bluuebunny/crossref_metadata_2025 huggingface dataset:
Predictors of COVID-19 vaccination uptake and reasons for decline of vaccination: a systematic review
Authors: Galanis Petros , Vraka Irene , Siskou Olga , Konstantakopoulou Olympia , Katsiroumpa Aglaia , Kaitelidou Daphne
Published: July 2021

Background

Various COVID-19 vaccines with proven safety and effectiveness are available now but vaccine hesitancy remains a public threat. COVID-19 vaccines uptake appears to have an essential role in the successful control of the COVID-19 pandemic.

Objective

To examine predictors of COVID-19 vaccination uptake and reasons for decline of vaccination.

Methods

We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines for this systematic review. We searched Medline, PubMed, Web of Science, Scopus, ProQuest, CINAHL, and a pre-print service (medRxiv) from inception to July 12, 2021. We used the following key-words: vaccin*, COVID-19, and uptake. We included all types of studies (quantitative, qualitative, and mixed methods) reporting COVID-19 vaccination uptake. The review protocol was registered with PROSPERO (CRD42021267460).

Results

Twelve studies met the inclusion and exclusion criteria. COVID-19 vaccination uptake ranged from 28.6% to 98% in the general population, while among healthcare workers ranged from 33.3% to 94.5%, and among patients ranged from 36% to 80%. The main predictors of COVID-19 vaccination uptake were male gender, white race, older age, higher socioeconomic status, higher self-perceived COVID-19 vulnerability, increased information about COVID-19 vaccines, and chronic illness. The most important reasons for decline of vaccination were concerns about the safety and effectiveness of vaccines, illness, medication, pregnancy, fertility, breastfeeding, religious reasons, ethical reasons, previous COVID-19 diagnosis, self-estimation that COVID-19 is not a severe disease, and limited knowledge about the vaccines.

Conclusions

Several factors affect COVID-19 vaccination uptake, while various reasons affect people’s decision to refuse to take a COVID-19 vaccine. These findings are essential to further enhance our understanding of COVID-19 vaccination uptake and design specific interventions. Given the high prevalence of COVID-19 vaccine hesitancy, our findings have major implications for the delivery of COVID-19 vaccination programmes in the public with special attention to people who are undecided or unlikely to take a COVID-19 vaccine.
Motivators and barriers to research participation for individuals with cerebral palsy and their families
Authors: Zvolanek Kristina M. , Goyal Vatsala , Hruby Alexandra , Ingo Carson , Sukal-Moulton Theresa
Published: July 2021

Objective(s)

Our objective was to investigate the motivators and barriers associated with the individual or family decision to participate in cerebral palsy research. Based on this information, we offer suggestions to increase the likelihood of participation in future CP studies.

Methods

A digital survey was administered to stakeholders affected by cerebral palsy across the US. Our analysis focused on variables related to personal interests, travel, and study-specific elements. Statistical tests investigated the effects of responder type, cerebral palsy type, and Gross Motor Function Classification System level on travel and study-specific element variables. Recommendations were informed by responses reflecting the majority of respondents.

Results

Based on 233 responses, we found that respondents highly valued research participation (on average 88.2/100) and compensation (on average 62.3/100). Motivators included the potential for direct benefit (62.2%) and helping others (53.4%). The primary barriers to participation were schedule limitations (48.9%) and travel logistics (32.6%). Schedule limitations were especially pertinent to caregivers, while individuals with more severe cerebral palsy diagnoses reported the necessity of additional items to comfortably travel.

Conclusions

Overall, we encourage the involvement of stakeholders affected by cerebral palsy in the research process. Researchers should consider offering flexible study times, accommodating locations, and compensation for time and travel expenses. We recommend a minimum compensation of $15/hour and a maximum time commitment of 4 hours/day to respect participants’ time and increase likelihood of research participation. Future studies should track how attitudes toward research change with time and experience.
Emerging and Continuing Trends in Opioid Overdose Decedent Characteristics during COVID-19
Authors: Garcia Gian-Gabriel P. , Stringfellow Erin J. , DiGennaro Catherine , Poellinger Nicole , Wood Jaden , Wakeman Sarah , Jalali Mohammad S.
Published: July 2021

Background

Since COVID-19 erupted in the United States, little is known about how state-level opioid overdose trends and decedent characteristics have varied throughout the country.

Objective

Investigate changes in annual overdose death rates, substances involved, and decedent demographics in opioid overdose deaths across nine states; assess whether 2019-2020 trends were emerging (i.e., change from 2019-2020 was non-existent from 2018-2019) or continuing (i.e., change from 2019-2020 existed from 2018-2019).

Design

Cross-sectional study using vital statistics data to conduct a retrospective analysis comparing 2020 to 2019 and 2019 to 2018 across nine states.

Setting

Alaska, Colorado, Connecticut, Indiana, Massachusetts, North Carolina, Rhode Island, Utah, and Wyoming.

Participants

Opioid-related overdose deaths in 2018, 2019, and 2020.

Measurements

Annual overdose death rate, proportion of overdose deaths involving specific substances, and decedent demographics (age, sex, race, and ethnicity).

