bluuebunny/crossref_metadata_2025 huggingface dataset:
Acquisition of plasmids conferring carbapenem and aminoglycoside resistance and loss of surface-exposed macromolecule structures as strategies for the adaptation of Acinetobacter baumannii CC104O/CC15P strains to the clinical setting
Authors: Cameranesi María M. , Paganini Julian , Limansky Adriana S. , Moran-Barrio Jorgelina , Salcedo Suzana P. , Viale Alejandro M. , Repizo Guillermo D.
Published: March 2020

Acinetobacter baumannii

(Aba) is an emerging opportunistic pathogen associated to nosocomial infections. The rapid increase in multidrug resistance (MDR) among Aba strains underscores the urgency of understanding how this pathogen evolves in the clinical environment. We conducted here a whole-genome sequence comparative analysis of three phylogenetically and epidemiologically related MDR Aba strains from Argentinean hospitals, assigned to the CC104O/CC15P clonal complex. While the Ab244 strain was carbapenem-susceptible, Ab242 and Ab825, isolated after the introduction of carbapenem therapy, displayed resistance to these last resource β-lactams. We found a high chromosomal synteny among the three strains, but significant differences at their accessory genomes. Most importantly, carbapenem resistance in Ab242 and Ab825 was attributed to the acquisition of a Rep_3 family plasmid carrying a bla
OXA-58 gene. Other differences involved a genomic island carrying resistance to toxic compounds and a Tn10 element exclusive to Ab244 and Ab825, respectively. Also remarkably, 44 insertion sequences (ISs) were uncovered in Ab825, in contrast with the 14 and 11 detected in Ab242 and Ab244, respectively. Moreover, Ab825 showed a higher killing capacity as compared to the other two strains in the Galleria mellonella infection model. A search for virulence and persistence determinants indicated the loss or IS-mediated interruption of genes encoding many surface-exposed macromolecules in Ab825, suggesting that these events are responsible for its higher relative virulence. The comparative genomic analyses of the CC104O/CC15P strains conducted here revealed the contribution of acquired mobile genetic elements such as ISs and plasmids to the adaptation of

A. baumannii

to the clinical setting.
Microbiome diversity and composition varies across body areas in a freshwater turtle
Authors: McKnight Donald T. , Zenger Kyall R. , Alford Ross A. , Huerlimann Roger
Published: March 2020

There is increasing recognition that microbiomes are important for host health and ecology, and understanding host microbiomes is important for planning appropriate conservation strategies. However, microbiome data are lacking for many taxa, including turtles. To further our understanding of the interactions between aquatic microbiomes and their hosts, we used next generation sequencing technology to examine the microbiomes of the Krefft’s river turtle (Emydura macquarii krefftii). We examined the microbiomes of the buccal (oral) cavity, skin on the head, parts of the shell with macroalgae and parts of the shell without macroalgae. Bacteria in the phylaProteobacteriaandBacteroideteswere the most common in most samples (particularly buccal samples), butCyanobacteria,Deinococcus-thermusandChloroflexiwere also common (particularly in external microbiomes). We found significant differences in community composition among each body area, as well as significant differences among individuals. The buccal cavity had lower bacterial richness and evenness than any of the external microbiomes, and it had many amplicon sequence variants (ASVs) with a low relative abundance compared to other body areas. Nevertheless, the buccal cavity also had the most unique ASVs. Parts of the shell with and without algae also had different microbiomes, with particularly obvious differences in the relative abundances of the familiesMethylomonaceae,SaprospiraceaeandNostocaceae. This study provides novel, baseline information about the external microbiomes of turtles and is a first step in understanding their ecological roles.
COVID-19 coronavirus vaccine design using reverse vaccinology and machine learning
Authors: Ong Edison , Wong Mei U , Huffman Anthony , He Yongqun
Published: March 2020

To ultimately combat the emerging COVID-19 pandemic, it is desired to develop an effective and safe vaccine against this highly contagious disease caused by the SARS-CoV-2 coronavirus. Our literature and clinical trial survey showed that the whole virus, as well as the spike (S) protein, nucleocapsid (N) protein, and membrane (M) protein, have been tested for vaccine development against SARS and MERS. However, these vaccine candidates might lack the induction of complete protection and have safety concerns. We then applied the Vaxign reverse vaccinology tool and the newly developed Vaxign-ML machine learning tool to predict COVID-19 vaccine candidates. By investigating the entire proteome of SARS-CoV-2, six proteins, including the S protein and five non-structural proteins (nsp3, 3CL-pro, and nsp8-10), were predicted to be adhesins, which are crucial to the viral adhering and host invasion. The S, nsp3, and nsp8 proteins were also predicted by Vaxign-ML to induce high protective antigenicity. Besides the commonly used S protein, the nsp3 protein has not been tested in any coronavirus vaccine studies and was selected for further investigation. The nsp3 was found to be more conserved among SARS-CoV-2, SARS-CoV, and MERS-CoV than among 15 coronaviruses infecting human and other animals. The protein was also predicted to contain promiscuous MHC-I and MHC-II T-cell epitopes, and linear B-cell epitopes localized in specific locations and functional domains of the protein. By applying reverse vaccinology and machine learning, we predicted potential vaccine targets for effective and safe COVID-19 vaccine development. We then propose that an “Sp/Nsp cocktail vaccine” containing a structural protein(s) (Sp) and a non-structural protein(s) (Nsp) would stimulate effective complementary immune responses.
Replication of SARS-CoV-2 in human respiratory epithelium
Authors: Milewska Aleksandra , Kula-Pacurar Anna , Wadas Jakub , Suder Agnieszka , Szczepanski Artur , Dabrowska Agnieszka , Owczarek Katarzyna , Ochman Marek , Stacel Tomasz , Rajfur Zenon , Labaj Pawel , Branicki Wojciech , Pyrc Krzysztof
Published: March 2020

