bluuebunny/crossref_metadata_2025 huggingface dataset:
COVID-19 vaccines for low- and middle-income countries
Authors: Choi Edward M
Published: February 2021

The COVID-19 pandemic is the biggest threat to public health in a century. Through hard work and ingenuity, scientists have developed a number of safe and effective vaccines against COVID-19 disease. However, demand far outstrips supply and countries around the world are competing for available vaccines. This review describes how low- and middle-income countries access COVID-19 vaccines, what is being done to distribute vaccines fairly, as well as the challenges ahead.
How to Review a Surgical Scientific Paper: A Guide for Critical Appraisal
Authors: Greco Stephanie H. , Davis Catherine H. , Hicks Caitlin W. , Kaye Alison E. , Maxwell Jessica E. , Salles Arghavan , Henry Marion C.W.
Published: February 2021

It is important for surgeons to participate in the peer-review process of scientific literature. As the number of published manuscripts continues to increase, there is a great need for volunteerism in this arena. However, there is little formal or informal training, which can help surgeons provide unbiased and meaningful reviews. Therefore, it is critical to provide more resources and guidelines to aid surgeons during the review process. The purpose of this paper is to provide a structured guide for a quality review of a surgical paper. This review represents the work of the Association of Women Surgeons Publications Committee.
A marine zooplankton community vertically structured by light across diel to interannual timescales
Authors: Hobbs Laura , Banas Neil S. , Cohen Jonathan H. , Cottier Finlo R. , Berge Jørgen , Varpe Øystein
Published: February 2021

The predation risk of many aquatic taxa is dominated by visually searching predators, commonly a function of ambient light. Several studies propose that changes in visual predation will become a major climate-change impact on polar marine ecosystems. The High Arctic experiences extreme seasonality in the light environment, from 24 h light to 24 h darkness, and therefore provides a natural laboratory for studying light and predation risk over diel to seasonal timescales. Here, we show that zooplankton (observed using acoustics) in an Arctic fjord position themselves vertically in relation to light. A single isolume (depth-varying line of constant light intensity, the value of which is set at the lower limit of photobehaviour reponses of
Calanus
spp. and krill) forms a ceiling on zooplankton distribution. The vertical distribution is structured by light across timescales, from the deepening of zooplankton populations at midday as the sun rises in spring, to the depth to which zooplankton ascend to feed during diel vertical migration. These results suggest that zooplankton might already follow a foraging strategy that will keep visual predation risk roughly constant under changing light conditions, such as those caused by the reduction of sea ice, but likely with energetic costs such as lost feeding opportunities as a result of altered habitat use.
Trade-offs between mobility restrictions and transmission of SARS-CoV-2
Authors: Gösgens Martijn , Hendriks Teun , Boon Marko , Steenbakkers Wim , Heesterbeek Hans , van der Hofstad Remco , Litvak Nelly
Published: February 2021

In their response to the COVID-19 outbreak, governments face the dilemma to balance public health and economy. Mobility plays a central role in this dilemma because the movement of people enables both economic activity and virus spread. We use mobility data in the form of counts of travellers between regions, to extend the often-used SEIR models to include mobility between regions. We quantify the trade-off between mobility and infection spread in terms of a single parameter, to be chosen by policy makers, and propose strategies for restricting mobility so that the restrictions are minimal while the infection spread is effectively limited. We consider restrictions where the country is divided into regions, and study scenarios where mobility is allowed within these regions, and disallowed between them. We propose heuristic methods to approximate optimal choices for these regions. We evaluate the obtained restrictions based on our trade-off. The results show that our methods are especially effective when the infections are highly concentrated, e.g. around a few municipalities, as resulting from superspreading events that play an important role in the spread of COVID-19. We demonstrate our method in the example of the Netherlands. The results apply more broadly when mobility data are available.
Injury-induced Cavl-expressing cells at lesion rostral side play major roles in spinal cord regeneration
Authors: Zeng Chih-Wei , Kamei Yasuhiro , Shigenobu Shuji , Sheu Jin-Chuan , Tsai Huai-Jen
Published: February 2021

The extent of cellular heterogeneity involved in neuronal regeneration after spinal cord injury (SCI) remains unclear. Therefore, we established stress-responsive transgenic zebrafish embryos with SCI. As a result, we found an SCI-induced cell population, termed SCI stress-responsive regenerating cells (SrRCs), essential for neuronal regeneration post-SCI. SrRCs were mostly composed of subtypes of radial glia (RGs-SrRCs) and neuron stem/progenitor cells (NSPCs-SrRCs) that are able to differentiate into neurons, and they formed a bridge across the lesion and connected with neighbouring undamaged motor neurons post-SCI. Compared to SrRCs at the caudal side of the SCI site (caudal-SrRCs), rostral-SrRCs participated more actively in neuronal regeneration. After RNA-seq analysis, we discovered that
caveolin 1
(
cav1
) was significantly upregulated in rostral-SrRCs and that
cav1
was responsible for the axonal regrowth and regenerative capability of rostral-SrRCs. Collectively, we define a specific SCI-induced cell population, SrRCs, involved in neuronal regeneration, demonstrate that rostral-SrRCs exhibit higher neuronal differentiation capability and prove that
cav1
is predominantly expressed in rostral-SrRCs, playing a major role in neuronal regeneration after SCI.
Evolution of thymopoietic microenvironments
Authors: Morimoto Ryo , Swann Jeremy , Nusser Anja , Trancoso Inês , Schorpp Michael , Boehm Thomas
Published: February 2021

