bluuebunny/crossref_metadata_2025 huggingface dataset:
Burkitt lymphoma: Age Specific Fertility Rate in 113 long-term female survivors after treatment with cyclophosphamide
Authors: Hesseling PhD Peter B , Afungchwi MSc Glenn M , Njamshi Dip. Nursing Vera , Kruger PhD Mariana , Kimbi Dip Nursing Comfort , Nfor BSc Patience , Wharin MD Paul , Draper MSc Heather , Kouya MD Francine
Published: February 2021

Introduction

Reduced fertility risk is a risk in females treated with a high cumulative cyclophosphamide (CPM) dose.

Objectives

The objective of this study is to establish the age at menarche, record all pregnancies, calculate age-specific fertility rate (ASFR) in female BL survivors, treated in Cameroon, in the age groups 15–19 and 20–24 years, and association with an increasing cumulative CPM dose.

Methods

Data collection included personal data and telephone interviews for female survivors, aged ≥12 years with regards to menarche age, their mothers’ menarche age, incidence and outcome of all pregnancies. The cumulative CPM/m2 dose was categorized as low (<4723 mg/m2), medium (4724–10 635 mg/m/2) or high (>10 635 mg/m2).

Results

The median age at first treatment for 113 patients was 8 years (range 3–17 years), with median current age 17 years (range 12–26 years); the median duration of follow-up was 9 years (range 1.2–13.3 years). The median age of patients at menarche (n = 109; 4 unknown) was 14 years (range 10–17 years, SD 1.19) and that of their mothers (n = 68; 45 unknown) 15 years (range 10–17 years, SD 1.53). The median time to first pregnancy following menarche (the fertility time) was 3.04 years (n = 10) with low-dose CPM, 6.09 years with medium-dose CPM (n = 81) and 6.04 years with high-dose CPM (n = 32) (log rank difference p = 0.420). The ASFR in the age group 15–19 years was 82.19 (n = 73) and in the age group 20–24 years was 863.6 (n = 22), with significantly lower ASFR (p > 0.001) in children treated before the age of 10 years.

Conclusion

Fertility rates of girls treated for BL with CPM were normal but reduced in patients who commenced treatment before the age of 10 years.
COVID-19 and international sale contracts: unprecedented grounds for exemption or business as usual?
Authors: Janssen André , Wahnschaffe Christian Johannes
Published: February 2021

The year 2020 has witnessed a health crisis of unparalleled dimensions that has triggered ongoing complications on a global scale. Through restrictions on economic activities and disruptions in supply chains, COVID-19 has severely impeded global trade. Among the ensuing problems, the question of excusing a party’s failure to perform its contractual obligations is of key interest. This contribution analyses the conditions for exemption from liability with view to contracts for the international sale of goods subject to the 1980 UN Convention on Contracts for the International Sale of Goods. It revisits the statutory requirements and illustrates COVID-19 scenarios that might satisfy the relevant thresholds. This article further examines the particular legal consequences following from an exemption from liability, including the controversial discussion as to the adequate remedies in cases of economic hardship. Finally, this contribution addresses the newly revised International Chamber of Commerce’s clauses on force majeure and hardship.
Sir Peter Mansfield. 9 October 1933—8 February 2017
Authors: Morris P. G.
Published: February 2021

Peter Mansfield's rise from humble origins to founding father of magnetic resonance imaging (MRI) is an inspirational and remarkable story. His first scientific contributions were in the field of solid state nuclear magnetic resonance (NMR), and it was whilst trying to develop an NMR version of X-ray crystallography that he developed the underpinning methodology for MRI. At that time (the early 1970s) NMR was an analytical tool, ubiquitous in chemistry departments. For most of those working in the field, there was no hint that it could be developed into a diagnostic imaging technique that would reveal internal anatomy in unprecedented detail. Yet that was what happened in the space of just a few years. The first MRI scans were slow, and Peter was driven to speed them up, making physiological and later functional brain imaging studies possible. The technical challenges were many, and eschewed by healthcare equipment providers, but Peter persisted and his brainchild, echo-planar imaging, came to dominate the high speed MRI field. Peter was a gifted physicist and archetypal inventor who devoted his life to the development of a technique that has saved millions of lives. In 2003, he shared the Nobel Prize for Physiology or Medicine, in recognition of his achievement.
Alterations of the endocannabinoid system and its therapeutic potential in autism spectrum disorder
Authors: Zou Mingyang , Liu Yu , Xie Shu , Wang Luxi , Li Dexin , Li Ling , Wang Feng , Zhang Yujue , Xia Wei , Sun Caihong , Wu Lijie
Published: February 2021

Autism spectrum disorder (ASD) is a group of developmental disabilities, the aetiology of which remains elusive. The endocannabinoid (eCB) system modulates neurotransmission and neuronal plasticity. Evidence points to the involvement of this neuromodulatory system in the pathophysiology of ASD. We investigated whether there is a disruption to the eCB system in ASD and whether pharmacological modulation of the eCB system might offer therapeutic potential. We examined three major components of the eCB system—endogenous cannabinoids, their receptors and associated enzymes—in ASD children as well as in the valproic acid (VPA) induced animal model in autism. Furthermore, we specifically increased 2-arachidonoylglycerol (2-AG) levels by administering JZL184, a selective inhibitor of monoacylglycerol lipase which is the hydrolytic enzyme for 2-AG, to examine ASD-like behaviours in VPA-induced rats. Results showed that autistic children and VPA-induced rats exhibited reduced eCB content, increased degradation of enzymes and upregulation of CBRs. We found that repetitive and stereotypical behaviours, hyperactivity, sociability, social preference and cognitive functioning improved after acute and chronic JZL184 treatment. The major efficacy of JZL184 was observed after administration of a dosage regimen of 3 mg kg
−1
, which affected both the eCB system and ASD-like behaviours. In conclusion, a reduced eCB signalling was observed in autistic children and in the ASD animal model, and boosting 2-AG could ameliorate ASD-like phenotypes in animals. Collectively, the results suggested a novel approach to ASD treatment.
Driving forces in the origins of life
Authors: Dill K. A. , Agozzino L.
Published: February 2021