SARS-CoV-2 emerged by the end of 2019 to rapidly spread in 2020. At present, it is of utmost importance to understand the virus biology and to rapidly assess the potential of existing drugs and develop new active compounds. While some animal models for such studies are under development, most of the research is carried out in the Vero E6 cells. Here, we propose fully differentiated human airway epithelium cultures as a model for studies on the SARS-CoV-2. Further, we also provide basic characteristics of the system.
Exploring Chromosomal Structural Heterogeneity Across Multiple Cell Lines
Authors: Cheng Ryan R. , Contessoto Vinicius , Aiden Erez Lieberman , Wolynes Peter G. , Di Pierro Michele , Onuchic José N.
Published: March 2020

We study the structural ensembles of human chromosomes across different cell types. Using computer simulations, we generate cell-specific 3D chromosomal structures and compare them to recently published chromatin structures obtained through microscopy. We demonstrate using a combination of machine learning and polymer physics simulations that epigenetic information can be used to predict the structural ensembles of multiple human cell lines. The chromosomal structures obtainedin silicoare quantitatively consistent with those obtained through microscopy as well as DNA-DNA proximity ligation assays. Theory predicts that chromosome structures are fluid and can only be described by an ensemble, which is consistent with the observation that chromosomes exhibit no unique fold. Nevertheless, our analysis of both structures from simulation and microscopy reveals that short segments of chromatin make transitions between a closed conformation and an open dumbbell conformation. This conformational transition appears to be consistent with a two-state process with an effective free energy cost of about four times the effective information theoretic temperature. Finally, we study the conformational changes associated with the switching of genomic compartments observed in human cell lines. Genetically identical but epigenetically distinct cell types appear to rearrange their respective structural ensembles to expose segments of transcriptionally active chromatin, belonging to the A genomic compartment, towards the surface of the chromosome, while inactive segments, belonging to the B compartment, move to the interior. The formation of genomic compartments resembles hydrophobic collapse in protein folding, with the aggregation of denser and predominantly inactive chromatin driving the positioning of active chromatin toward the surface of individual chromosomal territories.
A Multicenter Study of Coronavirus Disease 2019 Outcomes of Cancer Patients in Wuhan, China
Authors: Zhang Hongyan , Wang Linwei , Chen Yuanyuan , Shen Xiaokun , Wang Qun , Yan Youqin , Yu Yi , Wu Qiuji , Zhong Yahua , Chua Melvin L.K. , Xie Conghua
Published: March 2020

Background

At present, there is a global pandemic of coronavirus disease 2019 (COVID-19) pneumonia. For COVID-19 patients, cancer is a coexisting disease that should not be Here, we conducted a multicenter retrospective study to show the clinical information and outcomes of cancer patients infected with COVID-19.

Measurements

Medical records of COVID-19 patients with cancer admitted to hospitals from Jan 5, 2020 to Feb 18, 2020 were collected.

Results

Of the 67 patients (median age: 66 years), the median age of patients with severe illness was older than that of patients with mild symptoms (P<0.001). The proportion of severe patients had co-morbidities was higher than patients with mild disease (P=0.004). During the treatment of COVID-19 pneumonia, tumor progression and recurrence was not observed for those patients still at the anticancer treatment phase. Lymphocytopenia was the main laboratory finding accompanying increased C-reactive protein and procalcitonin in cancer patients, especially in severe cases. By Mar 10, 2020, 18 (26.9%) patients died from COVID-19. The median age of survivors was younger than that of deaths (P=0.014). Lung cancer (n=15, 22.4%) was the most common cancer type and accounted for the highest proportion COVID-19 resulted deaths (33.3%, 5/15). We observed a tendency that patients at the follow-up phase had a better prognosis than that at anticancer treatment phase (P=0.095).

Conclusion

This study showed COVID-19 patients with cancer seem to have a higher proportion of severe cases and poorer prognosis. We should pay more intensive attentions to cancer patients infected with COVID-19.
Neuron-glia Integrity: Functional Assessment, Molecular Underpinnings, and Implication for Higher Brain Functions
Authors: Zeng Haiyan , Zhang Xiaolei , Wang Wenqiang , Shen Zhiwei , Dai Zhuozhi , Yu Zhijia , Xu Shuqin , Yan Gen , Huang Qingjun , Wu Renhua , Chen Xi , Xu Haiyun
Published: March 2020

We developed a theory of neuron-glia integrity to underline the fact that neurons and glia cells work together in the central nervous system. Here we substantiated this theory and exemplified the implication of intact neuron-glia integrity for higher brain functions. An animal model of maternal separation with early weaning (MSEW) was applied to neonatal rats to mimic early life neglect and abuse in humans. Behavioral performance of rats was evaluated at adulthood, followed by functional assessments of neuron-glia integrity in living rats, and the demonstration of molecular underpinnings of impaired neuron-glia integrity in MSEW rats. MSEW rats showed higher levels of anxiety and explorative activity, higher glutamate level, but lower GABA level in PFC and hippocampus. MSEW procedure down-regulated protein levels of GLT-1 and ATP-α, but up-regulated GAD65 and GS, while had no effects on GLAST and PAG. Moreover, it reduced the fractional anisotropy values in various brain regions, in addition to increasing NAA levels. Concurrently, MSEW led to hypomyelination in PFC as evidenced by relevant cellular and molecular changes.
Characterization ofSalix nigrafloral insect community and activity of three nativeAndrenabees
Authors: Simon Sandra J. , Keefover-Ring Ken , Park Yong-Lak , Wimp Gina , Grady Julianne , DiFazio Stephen P.
Published: March 2020

