prosthetists and orthotists worldwide.

Methods:

Prosthetists and orthotists were invited to participate in a survey to explore work-related factors associated with MSP. Bivariate and regression modelling was used to examine associations between self-reported demographic and workplace characteristics including job satisfaction, work–life balance, and physical and psychosocial hazards.

Results:

Seventy-six percent of respondents (n = 173) reported MSP in the previous 6 months. However, MSP was associated with different factors in Australia compared with other countries. Among Australia-based prosthetists and orthotists, MSP was associated with sex, physical hazards, and psychosocial hazards. For the international sample, MSP was only associated with length of employment.

Conclusions:

Three-quarters of all respondents reported having MSP. Differences in associations between MSP and other factors by respondents' geographical location suggest the need for context-specific identification of hazards to enable the development of targeted and contextually appropriate prevention strategies.
Clinical Evaluation of Left Ventricular Diastolic Function Using Phase-contrast Cine Cardiovascular Magnetic Resonance Imaging: A Comparison With Steady-state Free Precession Cine Cardiovascular Magnetic Resonance Imaging and Echocardiography
Authors: Komi Shotaro , Inoue Yusuke , Hata Hirofumi , Miyatake Hiroki
Published: November 2021

Objective

We investigated a practical method using phase-contrast (PC) cine cardiovascular magnetic resonance imaging to estimate peak filling rate and early/atrial velocity (E/A) as left ventricular diastolic function indicators.

Methods

Peak filling rate and E/A were estimated in 32 patients using PC imaging with high spatial or high temporal resolution and compared with those estimated using steady-state free precession cine cardiovascular magnetic resonance imaging and echocardiography.

Results

Peak filling rate estimated using PC imaging significantly correlated with those estimated using steady-state free precession imaging despite apparent underestimation using PC imaging with high spatial resolution. The E/A estimated using PC imaging significantly correlated with those estimated using echocardiography.

Conclusions

Peak filling rate and E/A measurements using PC imaging with high temporal resolution is convenient and acceptably accurate, suggesting its potential for clinical use.
Changes in Peripheral Olfactory Pathways in Rheumatoid Arthritis
Authors: Kültür Turgut , Bayar Muluk Nuray , Inal Mikail , Kömürcü Erkmen Selmin Perihan , Rasulova Günel
Published: November 2021

Objectives

We investigated olfactory bulb (OB) volumes and olfactory sulcus (OS) depths in patients with rheumatoid arthritis (RA).

Methods

In this retrospective study, cranial magnetic resonance images of 68 adult patients were included. Group 1 consisted of 34 adult patients with RA. The control group (group 2) consisted of 34 adult patients without RA. In both groups, peripheral odor pathways (OB volumes and OS depths) were measured by magnetic resonance imaging.

Results

Our results showed that the OB volumes of the RA group were significantly lower than those in the control group bilaterally (P < 0.05). In each of the RA and control groups, the OS depth of the right side was found to be significantly higher than those on the left side (P < 0.05). On the left side, OS depth values of RA patients who used biological agents were significantly higher than those RA patients who did not use biological agents (P < 0.05). Correlation tests showed that there were positive correlations between OB volumes and OS depths bilaterally. In older patients with RA, bilateral OS depth values were decreased (P < 0.05).

Conclusions

Our study has shown that the peripheral olfactory pathways in patients with RA can be affected to a degree that is reflected in anatomical measurements. The use of biological agents contributes to the protection of odor functions to a certain extent. The importance of evaluating the sense of smell in patients with RA clinically and radiologically should be emphasized.
The Significance of Perfusion-Weighted Magnetic Resonance Imaging in Evaluating the Pathological Biological Activity of Cerebral Alveolar Echinococcosis
Authors: Wang Fei , Gao Xin , Rong Jie , Wang Jinying , Xing Hui , Yang Jing , Li Xiaohong , Qin Yongde , Wang Jian
Published: November 2021

Objectives

This study aimed to evaluate the value of perfusion-weighted magnetic resonance imaging (MR-PWI) in assessing cerebral alveolar echinococcosis (CAE) biological activity.

Methods

Totally, 15 cases of CAE patients who underwent surgery were enrolled. The MR-PWI perfusion parameters were measured and compared.

Results

The MR-PWI perfusion parameters cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time were different among different areas. Their values were in the descending order of lesion marginal area > contralateral normal brain area > lesion center area. However, time-to-peak value was in the ascending order of lesion marginal area < contralateral normal brain area < lesion center area. Spearman correlation analysis showed that CBF and CBV at the edge of the lesion were significantly positively correlated with microvessel density. Moreover, CBF and CBV at the edge of the lesion were also significantly positively correlated with maximum standardized uptake value.

Conclusions

Perfusion-weighted magnetic resonance imaging can be used to dynamically reflect the neovascularization of CAE lesions and may have a good application prospect in evaluating the biological activity of CAE.
Calcific Tendinosis Reduces Diagnostic Performance of Magnetic Resonance Imaging in the Detection of Rotator Cuff Tears
Authors: Sill Andrew P. , Zaw Taryar , Flug Jonathan A. , Hartigan David E. , Kransdorf Mark J. , Brinkman Joseph , Fox Michael G.
Published: November 2021

Objective

This study aimed to investigate the effect of calcific tendinosis on the diagnosis of rotator cuff tears (RCTs) on magnetic resonance imaging (MRI) and magnetic resonance arthrography (MRA).