Results

We find emerging increases in annual opioid-related overdose death rates in Alaska (55.3% [P=0.020]), Colorado (80.2% [P<0.001]), Indiana (40.1% [P=0.038]), North Carolina (30.5% [P<0.001]), and Rhode Island (29.6% [P=0.011]). Decreased heroin-involved overdose deaths were emerging in Alaska (−49.5% [P=0.001]) and Indiana (−58.8% [P<0.001]), and continuing in Colorado (−33.3% [P<0.001]), Connecticut (−48.2% [P<0.001]), Massachusetts (39.9% [P<0.001]), and North Carolina (−34.8% [P<0.001]). Increases in synthetic opioid presence were emerging in Alaska (136.5% [P=0.019]) and Indiana (27.6% [P<0.001]), and continuing in Colorado (44.4% [P<0.001]), Connecticut (3.6% [P<0.05]), and North Carolina (14.6% [P<0.001]). We find emerging increases in the proportion of male decedents in Colorado (15.2% [P=0.008]) and Indiana (12.0% [P=0.013]).

Limitations

Delays from state-specific death certification processes resulted in varying analysis periods across states.

Conclusion

These findings highlight emerging changes in opioid overdose dynamics across different states, which can inform state-specific public health interventions.
Clinical Determinants and Predictors for Prognosis of SARS-CoV-2 Infected Pediatric Patients in Saudi Arabia
Authors: Adam Khalid Mohamed , Elamin Bahaeldin K. , Alfaifi Jaber A. , Abbas Mohammed
Published: July 2021

Background

The significant variations in clinical characteristics and outcomes of COVID-19 that range from asymptomatic to severe fatal illness entail searching for potential prognostic determinants to help predict the disease course and early detection of patients at risk of developing life-threatening complications. Although children are less commonly infected by SARS-CoV-2 than their adult counterparts, and their symptoms are generally milder, a severe type of COVID-19 cannot be precluded.

Methods

At first, demographic, clinical, laboratory measurement data, and outcomes for 26 COVID-19 infected children of less than 12 years of age, admitted to King Abdallah Hospital, Bisha, Saudi Arabia, were retrieved from the electronic medical records for the observational retrospective study.

Later, electronic and manual database searches were carried out for pediatric severe COVID-19-related articles. The relevant data from 20 eligible studies and the present retrospective study were analyzed to assess the association of demographic characteristics and comorbidities with COVID-19 severity.

Results

In the retrospective study, 5 (19%) of the children presented with severe symptoms admitted to PICU, 18 (69%) presented with cough, 5 (19%) with diarrhea, 7 (27%) with underlying comorbidities, 4 (15%) with respiratory illnesses, 3 (12%) with cardiovascular diseases and 2 (8%) were obese. None of the patient characteristics showed any significant association with COVID-19 severity.

Of the 21 studies selected for meta-analyses, 14 studies were included in the analysis of the association between any comorbidity and disease severity, resulting in OR: 2.69, 95%CI: 1.38 – 5.26, P < 0.05, for analysis of the association between cardiovascular comorbidities and disease severity 14 studies were included giving OR: 4.06, 95%CI: 1.86 – 8.87, P < 0.05, for analysis of the association between respiratory comorbidity and disease severity 15 studies were included giving OR: 2.05, 95%CI: 1.54 – 2.74, P < 0.05, for analysis of the association between obesity and disease severity 10 studies were included, giving OR: 2.48, 95%CI: 1.16 – 5.32, P < 0.05, for analysis of the association between age <10 years old and diseases severity, 16 studies were included, giving OR: 0.80, 95%CI: 0.65 – 0.97, P < 0.05, and for analysis of the association between female gender and disease severity, 19 studies were included, giving OR: 0.83, 95%CI: 0.59 – 1.18, P > 0.05.

Conclusion

It can be concluded that COVID-19 pediatric patients with underlying comorbidities, being cardiovascular, respiratory, or obesity, are at high risk of developing severe illness, and young age has a protective role against the disease severity.
Variations in Non-Pharmaceutical Interventions by State Correlate with COVID-19 Disease Outcomes
Authors: Avery Annika J. , Wang Jiayi , Ma Xinyu , Pan Qingkai , McGrady Elizabeth E. , Yuan Zongyuan , Liang Yuqing , Nugent Rebecca , Lakdawala Seema S.
Published: July 2021

The COVID-19 pandemic highlighted the lack of understanding around effective public health interventions to curtail the spread of an emerging respiratory virus. Here, we examined the public health approaches implemented by each state to limit the spread and burden of COVID-19. Our analysis revealed that stronger statewide interventions positively correlated with fewer COVID-19 deaths, but some neighboring states with distinct intervention strategies had similar SARS-CoV-2 case trajectories. Additionally, more than two weeks is needed to observe an impact on SARS-CoV-2 cases after an intervention is implemented. These data provide a critical framework to inform future interventions during emerging pandemics.
Differential Deep Brain Stimulation Sites and Networks for Cervical vs. Generalized Dystonia
Authors: Horn Andreas , Reich Martin , Ewert Siobhan , Li Ningfei , Al-Fatly Bassam , Lange Florian , Roothans Jonas , Oxenford Simon , Horn Isabel , Paschen Steffen , Runge Joachim , Wodarg Fritz , Witt Karsten , Nickl Robert C. , Wittstock Matthias , Schneider Gerd-Helge , Mahlknecht Philipp , Poewe Werner , Eisner Wilhelm , Helmers Ann-Kristin , Matthies Cordula , Krauss Joachim K. , Deuschl Günther , Volkmann Jens , Kühn Andrea
Published: July 2021

Dystonia is a debilitating disease with few conservative treatment options but many types of isolated dystonia can be effectively treated using deep brain stimulation (DBS) to the internal pallidum.