Salix nigra(black willow) is a widespread tree that hosts many species of polylectic hymenopterans and oligolectic bees of the genusAndrena. The early flowering time ofS. nigramakes it an important nutritive resource for arthropods emerging from hibernation. However, sinceS. nigrais dioecious, not all insect visits will lead to successful pollination. Using both visual observation and pan-trapping we characterized the community of arthropods that visitedS. nigraflowers and assessed the differences among male and female trees as well as the chemical and visual drivers that influenced community composition across three years. We found that male trees consistently supported higher diversity of insects than female trees and only three insect species, allAndrenaspp., consistently visited both sexes. Additionally,A. nigrae, which was the only insect that occurred more on female than male flowers, correlated strongly to volatile cues. This suggests that cross-pollinators cue into specific aspects of floral scent, but diversity of floral visitors is driven strongly by visual cues. Through time the floral activity of twoAndrenaspecies remained stable, butA. nigraevisited less in 2017 when flowers bloomed earlier than other years. When native bee emergence does not synchronize with bloom, activity appears to be greatly diminished which could threaten species that only subsist on a single host. Despite the community diversity ofS. nigraflowers, its productivity depends on a small fraction of species that are not threatened by competition, but rather rapidly changing conditions that lead to host-insect asynchrony.
The role of islet lipid composition remodeling in regulation of beta-cell death via ADP-ribosyl-acceptor glycohydrolase ARH3 signaling in insulitis
Authors: Nakayasu Ernesto S. , Deiter Cailin , Kyle Jennifer E. , Guney Michelle A. , Sarbaugh Dylan , Yin Ruichuan , Cui Yi , Nicora Carrie D. , Syed Farooq , Juan-Mateu Jonas , Mirmira Raghavendra G. , Evans-Molina Carmella , Eizirik Decio L. , Webb-Robertson Bobbie-Jo M. , Burnum-Johnson Kristin , Orr Galya , Laskin Julia , Metz Thomas O. , Sussel Lori , Ansong Charles
Published: March 2020

Lipids have been implicated as mediators of insulitis and β-cell death in type 1 diabetes development, but the mechanisms underlying this association are poorly understood. Here, we investigated the changes in islet/β-cell lipid composition using three models of insulitis: human islets and EndoC-βH1 β-cells treated with the cytokines IL-1β and IFN-γ, and islets from non-obese diabetic mice. Across all three models, lipidomic analyses showed a consistent change in abundance of the lysophosphatidylcholine, phosphatidylcholine and triacylglycerol species. We also showed that lysophosphatidylcholine and its biosynthetic enzyme PLA2G6 are enriched in murine islets. We determined that the ADP-ribosyl-acceptor glycohydrolase ARH3 is regulated by cytokines downstream of PLA2G6, which in turn regulates proteins involved in apoptosis, lipid metabolism, antigen processing and presentation and chemokines. ARH3 reduced cytokine-induced apoptosis, which may represent a negative feedback mechanism. Overall, these data show the importance of lipid metabolism in regulating β-cell death in type 1 diabetes.

Highlights

Lipidomics of 3 insulitis models revealed commonly regulated lipid classes.

Identification of 35 proteins regulated by cytokines via PLA2G6 signaling.

ARH3 reduces cytokine-induced apoptosis via PLA2G6 regulation.

ARH3 regulates the levels of proteins related to insulitis and type 1 diabetes.
Vpr Co-assembles with Gag during HIV-1 Assembly
Authors: Bredbenner Kate , Simon Sanford M
Published: March 2020

The HIV-1 accessory protein Vpr is packaged into new virions at a 7:1 ratio of Gag/Vpr. Previous biochemical and genetic analysis has shown that Vpr gets packaged into virions via an LXXLF motif on the p6 domain of the Gag structural polyprotein. The kinetics of Vpr packaging compared to Gag assembly was previously unknown. Here, we confirm via biochemistry and imaging that fluorescently tagged Vpr gets packaged into virus-like particles only when the LXXLF motif is intact. When the LXXLF motif is mutated, Vpr is no longer recruited to Gag assemblies. When Vpr and Gag assembly are imaged together, we see that Vpr co-assembles with a slight delay compared to Gag suggesting that Vpr is not being recruited to the membrane with Gag but is instead being recruited to actively assembling Gag.