In vertebrates, the development of lymphocytes from undifferentiated haematopoietic precursors takes place in so-called primary lymphoid organs, such as the thymus. Therein, lymphocytes undergo a complex differentiation and selection process that culminates in the generation of a pool of mature T cells that collectively express a self-tolerant repertoire of somatically diversified antigen receptors. Throughout this entire process, the microenvironment of the thymus in large parts dictates the sequence and outcome of the lymphopoietic activity. In vertebrates, direct genetic evidence in some species and circumstantial evidence in others suggest that the formation of a functional thymic microenvironment is controlled by members of the Foxn1/4 family of transcription factors. In teleost fishes, both
Foxn1
and
Foxn4
contribute to thymopoietic activity, whereas
Foxn1
is both necessary and sufficient in the mammalian thymus. The evolutionary history of
Foxn1/4
genes suggests that an ancient
Foxn4
gene lineage gave rise to the
Foxn1
genes in early vertebrates, raising the question of the thymopoietic capacity of the ancestor common to all vertebrates. Recent attempts to reconstruct the early events in the evolution of thymopoietic tissues by replacement of the mouse
Foxn1
gene by
Foxn1
-like genes isolated from various chordate species suggest a plausible scenario. It appears that the primordial thymus was a bi-potent lymphoid organ, supporting both B cell and T cell development; however, during the course of vertebrate, evolution B cell development was gradually diminished converting the thymus into a site specialized in T cell development.
Ectopic positioning of the cell division plane is associated with single amino acid substitutions in the FtsZ-recruiting SsgB inStreptomyces
Authors: Xiao Xiansha , Willemse Joost , Voskamp Patrick , Li Xinmeng , Prota Andrea E. , Lamers Meindert , Pannu Navraj , Abrahams Jan Pieter , van Wezel Gilles P.
Published: February 2021

In most bacteria, cell division begins with the polymerization of the GTPase FtsZ at mid-cell, which recruits the division machinery to initiate cell constriction. In the filamentous bacteriumStreptomyces, cell division is positively controlled by SsgB, which recruits FtsZ to the future septum sites and promotes Z-ring formation. Here, we show that various amino acid (aa) substitutions in the highly conserved SsgB protein result in ectopically placed septa that sever spores diagonally or along the long axis, perpendicular to the division plane. Fluorescence microscopy revealed that between 3.3% and 9.8% of the spores of strains expressing SsgB E120 variants were severed ectopically. Biochemical analysis of SsgB variant E120G revealed that its interaction with FtsZ had been maintained. The crystal structure ofStreptomyces coelicolorSsgB was resolved and the key residues were mapped on the structure. Notably, residue substitutions (V115G, G118V, E120G) that are associated with septum misplacement localize in theα2–α3 loop region that links the final helix and the rest of the protein. Structural analyses and molecular simulation revealed that these residues are essential for maintaining the proper angle of helixα3. Our data suggest that besides altering FtsZ, aa substitutions in the FtsZ-recruiting protein SsgB also lead to diagonally or longitudinally divided cells inStreptomyces.
Temperature surpasses the effects of velocity and turbulence on swimming performance of two invasive non-native fish species
Authors: Muhawenimana V. , Thomas J. R. , Wilson C. A. M. E. , Nefjodova J. , Chapman A. C. , Williams F. C. , Davies D. G. , Griffiths S. W. , Cable J.
Published: February 2021

Global climate change continues to impact fish habitat quality and biodiversity, especially in regard to the dynamics of invasive non-native species. Using individual aquaria and an open channel flume, this study evaluated the effects of water temperature, flow velocity and turbulence interactions on swimming performance of two lentic, invasive non-native fish in the UK, pumpkinseed (
Lepomis gibbosus
) and topmouth gudgeon (
Pseudorasbora parva
). Burst and sustained swimming tests were conducted at 15, 20 and 25°C. Acoustic Doppler velocimetry was used to measure the flume hydrodynamic flow characteristics. Both
L. gibbosus
and
P. parva
occupied the near-bed regions of the flume, conserving energy and seeking refuge in the low mean velocities flow areas despite the relatively elevated turbulent fluctuations, a behaviour which depended on temperature. Burst swimming performance and sustained swimming increased by up to 53% as temperature increased from 15 to 20°C and 71% between 15 and 25°C. Furthermore, fish test area occupancy was dependent on thermal conditions, as well as on time-averaged velocities and turbulent fluctuations. This study suggests that invasive species can benefit from the raised temperatures predicted under climate change forecasts by improving swimming performance in flowing water potentially facilitating their further dispersal and subsequent establishment in lotic environments.
The cost of quantum locality
Authors: Bédard C. A.
Published: February 2021

It has been more than 20 years since Deutsch and Hayden demonstrated that quantum systems can be completely described locally—notwithstanding Bell’s theorem. More recently, Raymond-Robichaud proposed two other approaches to the same conclusion. In this paper, all these means of describing quantum systems locally are proved formally equivalent. The cost of such descriptions is then quantified by the dimensionality of their underlining space. The number of degrees of freedom of a single qubit’s local description is shown to grow exponentially with the total number of qubits considered as a global system. This apparently unreasonable cost to describe such a small system in a large Universe is nonetheless shown to be expected. Finally, structures that supplement the universal wave function are investigated.
Bulky auxeticity, tensile buckling and
deck-of-cards
kinematics emerging from structured continua
Authors: Palumbo S. , Carotenuto A. R. , Cutolo A. , Owen D. R. , Deseri L. , Fraldi M.
Published: February 2021