What were the physico-chemical forces that drove the origins of life? We discuss four major prebiotic ‘discoveries’: persistent sampling of chemical reaction space; sequence-encodable foldable catalysts; assembly of functional pathways; and encapsulation and heritability. We describe how a ‘proteins-first’ world gives plausible mechanisms. We note the importance of hydrophobic and polar compositions of matter in these advances.
Effects of social experience, aggressiveness and comb size on contest success in male domestic fowl
Authors: Favati Anna , Løvlie Hanne , Leimar Olof
Published: February 2021

The ability to dominate conspecifics and thereby gain access to resources depends on a number of traits and skills. Experience of dominance relationships during development is a potential source of learning such skills. We here study the importance of social experience, aggressiveness and morphological traits for competitiveness in social interactions (contest success) in male domestic fowl (Gallus gallus domesticus). We let males grow up either as a single (dominant) male or as an intermediately ranked male in a group of males, and measured their success in duels against different opponents. We found that single-raised males had lower contest success than group-raised males, and that aggression and comb size correlated positively with contest success. This indicates that experience of dominance interactions with other males increases future success in duels. We similarly studied the consequences of growing up as a dominant or subordinate in a pair of males, finding no statistically significant effect of the dominance position on contest success. Finally, we found that males were consistent over time in contest success. We conclude that social experience increases contest success in male domestic fowl, but that certain behavioural and morphological characteristics have an equal or even stronger covariation with contest success.
Effect of B-site Co substitution on the structure and magnetic properties of nanocrystalline neodymium orthoferrite synthesized by auto-combustion
Authors: Nforna Edwin Akongnwi , Tsobnang Patrice Kenfack , Fomekong Roussin Lontio , Tedjieukeng Hypolite Mathias Kamta , Lambi John Ngolui , Ghogomu Julius Numbonui
Published: February 2021

Samples of cobalt-doped neodymium orthoferrite compounds, NdCo
x
Fe
1−x
O
3
(0.0 ≤ x ≤ 0.5) were synthesized via glycine auto-combustion between 250 and 300°C and calcined at 500°C for 2 h. X-ray diffraction showed that all compounds had an orthorhombic perovskite structure with space group Pbnm. Increasing cobalt doping gradually reduced the lattice parameters and contracted the unit cell volume. Both X-ray diffraction and scanning electron microscopy showed that the particles were spherical and in the nano-sized range (19–52 nm) with pores between grains. Vibrating sample magnetometry at room temperature indicated that NdFeO
3
has a high coercive field (1950 Oe) and cobalt substitution for iron led to a decrease in the coercive field, saturation and remanent magnetization, which was as a result of decreased magnetic moments in the crystal and reduced canting of the FeO
6
octahedra. The increase in magnetization and coercive fields with increase of Co was connected to the microstructure (bond lengths and angles, defects, pores, grain boundaries) and crystallite size. The compounds NdCo
x
Fe
1−x
O
3
show antiferromagnetism with weak ferromagnetism due to uncompensated non-collinear moments. These compounds could serve as prototypes for tuning the properties of magnetic materials (ferromagnetic and antiferromagnetic) with potential applications in data storage, logic gates, switches and sensors.
Asymptotic analysis of extended two-dimensional narrow capture problems
Authors: Bressloff P. C.
Published: February 2021

In this paper, we extend our recent work on two-dimensional diffusive search-and-capture processes with multiple small targets (narrow capture problems) by considering an asymptotic expansion of the Laplace transformed probability flux into each target. The latter determines the distribution of arrival or capture times into an individual target, conditioned on the set of events that result in capture by that target. A characteristic feature of strongly localized perturbations in two dimensions is that matched asymptotics generates a series expansion in
ν
 = −1/ln
ϵ
rather than
ϵ
, 0 < 
ϵ
 ≪ 1, where
ϵ
specifies the size of each target relative to the size of the search domain. Moreover, it is possible to sum over all logarithmic terms non-perturbatively. We exploit this fact to show how a Taylor expansion in the Laplace variable
s
for fixed
ν
provides an efficient method for obtaining corresponding asymptotic expansions of the splitting probabilities and moments of the conditional first-passage-time densities. We then use our asymptotic analysis to derive new results for two major extensions of the classical narrow capture problem: optimal search strategies under stochastic resetting and the accumulation of target resources under multiple rounds of search-and-capture.
The demography of extinction in eastern North American birds
Authors: Smith Brian Tilston , Gehara Marcelo , Harvey Michael G.
Published: February 2021