Importance

HIV-1 affects over 30 million people around the globe, and although we have good treatments, there is still no cure. The virus encodes 15 distinct proteins, and four of those proteins are known as accessory proteins. Vpr is one of the accessory proteins that is packaged into HIV-1 by interacting with the Gag structural protein. Without Vpr, HIV-1 is not as infectious. Our research shows that Vpr is packaged into new viruses as the virus is being formed rather than being put in towards the end of the assembly of a virus. Getting a clearer view of each step in the process of assembling each virion will help inform future treatments and help with overall comparisons between the assembly of different viruses.
Comparison of the spatiotemporal characteristics of the COVID-19 and SARS outbreaks in mainland China
Authors: Zhang Xi , Rao Hua-Xiang , Wu Yuwan , Huang Yubei , Dai Hongji
Published: March 2020

Background

Both coronavirus disease 2019 (COVID-19) and severe acute respiratory syndrome (SARS) are caused by coronaviruses and have infected people in China and worldwide. We aimed to investigate whether COVID-19 and SARS exhibited similar spatial and temporal features at the provincial level in mainland China.

Methods

The number of people infected by COVID-19 and SARS were extracted from daily briefings on newly confirmed cases during the epidemics, as of Mar. 4, 2020 and Aug. 3, 2003, respectively. We depicted the spatiotemporal patterns of the COVID-19 and SARS epidemics using spatial statistics such as Moran’s I and the local indicators of spatial association (LISA).

Results

Compared to SARS, COVID-19 had a higher incidence. We identified 3 clusters (predominantly located in south-central China, highest RR=135.08) for COVID-19 and 4 clusters (mainly in Northern China, highest RR=423.51) for SARS. Fewer secondary clusters were identified after the “Wuhan lockdown”. The LISA cluster map detected a significantly high-low (Hubei) and low-high spatial clustering (Anhui, Hunan, and Jiangxi, in Central China) for COVID-19. Two significant high-high (Beijing and Tianjin) and low-high (Hebei) clusters were detected for SARS, although the global Moran’s I value was not significant.

Conclusions

The different spatiotemporal clustering patterns between COVID-19 and SARS could point to changes in social and demographic factors, local government containment strategies or differences in transmission mechanisms between these coronaviruses.
Estimating internationally imported cases during the early COVID-19 pandemic
Authors: Menkir Tigist F. , Chin Taylor , Hay James , Surface Erik D. , De Salazar Pablo M. , Buckee Caroline O. , Watts Alexander , Khan Kamran , Sherbo Ryan , Yan Ada W. C. , Mina Michael , Lipsitch Marc , Niehus Rene
Published: March 2020

Early in the COVID-19 pandemic, when cases were predominantly reported in the city of Wuhan, China, local outbreaks in Europe, North America, and Asia were largely predicted from imported cases on flights from Wuhan, potentially missing imports from other key source cities. Here, we account for importations from Wuhan and from other cities in China, combining COVID-19 prevalence estimates in 18 Chinese cities with estimates of flight passenger volume to predict for each day between early December 2019 to late February 2020 the number of cases exported from China. We predict that the main source of global case importation in early January was Wuhan, but due to the Wuhan lockdown and the rapid spread of the virus, the main source of case importation from mid February became Chinese cities outside of Wuhan. For destinations in Africa in particular, non-Wuhan cities were an important source of case imports (1 case from those cities for each case from Wuhan, range of model scenarios: 0.1-9.8). Our model predicts that 18.4 (8.5 - 100) COVID-19 cases were imported to 26 destination countries in Africa, with most of them (90%) predicted to have arrived between 7th January (±10 days) and 5th February (±3 days), and all of them predicted prior to the first case detections. We finally observed marked heterogeneities in expected imported cases across those locations. Our estimates shed light on shifting sources and local risks of case importation which can help focus surveillance efforts and guide public health policy during the final stages of the pandemic. We further provide a time window for the seeding of local epidemics in African locations, a key parameter for estimating expected outbreak size and burden on local health care systems and societies, that has yet to be defined in these locations.
Metabologenomics identified fecal biomarkers for bowel movement regulation byBifidobacterium longumcapsules: an RCT
Authors: Nakamura Y. , Suzuki S. , Murakami S. , Higashi K. , Watarai N. , Nishimoto Y. , Umetsu J. , Ishii C. , Ito Y. , Mori Y. , Kohno M. , Yamada T. , Fukuda S.
Published: March 2020

Background

Bifidobacterium longumsupplementation can be used to regulate bowel movement; however, individuals vary in the response toB. longumtreatment. One putative factor is the gut microbiota; recent studies have reported that the gut microbiota mediates diet or drug effects. Here, we investigated intestinal features related toB. longumeffectiveness in increasing bowel movement frequency.

Results

A randomized, double-blind controlled crossover trial was conducted with twenty Japanese subjects selected from 50 participants. The subjects received a two-week dietary intervention consisting ofB. longumin acid-resistant seamless capsules or similarly encapsulated starch powder. Bowel movement frequency was recorded daily, and time-series fecal collection was conducted for metabologenomic analyses. There were differences among subjects inB. longumintake-induced bowel movement frequency. The responders were predictable by machine learning based on the metabologenomic features of the fecal samples collected beforeB. longumintake. Between responders and non-responders, the abundances of nine bacterial genera and of three compounds were significantly different.

Conclusions

Thus, the gut microbiome and metabolome composition have a strong impact onB. longumsupplementation effectiveness in increasing bowel movement frequency, and gut metabologenomics enablesB. longum supplementation effect prediction before intake. These findings have implications for the development of personalized probiotic treatments.