While cervical and generalized forms of isolated dystonia have been targeted with a common approach to the posterior third of the nucleus, large-scale investigations between optimal stimulation sites and potential network effects in the two types of dystonia have not been carried out.

Here, we retrospectively investigate clinical results following DBS for cervical and generalized dystonia in a multi-center cohort of 80 patients. We model DBS electrode placement based on pre- and postoperative imaging and introduce a novel approach to map optimal stimulation sites to anatomical space. Second, we analyse stimulation in context of a detailed pathway model of the subcortex to investigate the modulation of which tracts accounts for optimal clinical improvements. Third, we investigate stimulation in context of a broad-lense whole-brain functional connectome to illustrate potential multisynaptic network effects. Finally, we construct a joint model using local, tract- and network-based effects to explain variance in clinical outcomes in cervical and generalized dystonia.

Our results show marked differences in optimal stimulation sites that map to the somatotopic structure of the internal pallidum. We further highlight that modulation of the pallidofugal main axis of the basal ganglia may be optimal for treatment of cervical dystonia, while pallidothalamic bundles account for effects in generalized dystonia. Finally, we show a common multisynaptic network substrate for both phenotypes in form of connectivity to cerebellum and somatomotor cortex.

Our results suggest a multi-level model that could account for effectivity of treatment in cervical and generalized dystonia and could potentially help guide DBS programming and surgery, in the future.
Tumor necrosis factor-α gene polymorphism is associated with short- and long-term kidney allograft outcomes
Authors: Poppelaars Felix , da Costa Mariana Gaya , Faria Bernardo , Eskandari Siawosh K. , Seelen Marc A. , Damman Jeffrey
Published: July 2021

Introduction

Kidney transplantation has excellent short-term results with current immunosuppression regimes, but long-term outcomes have barely improved. Hence, there is a need for new therapeutic options to increase long-term survival of kidney grafts. Drug development for transplantation has slowly plateaued, limiting progress while making drug repurposing an attractive alternative. We, therefore, investigated the impact of tumor necrosis factor-alpha (TNF-α) gene (TNF) polymorphisms on kidney graft survival.

Methods

We performed a prospective cohort study to assess the association of TNF polymorphisms (rs1800629 G>A and rs3093662 A>G) with primary non-function (PNF) and death-censored kidney allograft survival in 1,271 kidney transplant pairs from the University Medical Center Groningen in The Netherlands.

Results

The G-allele of the TNF rs3093662 polymorphism in donor kidneys was associated with a higher risk of PNF (odds ratio: 2.05; 95%-CI: 1.06-3.97; P = 0.032). Furthermore, the G-allele of this TNF rs3093662 polymorphism in the donor was also associated with worse 5-year, 10-year, and 15-year death-censored kidney graft survival (P < 0.05). The cumulative incidence of graft loss was 15.9% in the reference AA-genotype group and 25.2% in the AG/GG-genotype group, respectively. In multivariable analysis, the association between the TNF rs3093662 polymorphism in the donor and 15-year death-censored kidney graft survival remained significant (hazard ratio: 1.51; 95%-CI: 1.05-2.19, P = 0.028).

Conclusion

Kidney allografts possessing a high-producing TNF polymorphism have a greater risk of immediate and late graft loss. Our study adds to a growing body of literature indicating the potential of TNF-α blockade in improving kidney transplantation outcomes.
Prevalence and Time of Diagnosis of Endometriosis across Racial and Ethnic Groups in the US
Authors: Li Rui , Kreher Donna A , Gubbels Ashley L , Benjamin Amy R
Published: July 2021

Background

Endometriosis is associated with substantial adverse health and psychosocial consequences. However, the prevalence of endometriosis across different racial and ethnic groups in the US has not been established and to what extent the difference in prevalence might be associated with systemic barriers to receiving the diagnosis is unknown. We aimed to estimate the prevalence of endometriosis across different racial and ethnic groups and examine the association between race/ethnicity and the time of diagnosis

Methods

Using cross-sectional data from the National Health and Nutrition Examination Survey 1999-2006, we estimated race/ethnicity-specific prevalence of self-reported diagnosis of endometriosis among 5,557 women aged 20-54 years. Multivariable generalized linear regression model examined the association between race/ethnicity and the age of endometriosis diagnosis, accounting for socioeconomic indicators, health insurance, lifestyle and reproductive characteristics.

Results

Endometriosis was prevalent in 9.0% overall, 11.1% among non-Hispanic white, 5.8% among non-Hispanic black, 2.7% among Hispanic, and 6.4% among the other racial and ethnic groups combined. The mean age of endometriosis diagnosis was 29.0 years (range 13-52). Compared with non-Hispanic white, non-Hispanic black women were diagnosed on average at 2.6 years older (95% confidence interval [CI], 0.5-4.6), Hispanic women 3.8 years older (95% CI 1.5-6.2), and women in the other group 1.0 years younger (95% CI, -4.6 to 2.5).