Species are being lost at an unprecedented rate during the Anthropocene. Progress has been made in clarifying how species traits influence their propensity to go extinct, but the role historical demography plays in species loss or persistence is unclear. In eastern North America, five charismatic landbirds went extinct last century, and the causes of their extinctions have been heavily debated. Although these extinctions are most often attributed to post-colonial human activity, other factors such as declining ancestral populations prior to European colonization could have made these species particularly susceptible. We used population genomic data from these extinct birds and compared them with those from four codistributed extant species. We found extinct species harboured lower genetic diversity and effective population sizes than extant species, but both extinct and non-extinct birds had similar demographic histories of population expansion. These demographic patterns are consistent with population size changes associated with glacial–interglacial cycles. The lack of support for overall population declines during the Pleistocene corroborates the view that, although species that went extinct may have been vulnerable due to low diversity or small population size, their disappearance was driven by human activities in the Anthropocene.
Mastomys natalensis is a possible natural rodent reservoir for encephalomyocarditis virus
Authors: Kishimoto Mai , Hang’ombe Bernard M. , Hall William W. , Orba Yasuko , Sawa Hirofumi , Sasaki Michihito
Published: February 2021

Encephalomyocarditis virus (EMCV) infects a wide range of hosts and can cause encephalitis, myocarditis, reproductive disorders and diabetes mellitus in selected mammalian species. As for humans, EMCV infection seems to occur by the contact with animals and can cause febrile illnesses in some infected patients. Here we isolated EMCV strain ZM12/14 from a natal multimammate mouse (Mastomys natalensis: M. natalensis) in Zambia. Pairwise sequence similarity of the ZM12/14 P1 region consisting of antigenic capsid proteins showed the highest similarity of nucleotide (80.7 %) and amino acid (96.2%) sequence with EMCV serotype 1 (EMCV-1). Phylogenetic analysis revealed that ZM12/14 clustered into EMCV-1 at the P1 and P3 regions but segregated from known EMCV strains at the P2 region, suggesting a unique evolutionary history. Reverse transcription PCR (RT-PCR) screening and neutralizing antibody assays for EMCV were performed using collected tissues and serum from various rodents (n=179) captured in different areas in Zambia. We detected the EMCV genome in 19 M. natalensis (19/179=10.6 %) and neutralizing antibody for EMCV in 33 M. natalensis (33/179=18.4 %). However, we did not detect either the genome or neutralizing antibody in other rodent species. High neutralizing antibody litres (≧320) were observed in both RT-PCR-negative and -positive animals. Inoculation of ZM12/14 caused asymptomatic persistent infection in BALB/c mice with high antibody titres and high viral loads in some organs, consistent with the above epidemiological results. This study is the first report of the isolation of EMCV in Zambia, suggesting that M. natalensis may play a role as a natural reservoir of infection.
Sex disparities and neutralizing antibody durability to SARS-CoV-2 infection in convalescent individuals
Authors: Markmann Alena J. , Giallourou Natasa , Bhowmik D. Ryan , Hou Yixuan J. , Lerner Aaron , Martinez David R. , Premkumar Lakshmanane , Root Heather , van Duin David , Napravnik Sonia , Graham Stephen D. , Guerra Quique , Raut Rajendra , Petropoulos Christos J. , Wrin Terri , Cornaby Caleb , Schmitz John , Kuruc JoAnn , Weiss Susan , Park Yara , Baric Ralph , de Silva Aravinda M. , Margolis David M. , Bartelt Luther A.
Published: February 2021

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) has now caused over 2 million deaths worldwide and continues to expand. Currently, much is unknown about functionally neutralizing human antibody responses and durability to SARS-CoV-2. Using convalescent sera collected from 101 COVID-19 recovered individuals 21-212 days after symptom onset with forty-eight additional longitudinal samples, we measured functionality and durability of serum antibodies. We also evaluated associations between individual demographic and clinical parameters with functional neutralizing antibody responses to COVID-19. We found robust antibody durability out to six months, as well as significant positive associations with the magnitude of the neutralizing antibody response and male sex. We also show that SARS-CoV-2 convalescent neutralizing antibodies are higher in individuals with cardio-metabolic comorbidities.

Significance

In this study we found that neutralizing antibody responses in COVID-19 convalescent individuals vary in magnitude but are durable and correlate well with RBD Ig binding antibody levels compared to other SARS-CoV-2 antigen responses. In our cohort, higher neutralizing antibody titers are independently and significantly associated with male sex compared to female sex. We also show for the first time, that higher convalescent antibody titers in male donors are associated with increased age and symptom grade. Furthermore, cardio-metabolic co-morbidities are associated with higher antibody titers independently of sex. Here, we present an in-depth evaluation of serologic, demographic, and clinical correlates of functional antibody responses and durability to SARS-CoV-2.
Changes in Characteristics of Drug Overdose Death Trends during the COVID-19 Pandemic
Authors: DiGennaro Catherine , Garcia Gian-Gabriel P. , Stringfellow Erin J. , Wakeman Sarah , Jalali Mohammad S.
Published: February 2021

Background

Reports analyzing drug overdose (OD) mortality data during the COVID-19 pandemic are limited. Outcomes across states are heterogenous, necessitating assessments of associations between COVID-19 and OD deaths on a state-by-state level. This report aims to analyze trends in OD deaths in Massachusetts during COVID-19.

Methods

Analyzing 3,924 death records, we characterize opioid-, cocaine-, and amphetamine-involved OD mortality and substance co-presence trends from March 24-November 8 in 2020 as compared to 2018 and 2019.

Results

OD deaths involving amphetamines increased by 85% from 2019 to 2020 (61 vs. 113; P<0.001) but were steady from 2018 to 2019. Heroin’s presence continued to decrease (341 in 2018, 247 in 2019, 157 in 2020; P<0.001); however, fentanyl was present in more than 85% of all OD deaths across all periods. Among OD deaths, alcohol involvement consistently increased, present in 250 deaths in 2018, 299 in 2019 (P=0.02), and 350 in 2020 (P=0.04). In 2019, 78% of OD decedents were White and 7% were Black, versus 73% and 10% in 2020 (P=0.02).