Trial registration

UMIN-CTR, UMIN000018924. Registered 07 September 2015,https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000021894
Reconsidering the border between the visual and posterior parietal cortex of mice
Authors: Gilissen Sara R. J. , Farrow Karl , Bonin Vincent , Arckens Lutgarde
Published: March 2020

The posterior parietal cortex (PPC) contributes to multisensory and sensory-motor integration, as well as spatial navigation. Based on studies in primates, the PPC is composed of several subdivisions with differing connection patterns, including areas that exhibit retinotopy. In mice the exact anatomical location and composition of the PPC is poorly understood. We present a revised delineation in which we classify the higher-order visual areas RL, AM and MMA as subregions of the mouse PPC. Retrograde and anterograde tracing revealed connectivity, characteristic for primate PPC, with sensory, retrosplenial, orbitofrontal, cingulate and motor cortex, as well as with several thalamic nuclei and the superior colliculus in the mouse. Regarding cortical input, RL receives major input from the somatosensory barrel field, while AM receives more input from the trunk, whereas MMA receives strong inputs from retrosplenial, cingulate and orbitofrontal cortices. These input differences suggest that each new PPC sub-region has a distinct function. Summarized, we put forward a new refined cortical map, including a mouse PPC that contains at least 6 sub-regions, RL, AM, MMA and PtP, MPta, LPta/A. These results will facilitate a more detailed understanding about the role that the PPC and its subdivisions play in multisensory integration-based behavior in mice.

Highlights

Higher-order visual areas RL, AM and MMA are part of the posterior parietal cortex (PPC) of the mouse based on connectivity.

The mouse PPC contains at least 6 sub-regions, including RL, AM, MMA, PtP, LPtA/A and MPtA

Specialized cortical input patterns to the new PPC subdivisions may reflect division of function.

A new flattened map for mouse cortex represents refined auditory, visual, retrosplenial and PPC areas.
The consequences of size-selective fishing mortality for larval production and sustainable yield in species with obligate male care
Authors: Kindsvater Holly K. , Halvorsen Kim Tallaksen , Sørdalen Tonje Knutsen , Alonzo Suzanne H.
Published: March 2020

Size-based harvest limits or gear regulations are often used to manage fishing mortality and ensure the spawning biomass of females is sufficiently protected. Yet, management interactions with species’ mating systems that affect fishery sustainability and yield are rarely considered. For species with obligate male care, it is possible that size-specific harvest of males will decrease larval production. In order to examine how size-based management practices interact with mating systems, we modeled fisheries of two species with obligate care of nests, corkwing wrasse (Symphodus melops, Labridae) and lingcod (Ophiodon elongatus, Hexigrammidae) under two management scenarios, a minimum size limit and a harvest slot limit. We simulated the population dynamics, larval production, and yield to the fishery under a range of fishing mortalities. We also modeled size-dependent male care to determine its interaction with management. In both species, the slot limit decreased yield by less than 12% (relative to minimum size limits) at low fishing mortalities; at higher mortalities, individuals rarely survived to outgrow the slot and spawning potential decreased substantially relative to unfished levels, similar to minimum size limits. Spawning potential decreased less when managed with a slot limit if we included a positive feedback between male size, care, and hatching success, but the benefit of implementing the slot depended both on the relative proportions of each sex selected by the fishery, and on our assumptions regarding male size and care. This work highlights that the effects of size- and sex-selective fisheries management can be nuanced and produce counter-intuitive results.
Structural insights into assembly and function of the RSC chromatin remodeling complex
Authors: Baker Richard W. , Reimer Janice M. , Carman Peter J. , Arakawa Tsutomu , Dominguez Roberto , Leschziner Andres E.
Published: March 2020

Chromatin remodelers regulate the position and composition of nucleosomes throughout the genome, producing different remodeling outcomes despite a shared underlying mechanism based on a conserved RecA DNA translocase. How this functional diversity is achieved remains unknown despite recent cryo-electron microscopy (cryo-EM) reconstructions of several remodelers, including the yeast RSC complex. To address this, we have focused on a RSC subcomplex comprising its ATPase (Sth1), the essential actin-related proteins (ARPs) Arp7 and Arp9, and the fungal-specific protein Rtt102. Combining cryo-EM and biochemistry of this subcomplex, which exhibits regulation of remodeling by the ARPs, we show that ARP binding induces a helical conformation in the HSA domain of Sth1, which bridges the ATPase domain with the bulk of the complex. Surprisingly, the ARP module is rotated by 120° in the subcomplex relative to full RSC about a pivot point previously identified as a regulatory hub in Sth1, suggesting that large conformational changes are part of Sth1 regulation and RSC assembly. We also show that an interaction between Sth1 and the nucleosome acidic patch, which appears to be conserved among SWI/SNF remodelers, enhances remodeling. Taken together, our structural data shed light on the assembly and function of the RSC complex.
Effectiveness of current protection for Maui dolphin
Authors: Slooten Elisabeth
Published: March 2020

This paper describes changes to protected areas for Maui dolphin(Cephalorhynchus hectori mauii)implemented in 2012 and 2013, and estimates their effectiveness in reducing bycatch. An Expert Panel of New Zealand and international scientists, convened by the New Zealand government in 2012, estimated that five Maui dolphins were killed in fishing gear each year – one in trawl fisheries and four in gillnet fisheries. The estimated number of trawl mortalities is unchanged, as no additional protection from trawling has been implemented. The number of gillnet mortalities per year is estimated to have decreased to at best two per year. The International Whaling Commission has recommended that gillnet and trawl fisheries be banned in Maui dolphin habitat, reducing bycatch to as close as practicable to zero.
Day case versus inpatient total shoulder arthroplasty: A retrospective cohort study and cost-effectiveness analysis
Authors: Borakati Aditya , Ali Asad , Nagaraj Chetana , Gadikoppula Srinivas , Kurer Michael
Published: March 2020

Background

Day case total shoulder arthroplasty (TSA) is a novel approach, not widely practiced in Europe. We conducted a retrospective cohort study of patients comparing elective day case and inpatient TSAs in our UK centre.

