bluuebunny/crossref_metadata_2025 huggingface dataset:
Screening for SARS-CoV-2 in close contacts of individuals with confirmed infection: performance and operational considerations
Authors: Zobrist Stephanie , Oliveira-Silva Michelle , Vieira Alexia Martines , Bansil Pooja , Gerth-Guyette Emily , Leader Brandon T. , Golden Allison , Slater Hannah , de Lucena Cruz Catherine Duran , Garbin Eduardo , Sagalovsky Mariana , Pal Sampa , Gupta Vin , Wolansky Leo , Vieira Dall’Acqua Deusilene Souza , Naveca Felipe Gomes , do Nascimento Valdinete Alves , Villalobos Salcedo Juan Miguel , Drain Paul K. , Tavares Costa Alexandre Dias , Domingo Gonzalo J , Pereira Dhélio
Published: January 2022

Background

Point-of-care and decentralized testing for SARS-CoV-2 is critical to inform public health responses. Performance evaluations in priority use cases such as contact tracing can highlight trade-offs in test selection and testing strategies.

Methods

A prospective diagnostic accuracy study was conducted among close contacts of COVID-19 cases in Brazil. Two anterior nares swabs (ANS), a nasopharyngeal swab (NPS), and saliva were collected at all visits. Vaccination history and symptoms were assessed. Household contacts were followed longitudinally. Three rapid antigen tests and one molecular method were evaluated for usability and performance against reference RT-PCR on NPS.

Results

Fifty index cases and 214 contacts (64 household) were enrolled. Sixty-five contacts were RT-PCR positive during at least one visit. Vaccination did not influence viral load. Gamma variants were most prevalent; Delta emerged increasingly during implementation. Overall sensitivity of evaluated tests ranged from 33%–76%. Performance was higher among symptomatic cases and cases with Ct<34 and lower among oligo/asymptomatic cases. Assuming a 24-hour time-to-result for RT-PCR, the cumulative sensitivity of an ANS rapid antigen test was >70% and almost 90% after four days.

Conclusions

The near immediate time-to-result for antigen tests significantly offsets lower analytical sensitivity in settings where RT-PCR results are delayed or unavailable.
Persistently reduced humoral and cellular immune response following third SARS-CoV-2 mRNA vaccination in anti-CD20-treated multiple sclerosis patients
Authors: Bajwa Hamza Mahmood , Novak Frederik , Nilsson Anna Christine , Nielsen Christian , Holm Dorte K. , Østergaard Kamilla , Witt Agnes Hauschultz , Byg Keld-Erik , Johansen Isik S. , Mittl Kristen , Rowles William , Zamvil Scott S. , Bove Riley , Sabatino Joseph J. , Sejbaek Tobias
Published: January 2022

Objective

To examine humoral and cellular response in multiple sclerosis patients on anti-CD20 therapy after third BNT162b2 mRNA SARS-CoV-2 vaccination.

Methods

A prospective longitudinal study design from first throughout third vaccination in Danish and American MS centers. All participants were treated with ocrelizumab. Antibody (Ab) levels were assessed before and after third vaccination using SARS-CoV-2 IgG II Quant assay (Abbott Laboratories). B- and T-lymphocytes enumeration was done with BD Multitest™6-color TBNK reagent. Spike-specific T-cell responses were measured through PBMC stimulation with spike peptide pools (JPT Peptide Technologies).

Results

We found that 14.0%, 37.7%, and 33.3% were seropositive after first, second and third vaccination. The median Ab-levels were 74.2 BAU/mL (range: 8.5-2427), 43.7 BAU/ml (range: 7.8-366.1) and 31.3 BAU/mL (range: 7.9-507.0) after first, second and third vaccination, respectively. No difference was found in levels after second and third vaccination (p=0.1475). Seropositivity dropped to 25.0% of participants before the third vaccination, a relative reduction of 33.3% (p=0.0020). No difference was found between frequencies of spike reactive CD4+ and CD8+ T-cells after second (0.65 ± 0.08% and 0.95 ± 0.20%, respectively) and third vaccination (0.99 ± 0.22% and 1.3 ± 0.34%), respectively.

Conclusion

In this longitudinal cohort we found no significant increased humoral or cellular response with administration of a third SARS-CoV-2 mRNA vaccination. These findings suggest the need for clinical strategies to include allowance of B cell reconstitution before repeat vaccination and/or provision of pre-exposure prophylactic monoclonal antibodies.

Key Points

What is already known on this topic

Studies have described decreased humoral response and sustained T-cell reactivity after standard two-dose SARS-CoV-2 mRNA vaccination during anti-CD20 therapy in multiple sclerosis participants.

What this study adds

Persistently decreased humoral, but stable cellular reactivity following a third SARS-CoV-2 mRNA vaccination.