Complex mechanical behaviours are generally met in macroscopically homogeneous media as effects of inelastic responses or as results of unconventional material properties, which are postulated or due to structural systems at the meso/micro-scale. Examples are strain localization due to plasticity or damage and metamaterials exhibiting negative Poisson’s ratios resulting from special porous, eventually buckling, sub-structures. In this work, through
ad hoc
conceived mechanical paradigms, we show that several non-standard behaviours can be obtained simultaneously by accounting for kinematical discontinuities, without invoking inelastic laws or initial voids. By allowing mutual sliding among rigid tesserae connected by pre-stressed hyperelastic links, we find several unusual kinematics such as localized shear modes and tensile buckling-induced instabilities, leading to
deck-of-cards
deformations—uncapturable with classical continuum models—and unprecedented ‘bulky’ auxeticity emerging from a densely packed, geometrically symmetrical ensemble of discrete units that deform in a chiral way. Finally, after providing some analytical solutions and inequalities of mechanical interest, we pass to the limit of an infinite number of tesserae of infinitesimal size, thus transiting from discrete to continuum, without the need to introduce characteristic lengths. In the light of the theory of structured deformations, this result demonstrates that the proposed architectured material is nothing else than the first biaxial paradigm of
structured continuum
—a body that projects, at the macroscopic scale, geometrical changes and disarrangements occurring at the level of its sub-macroscopic elements.
Rods coiling about a rigid constraint: helices and perversions
Authors: Riccobelli D. , Noselli G. , DeSimone A.
Published: February 2021

Mechanical instabilities can be exploited to design innovative structures, able to change their shape in the presence of external stimuli. In this work, we derive a mathematical model of an elastic beam subjected to an axial force and constrained to smoothly slide along a rigid support, where the distance between the rod midline and the constraint is fixed and finite. Using both theoretical and computational techniques, we characterize the bifurcations of such a mechanical system, in which the axial force and the natural curvature of the beam are used as control parameters. We show that, in the presence of a straight support, the rod can deform into shapes exhibiting helices and perversions, namely transition zones connecting together two helices with opposite chirality. The mathematical predictions of the proposed model are also compared with some experiments, showing a good quantitative agreement. In particular, we find that the buckled configurations may exhibit multiple perversions and we propose a possible explanation for this phenomenon based on the energy landscape of the mechanical system.
Prandtl’s extended mixing length model applied to the two-dimensional turbulent classical far wake
Authors: Hutchinson Ashleigh J. , Hale Nicholas , Born Kendall , Mason David P.
Published: February 2021

Despite its limitations, Prandtl’s mixing length model is widely applied in modelling turbulent free shear flows. Prandtl’s extended model addresses many of the shortfalls of the original model, but is not so widely used, in part due to additional mathematical complexities that arise in its derivation and implementation. Furthermore, in both models, Prandtl neglects the kinematic viscosity on the basis that it is much smaller in magnitude than the turbulent viscosity. Recent work has shown that including the kinematic viscosity in the original model has both mathematical and physical advantages. In the present work, a novel derivation of the extended model is provided, and it is demonstrated that similar advantages are again obtained when the kinematic viscosity is included. Additionally, through the use of scaling techniques, similarity mean velocity profiles of the extended model are derived, resulting in a single nonlinear ordinary differential equation that is solved numerically with a Hermite spectral method. The computed profiles for the normalized similarity mean velocity and shear stress are compared with experimental observations and shown to be in excellent agreement.
Limited vocal compensation for elevated ambient noise in bearded seals: implications for an industrializing Arctic Ocean
Authors: Fournet Michelle E. H. , Silvestri Margherita , Clark Christopher W. , Klinck Holger , Rice Aaron N.
Published: February 2021

Vocalizing animals have several strategies to compensate for elevated ambient noise. These behaviours evolved under historical conditions, but compensation limits are quickly being reached in the Anthropocene. Acoustic communication is essential to male bearded seals that vocalize for courtship and defending territories. As Arctic sea ice declines, industrial activities and associated anthropogenic noise are likely to increase. Documenting how seals respond to noise and identifying naturally occurring behavioural thresholds would indicate either their resilience or vulnerability to changing soundscapes. We investigated whether male bearded seals modified call amplitudes in response to changing ambient noise levels. Vocalizing seals increased their call amplitudes until ambient noise levels reached an observable threshold, above which call source levels stopped increasing. The presence of a threshold indicates limited noise compensation for seals, which still renders them vulnerable to acoustic masking of vocal signals. This behavioural threshold and response to noise is critical for developing management plans for an industrializing Arctic.
Male-like female morphs in hummingbirds: the evolution of a widespread sex-limited plumage polymorphism
Authors: Diamant Eleanor S. , Falk Jay J. , Rubenstein Dustin R.
Published: February 2021