Conclusion

Increased deaths involving stimulants, alcohol, and fentanyl reflect concerning trends in the era of COVID-19. Rising OD death rates among Black residents underscore that interventions focused on racial equity are necessary.
Recognition of Diabetes in a Multi-ethnic Population: Results from a Nationally Representative Population-Based Study
Authors: Roystonn Kumarasan , Lau Jue Hua , AshaRani PV , Kumar Fiona Devi Siva , Wang Peizhi , Fang Sum Chee , Lee Eng Sing , Ann Chong Siow , Subramaniam Mythily
Published: February 2021

Background

The prevalence of diabetes is on the rise in developed countries. Yet discrepancies exist in reports regarding the level of knowledge of diabetes. This study evaluates the recognition of diabetes among residents in the Singapore population. Sociodemographic characteristics associated with the ability to correctly recognise diabetes were also examined.

Methods

This was a nationwide cross-sectional vignette-based study. Data were collected from 2895 residents aged 18 years and above through face-to-face interviews, of which 436 are persons with diabetes. Descriptive statistics, chi-square tests, and binary logistic regression were used in the analyses.

Results

In total, 82.7% (2418/2895) of respondents recognised diabetes correctly. In adjusted models, correct recognition was significantly higher among respondents aged 35-49 years (OR, 1.85; 95% CI, 1.15 to 2.98; P= 0.01), 50-64 years (odds ratio [OR], 2.06; 95% confidence interval [CI], 1.19 to 3.56; P= 0.01), ethnic Malays (OR, 1.39; 95% CI, 1.02 to 1.89; P= 0.04) (vs. Chinese) and persons with diagnosed diabetes (OR, 2.64; 95% CI, 1.38 to 5.08; P < 0.01). Being male (OR, 0.64; 95% CI, 0.46 to 0.90; P < 0.01), ethnic Others (OR, 0.59; 95% CI, 0.37 to 0.93; P < 0.01), and being unemployed (OR, 0.48; 95% CI, 0.25 to 0.92; P= 0.03), were significantly associated with poor recognition of diabetes.

Conclusion

Overall public recognition of diabetes is high, but the significant gaps in knowledge in certain demographic groups are of concern. Public health interventions aimed at preventing and controlling diabetes should continue to target all members of the population with accurate and appropriate information. Ongoing efforts of diabetes awareness and educational programs need to be improved, particularly for young adults, males, and the unemployed.
Deleterious effects of SARS-CoV-2 infection on human pancreatic cells
Authors: Shaharuddin Hanan , Wang Victoria , Santos Roberta S. , Gross Andrew , Wang Yizhou , Jawanda Harneet , Zhang Yi , Hasan Wohaib , Garcia Gustavo , Arumugaswami Vaithilingaraja , Sareen Dhruv
Published: February 2021

COVID-19 pandemic has infected more than 46 million people worldwide and caused more than 1.2 million deaths. It is transmitted by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and affects the respiratory tract as well as extra-pulmonary systems, including the pancreas, that express the virus entry receptor, Angiotensin-Converting Enzyme 2 (ACE2) receptor. Importantly, the endocrine and exocrine pancreas, the latter composed of ductal and acinar cells, express high levels of ACE2, which correlates to impaired functionality characterized as acute pancreatitis observed in some cases presenting with COVID-19. Since acute pancreatitis is already one of the most frequent gastrointestinal causes of hospitalization in the U.S. and the majority of studies investigating the effects of SARS-CoV-2 on the pancreas are clinical and observational, we utilized human iPSC technology to investigate the potential deleterious effects of SARS-CoV-2 infection on iPSC-derived pancreatic cultures containing endocrine and exocrine cells. Interestingly, SARS-CoV-2 is capable of infecting iPSC-derived pancreatic cells, thus perturbing their normal molecular and cellular phenotypes. The infection increased a key inflammatory cytokine, CXCL12, known to be involved in pancreas dysfunction. Transcriptome analysis of infected pancreatic cultures confirmed that SARS-CoV-2 hijacks the ribosomal machinery in these cells. Notably, the SARS-CoV-2 infectivity of the pancreas is confirmed in post-mortem tissues from COVID-19 patients, which showed co-localization of SARS-CoV-2 in pancreatic endocrine and exocrine cells and increased the expression of some pancreatic ductal stress response genes. Thus, we demonstrate for the first time that SARS-CoV-2 can directly infect human iPSC-derived pancreatic cells with supporting evidence of presence of the virus in post-mortem pancreatic tissue of confirmed COVID-19 human cases. This novel model of iPSC-derived pancreatic cultures will open new avenues for the comprehension of the SARS-CoV-2 infection and potentially establish a platform for endocrine and exocrine pancreas-specific antiviral drug screening.
Clozapine metabolism is associated with Absolute Neutrophil Count in individuals with treatment-resistant schizophrenia
Authors: Willcocks Isabella , Legge Sophie E. , Nalmpanti Mariana , Mazzeo Lucy , King Adrian , Jansen John , Helthuis Marinka , Owen Michael J. , O’Donovan Michael C. , Walters James T.R. , Pardiñas Antonio F.
Published: February 2021

AIM

To investigate the relationship between clozapine concentration and neutrophils in a European cohort of long-term clozapine users.