Conclusions

Prevalence of endometriosis varied across different racial and ethnic groups Among women with a diagnosis of endometriosis, black and Hispanic women were diagnosed at older ages than non-Hispanic white women. Future research is needed to determine whether such age disparity in endometriosis diagnosis persists.
Development and validation of a multimodal neuroimaging biomarker for electroconvulsive therapy outcome in depression: a multicenter machine learning analysis
Authors: Bruin Willem B. , Oltedal Leif , Bartsch Hauke , Abbott Christopher C. , Argyelan Miklos , Barbour Tracy , Camprodon Joan A. , Chowdhury Samadrita , Espinoza Randall , Mulders Peter C. R. , Narr Katherine L. , Oudega Mardien L. , Rhebergen Didi , ten Doesschate Freek , Tendolkar Indira , van Eijndhoven Philip , van Exel Eric , van Verseveld Mike , Wade Benjamin , van Waarde Jeroen , Zhutovsky Paul , Dols Annemiek , van Wingen Guido A.
Published: July 2021

Background

Electroconvulsive therapy (ECT) is the most effective intervention for patients with treatment resistant depression. A clinical decision support tool could guide patient selection to improve the overall response rate and avoid ineffective treatments with adverse effects. Initial small-scale, mono-center studies indicate that both structural magnetic resonance imaging (sMRI) and functional MRI (fMRI) biomarkers may predict ECT outcome, but it is not known whether those results can generalize to data from other centers.

Objective

To develop and validate neuroimaging biomarkers for ECT outcome in a multi-center setting.

Methods

Multimodal data (i.e., clinical, sMRI and resting-state fMRI) was collected from seven centers of the Global ECT-MRI Research Collaboration (GEMRIC). We used data from 189 depressed patients to evaluated which data modalities or combinations thereof could provide the best predictions for treatment response (≥50% symptom reduction) or remission (HAM-D score ≤7) using a support vector machine classifier.

Results

Remission classification using a combination of gray matter volume and functional connectivity led to good performing models with average 0.82-0.83 area under the curve (AUC) when trained and tested on samples coming from the three largest centers, and remained acceptable when validated using leave-one-site-out cross-validation (0.70-0.73 AUC).

Conclusions

These results show that multimodal neuroimaging data is able to provide good prediction of remission with ECT for individual patients across different treatment centers, despite significant variability in clinical characteristics across centers. This suggests that these biomarkers are robust, indicating that future development of a clinical decision support tool applying these biomarkers may be feasible.
Photosensitized Electrospun Nanofibrous Filters for Capturing and Killing Airborne Coronaviruses under Visible Light Irradiation
Authors: Shen Hongchen , Zhou Zhe , Wang Haihuan , Zhang Mengyang , Han Minghao , Shen Yun , Shuai Danmeng
Published: July 2021

To address the challenge of the airborne transmission of SARS-CoV-2, photosensitized electrospun nanofibrous membranes were fabricated to effectively capture and inactivate coronavirus aerosols. With an ultrafine fiber diameter (∼ 200 nm) and a small pore size (∼ 1.5 µm), the optimized membranes caught 99.2% of the aerosols of the murine hepatitis virus A59 (MHV-A59), a coronavirus surrogate for SARS-CoV-2. In addition, rose bengal was used as the photosensitizer for the membranes because of its excellent reactivity in generating virucidal singlet oxygen, and the membranes rapidly inactivated 98.9% of MHV-A59 in virus-laden droplets only after 15 min irradiation of simulated reading light. Singlet oxygen damaged the virus genome and impaired virus binding to host cells, which elucidated the mechanism of disinfection at a molecular level. Membrane robustness was also evaluated, and no efficiency reduction for filtering MHV-A59 aerosols was observed after the membranes being exposed to both indoor light and sunlight for days. Nevertheless, sunlight exposure photobleached the membranes, reduced singlet oxygen production, and compromised the performance of disinfecting MHV-A59 in droplets. In contrast, the membranes after simulated indoor light exposure maintained their excellent disinfection performance. In summary, photosensitized electrospun nanofibrous membranes have been developed to capture and kill airborne environmental pathogens under ambient conditions, and they hold promise for broad applications as personal protective equipment and indoor air filters.

Synopsis

Photosensitized electrospun nanofibrous filters with excellent capture-and-kill performance against coronaviruses were designed and implemented to prevent the airborne transmission of COVID-19.

Table of Contents
Accuracy verification of low-cost CO2 concentration measuring devices for general use as a countermeasure against COVID-19
Authors: Ishigaki Yo , Enoki Koji , Yokogawa Shinji
Published: July 2021

Within the context of the COVID-19 pandemic, CO2 sensors that measure ventilation conditions and thereby reduce the risk of airborne infection, are gaining increasing attention. We investigated and verified the accuracy of 12 relatively low-cost sensor models that retail for less than $45 and are advertised as infection control measures on a major e-commerce site. Our results indicate that 25% of the tested sensors can be used to identify trends in CO2 concentration, if correctly calibrated. However, 67% of sensors did not respond to the presence of CO2, which suggests that a type of pseudo-technique is used to display the CO2 concentration. We recommend that these sensors are not suitable for infection prevention purposes. We also found that all 67% of the sensors that did not respond to CO2 responded strongly to alcohol. Owing to the widespread use of alcohol in preventing the spread of infectious diseases, sensors that react to alcohol can display inaccurate values, resulting in inappropriate ventilation behavior. Therefore, we strongly recommended that these sensors not be used. Based on our results, we offer practical recommendations to the average consumer, who does not have special measuring equipment, on how to identify inaccurate CO2 sensors.
Epigenetic Divergence during Early Stages of Speciation in an African Crater Lake Cichlid Fish
Authors: Vernaz Grégoire , Hudson Alan G. , Emília Santos M. , Fischer Bettina , Carruthers Madeleine , Shechonge Asilatu H. , Gabagambi Nestory P. , Tyers Alexandra M. , Ngatunga Benjamin P. , Malinsky Milan , Durbin Richard , Turner George F. , Genner Martin J. , Miska Eric A.
Published: July 2021