How this study might affect research, practice or policy

The findings suggest the need for clinical strategies to include allowance of B cell reconstitution before repeat vaccination and/or provision of pre-exposure prophylactic monoclonal antibodies.
Identifying the regional substrates predictive of Alzheimer’s disease progression through a convolutional neural network model and occlusion
Authors: Kwak Kichang , Stanford William , Dayan Eran ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: January 2022

Progressive brain atrophy is a key neuropathological hallmark of Alzheimer’s disease (AD). However, atrophy patterns along the progression of AD are diffuse and variable. Consequently, identifying the major regional atrophy patterns underlying AD progression is challenging. In the current study, we propose a method that evaluates the degree to which specific regional atrophy are predictive of AD progression, while holding all other atrophy changes constant. We first trained a dense convolutional neural network model to differentiate individuals with mild cognitive impairment (MCI) who progress to AD vs. those with a stable MCI diagnosis. Then, we retested the model multiple times, each time occluding major regions from the model’s testing set’s input. This revealed that the hippocampus, fusiform, and inferior temporal gyri, were the strongest predictors of AD progression, in agreement with established staging models. These results shed light on the major regional patterns of atrophy predictive of AD progression.
Evaluation of the CD4+ T cell response to SARS-CoV-2 infection and cross reactivity to beta variant in children of all ages
Authors: Paul Kevin , Sibbertsen Freya , Weiskopf Daniela , Lütgehetmann Marc , Barroso Madalena , Danecka Marta K. , Glau Laura , Hecher Laura , Hermann Katharina , Kohl Aloisa , Oh Jun , zur Wiesch Julian Schulze , Sette Alessandro , Tolosa Eva , Vettorazzi Eik , Woidy Mathias , Zapf Antonia , Zazara Dimitra E. , Mir Thomas S. , Muntau Ania C. , Gersting Søren W. , Dunay Gábor A.
Published: January 2022

SARS-CoV-2 is still a major burden for global health despite effective vaccines. With the reduction of social distancing measures, infection rates are increasing in children, while data on the pediatric immune response to SARS-CoV-2 infection is still lacking. Although the typical disease course in children has been mild, emerging variants may present new challenges in this age group.

Peripheral blood mononuclear cells (PBMC) from 51 convalescent children, 24 seronegative siblings from early 2020, and 51 unexposed controls were stimulated with SARS-CoV-2-derived peptide MegaPools from the ancestral and beta variants. Flow cytometric determination of activation-induced markers and secreted cytokines were used to quantify the CD4+ T cell response.

The average time after infection was over 80 days. CD4+ T cell responses were detected in 61% of convalescent children and were markedly reduced in preschool children. Cross-reactive T cells for the SARS-CoV-2 beta variant were identified in 45% of cases after infection with an ancestral SARS-CoV-2 variant. The CD4+ T cell response was accompanied most predominantly by IFN-γ and Granzyme B secretion.

An antiviral CD4+ T cell response was present in children after ancestral SARS-CoV-2 infection, which was reduced in the youngest age group. We detected significant cross-reactivity of CD4+ T cell responses to the more recently evolved immune-escaping beta variant. Our findings have epidemiologic relevance for children regarding novel viral variants of concern and vaccination efforts.
Psychological Outcomes of Surgery Trainees in the Era of COVID-19 at a Tertiary Care Hospital of Karachi, Pakistan: A Cross-Sectional Study
Authors: Lakhani Gulzar , Bajwa Mohammad Hamza , Zahid Nida , Enam Syed Ather
Published: January 2022

Objectives

The COVID-19 pandemic has resulted in interruptions in training for surgical residents in particular. This has been compounded by burnout and mental health concerns among surgical trainees across the world. We aim to determine the impact of the COVID-19 pandemic on psychological outcomes of surgical trainees in a tertiary-care hospital in Pakistan.

Setting

A cross-sectional, online survey-based study was conducted at a private tertiary care hospital of Karachi, Pakistan.

Participants

All the surgery trainees including; residents, fellows and instructors acquiring training at a private tertiary care hospital of Karachi, Pakistan were included in the study.

Outcome measures

The participants were assessed for their perceptions, and concerns regarding the COVID-19 pandemic, impact on their quality of life and generalized anxiety disorder (GAD).

Results

A majority (85%) of surgical trainees were concerned regarding contracting COVID-19 infections. Residents were more concerned with fellow residents developing burnout and anxiety as compared to their own psychological concerns. A strong, significant positive correlation (r=0.66, p <0.001) was noted between negative impact on QoL scores and developing GAD in surgical residents. On multivariable analysis, significant associations with GAD remained for family system, and negative impact of COVID-19 on QoL. The increased working hours for junior trainees showed more likelihood of developing GAD as compared to senior trainees.

Conclusion

Our investigation on QoL and psychological outcomes of surgical residents showed significant rates of burnout and GAD, which were attributed to concerns with the COVID-19 pandemic. We showed the impact this had on surgical trainees’ perception regarding their training and concerns with infecting others. This calls for structural interventions to address mental health concerns and provide psychological and educational support to surgical residents.

Strengths and Limitations of the study

Validated measures were used for evaluating the outcomes

The study results can be generalized to all the surgery resident trainees working at private tertiary care hospitals.

The response rate of trainees was 50%, the authors attempted to mitigate this through regular follow-up emails and reminders for responses.
Neuroprotective effects of Canagliflozin: lessons from aged genetically diverse UM-HET3 mice
Authors: Jayarathne Hashan S. M. , Debarba Lucas K. , Jaboro Jacob J. , Miller Richard A. , Sadagurski Marianna
Published: January 2022