Materials and Methods

Calcific tendinosis was confirmed radiographically. Two musculoskeletal radiologists then retrospectively and independently reviewed the MRI/MRA examinations, with surgery or arthroscopy performed within 90 days of the MRI. Rotator cuffs were categorized as no tear, partial-thickness tear, and full-thickness tear. Partial-thickness tear/full-thickness tear groups were combined for analysis.

Results

Forty-eight MRI (mean age, 63.4 years; range, 37–83 years; female-to-male ratio, 29:19) and 7 MRA (mean age, 49.2 years; range, 25–60 years; female-to-male ratio, 4:3) patients were included. Reader 1 and reader 2 sensitivity/specificity values for RCTs on MRI were 95%/50% and 89%/30%, and the values on MRA were 100%/67% and 100%/100%, respectively. Overall agreement was present in 87% (48 of 55; κ = 0.55 [95% confidence interval, 0.26–0.85]).

Conclusions

Magnetic resonance imaging has decreased specificity in diagnosing RCTs when calcific tendinosis is present. Magnetic resonance arthrography performed better in this population and could be considered.
Prevalence and antibiotic resistance of Escherichia coli O157:H7 in beef at a commercial slaughterhouse in Moro, Kwara State, Nigeria
Authors: Ajuwon Busayo I. , Babatunde Sola K. , Kolawole Olatunji M. , Ajiboye Adeyinka E. , Lawal Abosede H.
Published: November 2021

Background. Gastroenteritis due to foodborne disease is a leading cause of death in developing countries. In Nigeria, there is an increasing demand for beef. Yet, there is no surveillance for

Escherichia coli

O157:H7 contamination of raw beef and little is known about the carriage of this pathogen in Nigeria’s livestock.

Methods. A total of 415 samples, including 180 cow carcass swabs, 180 caecal content samples, 16 water samples, 25 hand swabs and 14 knife swabs were collected at a large abattoir in the Moro region of Kwara State, Nigeria. The samples were enriched in modified tryptone broth containing novobiocine, and plated onto Sorbitol–MacConkey agar (Oxoid SR0172E) supplemented with 0.05 mg l−1 cefixime and 2.5 mg l−1 potassium tellurite (Oxoid) (CT-SMAC). Indole-producing isolates were confirmed serologically by serotyping with antisera specific for the O157 and H7 antigens. The

E. coli

O157:H7 isolates were further tested for their susceptibility to antibiotic agents using the disc diffusion method. Commercially available Gram-negative multi-discs (Oxoid) comprising nitrofurantoin (30 µg), ampicillin (5 µg), ceftazidime (30 µg), gentamicin (10 µg), ciprofloxacin (5 µg), augmentin (30 µg), ofloxacin (5 µg) and cefuroxime (30 µg) were tested.

Results. Overall, 16 (3.9 %) samples were contaminated with

E. coli

O157:H7, of which 10 (5.6 %) were isolated from carcass swabs, 4 (2.2 %) from caecal content samples and 2 (12.5 %) from water. All isolates were multidrug-resistant (MDR), with resistance to ampicillin, ceftazidime and cefuroxime being the most common.

Conclusion. This study provides evidence to suggest that

E. coli

O157:H7 exists in the beef production chain. The pathogen reveals a high frequency of multidrug resistance, suggesting that consumers and handlers of such meat are at risk of contracting antibiotic-resistant

E. coli

O157:H7-associated foodborne disease. Routine monitoring of antibiotic resistance is critical to uncovering novel therapeutic strategies that will help inform clinical practice guidelines.
Understanding the association between mental health knowledge and mental health service utilization among Black adults
Authors: Pederson Aderonke Bamgbose , Tsai Alexander C. , Hawkins Devan , Moskowitz Judith T. , Dixon Lisa
Published: November 2021

Mental health knowledge limitations may contribute to the treatment gap among Black adults. We conducted an online cross-sectional study of Black adults in the United States (n = 262, aged 18-65 years) from diverse ethnic backgrounds (African-Americans, African immigrants, Afro-Caribbean immigrants). Gamma regression using generalized linear models was used to estimate the associations between mental health knowledge and willingness to seek help from mental health professionals. After adjusting for age, education and ethnicity, participants with higher specific knowledge about mental health (such as recognition of schizophrenia as a mental illness) were 26% more likely to report willingness to seek help from a mental health professional for personal and emotional problems (RR = 1.26, CI: 1.12 – 1.41, p < 0.001). Knowledge building interventions (such as psychoeducation) that seek to increase specific knowledge (rather than general knowledge) may correlate more strongly with utilization of mental health services among Black adults.
Mapping the human genetic architecture of COVID-19: an update
Authors:   COVID-19 Host Genetics Initiative, Ganna Andrea
Published: November 2021