Epigenetic variation can alter transcription and promote phenotypic divergence between populations facing different environmental challenges. Here we assess the epigenetic basis of diversification during the early stages of speciation. We focus on the extent and functional relevance of DNA methylome divergence between two Astatotilapia calliptera ecomorphs in crater Lake Masoko, southern Tanzania. We report extensive genome-wide methylome divergence between populations linked to key biological processes, including transcriptional activity of ecologically-relevant genes. These include genes involved in steroid metabolism, haemoglobin composition and erythropoiesis, consistent with divergent habitat occupancy of the ecomorphs. Using a common garden experiment, we found that global methylation profiles are rapidly remodelled across generations, but ecomorph-specific differences can be inherited. Collectively, our study suggests an epigenetic contribution to early stages of vertebrate speciation.

One sentence summary

Inheritance and plasticity of epigenetic divergence characterise early stages of speciation in an incipient cichlid species of an African crater lake.
Mice with High FGF21 Serum Levels Had a Reduced Preference for Morphine and an Attenuated Development of Acute Antinociceptive Tolerance and Physical Dependence
Authors: Dorval Louben , Knapp Brian I. , Majekodunmi Olufolake A. , Eliseeva Sophia , Bidlack Jean M.
Published: July 2021

Because of increased opioid misuse, there is a need to identify new targets for minimizing opioid tolerance, and physical and psychological dependence. Previous studies showed that fibroblast growth factor 21 (FGF21) decreased alcohol and sweet preference in mice. In this study, FGF21-transgenic (FGF21-Tg) mice, expressing high FGF21 serum levels, and wildtype (WT) C57BL/6J littermates were treated with morphine and saline to determine if differences exist in their physiological and behavioral responses to opioids. FGF21-Tg mice displayed reduced preference for morphine in the conditioned place preference assay compared to WT littermates. Similarly, FGF21-Tg mice had an attenuation of the magnitude and rate of acute morphine antinociceptive tolerance development, and acute and chronic morphine physical dependence, but exhibited no change in chronic morphine antinociceptive tolerance. The ED50 values for morphine-induced antinociception in the 55°C hot plate and the 55°C warm-water tail withdrawal assays were similar in both strains of mice. Likewise, FGF21-Tg and WT littermates had comparable responses to morphine-induced respiratory depression. Overall, FGF21-Tg mice had a decrease in the development of acute analgesic tolerance, and the development of physical dependence, and morphine preference. FGF21 and its receptor have therapeutic potential for reducing opioid withdrawal symptoms and craving, and augmenting opioid therapeutics for acute pain patients to minimize tolerance development.
Activation of M1muscarinic receptors reduce pathology and slow progression of neurodegenerative disease
Authors: Dwomoh Louis , Rossi Mario , Scarpa Miriam , Khajehali Elham , Molloy Colin , Herzyk Pawel , Mistry Shailesh N. , Bottrill Andrew R. , Sexton Patrick M. , Christopoulos Arthur , Conn P. Jeffery , Lindsley Craig W. , Bradley Sophie J. , Tobin Andrew B.
Published: July 2021

The most prevalent types of dementias, including Alzheimer’s disease, are those that are propagated via the spread of“prion-like”misfolded proteins. Despite considerable effort no treatments are available to slow or stop the progression of these dementias. Here we investigate the possibility that activation of the M1-muscarinic receptor (M1-receptor), which is highly expressed in the brain and that shows pro-cognitive properties, might present a novel disease modifying target. We demonstrate that the progression of murine prion disease, which we show here displays many of the pathological, behavioural and biochemical hallmarks of human neurodegenerative disease, is slowed and normal behaviour maintained by the activation of the M1-receptor with a highly tolerated positive allosteric modulator (VU846). This correlates with a reduction in both neuroinflammation and indicators of mitochondrial dysregulation, as well as a normalisation in the expression of markers associated with neurodegeneration and Alzheimer’s disease. Furthermore, VU846 preserves expression of synaptic proteins and post-synaptic signalling components that are altered in disease. We conclude that allosteric regulation of M1-receptors has the potential to reduce the severity of neurodegenerative diseases caused by theprion-likepropagation of misfolded protein in a manner that extends life span and maintains normal behaviour.
Identification and characterization of novel mutants of Nsp13 protein among Indian SARS-CoV-2 isolates
Authors: Kumari Deepa , Kumari Namrata , Kumar Sudhir , Sinha Prabhat Kumar , Shahi Shivendra Kumar , Biswas Nihar Ranjan , Kumar Abhay
Published: July 2021