METHODS

Pearson’s Correlation and Linear Regression analyses were applied to a subset of the CLOZUK2 dataset (N = 208) to assess the association between Absolute Neutrophil Count (ANC) and plasma clozapine concentration. Norclozapine and the metabolic ratio between clozapine and norclozapine were also investigated, along with SNPs associated with clozapine metabolism

RESULTS

Association between ANC and plasma clozapine concentration was found to be significant in a linear regression model (β = −1.41, p = 0.009), with a decrease in ANC of approximately 141 cells/mm3 for every 0.1 mg/litre increase in clozapine concentration. This association was attenuated by the addition of the metabolic ratio, which was significantly negatively correlated with ANC (β=-0.69, p=0.021). In a further regression model, three SNPs previously associated with norclozapine plasma concentrations and clozapine/norclozapine ratio were also found to be significantly associated with ANC: rs61750900 (β=-0.410, p=0.048), rs2011425 (β=0.450, p=0.026) and rs1126545 (β=0.330, p=0.039)

CONCLUSION

ANC was found to be significantly negatively associated with plasma clozapine concentration. Further investigation has suggested that the relationship is mediated by the clozapine/norclozapine ratio, and potentially moderated by genetic variants with effects on clozapine metabolism
Limited specificity of SARS-CoV-2 antigen-detecting rapid diagnostic tests at low temperatures
Authors: Haage Verena , Moreira-Soto Andres , Sacks Jilian A. , Corman Victor , Drosten Christian , Drexler Felix
Published: February 2021

SARS-CoV-2 antigen-detecting rapid diagnostic tests (Ag-RDTs) are available within and outside of health care settings to enable increased access to COVID-19 diagnosis. These environments include provisional testing facilities, lacking temperature control; as outside temperatures fall, recommended testing temperatures cannot be guaranteed. We report impaired specificity in two out of six Ag-RDTs when used at 2-4°C, indicating that testing in cold settings might cause false-positive results potentially entailing unwarranted quarantine assignments and incorrect incidence estimates.
COVID-19 among bartenders and waiters before and after pub lockdown
Authors: Methi Fredrik , Telle Kjetil , Magnusson Karin
Published: February 2021

Aim

To study how different bans on serving alcohol in Norwegian bars and restaurants were related to the detection of SARS-CoV-2 in bartenders and waiters.

Methods

In 24,276 bartenders and waiters and 1,287,970 persons with other occupations (mean [SD] age 41.7 [12.8] years and 51.7% men), we examined the weekly rates of workers tested and detected with SARS-CoV-2, one to five weeks before and one to five weeks after implementation of different degrees of bans on serving alcohol in pubs and restaurants, across 56 Norwegian municipalities with: 1) full blanket ban, 2) partial ban with hourly restrictions (e.g. from 10 pm), or 3) no ban, adjusted for age, sex and testing behavior.

Results

In municipalities introducingfull ban, COVID-19 among bartenders and waiters had been reduced by 65% by three weeks (from 3.4 [95%CI=2.5-4.3] to 1.2 [95%CI=0.7-1.7] per 1000), i.e. to the same levels as that for persons with other occupations (1.8 [95%CI=1.7-1.9] vs 1.2 [95%CI=1.1-1.3] per 1000). Similarly, in municipalities introducingpartial ban, COVID-19 among bartenders and waiters had been reduced by 68% by three weeks (from 2.5 [95%CI=1.4-3.6] to 0.8 [95%CI=0.0-1.5] per 1000). However, there was more uncertainty to the estimated reduction for partial bans.

Conclusion

Municipalities with higher levels of confirmed COVID-19 among bartenders and waiters implemented stricter bans on serving of alcohol than other municipalities. Contraction of COVID-19 among bartenders and waiters declined similarly in municipalities with full and partial bans.
A survey of International Health Regulations National Focal Points experiences in carrying out their functions
Authors: Packer Corinne , Halabi Sam F. , Hollmeyer Helge , Mithani Salima S. , Wilson Lindsay , Ruckert Arne , Labonté Ronald , Fidler David P. , Gostin Lawrence O. , Wilson Kumanan
Published: February 2021

Background

The 2005 International Health Regulations (IHR (2005)) require States Parties to establish National Focal Points (NFPs) responsible for notifying the World Health Organization (WHO) of potential events that might constitute public health emergencies of international concern (PHEICs), such as outbreaks of novel infectious diseases. Given the critical role of NFPs in the global surveillance and response system supported by the IHR, we sought to assess their experiences in carrying out their functions.

Methods

In collaboration with WHO officials, we administered a voluntary online survey to all 196 States Parties to the IHR (2005) in Africa, Asia, Europe, and South and North America, from October to November 2019. The survey was available in six languages via a secure internet-based system.

Results

In total, 121 NFP representatives answered the 56-question survey; 105 in full, and an additional 16 in part, resulting in a response rate of 62% (121 responses to 196 invitations to participate). The majority of NFPs knew how to notify the WHO of a potential PHEIC, and believed they have the content expertise to carry out their functions. Respondents found training workshops organized by WHO Regional Offices helpful on how to report PHEICs. NFPs experienced challenges in four critical areas: 1) insufficient intersectoral collaboration within their countries, including limited access to, or a lack of cooperation from, key relevant ministries; 2) inadequate communications, such as deficient information technology systems in place to carry out their functions in a timely fashion; 3) lack of authority to report potential PHEICs; and 4) inadequacies in some resources made available by the WHO, including a key tool – the NFP Guide. Finally, many NFP representatives expressed concern about how WHO uses the information they receive from NFPs.