The Coronavirus Disease 2019 (COVID-19) pandemic continues to pose a major public health threat especially in countries with low vaccination rates. To better understand the biological underpinnings of SARS-CoV-2 infection and COVID-19 severity we formed the COVID19 Host Genetics Initiative. Here we present GWAS meta-analysis of up to 125,584 cases and over 2.5 million controls across 60 studies from 25 countries, adding 11 new genome-wide significant loci compared to those previously identified. Genes in novel loci include SFTPD, MUC5B and ACE2, reveal compelling insights regarding disease susceptibility and severity.
Insecticide susceptibility of Aedes (Stegomyia) aegypti (Linnaeus, 1762) and Aedes (Stegomyia) albopictus (Skuse, 1894) in Kinshasa, Democratic Republic of the Congo
Authors: Vulu Fabien , Ilombe Gillon , Vizcaino Lucrecia , Mariën Joachim , Morimoto Yasue , Weetman David , Lenhart Audrey , Irish Seth R. , Bobanga Thierry L.
Published: November 2021

Aedes aegypti and Aedes albopictus are arbovirus vectors of public health concern. Although the Democratic Republic of the Congo (DRC) faces a long-standing risk of Aedes-borne viruses, data on insecticide resistance of Aedes populations are absent. To address this gap, we investigated insecticide susceptibility of Ae. aegypti and Ae. albopictus in areas with a high risk of arbovirus transmission. We also investigated the frequency of knock-down resistance (kdr) mutations in Ae. aegypti. Immature stages of Ae. aegypti and Ae. albopictus were collected from two sites in Kinshasa (Lingwala and Cité Verte) between April and July 2017 and reared to the adult stage. Wild-caught adult Ae. aegypti were collected in 2016 in another site (Ngaliema). Female Ae. aegypti (from Lingwala) and Ae. albopictus (from Cité Verte) were used in WHO tube insecticide susceptibility tests. The F1534C, V1016I and V410L kdr mutations were genotyped in Ae. aegypti from Lingwala and Ngaliema. We observed Ae. aegypti to be susceptible to bendiocarb, propoxur and malathion, suspected resistant to permethrin, and resistant to deltamethrin and DDT. Aedes albopictus was susceptible to bendiocarb, propoxur, malathion and permethrin, suspected resistant to deltamethrin and resistant to DDT. While F1534C and V1016I were not detected, a few Ae. aegypti from Lingwala were heterozygous for the mutation V410L. This study reports for the first time the insecticide resistance status of Aedes spp. and the detection of the kdr mutation V410L in Ae. aegypti in DRC. Given the resistance profile, carbamates and potentially malathion are recommended insecticide options against Ae. aegypti in Kinshasa. It will be important to develop Aedes control strategies based on the resistance patterns of Aedes in Kinshasa.
Economic analyses of interventions for student mental health: protocol for a systematic review
Authors: Bell Eleanor , Pan Jia , Sampson Chris
Published: November 2021

Background

Students in higher education exhibit higher rates of mental health problems than the general population and often lack access to effective treatments and services. The COVID-19 pandemic has exacerbated already high levels of need. Policymakers must have the relevant evidence to inform resource allocation and investment decisions about student mental health services.

Aim

We aim to identify and summarise economic analyses of interventions to prevent and treat mental health problems in university students in terms of the studies’ findings and the methods used.

Method

We will review all published economic analyses relating to interventions designed to prevent or treat student mental health problems. We will search the following databases: PubMed, MEDLINE, Embase, Web of Science, EconLit, PsycINFO and the National Health Service Economic Evaluation Databases (NHS EED). The review will be conducted following PRISMA guidelines. Key data items relating to the methods and results of the included studies will be extracted, and the resulting database will be made publicly available.

Registration

This review is registered on PROSPERO (ID CRD42021250228)

Funding

This research is funded by UK Research and Innovation (grant number ES/S00324X/1).
Vaccine effectiveness against COVID-19 related hospital admission in the Netherlands: a test-negative case-control study
Authors: Niessen F.A. , Knol Mirjam J. , Hahné Susan J.M. ,   VECTOR study group, Bonten M.J.M. , Bruijning-Verhagen P.C.J.L.
Published: November 2021

Introduction

Real-world vaccine effectiveness (VE) estimates are essential to identify potential groups at higher risk of break-through infections and to guide policy. We assessed the VE of COVID-19 vaccination against COVID-19 hospitalization, while adjusting and stratifying for patient characteristics.

Methods

We performed a test-negative case-control study in six Dutch hospitals. The study population consisted of adults eligible for COVID-19 vaccination hospitalized between May 1 and June 28 2021 with respiratory symptoms. Cases were defined as patients who tested positive for SARS-CoV-2 by PCR during the first 48 hours of admission or within 14 days prior to hospital admission. Controls were patients tested negative at admission and did not have a positive test during the 2 weeks prior to hospitalization. VE was calculated using multivariable logistic regression, adjusting for calendar week, sex, age, comorbidity and nursing home residency. Subgroup analysis was performed for age, sex and different comorbidities. Secondary endpoints were ICU-admission and mortality.