SARS-CoV-2, the causative agent of COVID-19 has mutated rapidly which enabled them to adapt and evade the immune system of the host. Emerging SARS-CoV-2 variants with crucial mutations pose a global challenge in context of therapeutic drugs and vaccines being developed globally. There are currently no specific therapeutics or vaccines available to combat SARS-CoV-2 devastation. In view of this, the current study aimed to identify and characterize the mutations found in the Nsp13 of SARS-CoV-2 in Indian isolates. Non-structural protein, Nsp13 protein sequences from Indian isolates were analyzed by comparing with the first reported Severe acute respiratory syndrome Corona Virus-2 (SARS-CoV-2) protein sequence from Wuhan, China. Out of 825 Nsp13 protein sequences, a total of 38 mutations were observed among Indian isolates. Our data show that mutations in Nsp13 at various positions (H164Y, A237T, T214I, C309Y, S236I, P419S, V305E, G54S, H290Y, P53S, A308Y, and A308Y) have a significant impact on the protein’s stability and flexibility. Also, the impact of Nsp13 mutations on the protein function were predicted based on PROVEAN score that includes 15 mutants as neutral and 23 mutants as deleterious effect. Furthermore, B-cell epitopes contributed by Nsp13 were identified using various predictive immunoinformatic tools. Immunological Parameters of Nsp13 such as antigenicity, allergenicity and toxicity were evaluated to predict the potential B-cell epitopes. The predicted peptide sequences were correlated with the observed mutants. Our predicted data showed that there are seven high rank linear epitopes as well as 18 discontinuous B-cell epitopes based on immunoinformatic tools. Moreover, it was observed that out of total 38 identified mutations among Indian SARS-CoV-2 Nsp13 protein, four mutant residues at position 142 (E142), 245 (H245), 247 (V247) and 419 (P419) are localised in the predicted B cell epitopic region. Altogether, the results of the present in-silico study might help to understand the impact of the identified mutations in Nsp13 protein on its stability, flexibility and function.
AtpΘ is an inhibitor of F0F1 ATP synthase to arrest ATP hydrolysis during low-energy conditions in cyanobacteria
Authors: Song Kuo , Baumgartner Desirée , Hagemann Martin , Muro-Pastor Alicia M. , Maaß Sandra , Becher Dörte , Hess Wolfgang R.
Published: July 2021

Biological processes in all living cells are powered by ATP, a nearly universal molecule of energy transfer. ATP synthases produce ATP utilizing proton gradients that are usually generated by either respiration or photosynthesis. However, cyanobacteria are unique in combining photosynthetic and respiratory electron transport chains in the same membrane system, the thylakoids. How cyanobacteria prevent the futile reverse operation of ATP synthase under unfavorable conditions pumping protons while hydrolyzing ATP is mostly unclear. Here, we provide evidence that the small protein AtpΘ, which is widely conserved in cyanobacteria, is mainly fulfilling this task. The expression of AtpΘ becomes induced under conditions such as darkness or heat shock, which can lead to a weakening of the proton gradient. Translational fusions of AtpΘ to the green fluorescent protein revealed targeting to the thylakoid membrane. Immunoprecipitation assays followed by mass spectrometry and far Western blots identified subunits of ATP synthase as interacting partners of AtpΘ. ATP hydrolysis assays with isolated membrane fractions as well as purified ATP synthase complexes demonstrated that AtpΘ inhibits ATPase activity in a dose-dependent manner similar to the F0F1-ATP synthase inhibitor N,N-dicyclohexylcarbodimide. The results show that, even in a well-investigated process, crucial new players can be discovered if small proteins are taken into consideration and indicate that ATP synthase activity can be controlled in surprisingly different ways.
Lipid flippase dysfunction as a novel therapeutic target for endosomal anomalies in Alzheimer’s disease
Authors: Kaneshiro Nanaka , Komai Masato , Imaoka Ryosuke , Ikeda Atsuya , Kamikubo Yuji , Hashimoto Tadafumi , Iwatsubo Takeshi , Sakurai Takashi , Uehara Takashi , Takasugi Nobumasa
Published: July 2021

β-amyloid precursor protein (APP) and their metabolites are deeply involved in the development of Alzheimer’s disease (AD). Upon the upregulation of β-site APP cleaving enzyme 1 (BACE1), its product, the β-carboxyl-terminal fragment of APP (βCTF), is accumulated in the early stage of sporadic AD brains. βCTF accumulation is currently considered the trigger for endosomal anomalies to form enlarged endosomes, one of the earliest pathologies in AD. However, the details of the underlying mechanism remain largely unclear. In this study, using BACE1 stably-overexpressing cells, we describe that lipid flippase subcomponent TMEM30A interacts with accumulated βCTF. Among the lipid flippases in endosomes, those composed of TMEM30A and active subcomponent ATP8A1 transports phospholipid, phosphatidylserine (PS), to the cytosolic side of the endosomes. The lipid flippase activity and cytosolic PS distribution are critical for membrane fission and vesicle transport. Intriguingly, accumulated βCTF in model cells impaired lipid flippase physiological formation and activity, along with endosome enlargement. Moreover, in the brains of AD model mice before the amyloid-β (Aβ) deposition, the TMEM30A/βCTF complex formation occurred, followed by lipid flippase dysfunction. Importantly, our novel Aβ/βCTF interacting TMEM30A-derived peptide “T-RAP” improved endosome enlargement and reduced βCTF levels. These T-RAP effects could result from the recovery of lipid flippase activity. Therefore, we propose lipid flippase dysfunction as a key pathogenic event and a novel therapeutic target for AD.
Molecular dissection of carbapenem-resistant Acinetobacter baumannii circulating in Indian hospitals using Whole Genome Sequencing
Authors: Rose Steffimol , Shamanna Varun , Underwood Anthony , Nagaraj Geetha , Prasanna Akshatha , Govindan Vandana , Dharmavaram Sravani , Shincy M R , Argimón Silvia , Abrudan Monica , Aanensen David M , Ravikumar K. L.
Published: July 2021

Objectives

Carbapenem-resistant Acinetobacter baumannii (CRAB) has acquired worldwide recognition as a serious nosocomial infection. It poses a concern to hospitalized patients because of the limited therapeutic options available. Thus, we investigated the molecular epidemiology and antibiotic resistance profiles of A. baumannii isolates in India.