Conclusion

Our study, conducted just prior to the COVID-19 pandemic, illustrates key challenges experienced by NFPs that can affect States Parties and WHO performance when outbreaks occur. In order for NFPs to be able to rapidly and successfully communicate potential PHEICs such as COVID-19 in the future, continued measures need to be taken by both WHO and States Parties to ensure NFPs have the necessary authority, capacity, training, and resources to effectively carry out their functions as described in the IHR.
Estimating the effectiveness of the Pfizer COVID-19 BNT162b2 vaccine after a single dose. A reanalysis of a study of ‘real-world’ vaccination outcomes from Israel
Authors: Hunter Paul R , Brainard Julii
Published: February 2021

A distinctive feature of the roll out of vaccination against SARS-CoV-2 virus in the UK was the decision to delay the timing of the second injection till 12 weeks after the first. The logic behind this is to protect more people sooner and so reduce the total number of severe infections, hospitalisations, and deaths. This decision caused criticism from some quarters due in part to a belief that a single injection may not give adequate immunity. A recent paper based on Israel’s experience of vaccination suggested that a single dose may not provide adequate protection. Here we extract the primary data from the Israeli paper and then estimate the incidence per day for each day after the first injection and also estimate vaccine effectiveness for each day from day 13 to day 24. We used a pooled estimate of the daily incidence rate during days 1 to 12 as the counterfactual estimate of incidence without disease and estimated confidence intervals using Monte Carlo modelling. After initial injection case numbers increased to day 8 before declining to low levels by day 21. Estimated vaccine effectiveness was pretty much 0 at day 14 but then rose to about 90% at day 21 before levelling off. The cause of the initial surge in infection risk is unknown but may be related to people being less cautious about maintaining protective behaviours as soon as they have the injection. What our analysis shows is that a single dose of vaccine is highly protective, although it can take up to 21 days to achieve this. The early results coming from Israel support the UK policy of extending the gap between doses by showing that a single dose can give a high level of protection.
Increased mortality in community-tested cases of SARS-CoV-2 lineage B.1.1.7
Authors: Davies Nicholas G. , Jarvis Christopher I. ,   CMMID COVID-19 Working Group, Edmunds W. John , Jewell Nicholas P. , Diaz-Ordaz Karla , Keogh Ruth H.
Published: February 2021

SARS-CoV-2 lineage B.1.1.7, a variant first detected in the United Kingdom in September 20201, has spread to multiple countries worldwide. Several studies have established that B.1.1.7 is more transmissible than preexisting variants, but have not identified whether it leads to any change in disease severity2. We analyse a dataset linking 2,245,263 positive SARS-CoV-2 community tests and 17,452 COVID-19 deaths in England from 1 September 2020 to 14 February 2021. For 1,146,534 (51%) of these tests, the presence or absence of B.1.1.7 can be identified because of mutations in this lineage preventing PCR amplification of the spike gene target (S gene target failure, SGTF1). Based on 4,945 deaths with known SGTF status, we estimate that the hazard of death associated with SGTF is 55% (95% CI 39–72%) higher after adjustment for age, sex, ethnicity, deprivation, care home residence, local authority of residence and test date. This corresponds to the absolute risk of death for a 55–69-year-old male increasing from 0.6% to 0.9% (95% CI 0.8–1.0%) within 28 days after a positive test in the community. Correcting for misclassification of SGTF and missingness in SGTF status, we estimate a 61% (42–82%) higher hazard of death associated with B.1.1.7. Our analysis suggests that B.1.1.7 is not only more transmissible than preexisting SARS-CoV-2 variants, but may also cause more severe illness.
Microglia control glutamatergic synapses in the adult mouse hippocampus
Authors: Basilico Bernadette , Ferrucci Laura , Ratano Patrizia , Golia Maria T. , Grimaldi Alfonso , Rosito Maria , Ferretti Valentina , Reverte Ingrid , Marrone Maria C. , Giubettini Maria , De Turris Valeria , Salerno Debora , Garofalo Stefano , St-Pierre Marie-Kim , Carrier Micael , Renzi Massimiliano , Pagani Francesca , Raspa Marcello , Scavizzi Ferdinando , Gross Cornelius T. , Marinelli Silvia , Tremblay Marie E. , Caprioli Daniele , Maggi Laura , Limatola Cristina , Di Angelantonio Silvia , Ragozzino Davide
Published: February 2021

Microglial cells are active players in regulating synaptic development and plasticity in the brain. However, how these cells influence the normal functioning of synapses is largely unknown. In this study, we characterized the effects of pharmacological depletion of microglia, achieved by administration of PLX5622, on hippocampal CA3-CA1 synapses of adult wild type mice. Following microglial depletion, we observed a reduction of spontaneous and evoked glutamatergic activity associated with a decrease of dendritic spine density. We also observed the appearance of immature synaptic features accompanied by higher levels of plasticity. In addition, microglia depleted mice showed a deficit in the acquisition of the Novel Object Recognition task. Remarkably, microglial repopulation after PLX5622 withdrawal was associated with the recovery of hippocampal synapses and learning functions. Altogether, these data demonstrate that microglia contribute to normal synaptic functioning in the adult brain and that their removal induces reversible changes in synaptic organization and activity of glutamatergic synapses.
The ATF6β-calreticulin axis promotes neuronal survival under endoplasmic reticulum stress and excitotoxicity
Authors: Nguyen Dinh Thi , Le Thuong Manh , Hattori Tsuyoshi , Takarada-Iemata Mika , Ishii Hiroshi , Roboon Jureepon , Tamatani Takashi , Kannon Takayuki , Hosomichi Kazuyoshi , Tajima Atsushi , Taniuchi Shusuke , Miyake Masato , Oyadomari Seiichi , Saito Shunsuke , Mori Kazutoshi , Hori Osamu
Published: February 2021