The aging brain is characterized by a progressive increase in neuroinflammation and central insulin resistance, which contribute to neurodegenerative diseases and cognitive impairment. Recently, the Interventions Testing Program (ITP) demonstrated that the anti-diabetes drug, Canagliflozin (Cana), a sodium-glucose transporter 2 inhibitor (SGLT2i), led to lower fasting glucose and improved glucose tolerance in both sexes, but extended median lifespan by 14% only in male mice. Here we show that Cana treatment significantly improved central insulin sensitivity in the hypothalamus and the hippocampus of 30-month-old male mice. Remarkably, Cana-treated mice showed significant reductions in age-associated hypothalamic gliosis with a decrease in inflammatory cytokine production by microglia in both sexes. In the hippocampus, Cana reduced microgliosis and astrogliosis in males, but not in female mice. The decrease in microgliosis was partially dependent on mTOR signaling, as evidenced by reduced phosphorylation of S6 kinase in microglia of Cana-treated aged male, but not female mice. Remarkably, Cana treatment improved exploratory and locomotor activity of 30-month-old male but not female mice. Taken together, our findings demonstrate sex-specific neuroprotective effects of Cana treatment, suggesting its application for the potential treatment of neurodegenerative diseases.
COVID-19 self-testing in Nigeria: Stakeholders’ opinions and perspective on its value for case detection
Authors: Undelikwo Veronica A. , Shilton Sonjelle , Folayan Morenike Oluwatoyin , Alaba Oluwatoyin , Reipold Elena Ivanova , Martínez-Pérez Guillermo Z.
Published: January 2022

Background

COVID-19 testing coverage is limited in Nigeria. Access to SARS-CoV-2 self-testing kits may help improve the detection of asymptomatic and mildly symptomatic cases and increase the currently low rate of COVID-19 testing in the country. Before implementing SARS-CoV-2 self-testing in Nigeria, it is imperative to assess the populations’ perceptions regarding this innovation. We therefore conducted a qualitative study to investigate people’s values and preferences for SARS-CoV-2 self-testing in Nigeria.

Methods

We used semi-structured interviews and focus group discussions among healthcare workers, community representatives, and public health implementors to explore values and perceptions around various aspects of COVID-19 testing, including conventional COVID-19 testing, SARS-CoV-2 self-testing, the safe and effective use of SARS-CoV-2 self-testing, actions upon receiving a positive SARS-CoV-2 self-test result, and future prospects for SARS-CoV-2 self-testing.

Results

Respondents reported that there is limited availability of conventional SARS-CoV-2 testing in Nigeria. While just a few respondents were familiar with SARS-CoV-2 testing, respondents generally supported the use of SARS-CoV-2 self-testing as they felt it could assist with early case detection and improve access to testing. Concerns relating to the use of SARS-CoV-2 self-testing were majorly about the ability among low literacy populations to use and interpret the test, the affordability of tests, equity of access, and the availability of healthcare system support for those who test positive.

Conclusion

Though the public perceive multiple benefits associated with access to SARS-CoV-2 self-testing, the efficiency of the national health service delivery system may limit access of the users of the kits to psychosocial and clinical support. In Nigeria, where COVID-19 vaccine coverage is low and the risk of further waves of COVID-19 is high, self-testing may assist in the prompt detection of cases and contribute to halting the spread of the virus.
Wastewater surveillance for COVID-19 response at multiple geographic scales: Aligning wastewater and clinical results at the census-block level and addressing pervasiveness of qPCR non-detects
Authors: Safford Hannah , Zuniga-Montanez Rogelio E. , Kim Minji , Wu Xiaoliu , Wei Lifeng , Sharpnack James , Shapiro Karen , Bischel Heather
Published: January 2022

Wastewater surveillance is a useful complement to clinical testing for managing COVID-19. While good agreement has been found between community-scale wastewater and clinical data, little is known about sub-community relationships between the two data types. Moreover, effects of non-detects in qPCR wastewater data have been largely overlooked. We used data collected from September 2020–June 2021 in Davis, California (USA) to address these gaps. By applying a predictive probability model to spatially disaggregate clinical results, we compared wastewater and clinical data at the community scale, in 16 sampling zones isolating city sub-regions, and in seven zones isolating high-priority building complexes or neighborhoods. We found reasonable agreement between wastewater and clinical data at all scales. Greater activity (i.e., more frequent detections) in clinical data tended to be mirrored in wastewater data. Small, isolated clinical-data spikes were often matched as well. We also developed a method for handling such non-detects using multiple imputation and compared results to (i) single imputation using half the qPCR limit of detection, (ii) single imputation using maximum qPCR cycle number, and (iii) non-detect censoring. Apparent wastewater trends were significantly influenced by non-detect handling. Multiple imputation improved correlation relative to single imputation, though not necessarily relative to censoring.
Neutralizing Activities against the Omicron Variant after a Heterologous Booster in Healthy Adults Receiving Two Doses of CoronaVac Vaccination
Authors: Assawakosri Suvichada , Kanokudom Sitthichai , Suntronwong Nungruthai , Auphimai Chompoonut , Nilyanimit Pornjarim , Vichaiwattana Preeyaporn , Thongmee Thanunrat , Duangchinda Thaneeya , Chantima Warangkana , Pakchotanon Pattarakul , Srimuan Donchida , Thatsanatorn Thaksaporn , Klinfueng Sirapa , Yorsang Ritthideach , Sudhinaraset Natthinee , Wanlapakorn Nasamon , Mongkolsapaya Juthathip , Honsawek Sittisak , Poovorawan Yong
Published: January 2022

Background

The use of an inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine (CoronaVac) against SARS-CoV-2 is implemented worldwide. However, waning immunity and breakthrough infections have been observed. Therefore, we hypothesized that the heterologous booster might improve the protection against the delta and omicron variants.