Materials and Methods

We characterized 306 retrospective A. baumannii clinical isolates collected from 18 centers across 10 states and 1 Union Territory of India between 2015 and 2019. Molecular epidemiology, and carbapenem resistance were studied by Whole Genome Sequencing.

Results

A total of 105 different Sequence Types (STs) were identified including 48 reported STs and 57 Novel STs. 99 isolates were classified into Clonal Complex 451 (CC451) among which ST848 and ST1956 were the common STs. Carbapenemase resistance was confirmed in all the isolates with the presence of intrinsic blaOXA-51-like genes, and the acquired blaOXA-23 and blaNDM-1 genes.

Conclusion

Most of the isolates were grouped under clonal complex 451. ST1053 caused an outbreak in Northern India during 2018 and 2019. Novel MLST alleles and STs were also detected, underlining an evolutionary divergence in India. The carbapenem-resistance was dominated by OXA-type carbapenemases and further surveillance of these carbapenem-resistant A. baumannii and antimicrobial stewardship should be strengthened.
Modeling the mechanics of growing epithelia with a bilayer plate theory
Authors: Ackermann Joseph , Qu Paul-Qiuyang , LeGoff Loïc , Amar Martine Ben
Published: July 2021

Epithelia, which consists of cell sheets lying on a substrate, are prevalent structures of multi-cellular organisms. The physical basis of epithelial morphogenesis has been intensely investigated in recent years. However, as 2D mechanics focused most attention, we still lack a rigorous description of how the mechanical interactions between the cell layer and its substrate can lead to 3D distortions. This work provides a complete description of epithelial mechanics using the most straightforward model of an epithelium: a thin elastic bilayer. We first provide experimental evidence inDrosophilatissues that localized alterations of the cell-substrate (the extracellular matrix) can lead to profound 3D shape changes in epithelia. We then develop an analytical model modifying the Föppl-von Kármán equation with growth for bilayers. We provide a complete description of all contributions from biophysical characteristics of epithelia. We show how any localized inhomogeneity of stiffness or thickness drastically changes the bending process when the two layers grow differently. Comparison with finite-element simulations and experiments performed onDrosophilawing imaginal discs validate this approach for thin epithelia.
PROTECTIVE ROLE FOR SMOOTH MUSCLE CELL HEPCIDIN IN ABDOMINAL AORTIC ANEURYSM
Authors: Loick P , Mohammad G , Cassimjee I , Chandrashekar A , Lapolla P , Carrington A , Handa A , Lee R , Lakhal-Littleton S
Published: July 2021

Rationale

Hepcidin (HAMP) is a hormone produced primarily in the liver. It controls systemic iron homeostasis by inhibiting the iron exporter ferroportin (FPN) in the gut and spleen, respective sites of iron absorption and recycling. HAMP and FPN are also found ectopically in tissues not involved in systemic iron homeostasis. The physiological functions of ectopic HAMP and FPN are only just beginning to be uncovered. We observed that HAMP expression is markedly increased in smooth muscle cells (SMCs) of abdominal aortic aneurysms (AAA), both in patients and in an experimental mouse model of AAA.

Objective

To understand the role of SMC-derived HAMP in the pathophysiology of AAA.

Methods and Results

We generated mice harbouring an inducible, SMC-specific deletion of the hamp gene. We then applied the experimental model of AAA and simultaneously induced deletion of hamp in SMCs. We found that these mice developed large aneurysms and had greater incidences of rupture and of fatal dissection than mice with intact hamp in SMCs. A similar phenotype was observed in mice harbouring an inducible SMC-specific knock-in of HAMP-resistant FPNC326Y. Additionally, we observed that expression of Lipocalin-2 (LCN2), a protein known to promote AAA, was suppressed in AAA tissue from patients and from mice with intact hamp in SMCs, but not in mice lacking hamp in SMCs. Treatment of these mice with a LCN2-neutralising antibody protected them from the otherwise detrimental effects of loss of hamp in SMCs.

Conclusions

The present study demonstrates that the rise in SMC-derived HAMP within the aneurysm tissue is protective in the setting of AAA, and that such protection involves the cell-autonomous action of HAMP, and suppression of local LCN2. These findings are the first example of a protective role for ectopic HAMP in disease. They expand understanding of the multifaceted functions of HAMP outside the liver.
Two step aggregation kinetics of Amyloid-β proteins from fractal analysis
Authors: Mukhopadhyay Soham , Bera Subhas C. , Ramola Kabir
Published: July 2021

Self-aggregation in proteins has long been studied and modeled due to its ubiquity and importance in many biological contexts. Several models propose a two step aggregation mechanism, consisting of linear growth of fibrils and branch formation. Single molecule imaging techniques such as total internal reflection fluorescence (TIRF) microscopy can provide direct evidence of such mechanisms, however, analyzing such large datasets is challenging. In this paper, we analyze for the first time, images of growing amyloid fibrils obtained from TIRF microscopy using the techniques of fractal geometry, which provides a natural framework to disentangle the two types of growth mechanisms at play. We find that after an initial linear growth phase, identified by a plateau in the average fractal dimension with time, the occurrence of branching events leads to a further increase in the fractal dimension with a final saturation value ≈ 2. We also simulate the aggregation process using the identified linear growth and secondary nucleation mechanisms, using an event driven algorithm. We theoretically model this system using a set of coupled nonlinear differential equations describing a mean field model for branching and linear growth, which we use to characterize the growth process observed in simulations as well as experiments. Finally, we provide estimates for the parameter regimes that govern the two step aggregation process observed in experiments.
Genomic and chemical decryption of the Bacteroidetes phylum for its potential to biosynthesize natural products
Authors: Brinkmann Stephan , Kurz Michael , Patras Maria A. , Hartwig Christoph , Marner Michael , Leis Benedikt , Billion André , Kleiner Yolanda , Bauer Armin , Toti Luigi , Pöverlein Christoph , Hammann Peter E. , Vilcinskas Andreas , Glaeser Jens , Spohn Marius S. , Schäberle Till F.
Published: July 2021