Results

379 cases and 255 controls were included of whom 157 (18%) were vaccinated prior to admission. Five cases (1%) and 40 controls (16%) were fully vaccinated (VE: 93%; 95% CI: 81 – 98), and 40 cases (11%) and 70 controls (27%) were partially vaccinated (VE: 70%; 95% CI: 50-82). A strongly protective effect of vaccination was found in all comorbidity subgroups. No ICU-admission or mortality were reported among fully vaccinated cases. Of unvaccinated cases, mortality was 10% and 19% was admitted at the ICU

Conclusion

COVID-19 vaccination provides a strong protective effect against COVID-19 related hospital admission, in patients with and without comorbidity.
Antioxidants green tea extract and nordihydroguaiaretic acid confer species and strain specific lifespan and health effects in Caenorhabditis nematodes
Authors: Banse Stephen A. , Sedore Christine A. , Johnson Erik , Coleman-Hulbert Anna L. , Onken Brian , Hall David , Jackson E. Grace , Huynh Phu , Foulger Anna C. , Guo Suzhen , Garrett Theo , Xue Jian , Inman Delaney , Morshead Mackenzie L. , Plummer W. Todd , Chen Esteban , Bhaumik Dipa , Chen Michelle K. , Harinath Girish , Chamoli Manish , Quinn Rose P. , Falkowski Ron , Edgar Daniel , Schmidt Madeline O. , Lucanic Mark , Guo Max , Driscoll Monica , Lithgow Gordon J. , Phillips Patrick C.
Published: November 2021

The Caenorhabditis Intervention Testing Program (CITP) is an NIH-funded research consortium of investigators who conduct analyses at three independent sites to identify chemical interventions that reproducibly promote health and lifespan in a robust manner. The founding principle of the CITP is that compounds with positive effects across a genetically diverse panel of Caenorhabditis species and strains are likely engaging conserved biochemical pathways to exert their effects. As such, interventions that are broadly efficacious might be considered prominent compounds for translation for pre-clinical research and human clinical applications. Here, we report results generated using a recently streamlined pipeline approach for the evaluation of the effects of chemical compounds on lifespan and health. We studied five compounds previously shown to extend C. elegans lifespan or thought to promote mammalian health: 17α-estradiol, acarbose, green tea extract, nordihydroguaiaretic acid, and rapamycin. We found that green tea extract and nordihydroguaiaretic acid extend Caenorhabditis lifespan in a species-specific manner. Additionally, these two antioxidants conferred assay-specific effects in some studies—for example, decreasing survival for certain genetic backgrounds in manual survival assays in contrast with extended lifespan as assayed using automated C. elegans Lifespan Machines. We also observed that GTE and NDGA impact on older adult mobility capacity is dependent on genetic background, and that GTE reduces oxidative stress resistance in some Caenorhabditis strains. Overall, our analysis of the five compounds supports the general idea that genetic background and assay type can influence lifespan and health effects of compounds, and underscores that lifespan and health can be uncoupled by chemical interventions.
Clinically relevant SMAC mimetics do not enhance human T cell proliferation or cytokine production
Authors: Burton Ashley , Ligman Brittany , Kearney Claire , Murray Susan E.
Published: November 2021

Secondary mitochondria-derived activator of caspases (SMAC) mimetics are being tested in dozens of clinical trials to treat cancer. These targeted therapies mimic endogenous molecules that promote apoptosis by antagonizing inhibitors of apoptosis (IAPs), which are commonly overexpressed in cancer cells. In T cells, IAPs function to restrain non-canonical NF-kB signaling. Thus, it has been suggested that in addition to their direct anti-cancer mechanism of action, SMAC mimetics may activate T cells, thereby promoting anti-tumor immunity. Here, we tested the effect of three clinically relevant SMAC mimetics on the proliferation and activation of primary human T cells. As previously reported, SMAC mimetics killed tumor cells and activated non-canonical NF-kB in T cells at clinically relevant doses. Surprisingly, none of the SMAC mimetics augmented T cell proliferation or effector function. These results question the assumption that SMAC mimetics are likely to boost anti-tumor immunity in cancer patients.
Absence of the Z-disc protein α-actinin-3 impairs the mechanical stability of Actn3KO mouse fast-twitch muscle fibres without altering their contractile properties or twitch kinetics
Authors: Haug Michael , Reischl Barbara , Nübler Stefanie , Kiriaev Leonit , Mázala Davi A.G. , Houweling Peter J. , North Kathryn N. , Friedrich Oliver , Head Stewart I.
Published: November 2021

Background

A common polymorphism (R577X) in the ACTN3 gene results in complete absence of the Z-disc protein α-actinin-3 from fast-twitch muscle fibres in ~16% of the world’s population. This single gene polymorphism has been subject to strong positive selection pressure during recent human evolution. Previously, using an Actn3KO mouse model, we have shown in fast-twitch muscles, eccentric contractions at L0+ 20% stretch did not cause eccentric damage. In contrast, L0+ 30% stretch produced a significant ~40% deficit in maximum force; here we use isolated single fast-twitch skeletal muscle fibres from the Actn3KO mouse to investigate the mechanism underlying this.

Methods

Single fast-twitch fibres are separated from the intact muscle by a collagenase digest procedure. We use label-free second harmonic generation (SHG) imaging, ultra-fast video microscopy and skinned fibre measurements from our MyoRobot automated biomechatronics system to study the morphology, visco-elasticity, force production and mechanical strength of single fibres from the Actn3KO mouse. Data are presented as means ± SD and tested for significance using ANOVA.