Differences in the way males and females look or behave are common in animals. However, discrete variation within sexes (sex-limited polymorphism) also occurs in several vertebrate and invertebrate lineages. In birds, female-limited polymorphism (FLP) in which some females resemble males in coloration is most prominent in hummingbirds, a group known for its morphological and behavioural sexual dimorphism. Yet, it remains unclear whether this intrasexual colour variation in hummingbirds arises through direct selection on females, or indirectly as a non-adaptive byproduct resulting from selection on males. Here, we analysed specimens from more than 300 hummingbird species to determine the extent, evolutionary history and function of FLP. We found that FLP evolved independently in every major clade and occurs in nearly 25% of hummingbird species. Using phylogenetically informed analyses, we rejected non-adaptive hypotheses that FLP is the result of indirect selection or pleiotropy across species. Instead, FLP is associated with ecology, migratory status, and marginally with social dominance, suggesting a socioecological benefit to females. Ultimately, we show that FLP is not only widespread in hummingbirds and likely adaptive, but may also be useful for understanding the evolution of female ornamentation in systems under strong sexual selection.
The immunomodulatory activity of secnidazole–nitazoxanide in a murine cryptosporidiosis model
Authors: Madbouly Neveen , El Amir Azza , Abdel Kader Asmaa , Rabee Ibraheem , Farid Alyaa
Published: February 2021

Introduction.
Cryptosporidium parvum causes intestinal parasitic infections affecting both immunosuppressed and immunocompetent individuals.

Gap statement. Given the absence of effective treatments for cryptosporidiosis, especially in immunodeficient patients, the present study was designed to assess the therapeutic efficacy of secnidazole (SEC) and its combination with nitazoxanide (NTZ) in comparison to single NTZ treatment in relation to the immune status of a murine model of C. parvum infection.

Methodology. The infected groups were administered NTZ, SEC or NTZ–SEC for three or five successive doses. At days 10 and 12 post-infection (p.i.), the mice were sacrificed, and the efficacy of the applied drugs was evaluated by comparing the histopathological alterations in ileum and measuring the T helper Th1 (interferon gamma; IFN-γ), Th2 [interleukin (IL)-4 and IL-10] and Th17 (IL-17) cytokine profiles in serum.

Results. The NTZ–SEC combination recorded the maximal reduction of C. parvum oocyst shedding, endogenous stages count and intestinal histopathology, regardless of the immune status of the infected mice. The efficacy of NTZ–SEC was dependent on the period of administration, as the 5 day-based treatment protocol was also more effective than the 3 day-based one in terms of immunocompetence and immunosuppression. The present treatment schedule induced an immunomodulatory effect from SEC that developed a protective immune response against C. parvum infection with reduced production of serum IL-17, IFN-γ, IL-4 and IL-10.

Conclusions. Application of NTZ–SEC combined therapy may be useful in treatment of C. parvum, especially in cases involving immunosuppression.
Deep neural network estimated electrocardiographic-age as a mortality predictor
Authors: Lima Emilly M , Ribeiro Antônio H , Paixão Gabriela MM , Ribeiro Manoel Horta , Filho Marcelo M Pinto , Gomes Paulo R , Oliveira Derick M , Sabino Ester C , Duncan Bruce B , Giatti Luana , Barreto Sandhi M , Meira Wagner , Schön Thomas B , Ribeiro Antonio Luiz P
Published: February 2021

The electrocardiogram (ECG) is the most commonly used exam for the screening and evaluation of cardiovascular diseases. Here we propose that the age predicted by artificial intelligence (AI) from the raw ECG tracing (ECG-age) can be a measure of cardiovascular health and provide prognostic information. A deep convolutional neural network was trained to predict a patient’s age from the 12-lead ECG using data from patients that underwent an ECG from 2010 to 2017 - the CODE study cohort (n=1,558,415 patients). On the 15% hold-out CODE test split, patients with ECG-age more than 8 years greater than chronological age had a higher mortality rate (hazard ratio (HR) 1.79, p<0.001) in a mean follow-up of 3.67 years, whereas those with ECG-age more than 8 years less than chronological age had a lower mortality rate (HR 0.78, p<0.001). Similar results were obtained in the external cohorts ELSA-Brasil (n=14,236) and SaMi-Trop (n=1,631). The ability to predict mortality from the ECG predicted age remains even when we adjust the model for cardiovascular risk factors. Moreover, even for apparent normal ECGs, having a predicted ECG-age 8 or more years greater than chronological age remained a statistically significant predictor of risk (HR 1.53, p<0.001 in CODE 15% test split). These results show that AI-enabled analysis of the ECG can add prognostic information to the interpretation of the 12-lead ECGs.
Diagnostic value in colorectal tumorous lesions of SDC2/TFPI2 methylation based on bowel subsite difference
Authors: Zhang Lianglu , Dong Lanlan , Lu Changming , Huang Wenxian , Yang Cuiping , Wang Qian , Wang Qian , Lei Ruixue , Sun Rui , Wan Kangkang , Li Tingting , Sun Fan , Gan Tian , Lin Jun , Yin Lei
Published: February 2021

Background

SDC2 methylation is a potential biomarker for colorectal cancer detection with specificity over 90%, but its sensitivity is usually less than 90%. The study aims to improve the sensitivity and specificity by adding TFPI2 methylation as a complement.

Methods

TFPI2 was identified using colorectal cancer samples from TCGA database with SDC2 methylation level lower than 0.2. SDC2/TFPI2 methylation specific PCR was performed using tissue samples (184 cancer and 54 healthy control) and stool samples (289 cancer, 190 adenoma and 217 healthy control). Detection sensitivity was calculated among tumors from different biopsy locations.