With progress in genome sequencing and data sharing, 1000s of bacterial genomes are publicly available. Genome mining – using bioinformatics tools in terms of biosynthetic gene cluster (BGC) identification, analysis and rating – has become a key technology to explore the capabilities for natural product (NP) biosynthesis. Comprehensively, analyzing the genetic potential of the phylum Bacteroidetes revealed Chitinophaga as the most talented genus in terms of BGC abundance and diversity. Guided by the computational predictions, we conducted a metabolomics and bioactivity driven NP discovery program on 25 Chitinophaga strains. High numbers of peerless strain-specific metabolite buckets confirmed the upfront predicted biosynthetic potential and revealed a tremendous uncharted chemical space. Sourcing this dataset, we isolated the new iron chelating nonribosomally-synthesized cyclic tetradeca- and pentadecalipodepsipeptide antibiotics chitinopeptins with activity against Candida, produced by C. eiseniae DSM 22224 and C. flava KCTC 62435, respectively.

Teaser

Combination of omics-technologies revealed taxonomical hotspots for specialized metabolites within Bacteroidetes.
A fluorescent sensor for the real-time measurement of extracellular oxytocin dynamics in the brain
Authors: Ino Daisuke , Hibino Hiroshi , Nishiyama Masaaki
Published: July 2021

Oxytocin (OT), a hypothalamic neuropeptide that acts as a neuromodulator in the brain, orchestrates a variety of animal behaviors. However, the relationship between brain OT dynamics and complex animal behaviors remains largely elusive, partly because of the lack of a suitable technique for its real-time recording in vivo. Here, we describe MTRIAOT, a G protein-coupled receptor-based green fluorescent OT sensor with a large dynamic range, optimal affinity, ligand specificity to OT orthologs, minimal effects on downstream signaling, and long-term fluorescence stability. By combining viral gene delivery and fiber photometry-mediated fluorescence measurements, we demonstrated the utility of MTRIAOT for real-time detection of brain OT dynamics in living mice. Importantly, MTRIAOT-mediated measurements revealed “OT oscillation,” a hitherto unknown rhythmic change in OT levels in the brain. MTRIAOT will allow the analysis of OT dynamics in a wide variety of physiological and pathological processes.
Reduced glutathione decreases cell adhesion and increases cell volume
Authors: Géloën Alain , Berger Emmanuelle
Published: July 2021

Glutathione is the most abundant thiol in animal cells. Reduced glutathione (GSH) is a major intracellular antioxidant neutralizing free radicals and detoxifying electrophiles. It plays important roles in many cellular processes, including cell differentiation, proliferation, and apoptosis. In the present study we demonstrate that extracellular concentration of reduced glutathione markedly increases cell volume within few hours, in a dose-response manner. Pre-incubation of cells with BSO, the inhibitor of γ-glutamylcysteine synthetase, responsible for the first step in intracellular glutathione synthesis did not change the effect of reduced glutathione on cell volume suggesting a mechanism limited to the interaction of extracellular reduced glutathione on cell membrane. Similarly, inhibition of γ-glutamylcyclotransferase involved in intracellular glutamate production had no effect on the action of reduced glutathione. Oxidized glutathione exerted no effect on cell volume. Results show that reduced GSH decreases cell adhesion resulting in an increased cell volume. Since many cell types are able to export GSH, the present results suggest that this could be a fundamental self-regulation of cell volume, giving the cells a self-control on their adhesion proteins.
Directed biosynthesis of fluorinated polyketides
Authors: Rittner Alexander , Joppe Mirko , Schmidt Jennifer J. , Mayer Lara Maria , Heid Elia , Sherman David H. , Grininger Martin
Published: July 2021

Modification of polyketides with fluorine offers a promising approach to develop new pharmaceuticals. While synthetic chemical methods for site-specific incorporation of fluorine in complex molecules have improved in recent years, approaches for the direct biosynthetic fluorination of natural compounds are still rare. Herein, we present a broadly applicable approach for site-specific, biocatalytic derivatization of polyketides with fluorine. Specifically, we exchanged the native acyltransferase domain (AT) of a polyketide synthase (PKS), which acts as the gatekeeper for selection of extender units, with an evolutionarily related but substrate tolerant domain from metazoan type I fatty acid synthase (FAS). The resulting PKS/FAS hybrid can utilize fluoromalonyl coenzyme A and fluoromethylmalonyl coenzyme A for polyketide chain extension, introducing fluorine or fluoro-methyl disubstitutions in polyketide scaffolds. Addition of a fluorine atom is often a decisive factor toward developing superior properties in next-generation antibiotics, including the macrolide solithromycin. We demonstrate the feasibility of our approach in the semisynthesis of a fluorinated derivative of the macrolide antibiotic YC-17.