Results

We show that the absence of α-actinin-3 does not affect the unloaded maximum speed of contraction, visco-elastic properties or myofibrillar force production. Eccentric contractions demonstrated that chemically skinned Actn3KO fibres are mechanically weaker being prone to breakage when eccentrically contracted. Furthermore, SHG images reveal disruptions in the myofibrillar alignment of Actn3KO fast-twitch fibres with an increase in Y-shaped myofibrillar lattice shifts.

Conclusions

Absence of α-actinin-3 from the Z-disc in fast-twitch fibres disrupts the organisation of the myofibrillar proteins, leading to structural weakness. This provides a mechanistic explanation for our earlier findings that, in vitro intact Actn3KO fast-twitch muscles are significantly damaged by L0+ 30%, but not, L0+ 20%, eccentric contraction strains. Our study also provides a possible mechanistic explanation as to why α-actinin-3 deficient humans have been reported to have a faster decline in muscle function with increasing age, that is; as sarcopenia reduces muscle mass and force output, the eccentric stress on the remaining functional α-actinin-3 deficient fibres will be increased, resulting in fibres breakages.
Deamidated TPI is an efficacious target for cell-selective therapy in triple-negative breast cancer
Authors: Enríquez-Flores Sergio , Flores- López Luis A. , Mora-De la Mora Ignacio De la , García-Torres Itzhel , Gracia-Mora Isabel , Gutiérrez-Castrellón Pedro , Fernández-Lainez Cynthia , Martínez-Pérez Yoalli , Olaya-Vargas Alberto , de Vos Paul , López-Velázquez Gabriel
Published: November 2021

Human TPI (HsTPI) is a central and essential glycolytic enzyme for energy supply and is overexpressed in cancer cells. Here, we investigated HsTPI as a potential target for inducing cell death in triple-hormone receptor-negative breast cancer, which is highly dependent on glycolysis, and therapies for its treatment are limited. We found endogenous accumulation of deamidated HsTPI in human breast cancer cells, which might be caused by the lower activity of the HsTPI-degrading caspase-1 in breast cancer cells.In silicoandin vitroanalyses of deamidated HsTPI demonstrated the efficacy of thiol-reactive drugs in blocking enzyme activity. The cancer cells were selectively programmed to undergo apoptosis with thiol-reactive drugs by inducing the production of methylglyoxal (MGO) and advanced glycation-end products (AGEs).In vivoin mice, the thiol-reactive drug effectively inhibited the growth of human tumors by targeting HsTPI as underlying mechanism. Our findings demonstrate deamidated HsTPI as a novel target to develop therapeutic strategies for treating cancers and other pathologies in which this post-translationally modified protein accumulates.
Sensitivity optimization of a rhodopsin-based fluorescent voltage indicator
Authors: Abdelfattah Ahmed S , Zheng Jihong , Reep Daniel , Tsegaye Getahun , Tsang Arthur , Arthur Benjamin J , Rehorova Monika , Olson Carl VL , Huang Yi-Chieh , Shuai Yichun , Koyama Minoru , Moya Maria V , Weber Timothy D , Lemire Andrew L , Baker Christopher A , Falco Natalie , Zheng Qinsi , Grimm Jonathan B , Yip Mighten C , Walpita Deepika , Forest Craig R , Chase Martin , Campagnola Luke , Murphy Gabe , Wong Allan M , Mertz Jerome , Economo Michael N , Turner Glenn , Lin Bei-Jung , Chen Tsai-Wen , Novak Ondrej , Lavis Luke D , Svoboda Karel , Korff Wyatt , Schreiter Eric R , Hasseman Jeremy P , Kolb Ilya
Published: November 2021

The ability to optically image cellular transmembrane voltage at millisecond-timescale resolution can offer unprecedented insight into the function of living brains in behaving animals. The chemigenetic voltage indicator Voltron is bright and photostable, making it a favorable choice for long in vivo imaging of neuronal populations at cellular resolution. Improving the voltage sensitivity of Voltron would allow better detection of spiking and subthreshold voltage signals. We performed site saturation mutagenesis at 40 positions in Voltron and screened for increased ΔF/F0 in response to action potentials (APs) in neurons. Using a fully automated patch-clamp system, we discovered a Voltron variant (Voltron.A122D) that increased the sensitivity to a single AP by 65% compared to Voltron. This variant (named Voltron2) also exhibited approximately 3-fold higher sensitivity in response to sub-threshold membrane potential changes. Voltron2 retained the sub-millisecond kinetics and photostability of its predecessor, with lower baseline fluorescence. Introducing the same A122D substitution to other Ace2 opsin-based voltage sensors similarly increased their sensitivity. We show that Voltron2 enables improved sensitivity voltage imaging in mice, zebrafish and fruit flies. Overall, we have discovered a generalizable mutation that significantly increases the sensitivity of Ace2 rhodopsin-based sensors, improving their voltage reporting capability.
VALIS: Virtual Alignment of pathoLogy Image Series
Authors: Gatenbee Chandler D. , Baker Ann-Marie , Prabhakaran Sandhya , Slebos Robbert J. C. , Mandal Gunjan , Mulholland Eoghan , Leedham Simon , Conejo-Garcia Jose R. , Chung Christine H. , Robertson-Tessi Mark , Graham Trevor A. , Anderson Alexander R.A.
Published: November 2021