Aim

To evaluate the efficacy and cost-effectiveness of day case total shoulder arthroplasty (TSA) compared to standard inpatient total shoulder arthroplasty.

Methods

All patients undergoing TSA between January 2017 and July 2018 were included. Outcome measures were: change in abduction and extension 3 months postoperatively; 30 day postoperative adverse events and re-admissions in day case and inpatient groups. We also conducted an economic evaluation of outpatient arthroplasty. Multivariate linear and logistic regression were used to adjust for demographic and operative covariates.

Results

59 patients were included, 18 day cases and 41 inpatients. There were no adverse events or re-admissions at 30 days postoperatively in either group. There were no significant differences in adjusted flexion (mean difference 16.4°; 95% CI -17.6° to 50.5°, p=0.337) or abduction (mean difference 13.2° 95% CI; -18.4° to 44.9°, p=0.405) postoperatively between groups. Median savings with outpatient arthroplasty were GBP 529 (IQR 247.33 to 789, p<0.0001).

Conclusion

Day case TSA is a safe, effective procedure, with significant cost benefit. Wider use may be warranted in the UK and beyond, with potential for significant cost savings and improved efficiency.

Core tip

In this article we show that day case total shoulder arthroplasty is a feasible, safe and effective alternative to inpatient admission for the same procedure, with an associated average cost saving of GBP 529.
Analysis of HCM in an understudied population reveals a new mechanism of pathogenicity
Authors: Allouba Mona , Aguib Yasmine , Walsh Roddy , Afify Alaa , Theotokis Pantazis I. , Galal Aya , Halawa Sarah , Shorbagy Sara , Ibrahim Ayman M. , Kassem Heba Sh. , Ellithy Amany , Buchan Rachel , Hosny Mohammed , Whiffin Nicola , Elguindy Ahmed , Anwer Shehab , Cook Stuart A , Ware James S , Barton Paul J , Yacoub Magdi
Published: March 2020

Hypertrophic Cardiomyopathy (HCM) is an inherited disease characterized by genetic and phenotypic heterogeneity. MYH7 represents one of the main sarcomere-encoding genes associated with HCM. Missense variants in this gene cause HCM through gain-of-function actions, whereby variants produce an abnormal activated protein which incorporates into the sarcomere as a ‘poison peptide’. Here we report a frameshift variant in MYH7, c.5769delG, that is associated with HCM in an Egyptian cohort (3.3%) compared with ethnically-matched controls. This variant is absent from previously published large-scale Caucasian HCM cohorts. We further demonstrate strong evidence of co-segregation of c.5769delG with HCM in a large family (LOD score: 3.01). The predicted sequence of the variant MYH7 transcript shows that the frameshift results in a premature termination codon (PTC) downstream of the last exon-exon junction of the gene that is expected to escape nonsense-mediated decay (NMD). RNA sequencing of myocardial tissue obtained from a patient with the variant during surgical myectomy confirmed the expression of the variant MYH7 transcript. Our analysis reveals a new mechanism of pathogenicity in the understudied Egyptian population whereby distal PTC in MYH7 may lead to the expression of an abnormal protein.
Estimating the ascertainment rate of SARS-CoV-2 infection in Wuhan, China: implications for management of the global outbreak
Authors: Lytras Theodore , Panagiotakopoulos Georgios , Tsiodras Sotirios
Published: March 2020

We sought to estimate the ascertainment ratio of SARS-CoV-2 infection in Wuhan, China, using a modified Bayesian SEIR model with publicly reported case data. We estimated it at 0.465% (95%CI: 0.464–0.466%), implying that the outbreak in Wuhan was abated by depletion of susceptibles, rather than public health action alone. This suggests a high-transmissibility/low-severity profile for the current pandemic and raises doubt about whether suppression, rather than mitigation, is a feasible goal.
Applying time series analyses on continuous accelerometry data – a clinical example in older adults with and without cognitive impairment
Authors: Rackoll Torsten , Neumann Konrad , Passmann Sven , Grittner Ulrike , Külzow Nadine , Ladenbauer Julia , Flöel Agnes
Published: March 2020

Introduction

Current analysis approaches of accelerometry data use sum score measures which do not provide insight in activity patterns over 24 hours, and thus do not adequately depict circadian activity patterns. Here, we used a functional approach to analyze accelerometer data that models activity pattern and circadian rhythm. As a test case, we demonstrated its application in patients with mild cognitive impairment (MCI) and age-matched healthy older volunteers (HOV). Moreover, we assessed the impact of chronotype on distribution of activity data.

Methods

Data of two studies were pooled for this analysis. Following baseline cognitive assessment participants were provided with accelerometers for seven consecutive days. A function on scalar regression (FoSR) approach was used to analyze 24 hours accelerometer data. In a second step, analyses were controlled for chronotype using the German version of the morningness-eveningness questionnaire (d-MEQ).