Methods

A total of 224 individuals who completed the two-dose CoronaVac for six months were included. We studied reactogenicity and immunogenicity following a heterologous booster with the inactivated vaccine (BBIBP), the viral vector vaccine (AZD1222), and the mRNA vaccine (both BNT162B2 and mRNA-1273). We also determined immunogenicity at 3- and 6-months boosting intervals.

Results

The solicited adverse events (AEs) were mild to moderate and well-tolerated. Total RBD immunoglobulin (Ig), anti-RBD IgG, focus reduction neutralization test (FRNT50) against delta and omicron variants, and T cell response were highest in the mRNA-1273 group followed by the BNT162b2, AZD1222 and BBIBP groups, respectively. We also witnessed a higher total Ig anti-RBD in the long-interval than in the short-interval groups.

Conclusions

All four booster vaccines significantly increased binding and NAbs in individuals immunized with two doses of CoronaVac. The present evidence may benefit vaccine strategies development to thwart variants of concern, including the omicron variant.
Maternal Disrespect and Abuse by Health Care Providers among postpartum women attending Mizan-Tepi University Teaching Hospital, South West Ethiopia
Authors: Kebede Dereje Sisay , Dachew Aklilu Mamo , Abota Tafesse Lamaro
Published: January 2022

Background

In Ethiopia, only 48% of all births occur at health facilities. Maternal disrespect and abuse by health care providers during child birth is one of the main reasons that affect health care seeking behaviors from health facilities. Thus, this study aims to assess magnitude of maternal disrespect and abuse during institutional delivery among postpartum women at Mizan -Tepi University Teaching Hospital (MTUTH), Bench Sheko Zone, South west Ethiopia

Methods

Institution-based cross-sectional study design was employed. A total of 409 postpartum women were enrolled using systematic random sampling technique between Augusts to September, in 2021. Pré-tested and structured questionnaire used for face-to-face interview. Data were coded, edited, and analyzed using SPSS version 25. Bivariate and multivariable logistic regression analyses were done. The presence and strength of association were determined using AOR with its 95% CI. Variables with P value of less than 0.05 were considered as statistically significant

Results

About half (52.1%) of the postpartum women experienced at least one category of maternal disrespect and abuse during institutional delivery. No formal education status during labor [AOR=2.216; 95% CI:1.266, 3.879], delivery during night shifts [(AOR=2.2; 95% CI: 1.306, 3.772], living in rural area [AOR=3.014;95% CI:1.630,5.572], number of health provider 2-3[AOR=4.101; 95%CI:2.70,6.23] and number of health provider above three[AOR=8.13; 95%CI:2.12,5.62] were found to be strongly associated with reporting maternal disrespect and abuse.

Conclusions

The study highlights that large proportion of mothers are experiencing maternal disrespect and abuse during institutional delivery in this study setting. Thus, appropriate interventions should be designed, focusing on supervision during night shifts, empowering childbearing women about their rights at health facilities and providing training for health care providers about respectful maternity care need to be emphatise.
A mixed methods analysis of participation in social contact surveys
Authors: Nixon Emily , Silvonen Taru , Barreaux Antoine , Kwiatkowska Rachel , Trickey Adam , Thomas Amy , Ali Becky , Treneman-Evans Georgia , Christensen Hannah , Brooks-Pollock Ellen , Denford Sarah
Published: January 2022

Background

Social contact survey data forms a core component of modern epidemic models: however, there has been little assessment of the potential biases in such data.

Methods

We conducted focus groups with university students who had (n=13) and had not (n=14) completed a social contact survey during the COVID-19 pandemic. Qualitative findings were explored quantitatively by analysing participation data.

Results

The opportunity to contribute to COVID-19 research, to be heard and feel useful were frequently reported motivators for participating in the contact survey. Reductions in survey engagement following lifting of COVID-19 restrictions may have occurred because the research was perceived to be less critical and/ or because the participants were busier and had more contacts. Having a high number of contacts to report, uncertainty around how to report each contact, and concerns around confidentiality were identified as factors leading to inaccurate reporting. Focus groups participants thought that financial incentives or provision of study results would encourage participation.

Conclusions

Incentives could improve engagement with social contact surveys. Qualitative research can inform the format, timing, and wording of surveys to optimise completion and accuracy.

Graphical abstract
Comparative effectiveness of COVID-19 vaccination against death and severe disease in an ongoing nationwide mass vaccination campaign
Authors: Lytras Theodore , Kontopidou Flora , Lambrou Angeliki , Tsiodras Sotirios
Published: January 2022

Background

As national COVID-19 mass vaccination campaigns are rolled out, it is important to demonstrate and measure their public health benefit. We aimed to estimate COVID-19 Vaccine Effectiveness (VE) against severe disease and death in the Greek population, for all vaccines in use.

Methods

Nationwide active surveillance and vaccination registry data during January-December 2021 were used to estimate VE via quasi-Poisson regression, as one minus the Incidence Rate Ratio, adjusted for age and calendar time. Interaction terms were included to assess VE by age group, against the “delta” SARS-CoV-2 variant and waning of VE over time.

Results

Two doses of BNT162b2, mRNA-1273 or ChAdOx1 nCov-19 vaccines offered very high (>90%) VE against both intubation and death across all age groups, similar against both “delta” and previous variants, with one-dose Ad26.COV2.S slightly lower. There was some waning over time but VE remained >80% at six months, and three doses increased VE again to near 100%. Vaccination prevented an estimated 19,691 COVID-19 deaths (95% CI: 18,890-20,788) over the study period.