Results

88% of 50 TCGA specimens of colorectal cancer with SDC2 methylation level lower than 0.2 showed TFPI2 methylation level higher than 0.2. SDC2/TFPI2 combined detection in stool specimens showed AUC value of 0.98 with the specificity of 96.40% and sensitivity of 96.60% for cancer vs control, AUC value of 0.87 with the specificity of 95.70% and sensitivity of 80.00% for adenoma vs control. The sensitivities were much higher than those of SDC2, and the improvement was most significant in lesions from left colon and rectum.

Conclusions

This research indicated that the addition of TFPI2 can reduce the miss detection rate of colorectal cancer and adenomas while maintaining high specificity, probably by finding neoplasms in left colon.The method is non-invasive and has good compliance, also avoiding the pain of bowel preparation and risk of cross infection during endoscopy, so it will provide an easy and precise tool for colorectal cancer and its precancerous lesions screening.
Using mixed-effects modeling to estimate decay kinetics of response to SARS-CoV-2 infection
Authors: Bottino D. , Hather G. , Yuan L. , Stoddard M. , White L. , Chakravarty A.
Published: February 2021

The duration of natural immunity in response to SARS-CoV-2 is a matter of some debate in the literature at present. For example, in a recent publication characterizing SARS-CoV-2 immunity over time, the authors fit pooled longitudinal data, using fitted slopes to infer the duration of SARS-CoV-2 immunity. In fact, such approaches can lead to misleading conclusions as a result of statistical model-fitting artifacts. To exemplify this phenomenon, we reanalyzed one of the markers (pseudovirus neutralizing titer) in the publication, using mixed-effects modeling, a methodology better suited to longitudinal datasets like these. Our findings showed that the half-life was both longer and more variable than reported by the authors. The example selected by us here illustrates the utility of mixed-effects modeling in provide more accurate estimates of the duration and heterogeneity of half-lives of molecular and cellular biomarkers of SARS-CoV-2 immunity.
Microbial signatures in the lower airways of mechanically ventilated COVID19 patients associated with poor clinical outcome
Authors: Sulaiman Imran , Chung Matthew , Angel Luis , Tsay Jun-Chieh J. , Wu Benjamin G. , Yeung Stephen T. , Krolikowski Kelsey , Li Yonghua , Duerr Ralf , Schluger Rosemary , Thannickal Sara A. , Koide Akiko , Rafeq Samaan , Barnett Clea , Postelnicu Radu , Wang Chang , Banakis Stephanie , Perez-Perez Lizzette , Jour George , Shen Guomiao , Meyn Peter , Carpenito Joseph , Liu Xiuxiu , Ji Kun , Collazo Destiny , Labarbiera Anthony , Amoroso Nancy , Brosnahan Shari , Mukherjee Vikramjit , Kaufman David , Bakker Jan , Lubinsky Anthony , Pradhan Deepak , Sterman Daniel H. , Weiden Michael , Hegu Adriana , Evans Laura , Uyeki Timothy M. , Clemente Jose C. , De wit Emmie , Schmidt Ann Marie , Shopsin Bo , Desvignes Ludovic , Wang Chan , Li Huilin , Zhang Bin , Forst Christian V. , Koide Shohei , Stapleford Kenneth A. , Khanna Kamal M. , Ghedin Elodie , Segal Leopoldo N.
Published: February 2021

Mortality among patients with COVID-19 and respiratory failure is high and there are no known lower airway biomarkers that predict clinical outcome. We investigated whether bacterial respiratory infections and viral load were associated with poor clinical outcome and host immune tone. We obtained bacterial and fungal culture data from 589 critically ill subjects with COVID-19 requiring mechanical ventilation. On a subset of the subjects that underwent bronchoscopy, we also quantified SARS-CoV-2 viral load, analyzed the microbiome of the lower airways by metagenome and metatranscriptome analyses and profiled the host immune response. We found that isolation of a hospital-acquired respiratory pathogen was not associated with fatal outcome. However, poor clinical outcome was associated with enrichment of the lower airway microbiota with an oral commensal (Mycoplasma salivarium), while high SARS-CoV-2 viral burden, poor anti-SARS-CoV-2 antibody response, together with a unique host transcriptome profile of the lower airways were most predictive of mortality. Collectively, these data support the hypothesis that 1) the extent of viral infectivity drives mortality in severe COVID-19, and therefore 2) clinical management strategies targeting viral replication and host responses to SARS-CoV-2 should be prioritized.
An evaluation of toxigenic Clostridioides difficile positivity as a patient outcome metric of antimicrobial stewardship in Saudi Arabia
Authors: Okeahialam Christopher A. , Rabaan Ali A. , Bolhuis Albert
Published: February 2021

Background

Antimicrobial stewardship has been associated with a reduction in the incidence of health care associated Clostridium difficile infection (HA-CDI). However, CDI remains under-recognized in many low and middle-income countries where clinical and surveillance resources required to identify HA-CDI are often lacking. The rate of toxigenic C. difficile stool positivity in the stool of hospitalized patients may offer an alternative metric for these settings, but its utlity remains largely untested.