While ATF6α plays a central role in the endoplasmic reticulum (ER) stress response, the function of ATF6β is largely unknown. Here, we demonstrate that ATF6β is highly expressed in the hippocampus of the brain, and specifically regulates the expression of calreticulin, a molecular chaperone in the ER with a high Ca2+-binding capacity. Calreticulin expression was reduced to ~50% in the central nervous system ofAtf6b−/−mice, and restored by ATF6β. Analysis using cultured hippocampal neurons revealed that ATF6β deficiency reduced Ca2+stores in the ER and enhanced ER stress-induced death, which was rescued by ATF6β, calreticulin, Ca2+-modulating reagents such as BAPTA-AM and 2-APB, and ER stress inhibitor salubrinal.In vivo, kainate-induced neuronal death was enhanced in hippocampi ofAtf6b−/−andCalr+/−mice, and restored by 2-APB and salubrinal. These results suggest that the ATF6β-calreticulin axis plays a critical role in the neuronal survival by improving Ca2+homeostasis under ER stress.
Mechanisms of speed encoding in the human middle temporal cortex measured by 7T fMRI
Authors: Gaglianese Anna , Fracasso Alessio , Fernandes Francisco G. , Harvey Ben , Dumoulin Serge O. , Petridou Natalia
Published: February 2021

Perception of dynamic scenes in our environment results from the evaluation of visual features such as the fundamental spatial and temporal frequency components of a moving object. The ratio between these two components represents the object’s speed of motion. The human middle temporal cortex hMT+ has a crucial biological role in the direct encoding of object speed. However, the link between hMT+ speed encoding and the spatiotemporal frequency components of a moving object is still under explored. Here, we recorded high resolution 7T blood oxygen level-dependent BOLD responses to different visual motion stimuli as a function of their fundamental spatial and temporal frequency components. We fitted each hMT+ BOLD response with a 2D Gaussian model allowing for two different speed encoding mechanisms: 1) distinct and independent selectivity for the spatial and temporal frequencies of the visual motion stimuli 2) pure tuning for the speed of motion. We show that both mechanisms occur but in different neuronal groups within hMT+, with the largest subregion of the complex showing separable tuning for the spatial and temporal frequency of the visual stimuli. Both mechanisms were highly reproducible within participants, reconciling single cell recordings from MT in animals that have showed both encoding mechanisms. Our findings confirm that a more complex process is involved in the perception of speed than initially thought and suggest that hMT+ plays a primary role in the evaluation of the spatial features of the moving visual input.
Pseudogenization oftrnT-GGUin chloroplast genomes of the plant family Asteraceae
Authors: Abdullah  , Mehmood Furrukh , Heidari Parviz , Ahmed Ibrar , Poczai Peter
Published: February 2021

The chloroplast genome evolves through the course of evolution. Various types of mutational events are found within the chloroplast genome, including insertions-deletions (InDels), substitutions, inversions, gene rearrangement, and pseudogenization of genes. The pseudogenization of thetrnT-GGUgene was previously reported in theCryptomeria japonica(Cupressaceae), Pelargonium x hortorum (Geraniaceae), and in the two species of the tribe Gnaphalieae (Asteroideae, Asteraceae). Here, we performed a broad analysis of thetrnT-GGUgene among the species of twelve subfamilies of Asteraceae and found pseudogenization of this gene is not limited to the two species of Gnaphalieae or the tribe Gnaphalieae. We report for the first time that this gene is pseudo in the species of three subfamilies of Asteraceae, including Gymnarrhenoideae, Cichorioideae and Asteroideae. The analyses of the species of 78 genera of Asteroideae revealed that this pseudogenization event is linked to the insertion within the 5′ acceptor stem and not linked to the habit, habitat, and geographical distribution of the plant.
Variation in Placental microRNA Expression Associates with Familial Cardiovascular Disease
Authors: Tehrani Jesse M. , Kennedy Elizabeth M. , Tian Fu-Ying , Everson Todd M. , Deyssenroth Maya , Burt Amber , Hermetz Karen , Hao Ke , Chen Jia , Koestler Devin C. , Marsit Carmen J.
Published: February 2021

In the United States, cardiovascular disease is the leading cause of death, and the rate of maternal mortality remains among the highest of any industrialized nation. Maternal cardiometabolic health throughout gestation and postpartum is representative of placental health and physiology. Both proper placental functionality and placental microRNA expression are essential to successful pregnancy outcomes, and both are highly sensitive to genetic and environmental sources of variation. While placental pathologies, such as preeclampsia, are associated with maternal cardiovascular health and may contribute to the developmental programming of cardiovascular disease, the role of more subtle alterations to placental function and microRNA expression in this relationship remains poorly understood. To develop a more comprehensive understanding of how cardiometabolic health influences placental microRNA expression, and how this shapes placental functionality, we performed small RNA sequencing to investigate microRNA in the placentae from the Rhode Island Child Health Study (n=230). We modeled microRNA counts on maternal family history of cardiovascular disease using negative binomial generalized linear models, and identified microRNAs that were differential expressed (DEmiRs) at a false discovery rate (FDR) less than 0.10. Utilizing parallel mRNA sequencing data and bioinformatic target prediction software, we identified potential mRNA targets of these DEmiRs. We identified 9 DEmiRs, with predicted targets of those miRNA enriched overwhelmingly in the TGFβ signaling pathway but also in pathways involving cellular metabolism and immunomodulation. Overall, we identified a robust association existing between familial cardiovascular disease and placental microRNA expression which may be implicated in both placental insufficiencies and the developmental programming of cardiovascular disease.
Stage-specific, morphological and molecular markers of encystation inGiardia lamblia
Authors: Thomas Elizabeth B. , Sutanto Renaldo , Johnson Richard S. , Shih Han-Wei , Krtková Jana , MacCoss Michael J. , Paredez Alexander R.
Published: February 2021