Conclusions

All approved vaccines were very highly effective in preventing COVID-19 severe disease and death. Every effort should be made to vaccinate the population with at least two doses, in order to reduce the mortality and morbidity impact of the pandemic.
Cerebro-cerebellar networks facilitate learning through feedback decoupling
Authors: Boven Ellen , Pemberton Joseph , Chadderton Paul , Apps Richard , Costa Rui Ponte
Published: January 2022

Behavioural feedback is critical for learning in the cerebral cortex. However, such feedback is often not readily available. How the cerebral cortex learns efficiently despite the sparse nature of feedback remains unclear. Inspired by recent deep learning algorithms, we introduce a systems-level computational model of cerebro-cerebellar interactions. In this model a cerebral recurrent network receives feedback predictions from a cerebellar network, thereby decoupling learning in cerebral networks from future feedback. When trained in a simple sensorimotor task the model shows faster learning and reduced dysmetria-like behaviours, in line with the widely observed functional impact of the cerebellum. Next, we demonstrate that these results generalise to more complex motor and cognitive tasks. Finally, the model makes several experimentally testable predictions regarding (1) cerebro-cerebellar task-specific representations over learning, (2) task-specific benefits of cerebellar predictions and (3) the differential impact of cerebellar and inferior olive lesions. Overall, our work offers a theoretical framework of cerebro-cerebellar networks as feedback decoupling machines.
Extending Bayesian Elo-rating to quantify the steepness of dominance hierarchies
Authors: Neumann Christof , Fischer Julia
Published: January 2022

The steepness of dominance hierarchies provides information about the degree of competition within animal social groups and is thus an important concept in socioecology. The currently most widely-used metrics to quantify steepness are based on David’s scores (DS) derived from dominance interaction networks. One serious drawback of these DS-based metrics is that they are biased, i.e., network density systematically decreases steepness values. Here, we provide a novel approach to estimate steepness based on Elo-ratings, implemented in a Bayesian framework (STEER: Steepness estimation with Elo-rating). Our new metric has two key advantages. First, STEER is unbiased, precise and more robust to data density than DS-based steepness. Second, it provides explicit probability distributions of the estimated steepness coefficient, which allows uncertainty assessment. In addition, it relies on the same underlying concept and is on the same scale as the original measure, and thus allows comparison to existing published results. We evaluate and validate performance of STEER by means of experimentation on empirical and artificial data sets and compare its performance to that of several other steepness estimators. Our results suggest that STEER provides a considerable improvement over existing methods to estimate dominance hierarchy steepness. We provide an R packageEloSteepnessto calculate the new steepness measure, and also show an example of using steepness in a comparative analysis.
Decline in Environmental Quality and Spatial Dynamics of New City Area Development Metropolitan Mamminasata, South Sulawesi, Indonesia
Authors: Surya Batara , Salim Agus , Sariman Syahrul , Hernita Hernita , Saleh Haeruddin , Suriani Seri , Nasrullah Nasrullah , Rasyidi Emil Salim
Published: January 2022

Abstracts

The expansion of urban areas towards the development of new urban areas has an impact on changes in land use, socio-economic dynamics and a decrease in environmental quality. This study aims to analyze land use change as a determinant of environmental degradation and the spatial dynamics of metropolitan urban areas, the effect of land use change, housing development, infrastructure development, and land reclamation on the environmental degradation of the new city area, and control strategies environmental pollution and sustainable development of the new city area. This study uses a quantitative-qualitative concurrent triangulation design approach. Elaboration of data through observation, in-depth interviews, surveys, and documentation is used to describe the socio-economic community, and the decline in the environmental quality of new city area development in relation to the spatial dynamics of metropolitan urban areas. The results of the study show that the intensity of land use change coupled with an increase in socio-economic activities in the development of new city areas is positively associated with a decrease in environmental quality and segregation towards the spatial dynamics of metropolitan urban areas. Changes in land use, housing development, infrastructure development, and land reclamation simultaneously affect environmental quality degradation with a coefficient of determination of 64.96%. This study recommends strategies for controlling environmental pollution and sustainable development of new city areas for the needs of formulating urban development policies for Mamminasata Metropolitan South Sulawesi, Indonesia.
Does a single exposure to social defeat render rats more vulnerable to chemically induced colitis than brief inescapable foot-shocks?
Authors: Milde Anne Marita , Rød Anne Marie Kinn , Brekke Silvia , Gjøen Hedda , Mesfin Ghenet , Murison Robert
Published: January 2022

All social species are to different degrees exposed to stressors being physical or social environmental, which may affect health and well-being. Stressful and traumatic situations have direct effect on immune responses that may underlie susceptibility of developing somatic illness. In animal research, different types of stressors have been investigated in studying the effect on bowel disorders, some stressor being more or less of environmental origin. We aimed therefore to explore whether a more natural stressor would differ from a stressor of more unnatural characteristics on dextran sulphate sodium (DSS) induced colitis in adult rats. Specifically, if social stress within a single social defeat (SD) paradigm would be a more potent stressor than brief inescapable foot-shocks (IFS) in causing elevated faecal granulocyte marker protein (GMP), crypt- and inflammation score in colon tissue. Three groups of male Wistar rats were used; socially defeated rats; inescapable foot-shock rats; and comparison rats. Main findings showed no difference between the groups on GMP levels, however, there was a significant difference on inflammation and crypt score for the distal part of colon, detected through histology, where socially defeated rats were more susceptible. A single SD seems to be more adverse for these animals, but further studies are recommended to validate a broader range of different outcomes comparing two such different rodent stress models.
Campylobacter jejuni induces differentiation of human neutrophils to the CD16hi/CD62Llo subtype which possess cancer promoting activities
Authors: Dolislager Carolina G. , Callahan Sean M. , Donohoe Dallas R. , Johnson Jeremiah G.
Published: January 2022