Results

Information on 47 HOV (mean age 66 SD 6 years) and 13 patients with MCI (mean age 69, SD 8 years) were available for this analysis. MCI patients displayed slightly higher activity in the morning hours as compared to HOV (maximum relative activity at 7:35 am: 75.6%, 95% CI 2.6 to 200.4%, p = 0.031). After controlling for d-MEQ, disturbed activity patterns were found in MCI of intermediate or evening chronotype, compared to HOV, i.e., MCI presented with higher activities in the morning hours (peak at 8:40 am: 357.6%, 95% CI 92.9 to 985.1, p < 0.001) and early afternoon hours (peak at 1:40 pm: 401.8%, 95% CI 63.9 to 1436.4, p < 0.001).

Discussion

Using a novel approach of FoSR, we found timeframes with higher activity levels in MCI patients compared to HOV which were not evident if sum scores of amount of activity were used. In addition, we found that previously described activity patterns as a function of chronotype swere altered in MCI patients, possibly indicating that changes in circadian rhythmicity in neurodegenerative disease are detectable using easy-to-administer accelerometry.

Clinical Trials

Effects of Brain Stimulation During Nocturnal Sleep on Memory Consolidation in Patients With Mild Cognitive Impairments, https://clinicaltrials.gov/ct2/show/NCT01782391?term=NCT01782391&rank=1,

ClinicalTrial.gov identifier: NCT01782391

Effects of Brain Stimulation During a Daytime Nap on Memory Consolidation in Patients With Mild Cognitive Impairment,

https://clinicaltrials.gov/ct2/show/NCT01782365?term=NCT01782365&rank=1,

ClinicalTrial.gov identifier: NCT01782365
Acute kidney injury at early stage as a negative prognostic indicator of patients with COVID-19: a hospital-based retrospective analysis
Authors: Xu Shen , Fu Lin , Fei Jun , Xiang Hui-Xian , Xiang Ying , Tan Zhu-Xia , Li Meng-Die , Liu Fang-Fang , Li Ying , Han Ming-Feng , Li Xiu-Yong , Yu De-Xin , Zhao Hui , Xu De-Xiang
Published: March 2020

Coronavirus disease 2019 (COVID-19) is a newly emerged infection of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and has been pandemic all over the world. This study described acute kidney injury (AKI) at early stage of COVID-19 and its clinical significance. Three-hundred and fifty-five COVID-19 patients with were recruited and clinical data were collected from electronic medical records. Patient’s prognosis was tracked and risk factors of AKI was analyzed. Of 355 COVID-19 patients, common, severe and critical ill cases accounted for 63.1%, 16.9% and 20.0%, respectively. On admission, 56 (15.8%) patients were with AKI. Although AKI was more common in critical ill patients with COVID-19, there was no significant association between oxygenation index and renal functional indices among COVID-19 patients with AKI. By multivariate logistic regression, male, older age and comorbidity with diabetes were three important independent risk factors predicting AKI among COVID-19 patients. Among 56 COVID-19 patients with AKI, 33.9% were died on mean 10.9 day after hospitalization. Fatality rate was obviously higher among COVID-+19 patients with AKI than those without AKI (RR=7.08,P<0.001). In conclusion, male elderly COVID-19 patients with diabetes are more susceptible to AKI. AKI at early stage may be a negative prognostic indicator for COVID-19.
Human Mobility Restrictions and the Spread of the Novel Coronavirus (2019-nCoV) in China
Authors: Fang Hanming , Wang Long , Yang Yang
Published: March 2020

We quantify the causal impact of human mobility restrictions, particularly the lockdown of the city of Wuhan on January 23, 2020, on the containment and delay of the spread of the Novel Coronavirus (2019-nCoV). We employ a set of difference-in-differences (DID) estimations to disentangle the lockdown effect on human mobility reductions from other confounding effects including panic effect, virus effect, and the Spring Festival effect. We find that the lockdown of Wuhan reduced inflow into Wuhan by 76.64%, outflows from Wuhan by 56.35%, and within-Wuhan movements by 54.15%. We also estimate the dynamic effects of up to 22 lagged population inflows from Wuhan and other Hubei cities, the epicenter of the 2019-nCoV outbreak, on the destination cities’ new infection cases. We find, using simulations with these estimates, that the lockdown of the city of Wuhan on January 23, 2020 contributed significantly to reducing the total infection cases outside of Wuhan, even with the social distancing measures later imposed by other cities. We find that the COVID-19 cases would be 64.81% higher in the 347 Chinese cities outside Hubei province, and 52.64% higher in the 16 non-Wuhan cities inside Hubei, in the counterfactual world in which the city of Wuhan were not locked down from January 23, 2020. We also find that there were substantial undocumented infection cases in the early days of the 2019-nCoV outbreak in Wuhan and other cities of Hubei province, but over time, the gap between the officially reported cases and our estimated “actual” cases narrows significantly. We also find evidence that enhanced social distancing policies in the 63 Chinese cities outside Hubei province are effective in reducing the impact of population inflows from the epi-center cities in Hubei province on the spread of 2019-nCoV virus in the destination cities elsewhere.