Aim/Objective

To examine the impact of an antimicrobial stewardship on the rate of toxigenic C. difficile positivity among hospitalized patients presenting with diarrhoea

Methods

A 12-year retrospective review of laboratory data was conducted to compare the rates of toxigenic C. difficile in diarrhoea stool of patients in a hospital in Saudi Arabia, before and after implementation of an antimicrobial stewardship program

Result

There was a significant decline in the rate of toxigenic C difficile positivity from 9.8 to 7.4% following the implementation of the antimicrobial stewardship program, and a reversal of a rising trend.

Discussion

The rate of toxigenic C. difficile positivity may be a useful patient outcome metric for evaluating the long term impact of antimicrobial stewardship on CDI, especially in settings with limited surveillance resources. The accuracy of this metric is however dependent on the avoidance of arbitrary repeated testing of a patient for cure, and testing only unformed or diarrhoea stool specimens. Further studies are required within and beyond Saudi Arabia to examine the utility of this metric.
Adverse childhood experiences and multiple mental health outcomes through adulthood: a prospective birth cohort study
Authors: Gondek Dawid , Patalay Praveetha , Lacey Rebecca E
Published: February 2021

This study examined the association between adverse childhood experiences (ACEs) and mental health-related outcomes spanning ages 16-55 years, using a prospective birth cohort representative of those born around 1958 in Great Britain.

We found a dose-response association between prospectively and retrospectively reported ACEs and all studied mental health-related outcomes, after accounting for multiple covariates. Among those with 2+ (vs 0) prospective ACEs, the risk of clinically significant psychological distress was up to 2.14 times higher, and of seeing a mental health specialist up to 2.85 times higher. Our findings reiterate the need for early-life interventions to reduce inequalities in mental health.
Recruitment of KRAS downstream target ARL4C to membrane protrusions accelerates pancreatic cancer cell invasion
Authors: Harada Akikazu , Matsumoto Shinji , Yasumizu Yoshiaki , Akama Toshiyuki , Eguchi Hidetoshi , Kikuchi Akira
Published: February 2021

Pancreatic cancer (PC) has a high mortality rate due to metastasis. Whereas KRAS is mutated in most PC patients, controlling KRAS or its downstream effectors has not been succeeded clinically. ARL4C is a small G protein whose expression is induced by the Wnt and EGF–RAS pathways. In the present study, we found that ARL4C is frequently overexpressed in PC patients and showed that its unique localization to membrane protrusions is required for cancer cell invasion. IQGAP1 was identified as a novel interacting protein for ARL4C. ARL4C recruited IQGAP1 and its downstream effector, MMP14, to membrane protrusions. Specific localization of ARL4C, IQGAP1, and MMP14 was the active site of invasion, which induced degradation of the extracellular matrix. Moreover, subcutaneously injected antisense oligonucleotide (ASO) against ARL4C into tumor-bearing mice suppressed metastasis of PC. These results suggest that ARL4C–IQGAP1–MMP14 signaling is activated at membrane protrusions of PC cells.
Extracellular vesicles mediate the intercellular exchange of nanoparticles
Authors: Wu Xian , Tang Tang , Wei Yushuang , Cummins Katherine A. , Wood David K. , Pang Hong-Bo
Published: February 2021

In order to exert their therapeutic effects, nanoparticles (NPs) often need to travel into the tissues composed of multilayered cells. Accumulative evidence has revealed the crucial role of transcellular transport route (entry into one cell, exocytosis, and re-entry into another) in this process. While NP endocytosis and subcellular transport have been intensively characterized, the exocytosis and re-entry steps are poorly understood, which becomes a barrier to improve NP delivery into complex tissues. Here, we termed the exocytosis and re-entry steps together as intercellular exchange. We developed a collagen-based 3D assay to specifically monitor and quantify the intercellular exchange events of NPs, and distinguish the contributions of several potential mechanisms. Our results showed that NPs can be exocytosed freely or enclosed inside extracellular vesicles (EVs) for re-entry, while direct cell-cell contact is hardly involved. EVs account for a significant fraction of NP intercellular exchange, and its importance in NP transport was demonstratedin vitroandin vivo. Intriguingly, while freely released NPs engage with the same cellular receptors for re-entry, EV-enclosed ones bypass this dependence. These studies provide an easy and precise system to investigate the intercellular exchange stage of NP delivery, and shed the first light in the importance of EVs in NP transport between cells and across complex tissues.
A Phosphorylated Histone H2A Variant Displays Properties of Chromatin Insulator Proteins inDrosophila
Authors: Simmons James R. , An Ran , Amankwaa Bright , Zayac Shannon , Kemp Justin , Labrador Mariano
Published: February 2021

Chromatin insulators are responsible for mediating long-range interactions between enhancers and promoters throughout the genome and align with the boundaries of topologically associating domains (TADs). Here, we demonstrate an interaction between proteins that associate with thegypsyinsulator and the phosphorylated histone variant H2Av (γH2Av), a marker of DNA double strand breaks.Gypsyinsulator components colocalize with γH2Av throughout the genome. Mutation of insulator components prevents stable H2Av phosphorylation in polytene chromatin. Phosphatase inhibition strengthens the association between insulator components and γH2Av and rescues γH2Av localization in insulator mutants. We also show that γH2Av is a component of insulator bodies, and that phosphatase activity is required for insulator body dissolution after recovery from osmotic stress. We further demonstrate a tight association between γH2Av and TAD boundaries. Together, our results indicate a novel mechanism linking insulator function with a histone H2A variant and with genome stability.
Rickettsia japonicain ticks infesting a wild mammal in Thailand
Authors: Hirunkanokpun Supanee , Ahantarig Arunee , Baimai Visut , Pramual Pairot , Trinachartvanit Wachareeporn
Published: February 2021