The discovery of neutrophil subtypes has expanded what is known about neutrophil functions, yet there is still much to learn about the role of these subtypes during bacterial infection. We investigated whether Campylobacter jejuni induced differentiation of human neutrophils into the hypersegmented, CD16hi/CD62Llo subtype. In addition, we investigated whether C. jejuni-dependent differentiation of this neutrophil subtype induced cancer promoting activities of human T cells and colonocytes, which were observed in other studies of hypersegmented, CD16hi/CD62Llo neutrophils. We found that C. jejuni causes a significant shift in human neutrophil populations to the hypersegmented, CD16hi/CD62Llo subtype and that those populations exhibit delayed apoptosis, elevated arginase-1 expression, and increased reactive oxygen species production. Furthermore, incubation of C. jejuni-infected neutrophils with human T cells resulted in decreased expression of the ζ-chain of the T cell receptor (TCRζ), which was restored upon supplementation with exogenous L-arginine. In addition, incubation of C. jejuni-infected neutrophils with human colonocytes resulted in increased HIF-1α stabilization and NF-κB activation in those colonocytes, which may result in the upregulation of pro-tumorigenic genes. This response, coupled with the ability of C. jejuni-infected neutrophils to suppress TCRζ expression in T cells, could result in the promotion of colorectal tumorigenesis during infection with C. jejuni.
In vivo correction of cystic fibrosis mediated by PNA nanoparticles
Authors: Piotrowski-Daspit Alexandra S. , Barone Christina , Lin Chun-Yu , Deng Yanxiang , Wu Douglas , Binns Thomas C. , Xu Emily , Ricciardi Adele S. , Putman Rachael , Nguyen Richard , Gupta Anisha , Fan Rong , Glazer Peter M. , Saltzman W. Mark , Egan Marie. E.
Published: January 2022

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. We sought to correct the multiple organ dysfunction of the F508del CF-causing mutation using systemic delivery of peptide nucleic acid gene editing technology mediated by biocompatible polymeric nanoparticles. We confirmed phenotypic and genotypic modification in vitro in primary nasal epithelial cells from F508del mice grown at air-liquid interface and in vivo in F508del mice following intravenous delivery. In vivo treatment resulted in a partial gain of CFTR function in epithelia as measured by in situ potential differences and Ussing chamber assays and correction of CFTR in both airway and GI tissues with no off-target effects above background. This is the first report of systemic gene editing for CF. Our data suggest that systemic delivery of PNA NPs designed to correct CF-causing mutations is a viable option to ameliorate the disease in multiple affected organs.
Hsp78-interaction proteome highlights chaperone role during protein aggregation in mitochondria under heat stress
Authors: Jaworek Witold , Sylvester Marc , Cenini Giovanna , Voos Wolfgang
Published: January 2022

Proteins of the Hsp100 chaperone family support protein homeostasis, the maintenance of protein activity under stress, by refolding aggregated proteins or targeting them for degradation. Hsp78, the ClpB-type mitochondrial member of the Hsp100 family, can be found in lower eukaryotes like yeast. Although Hsp78 has been shown to contribute to protection against elevated temperatures in yeast, the biochemical mechanisms underlying this mitochondria-specific thermotolerance are still largely unclear. To identify endogenous chaperone substrate proteins, we generated an Hsp78-ATPase mutant with a stabilized substrate binding behaviour. We used two SILAC-based quantitative mass spectrometry approaches to analyze the role of Hsp78 during heat stress-induced mitochondrial protein aggregation and disaggregation processes on a proteomic level. In the first setup, Hsp78-interacting polypeptides were identified to reveal the endogenous substrate spectrum of the chaperone. Our analysis revealed that Hsp78 is interacting with a wide variety of proteins related to metabolic functions including energy production and protein synthesis, as well as other chaperones, thus maintaining crucial functions for mitochondrial stress resistance. We compared these interaction data with a second experimental setup that focussed on the on overall aggregation and disaggregation processes in mitochondria under heat stress on a proteomic level. This revealed specific aggregation-prone protein populations and demonstrated the direct quantitative impact of Hsp78 on stress-dependent protein solubility under different conditions. We conclude that Hsp78 together with its cofactors represents a recovery system that protects major mitochondrial metabolic functions during heat stress as well restores protein biogenesis capacity after return to normal conditions.
Where Honey Bee Vitellogenin may Bind Zn2+-Ions
Authors: Leipart Vilde , Enger Øyvind , Turcu Diana Cornelia , Dobrovolska Olena , Drabløs Finn , Halskau Øyvind , Amdam Gro V.
Published: January 2022