JEL Codes

I18, I10.
Multiple blood feeding in mosquitoes shortens the Plasmodium falciparum incubation period and increases malaria transmission potential
Authors: Shaw W. Robert , Holmdahl Inga E. , Itoe Maurice A. , Werling Kristine , Marquette Meghan , Paton Douglas G. , Singh Naresh , Buckee Caroline O. , Childs Lauren M. , Catteruccia Flaminia
Published: March 2020

Many mosquito species, including the major malaria vector Anopheles gambiae, naturally undergo multiple reproductive cycles of blood feeding, egg development and egg laying in their lifespan. Such complex mosquito behavior is regularly overlooked when mosquitoes are experimentally infected with malaria parasites, limiting our ability to accurately describe potential effects on transmission. Here, we examine how Plasmodium falciparum development and transmission potential is impacted when infected mosquitoes feed an additional time. We measured P. falciparum oocyst size and performed sporozoite time course analyses to determine the parasite’s extrinsic incubation period (EIP), i.e. the time required by parasites to reach infectious sporozoite stages, in An. gambiae females blood fed either once or twice. An additional blood feed at 3 days post infection drastically accelerates oocyst growth rates, causing earlier sporozoite accumulation in the salivary glands, thereby shortening the EIP (reduction of 2.25 ± 0.39 days). Moreover, parasite growth is further accelerated in transgenic mosquitoes with reduced reproductive capacity, which mimic genetic modifications currently proposed in population suppression gene drives. We incorporate our shortened EIP values into a measure of transmission potential, the basic reproduction number R0, and find the average R0 is remarkably higher (range: 10.1%–12.1% increase) across sub-Saharan Africa than when using traditional EIP measurements. These data suggest that malaria elimination may be substantially more challenging and that younger mosquitoes or those with reduced reproductive ability may provide a larger contribution to infection than currently believed. Our findings have profound implications for current and future mosquito control interventions.

Significance Statement

In natural settings the female Anopheles gambiae mosquito, the major malaria vector, blood feeds multiple times in her lifespan. Here we demonstrate that an additional blood feed accelerates the growth of Plasmodium falciparum malaria parasites in this mosquito. Incorporating these data into a mathematical model across sub-Saharan Africa reveals that malaria transmission potential is likely to be substantially higher than previously thought, making disease elimination more difficult. Additionally, we show that control strategies that manipulate mosquito reproduction with the aim of suppressing Anopheles populations may inadvertently favor malaria transmission. Our data also suggest that parasites can be transmitted by younger mosquitoes, which are less susceptible to insecticide killing, with negative implications for the success of insecticide-based strategies.
Quality control of HLA-DR molecules by the lysosomal aspartyl protease, cathepsin D
Authors: Shah Nakul , McDonald Sarah , Parker Charles T.A. , Robinson Ryan W. M. , Oomatia Amin , De Riva Alessandra , Deery Michael J. , Mellins Elizabeth D. , Busch Robert
Published: March 2020

Major histocompatibility complex class II (MHCII) molecules display peptides on antigen-presenting cells (APCs) for inspection by CD4+ T cells. MHCII surface levels and life span are regulated post-translationally by peptide loading and ubiquitin-dependent lysosomal targeting, but proteases responsible for MHCII protein degradation remain unidentified. Here, we examined the role of aspartyl proteases in MHCII protein degradation and characterised the form of MHCII that is degraded. Exposure of immature monocyte-derived dendritic cells (MoDCs) and KG-1 acute myeloid leukaemia cells to the aspartyl protease inhibitor, pepstatin A (PepA), caused accumulation of human leukocyte antigen (HLA)-DR molecules in intracellular vesicles. Statistically significant PepA effects on MHCII protein expression were also observed in murine APCs. In KG-1 cells, cathepsin D (CatD) was the sole expressed aspartyl protease, and shRNA-mediated knockdown ablated the PepA effect, providing formal proof of CatD involvement. In vitro, CatD initiated specific cleavage of recombinant DR at αF54, a site flanking the peptide-binding groove. Immunochemical characteristics of PepA-rescued DR molecules in KG-1 cells were consistent with selective CatD attack on HLA-DR molecules that lack association with the MHCII chaperone, invariant chain, or with stably bound peptide. We propose that CatD has a critical role in the selective lysosomal disposal of mature HLA-DR molecules that have lost, or never acquired, bound peptide, explaining how MHCII protein life span is coupled to peptide loading.
Capsular polysaccharides cross-regulation modulatesBacteroides thetaiotaomicronbiofilm formation
Authors: Bechon Nathalie , Mihajlovic Jovana , Vendrell-Fernández Sol , Chain Florian , Langella Philippe , Beloin Christophe , Ghigo Jean-Marc
Published: March 2020

Bacteroides thetaiotaomicronis one of the most abundant gut symbiont species, whose contribution to host health through its ability to degrade diet polysaccharides and mature the immune system is under untense scrutiny. By contrast, adhesion and biofilm formation, which are potentially involved in gut colonization, microbiota structure and stability, have hardly been investigated in this intestinal bacterium. To uncoverB. thetaiotaomicronbiofilm-related functions, we performed a transposon mutagenesis in the poor biofilm-forming reference strain VPI 5482 and showed that capsule 4, one of the eightB. thetaiotaomicroncapsules, hinders biofilm formation. We then showed that the production of capsules 1, 2, 3, 5 and 6 also inhibits biofilm formation and that decreased capsulation of the population correlated with increased biofilm formation, suggesting that capsules could be masking adhesive surface structures. We also showed that, by contrast, capsule 8 displayed intrinsic adhesive properties. Finally, we demonstrated thatBT2934, thewzxhomolog ofB. thetaiotaomicronglycosylation locus, competes with capsule production and therefore impacts its adhesion capacity. This study identified regulation of capsular polysaccharides as a major determinant ofB. thetaiotaomicronbiofilm formation, providing new insights into how modulation of differentB. thetaiotaomicronsurface structures affectin vitrobiofilm formation.