Spatial analyses can reveal important interactions between and among cells and their microenvironment. However, most existing staining methods are limited to a handful of markers per slice, thereby limiting the number of interactions that can be studied. This limitation is frequently overcome by registering multiple images to create a single composite image containing many markers. While there are several existing image registration methods for whole slide images (WSI), most have specific use cases. Here, we present the Virtual Alignment of pathoLogy Image Series (VALIS), a fully automated pipeline that opens, registers (rigid and/or non-rigid), and saves aligned slides in the ome.tiff format. VALIS has been tested with 273 immunohistochemistry (IHC) samples and 340 immunofluorescence (IF) samples, each of which contained between 2-69 images per sample. The registered WSI tend to have low error and are completed within a matter of minutes. In addition to registering slides, VALIS can also using the registration parameters to warp point data, such as cell centroids previously determined via cell segmentation and phenotyping. VALIS is written in Python and requires only few lines of code for execution. VALIS therefore provides a free, opensource, flexible, and simple pipeline for rigid and non-rigid registration of IF and/or IHC that can facilitate spatial analyses of WSI from novel and existing datasets.
Audiovisual task switching rapidly modulates sound encoding in mouse auditory cortex
Authors: Morrill Ryan J. , Bigelow James , DeKloe Jefferson , Hasenstaub Andrea R.
Published: November 2021

In everyday behavior, sensory systems are in constant competition for attentional resources, but the cellular and circuit-level mechanisms of modality-selective attention remain largely uninvestigated. We conducted translaminar recordings in mouse auditory cortex (AC) during an audiovisual (AV) attention shifting task. Attending to sound elements in an AV stream reduced both pre-stimulus and stimulus-evoked spiking activity, primarily in deep layer neurons. Despite reduced spiking, stimulus decoder accuracy was preserved, suggesting improved sound encoding efficiency. Similarly, task-irrelevant probe stimuli during intertrial intervals evoked fewer spikes without impairing stimulus encoding, indicating that these attention influences generalized beyond training stimuli. Importantly, these spiking reductions predicted trial-to-trial behavioral accuracy during auditory attention, but not visual attention. Together, these findings suggest auditory attention facilitates sound discrimination by filtering sound-irrelevant spiking in AC, and that the deepest cortical layers may serve as a hub for integrating extramodal contextual information.
A novel cryo-electron microscopy support film based on 2D crystal of HFBI protein
Authors: Fan Hongcheng , Wang Bo , Zhang Yan , Zhu Yun , Song Bo , Xu Haijin , Zhai Yujia , Qiao Mingqiang , Sun Fei
Published: November 2021

Cryo-electron microscopy (cryo-EM) has become the most powerful tool to resolve the high-resolution structures of biomacromolecules in solution. However, the air-water interface induced preferred orientation, dissociation or denaturation of biomacromolecules during cryo-vitrification is still a major limitation factor for many specimens. To solve this bottleneck, we developed a new type of cryo-EM support film using the 2D crystal of hydrophobin I (HFBI) protein. The HFBI-film utilizes its hydrophilic side to adsorb protein particles via electrostatic interactions and keep air-water interface away, allowing thin-enough ice and high-quality data collection. The particle orientation distribution can be optimized by changing the buffer pH. We, for the first time, solved the cryo-EM structure of catalase (2.28-Å) that exhibited strong preferred orientation using conventional cryo-vitrification protocol. We further proved the HFBI-film is suitable to solve the high-resolution structures of small proteins including aldolase (150 kDa, 3.34-Å) and hemoglobin (64 kDa, 3.6-Å). Our work implied that the HFBI-film will have a wide application in the future to increase the successful rate and efficiency of cryo-EM.
Cortico-striatal activity characterizes human safety learning via Pavlovian conditioned inhibition
Authors: Laing Patrick A.F. , Steward Trevor , Davey Christopher G. , Felmingham Kim L. , Fullana Miguel Angel , Vervliet Bram , Greaves Matthew D. , Moffat Bradford , Glarin Rebecca K. , Harrison Ben J.
Published: November 2021

Safety learning generates associative links between neutral stimuli and the absence of threat, promoting the inhibition of fear and security-seeking behaviours. Precisely how safety learning is mediated at the level of underlying brain systems, particularly in humans, remains unclear. Here, we integrated a novel Pavlovian conditioned inhibition task with ultra-high field (UHF) fMRI to examine the neural basis of inhibitory safety learning in 49 healthy participants. In our task, participants were conditioned to two safety signals: a conditioned inhibitor that predicted threat-omission when paired with a known threat signal (A+/AX-), and a standard safety signal that generally predicted threat-omission (BC-). Both safety signals evoked equivalent autonomic and subjective learning responses but diverged strongly in terms of underlying brain activation. The conditioned inhibitor was characterized by more prominent activation of the dorsal striatum, anterior insular and dorsolateral prefrontal cortex compared to the standard safety signal, whereas the latter evoked greater activation of the ventromedial prefrontal cortex, posterior cingulate and hippocampus, among other regions. Further analyses of the conditioned inhibitor indicated that its initial learning was characterized by consistent engagement of dorsal striatal, midbrain, thalamic, premotor, and prefrontal subregions. These findings suggest that safety learning via conditioned inhibition involves a distributed cortico-striatal circuitry, separable from broader cortical regions involved with processing standard safety signals (e.g., CS-). This cortico-striatal system could represent a novel neural substrate of safetylearning, underlying the initial generation of ‘stimulus-safety’ associations, distinct from wider cortical correlates of safety processing, which facilitate the behavioraloutcomesof learning.