The protein Vitellogenin (Vg) plays a central role in lipid transportation in most egg-laying animals. High Vg levels correlate with stress resistance and lifespan potential in honey bees (Apis mellifera). Vg is the primary circulating zinc-carrying protein in honey bees. Zinc is an essential metal ion in numerous biological processes, including the function and structure of many proteins. Measurements of Zn2+ suggest a variable number of ions per Vg molecule in different animal species, but the molecular implications of zinc-binding by this protein are not well understood. We used inductively coupled plasma mass spectrometry (ICP-MS) to determine that, on average, each honey bee Vg molecule binds 3 Zn2+-ions. Our full-length protein structure and sequence analysis revealed seven potential zinc-binding sites. These are located in the β-barrel and α-helical subdomains of the N-terminal domain, the lipid binding site, and the cysteine-rich C-terminal region of unknown function. Interestingly, two potential zinc-binding sites in the β-barrel can support a proposed role for this structure in DNA-binding. Overall, our findings illustrate the capacity of honey bee Vg to bind zinc at several functional regions, indicating that Zn2+-ions are important for many of the activities of this protein. In addition to being potentially relevant for other egg-laying species, these insights provide a platform for studies of metal ions in bee health, which is of global interest due to recent declines in pollinator numbers.
Water-Only Look-Locker Inversion recovery (WOLLI) T1 mapping
Authors: Garrison Liam D. , Levick Christina , Pavlides Michael , Marjot Thomas , Mozes Ferenc , Hodson Leanne , Neubauer Stefan , Robson Matthew D. , Rodgers Christopher T.
Published: January 2022

Purpose

Modified Look-Locker Inversion recovery (MOLLI) and Shortened MOLLI (ShMOLLI) T1 values can deviate substantially from the water T1 in voxels containing large amounts of water and fat. We introduce Water-Only Look-Locker Inversion recovery (WOLLI) to map water T1 in tissue containing fat.

Theory

WOLLI comprises adiabatic water-selective inversion and several balanced steady-state free precession (bSSFP) readouts, followed immediately by adiabatic fat-selective inversion and bSSFP readout(s). Data are fitted pixel-wise and an adapted Deichmann-Haase saturation-correction gives the water T1.

Methods

We compared two WOLLI protocols (WOLLI-w7f1 and WOLLI-w7f2f1), ShMOLLI and single-voxel spectroscopy at 3T in: simulations, fat/water phantoms, and 12 subjects’ livers.

Results

In simulations with 0-40% fat fraction, T1 varied by: <0.5% (WOLLI-w7f1), <12% (WOLLI-w7f2f1), and >100% (MOLLI). In phantoms, the accuracy of the methods (i.e. worst-case T1w difference vs spectroscopy) was: WOLLI-w7f1 (best, maximum difference of 10.2%), WOLLI-w7f2f1 (max. 10.5%), and ShMOLLI (max. 81.5%). In the liver, the root-mean-squared deviations vs spectroscopy were: 374ms (WOLLI-w7f1), 645ms (WOLLI-w7f2f1), and 700ms (ShMOLLI).

Conclusion

Compared to ShMOLLI, WOLLI is less influenced by fat, but more by B0-inhomogeneity. WOLLI was a clear improvement in phantoms but less so in vivo. WOLLI may be suited to scan organs with high fat content such as the liver.
Tardigrade community microbiomes in North American orchards include putative endosymbionts and plant pathogens
Authors: Tibbs-Cortes Laura E. , Tibbs-Cortes Bienvenido W. , Schmitz-Esser Stephan
Published: January 2022

The microbiome of tardigrades, a phylum of microscopic animals best known for their ability to survive extreme conditions, is poorly studied worldwide and completely unknown in North America. An improved understanding of tardigrade-associated bacteria is particularly important because tardigrades have been shown to act as vectors of the plant pathogen Xanthomonas campestris in the laboratory. However, the potential role of tardigrades as reservoirs and vectors of phytopathogens has not been investigated further. This study analyzed the microbiota of tardigrades from six apple orchards in central Iowa, USA, and is the first analysis of the microbiota of North American tardigrades. It is also the first ever study of the tardigrade microbiome in an agricultural setting. We utilized 16S rRNA gene amplicon sequencing to characterize the tardigrade community microbiome across four contrasts: location, substrate type (moss or lichen), collection year, and tardigrades versus their substrate. Alpha diversity of the tardigrade community microbiome differed significantly by location and year of collection but not by substrate type. Our work also corroborated earlier findings, demonstrating that tardigrades harbor a distinct microbiota from their environment. We also identified tardigrade-associated taxa that belong to genera known to contain phytopathogens (Pseudomonas, Ralstonia, and the Pantoea/Erwinia complex). Finally, we observed members of the genera Rickettsia and Wolbachia in the tardigrade microbiome; because these are obligate intracellular genera, we consider these taxa to be putative endosymbionts of tardigrades. These results suggest the presence of putative endosymbionts and phytopathogens in the microbiota of wild tardigrades in North America.
Dynamic changes to signal allocation rules in response to variable social environments in house mice
Authors: Miller Caitlin H , Hillock Matthew F , Yang Jay , Carlson-Clarke Brandon , Haxhillari Klaudio , Lee Annie Y , Warden Melissa R , Sheehan Michael J
Published: January 2022