Differentiation into environmentally resistant cysts is required for transmission of the ubiquitous intestinal parasiteGiardia lamblia. Encystation inGiardiarequires the production, processing and transport of Cyst Wall Proteins (CWPs) in developmentally-induced, Golgi-like, Encystation Specific Vesicles (ESVs). Progress through this trafficking pathway can be followed by tracking CWP localization over time. However, there is no recognized system to distinguish the advancing stages of this process which can complete at variable rates depending how encystation is induced. Here we propose a staging system for encystingGiardiabased on the morphology of CWP1-stained ESVs. We demonstrate the molecular distinctiveness of maturing ESVs at these stages by followingGlRab GTPases through encystation. Previously, we established thatGiardia’s sole Rho family GTPase,GlRac, associates with ESVs and has a role in regulating their maturation and the secretion of their cargo. As a proof of principle, we delineate the relationship betweenGlRac and ESV stages. Through proteomic studies, we identify putative interactors ofGlRac that could be used as additional stage-specific ESV markers. This staging system provides a common descriptor of ESV maturation regardless of the source of encysting cells. Furthermore, the identified set of molecular markers for ESV stages will be a powerful tool for characterizing trafficking mutants that impair ESV maturation and morphology.

Importance

Giardiasisis a diarrheal disease that affects 280 million people worldwide. It is caused byGiardia lamblia, a protozoan parasite which rely on differentiating from host-dwelling trophozoites to environmentally-resistant cysts for transmission and survival. This encystation process requires the transport of Cyst Wall Proteins (1-3) within membrane-bound compartments called Encystation Specific Vesicles (ESV) from the endoplasmic reticulum to the surface of the cell. The whole process takes 24 hours to complete and these compartments are the only recognizable equivalent of Golgi apparatus in this minimalistic organism. Progress of this trafficking pathway can be followed by localizing Cyst Wall Protein 1 over time post induction of encystation but this can be ambiguous when specific molecular events need to be specified. Here we propose a staging system that is based on ESV morphology changes by capitalizing on the secretory/processing events we already know they represent. We validate the molecular distinctiveness of these stages by followingGiardiaRabs through the pathway and characterize putative interactors of an established regulator of encystation,GlRac, to provide additional stage-specific molecular markers. This staging system will provide a definitive, yet adaptable, framework to map out functions of yet-to-be discovered players of this important pathway.
Transport engineering for improving production and secretion of valuable alkaloids inEscherichia coli
Authors: Yamada Yasuyuki , Urui Miya , Oki Hidehiro , Inoue Kai , Matsui Haruyuki , Ikeda Yoshito , Nakagawa Akira , Sato Fumihiko , Minami Hiromichi , Shitan Nobukazu
Published: February 2021

Metabolic engineering of microorganisms to produce specialized plant metabolites has been established. However, these methods are limited by low productivity and the intracellular accumulation of metabolites. Here, we aimed to use transport engineering for producing reticuline, an important intermediate in the alkaloid biosynthetic pathway. We established a reticuline-producingEscherichia colistrain and introduced a multidrug and toxic compound extrusion transporter,ArabidopsisAtDTX1, into it. AtDTX1 was selected due to its suitable expression inE. coliand its reticuline-transport activity. Expression of AtDTX1 significantly enhanced reticuline production by 11-fold; produced reticuline was secreted into the medium. AtDTX1 expression conferred high plasmid stability, and up- or downregulated genes associated with biological processes including metabolic pathways for reticuline biosynthesis, leading to a high production and secretion of reticuline. The successful application of a transporter for alkaloid production suggests that the transport engineering approach may improve the biosynthesis of specialized metabolites via metabolic engineering.
Effective prediction of biosynthetic pathway genes involved in bioactive polyphyllins in Paris polyphylla
Authors: Hua Xin , Song Wei , Wang Kangzong , Yin Xue , Hao Changqi , Duan Baozhong , Xu Zhichao , Su Tongbing , Xue Zheyong
Published: February 2021

The genes in polyphyllins pathway mixed with other steroid biosynthetic genes form an extremely complex biosynthetic network inParis polyphyllawith a giant genome. The lack of genomic data and tissue specificity causes the study of the biosynthetic pathway notably difficult. Here, we report an effective method for the prediction of key genes of polyphyllin biosynthesis. Full-length transcriptome from eight different organs via hybrid sequencing of next generation sequencingand third generation sequencing platforms annotated two 2,3-oxidosqualene cyclases (OSCs), 216 cytochrome P450s (CYPs), and 199 UDP glycosyltransferases (UGTs). Combining metabolic differences, gene-weighted co-expression network analysis, and phylogenetic trees, the candidate ranges ofOSC, CYP, andUGTgenes were further narrowed down to 2, 15, and 24, respectively. Beside the three previously characterized CYPs, we identified the OSC involved in the synthesis of cycloartenol and the UGT (PpUGT73CR1) at the C-3 position of diosgenin and pennogenin inP. polyphylla. This study provides a idea for the investigation of gene cluster deficiency biosynthesis pathways in medicinal plants.