Significance statement

Identifying safety is critical for maintaining adaptive levels of anxiety, but the neural mechanisms of human safety learning remain unclear. Using ultra-high field fMRI, we compared learning-related brain activity for a conditioned inhibitor, which actively predicted threat-omission, and a standard safety signal (CS-), which was passively unpaired with threat. The inhibitor engaged an extended circuitry primarily featuring the dorsal striatum, along with thalamic, midbrain, and premotor/prefrontal cortex regions. The CS-exclusively involved cortical safety-related regions observed in basic safety conditioning, such as the vmPFC. These findings extend current models to include learning-specific mechanisms for encoding stimulus-safety associations, which might be distinguished from expression-related cortical mechanisms. These insights may suggest novel avenues for targeting dysfunctional safety learning in psychopathology.
An evolutionary divergent thermodynamic brake in ZAP-70 fine-tunes the kinetic proofreading in T cell
Authors: Gangopadhyay Kaustav , Roy Arnab , Chandradasan Athira C. , Roy Swarnendu , Debnath Olivia , SenGupta Soumee , Chowdhury Subhankar , Das Dipjyoti , Das Rahul
Published: November 2021

T cell signaling starts with assembling several tyrosine kinases and adaptor proteins to the T cell receptor (TCR), following the antigen binding. The lifetime of the TCR: antigen complex and the time delay between the recruitment and activation of each kinase determines the T cell response. The mechanism by which the time delays are implemented in TCR signaling is not fully understood. Combining experiments and kinetic modeling, we here report a thermodynamic-brake in the regulatory module of ZAP-70, which determines the ligand selectivity, and may delay the ZAP-70 activation in TCR. Phylogenetic analysis revealed that the evolution of the thermodynamic-brake coincides with the divergence of the adaptive immune system to the cell-mediated and humoral responses. Paralogous kinase Syk expressed in B cells, does not possess such a functional thermodynamic brake, which may explain higher basal activation and lack of ligand selectivity by Syk.
Aspergillus fumigatus drives tissue damage via iterative assaults upon mucosal integrity and immune homeostasis
Authors: Okaa Uju Joy , Bertuzzi Margherita , Fortune-Grant Rachael , Thomson Darren D. , Moyes David L. , Naglik Julian R. , Bignell Elaine
Published: November 2021

The human lung is constantly exposed to Aspergillus fumigatus spores, the most prevalent worldwide cause of fungal respiratory disease. Pulmonary tissue damage is a unifying feature of Aspergillus-related diseases; however, the mechanistic basis of damage is not understood. In the lungs of susceptible hosts A. fumigatus undergoes an obligatory morphological switch involving spore germination and hyphal growth. We modelled A. fumigatus infection in cultured A549 human pneumocytes, capturing phosphoactivation status of five host signalling pathways, nuclear translocation & DNA binding of eight host transcription factors, and expression of nine host response proteins over six time points encompassing exposures to live fungus and the secretome thereof. The resulting dataset, comprised of more than 1000 data points, reveals that pneumocytes mount differential responses to A. fumigatus spores, hyphae and soluble secreted products via the NF-kB, JNK, and JNK + p38 pathways respectively. Importantly, via selective degradation of host pro-inflammatory (IL-6 and IL-8) cytokines and growth factors (FGF-2), fungal secreted products reorchestrate the host response to fungal challenge as well as driving multiparametric epithelial damage, culminating in cytolysis. Dysregulation of NF-kB signalling, involving iterative stimulation of canonical and non-canonical signalling, was identified as a significant feature of host damage both in vitro and in a mouse model of invasive aspergillosis. Our data demonstrate that composite tissue damage results from iterative exposures to different fungal morphotypes and secreted products and suggest that modulation of host responses to fungal challenge might represent a unified strategy for therapeutic control of pathologically distinct types of Aspergillus-related disease.