We report the first case ofRickettsia japonicainHaemaphysalis hystricisticks collected from a Burmese ferret-badger in Loei province, northeastern Thailand. Phylogenetic analyses ofompA andompB genes clearly showed that it was almost identical toR. japonicafound in ticks and Japanese spotted fever (JSF) patients previously reported.
The proximal proteome of 17 SARS-CoV-2 proteins links to disrupted antiviral signaling and host translation
Authors: Meyers Jordan M , Ramanathan Muthukumar , Shanderson Ronald L , Donohue Laura , Ferguson Ian , Guo Margaret G , Rao Deepti S , Miao Weili , Reynolds David , Yang Xue , Zhao Yang , Yang Yen-Yu , Wang Yinsheng , Khavari Paul A
Published: February 2021

Viral proteins localize within subcellular compartments to subvert host machinery and promote pathogenesis. To study SARS-CoV-2 biology, we generated an atlas of 2422 human proteins vicinal to 17 SARS-CoV-2 viral proteins using proximity proteomics. This identified viral proteins at specific intracellular locations, such as association of accessary proteins with intracellular membranes, and projected SARS-CoV-2 impacts on innate immune signaling, ER-Golgi transport, and protein translation. It identified viral protein adjacency to specific host proteins whose regulatory variants are linked to COVID-19 severity, including the TRIM4 interferon signaling regulator which was found proximal to the SARS-CoV-2 M protein. Viral NSP1 protein adjacency to the EIF3 complex was associated with inhibited host protein translation whereas ORF6 localization with MAVS was associated with inhibited RIG-I 2CARD-mediatedIFNB1promoter activation. Quantitative proteomics identified candidate host targets for the NSP5 protease, with specific functional cleavage sequences in host proteins CWC22 and FANCD2. This data resource identifies host factors proximal to viral proteins in living human cells and nominates pathogenic mechanisms employed by SARS-CoV-2.

Author Summary

SARS-CoV-2 is the latest pathogenic coronavirus to emerge as a public health threat. We create a database of proximal host proteins to 17 SARS-CoV-2 viral proteins. We validate that NSP1 is proximal to the EIF3 translation initiation complex and is a potent inhibitor of translation. We also identify ORF6 antagonism of RNA-mediate innate immune signaling. We produce a database of potential host targets of the viral protease NSP5, and create a fluorescence-based assay to screen cleavage of peptide sequences. We believe that this data will be useful for identifying roles for many of the uncharacterized SARS-CoV-2 proteins and provide insights into the pathogenicity of new or emerging coronaviruses.
Integrative analyses uncover mechanisms by which aging drives B cell lymphoma
Authors: Castro José P. , Shindyapina Anastasia V. , Barbieri Alessandro , Ying Kejun , Strelkova Olga S. , Paulo João A. , Tyshkovskiy Alexander , Meinl Rico , Kerepesi Csaba , Petrashen Anna P. , Mariotti Marco , Meer Margarita , Hu Yan , Karamyshev Alexander , Losyev Grigoriy , Indzhykulian Artur A. , Gygi Steven P. , Sedivy John M. , Manis John P. , Gladyshev Vadim N.
Published: February 2021

While cancer is an age-related disease, many cancer studies utilize younger animal models. Here, we uncover how a cancer, B-cell lymphoma, develops as a consequence of a naturally aged system. We show that this malignancy is associated with increased cell size, splenomegaly, and a newly discovered age-associated clonal B-cell (ACBC) population. Driven by exogenous c-Myc activation, hypermethylated promoters and somatic mutations, ACBC cells clonally expand independent of germinal centers (IgM+) and show increased biological age and hypomethylation in partially methylated domains related to mitotic solo-CpGs. Epigenetic changes in transformed mouse B cells are enriched for changes observed in human B-cell lymphomas. Mechanistically, the data suggest that cancerous ACBC cells originate from age-associated B cells, in part involving CD22 protein signaling fostered by the aging microenvironment. Transplantation assays demonstrate that ACBC evolve to become self-sufficient and support malignancy when transferred into young recipients. Inhibition of mTOR or c-Myc in old mice attenuates premalignant changes in B cells during aging and emerges as a therapeutic strategy to delay the onset of age-related lymphoma. Together, we show how aging contributes to B-cell lymphoma through a previously unrecognized mechanism involving cell-intrinsic changes and the aged microenvironment, characterize a model that captures the origin and progression of spontaneous cancer during aging and identify candidate interventions against age-associated lymphoma.
Mental individuation of imagined finger movements can be achieved using TMS-based neurofeedback
Authors: Mihelj Ernest , Bächinger Marc , Kikkert Sanne , Ruddy Kathy , Wenderoth Nicole
Published: February 2021