Male house mice use metabolically costly urine marks in intrasexual competition and mate attraction. Given the high costs of signaling and the depletable nature of urine reserves, males should dynamically modulate signal allocation as the social landscape is updated with new information. We investigate which aspects of male urine marking behavior are static or dynamic in light of changing social environments. To do this, we use thermal imaging to capture spatiotemporal data of urine deposition decisions. This novel method reveals fine-scale variation in urinary motor patterns in response to competition and social odors. Males demonstrate striking winner-loser effects in both the total allocation effort and temporal dynamics of scent marking. We find that competitive experience primes key temporal features of signal allocation and modulates responses to familiar and unfamiliar male scents. Males adjust their signaling effort, mark latency, and scent mark rhythm, depending on the scent identities present in the environment. Winners dramatically increase marking effort toward unfamiliar compared to familiar male scent, consistent with a ‘dear enemy’ effect. Losers, in contrast, greatly reduce marking to unfamiliar scent but increase marking effort to the scent of their familiar rival, consistent with a ‘nasty neighbor’ effect. Counter to the high lability of many features, the initial signal investment pattern influences allocation decisions days later, revealing the possibility of alternative scent mark strategies among competitive males. Thus, different features of urine mark signal allocation vary in responsiveness to fluctuating social landscapes, suggesting there are multiple distinct behavioral modules underlying marking behavior.
Interaction with TopBP1 mediates human papillomavirus 16 E2 plasmid segregation/retention function and stability during the viral life cycle
Authors: Prabhakar Apurva T. , James Claire D. , Das Dipon , Fontan Christian T. , Otoa Raymonde , Wang Xu , Bristol Molly L. , Morgan Iain M.
Published: January 2022

Human papillomavirus 16 (HPV16) E2 is a DNA binding protein that regulates transcription, replication and potentially, segregation of the HPV16 genome during the viral life cycle. In the segregation model, E2 simultaneously binds to viral and host chromatin, acting as a bridge to ensure that viral genomes reside in daughter nuclei following cell division. The host chromatin receptor for E2 mediating this function is unknown. Recently, we demonstrated that CK2 phosphorylation of E2 on serine 23 (S23) is required for interaction with TopBP1, and that this interaction promotes E2 and TopBP1 recruitment to mitotic chromatin. Here, we demonstrate that in U2OS and N/Tert-1 cells expressing wild type E2 and a non-TopBP1 binding mutant (S23A, serine 23 mutated to alanine), interaction with TopBP1 is essential for E2 recruitment of plasmids to mitotic chromatin. Using a novel quantitative segregation assay, we demonstrate that interaction with TopBP1 is required for E2 plasmid segregation. The interaction of E2 with TopBP1 promotes increased levels of E2 protein during mitosis in U2OS and N/Tert-1 cells, as well as in human foreskin keratinocytes immortalized by the HPV16 genome. Additionally, interaction with TopBP1 is required for expression of the E2 protein during the viral life cycle. Overall, our results demonstrate that E2 has plasmid segregation activity, and that the E2-TopBP1 interaction is essential for this E2 function and for E2 expression during the viral life cycle.

Importance

HPV16 causes 3-4% of all human cancers. During the viral life cycle, it is proposed that the viral genome is actively segregated into daughter nuclei, ensuring viral replication in the subsequent S phase. The E2 protein potentially bridges the viral and host genomes during mitosis to mediate segregation of the circular viral plasmid. Here, we demonstrate that E2 has the ability to mediate plasmid segregation, and that this function is dependent upon interaction with the host protein TopBP1. Additionally, we demonstrate that the E2-TopBP1 interaction promotes enhanced E2 expression during mitosis which likely promotes the plasmid segregation function of E2. Overall, our results present a mechanism of how HPV16 can segregate its viral genome during an active infection, a critical aspect of the viral life cycle.
Evolution of β-lactamase mediated cefiderocol resistance
Authors: Fröhlich Christopher , Sørum Vidar , Tokuriki Nobuhiko , Johnsen Pål Jarle , Samuelsen Ørjan
Published: January 2022

Cefiderocol is a novel siderophore β-lactam with improved hydrolytic stability toward β-lactamases, including carbapenemases, achieved by combining structural moieties of two clinically efficient cephalosporins, ceftazidime and cefepime. Consequently, cefiderocol represents a treatment alternative for infections caused by multi-drug resistant Gram-negatives. Using directed evolution on a wide variety of different β-lactamases, such as KPC-2 and CTX-M-15 (Ambler class A), NDM-1 (class B), CMY-2 (class C) and OXA-48 (class D), we studied the role of cefiderocol during β-lactamase-mediated resistance development. First, we investigated how the expression of different β-lactamases causes changes in cefiderocol susceptibility. In a low-copy number vector, we found that OXA-48 and KPC-2 conferred non or marginal decreases in cefiderocol susceptibility, respectively. On the contrary, CMY-2, CTX-M-15 and NDM-1 substantially decreased cefiderocol susceptibility by 16-, 8- and 32-fold, respectively. Second, we determined the evolutionary potential of these enzymes to adapt to increasing concentrations of cefiderocol. Our data show that with the acquisition of only 1 to 2 mutations, all β-lactamases were evolvable to further cefiderocol resistance by 2- (NDM-1, CTX-M-15), 4- (CMY-2), 8- (OXA-48) and 16-fold (KPC-2). Cefiderocol resistance development was often associated with collateral susceptibility changes including increased resistance to ceftazidime and ceftazidime-avibactam as well as functional trade-offs against different β-lactam drugs. Taken together, contemporary β-lactamases of all Ambler classes can potentially contribute to cefiderocol resistance development and can acquire mutations allowing them to adapt to increasing cefiderocol concentration. At the same time, resistance development caused clinically important cross-resistance, especially against ceftazidime combinations.

Despite the reported higher stability of cefiderocol against β-lactamase hydrolysis, we show that the expression of β-lactamases from different Ambler classes significantly contributes to cefiderocol resistance and that these enzymes have the evolutionary potential to evolve towards increasing cefiderocol concentrations.