IMPORTANCE

Pulmonary aspergillosis is a spectrum of diseases caused primarily by Aspergillus fumigatus. This fungus is ubiquitous in the environment and grows as a mold, which harbors and disperses spores into the environment. Like other airborne pathogens, the lung mucosa is the first point of contact with the fungus post inhalation. The outcome and severity of disease depends on the host-fungal interaction at the lung interface. We studied how the human lung interacts with spore, germ tube and hyphae growth forms to understand the sequence and dynamics of the early events, which are critical drivers of disease development and progression. Our work is significant in identifying, in response to fungal secreted products, non-canonical NF-kB activation via RelB as being a driving factor in fungus-mediated lung damage. This process could be modulated therapeutically to protect the integrity of infected lung mucosae.
Antibody decay, T cell immunity and breakthrough infections following two SARS-CoV-2 vaccine doses in infliximab- and vedolizumab-treated patients
Authors: Lin Simeng , Kennedy Nicholas A , Saifuddin Aamir , Sandoval Diana Muñoz , Reynolds Catherine J , Seoane Rocio Castro , Kottoor Sherine H , Pieper Franziska P , Lin Kai-Min , Butler David K. , Chanchlani Neil , Nice Rachel , Chee Desmond , Bewshea Claire , Janjua Malik , McDonald Timothy J , Sebastian Shaji , Alexander James L , Constable Laura , Lee James C , Murray Charles D , Hart Ailsa L , Irving Peter M , Jones Gareth-Rhys , Kok Klaartje B , Lamb Christopher A , Lees Charlie W , Altmann Daniel M , Boyton Rosemary J , Goodhand James R , Powell Nick , Ahmad Tariq ,   Contributors of the CLARITY IBD study
Published: November 2021

We report SARS-CoV-2 vaccine-induced immunity and risk of breakthrough infections in patients with inflammatory bowel disease treated with infliximab, a commonly used anti-TNF drug and those treated with vedolizumab, a gut-specific antibody targeting integrin a4b7 that does not impact systemic immunity. In infliximab-treated patients, the magnitude of anti-SARS-CoV2 antibodies was reduced 4-6-fold. One fifth of both infliximab- and vedolizumab-treated patients did not mount a T cell response. Antibody half-life was shorter in infliximab-treated patients. Breakthrough SARS-CoV-2 infections occurred more frequently in infliximab-treated patients and the risk was predicted by the level of antibody response after second vaccine dose. Overall, recipients of two doses of the BNT162b2 vaccine had higher anti-SARS-CoV-2 antibody concentrations, higher seroconversion rates, shorter antibody half-life and less breakthrough infections compared to ChAdOx1 nCoV-19 vaccine recipients. Irrespective of biologic treatment, higher, more sustained antibody levels were observed in patients with a history of SARS-CoV-2 infection prior to vaccination. Patients treated with anti-TNF therapy should be offered third vaccine doses.
DiagnosisQA: A semi-automated pipeline for developing clinician validated diagnosis specific QA datasets
Authors: Mishra Shreya , Awasthi Raghav , Papay Frank , Maheshawari Kamal , Cywinski Jacek B , Khanna Ashish , Mathur Piyush
Published: November 2021

Question answering (QA) is one of the oldest research areas of AI and Computational Linguistics. QA has seen significant progress with the development of state-of-the-art models and benchmark datasets over the last few years. However, pre-trained QA models perform poorly for clinical QA tasks, presumably due to the complexity of electronic healthcare data. With the digitization of healthcare data and the increasing volume of unstructured data, it is extremely important for healthcare providers to have a mechanism to query the data to find appropriate answers. Since diagnosis is central to any decision-making for the clinicians and patients, we have created a pipeline to develop diagnosis-specific QA datasets and curated a QA database for the Cerebrovascular Accident (CVA). CVA, also commonly known as Stroke, is an important and commonly occurring diagnosis amongst critically ill patients. Our method when compared to clinician validation achieved an accuracy of 0.90(with 90% CI [0.82,0.99]). Using our method, we hope to overcome the key challenges of building and validating a highly accurate QA dataset in a semiautomated manner which can help improve performance of QA models.
Plasma biomarkers associated with survival and thrombosis in hospitalized COVID-19 patients
Authors: Cabrera-Garcia David , Miltiades Andrea , Yim Peter , Parsons Samantha , Elisman Katerina , Mansouri Mohammad Taghi , Wagener Gebhard , Harrison Neil L.
Published: November 2021

Severe coronavirus disease-19 (COVID-19) has been associated with fibrin-mediated hypercoagulability and thromboembolic complications. To evaluate potential biomarkers of coagulopathy and disease severity in COVID-19, we measured plasma levels of eight biomarkers potentially associated with coagulation, fibrinolysis, and platelet function in 43 controls and 63 COVID-19 patients, including 47 patients admitted to the intensive care unit (ICU) and 16 non-ICU patients. COVID-19 patients showed significantly elevated levels of fibrinogen, tissue plasminogen activator (t-PA), and its inhibitor plasminogen activation inhibitor 1 (PAI-1), as well as ST2 (the receptor for interleukin 33) and von Willebrand factor (vWF) compared to the control group. We found that higher levels of t-PA, ST2, and vWF at the time of admission were associated with lower survival rates, and that thrombotic events were more frequent in patients with initial higher levels of vWF. These results support a predictive role of specific biomarkers such as t-PA and vWF in the pathophysiology of COVID-19. The data provide support for the case that hypercoagulability in COVID-19 is fibrin-mediated, but also highlights the important role that vWF may play in the genesis of thromboses in the pathophysiology of COVID-19. Interventions designed to enhance fibrinolysis and reduce platelet aggregation might prove to be useful adjuncts in the treatment of coagulopathy in a subset of COVID-19 patients.