Neurofeedback (NF) in combination with motor imagery (MI) can be used for training individuals to volitionally modulate sensorimotor activity without producing overt movements. However, until now, NF methods were of limited utility for mentally training specific hand and finger actions. Here we employed a novel transcranial magnetic stimulation (TMS) based protocol to probe and detect MI-induced motor activity patterns in the primary motor cortex (M1) with the aim to reinforce selective facilitation of single finger representations. We showed that TMS-NF training but not MI training with uninformative feedback enabled participants to selectively upregulate corticomotor excitability of one finger, while simultaneously downregulating excitability of other finger representations within the same hand. Successful finger individuation during MI was accompanied by strong desynchronisation of sensorimotor brain rhythms, particularly in the beta band, as measured by electroencephalography. Additionally, informative TMS-NF promoted more dissociable EEG activation patterns underlying single finger MI, when compared to MI of the control group where no such feedback was provided. Our findings suggest that selective TMS-NF is a new approach for acquiring the ability of finger individuation even if no overt movements are performed. This might offer new treatment modality for rehabilitation after stroke or spinal cord injury.
Likelihood-based Tests for Detecting Circadian Rhythmicity and Differential Circadian Patterns in Transcriptomic Applications
Authors: Ding Haocheng , Meng Lingsong , Liu Andrew C. , Gumz Michelle L. , Bryant Andrew J. , Mcclung Colleen A. , Tseng George C. , Esser Karyn A. , Huo Zhiguang
Published: February 2021

Circadian rhythmicity in transcriptomic profiles has been shown in many physiological processes, and the disruption of circadian patterns has been founded to associate with several diseases. In this paper, we developed a series of likelihood-based methods to detect (i) circadian rhythmicity (denoted as LR rhythmicity) and (ii) differential circadian patterns comparing two experimental conditions (denoted as LR diff). In terms of circadian rhythmicity detection, we demonstrated that our proposed LR rhythmicity could better control the type I error rate compared to existing methods under a wide variety of simulation settings. In terms of differential circadian patterns, we developed methods in detecting differential amplitude, differential phase, differential basal level, and differential fit, which also successfully controlled the type I error rate. In addition, we demonstrated that the proposed LR diff could achieve higher statistical power in detecting differential fit, compared to existing methods. The superior performance of LR rhythmicity and LR diff was demonstrated in two real data applications, including a brain aging data (gene expression microarray data of human postmortem brain) and a time-restricted feeding data (RNA sequencing data of human skeletal muscles). An R package for our methods is publicly available on GitHubhttps://github.com/diffCircadian/diffCircadian.
Draft metagenomes of endolithic cyanobacteria and co-habitants from hyper-arid deserts
Authors: Murray Bayleigh , Dailey Micah , Ertekin Emine , DiRuggiero Jocelyne
Published: February 2021

Cyanobacteria are essential to microbial communities inhabiting translucent rocks in hyper-arid deserts. Metagenomic studies revealed unique adaptations of these cyanobacteria but validation of the corresponding metabolic pathways remained challenging without access to isolates. Here we present high-quality metagenome assembled genomes for cyanobacteria, and their heterotrophic companions, isolated from endolithic substrates.
Spatially-Resolved Proteomic Analysis of the Lens Extracellular Diffusion Barrier
Authors: Wang Zhen , Schey Kevin L
Published: February 2021

Purpose

The presence of a physical barrier to molecular diffusion through lenticular extracellular space has been repeatedly detected in multiple species. This extracellular diffusion barrier has been proposed to restrict the movement of solutes into the lens and to direct nutrients into the lens core via the sutures at both poles. The purpose of this study is to characterize the molecular components that could contribute to the formation of this barrier.

Methods

Three distinct regions in the bovine lens cortex were captured by laser capture microdissection guided by dye penetration. Proteins were digested by endoproteinase Lys C and trypsin. Mass spectrometry-based quantitative proteomic analysis followed by gene ontology (GO) and protein-protein interaction network analysis was performed.

Results

Dye penetration showed that lens fiber cells first shrink the extracellular spaces of the broad sides of fiber cells followed by closure of the extracellular space between narrow sides at normalized lens distance (r/a) of 0.9. Accompanying the closure of extracellular space of the broad sides, dramatic proteomic changes were detected including up-regulation of several cell junctional proteins. AQP0 and its interacting partners ERM proteins were among a few proteins that were upregulated accompanying the closure of extracellular space of the narrow sides suggesting a particularly important role for the major lens membrane protein AQP0 in controlling the narrowing of the extracellular spaces between lens fiber cells. The results also provided important information related to biological processes that occur during fiber cell differentiation such as organelle degradation, cytoskeletal remodeling and GSH synthesis.

Conclusions

The formation of lens extracellular diffusion barrier is accompanied by significant membrane and cytoskeletal protein remodeling.
Structure of macrophage migration inhibitory factor in complex with methotrexate
Authors: Fukushima Kei , Furuya Minoru , Kamimura Takashi , Takimoto-Kamimura Midori
Published: February 2021

Methotrexate (MTX) is an anticancer and anti-rheumatoid arthritis drug that is considered to block nucleotide synthesis and the cell cycle mainly by inhibiting the activity of dihydrofolate reductase (DHFR). Using affinity-matrix technology and X-ray analysis, the present study shows that MTX also interacts with macrophage migration inhibitory factor (MIF). Fragment molecular-orbital calculations quantified the interaction between MTX and MIF based on the structure of the complex and revealed the amino acids that are effective in the interaction of MTX and MIF. It should be possible to design new small-molecule compounds that have strong inhibitory activity towards both MIF and DHFR by structure-based drug discovery.