bluuebunny/crossref_metadata_2025 huggingface dataset:
Large-scale CRISPRi and transcriptomics ofStaphylococcus epidermidisidentify genetic factors implicated in commensal-pathogen lifestyle versatility
Authors: Spoto Michelle , Riera Puma Johanna P. , Fleming Elizabeth , Guan Changhui , Nzutchi Yvette Ondouah , Kim Dean , Oh Julia
Published: April 2021

Staphylococcus (S.) epidermidisis a ubiquitous human commensal skin bacterium that is also one of the most prevalent nosocomial pathogens. The genetic factors underlying this remarkable lifestyle plasticity are incompletely understood, much due to the difficulties of genetic manipulation, precluding high-throughput functional profiling of this species. To probeS. epidermdis’versatility to survive across a diversity of skin sites and infection niches, we developed a large-scale CRISPR interference (CRISPRi) screen complemented by transcriptional profiling (RNA-seq) across 24 diverse environmental conditions and piloted a droplet-based CRISPRi approach to enhance throughput and sensitivity. We identified putative essential genes, importantly, revealing amino acid metabolism as crucial to survival across diverse environments and demonstrated the importance of trace metal uptake for survival under multiple stress conditions. We identified pathways significantly enriched and repressed across our range of stress and nutrient limited conditions, demonstrating the considerable plasticity ofS. epidermidisin responding to environmental stressors. We postulate a mechanism by which nitrogen metabolism is linked to lifestyle versatility in response to hyperosmotic challenges, such as those encountered on human skin. Finally, we examinedS. epidermidissurvival under acid stress and hypothesize a role for cell wall modification as a vital component of the survival response in acidic conditions. Taken together, this study integrates large scale CRISPRi and transcriptomics data across multiple environments to provide insights into a keystone member of the human skin microbiome. Our results additionally provide a valuable benchmarking analysis for CRISPRi screens and are rich resource for other staphylococcal researchers.

Author summary

Staphylococcus epidermidisis an important bacteria of the skin microbiome. While it has an important role in skin health, it can also be a major infectious agent, especially in bloodstream and catheter infections. Understanding the underlying genes and pathways that contribute toS. epidermidis’ability to have both health and disease-associated abilities will be important to promoting the former and targeting the latter. Yet the function of manyS. epidermidisgenes, particularly in skin and infection environments, remains unknown. We developed a CRISPRi platform to knock down the function ofS. epidermidisgenes to better understand to what degree they are essential for growth in these environments. We complemented this gene essentiality data with gene expression data in the same environments to understand how regulation of these genes contribute toS. epidermidis’survival. These large-scale data generated numerous hypotheses for new genetic links toS. epidermidis’growth versatility.
STDP and the distribution of preferred phases in the whisker system
Authors: Sherf Nimrod , Shamir Maoz
Published: April 2021

Rats and mice use their whiskers to probe the environment. By rhythmically swiping their whiskers back and forth they can detect the existence of an object, locate it, and identify its texture. Localization can be accomplished by inferring the position of the whisker. Rhythmic neurons that track the phase of the whisking cycle encode information about the azimuthal location of the whisker. These neurons are characterized by preferred phases of firing that are narrowly distributed. Consequently, pooling the rhythmic signal from several upstream neurons is expected to result in a much narrower distribution of preferred phases in the downstream population, which however has not been observed empirically. Here, we show how spike timing dependent plasticity (STDP) can provide a solution to this conundrum. We investigated the effect of STDP on the utility of a neural population to transmit rhythmic information downstream using the framework of a modeling study. We found that under a wide range of parameters, STDP facilitated the transfer of rhythmic information despite the fact that all the synaptic weights remained dynamic. As a result, the preferred phase of the downstream neuron was not fixed, but rather drifted in time at a drift velocity that depended on the preferred phase, thus inducing a distribution of preferred phases. We further analyzed how the STDP rule governs the distribution of preferred phases in the downstream population. This link between the STDP rule and the distribution of preferred phases constitutes a natural test for our theory.

Author summary

The distribution of preferred phases of whisking neurons in the somatosensory system of rats and mice presents a conundrum: a simple pooling model predicts a distribution that is an order of magnitude narrower than what is observed empirically. Here, we suggest that this non-trivial distribution may result from activity-dependent plasticity in the form of spike timing dependent plasticity (STDP). We show that under STDP, the synaptic weights do not converge to a fixed value, but rather remain dynamic. As a result, the preferred phases of the whisking neurons vary in time, hence inducing a non-trivial distribution of preferred phases, which is governed by the STDP rule. Our results imply that the considerable synaptic volatility which has long been viewed as a difficulty that needs to be overcome, may actually be an underlying principle of the organization of the central nervous system.
The natural stilbenoid (–)-hopeaphenol inhibits cellular entry of SARS-CoV-2 USA-WA1/2020, B.1.1.7 and B.1.351 variants
Authors: Tietjen Ian , Cassel Joel , Register Emery T. , Zhou Xiang Yang , Messick Troy E. , Keeney Frederick , Lu Lily D. , Beattie Karren D. , Rali Topul , Ertl Hildegund C. J. , Salvino Joseph M. , Davis Rohan A. , Montaner Luis J.
Published: April 2021

Antivirals are urgently needed to combat the global SARS-CoV-2/COVID-19 pandemic, supplement existing vaccine efforts, and target emerging SARS-CoV-2 variants of concern. Small molecules that interfere with binding of the viral spike receptor binding domain (RBD) to the host ACE2 receptor may be effective inhibitors of SARS-CoV-2 cell entry. Here we screened 512 pure compounds derived from natural products using a high-throughput RBD/ACE2 binding assay and identified (–)-hopeaphenol, a resveratrol tetramer, in addition to vatalbinoside A and vaticanol B, as potent and selective inhibitors of RBD/ACE2 binding and viral entry. For example, (–)-hopeaphenol disrupted RBD/ACE2 binding with a 50% inhibitory concentration (IC50) of 0.11 μM in contrast to an IC50 of 28.3 μM against the unrelated host ligand/receptor binding pair PD-1/PD-L1 (selectivity index = 257.3). When assessed against the USA-WA1/2020 variant, (–)-hopeaphenol also inhibited entry of a VSVΔG-GFP reporter pseudovirus expressing SARS-CoV-2 spike into ACE2-expressing Vero-E6 cells andin vitroreplication of infectious virus in cytopathic effect assays (IC50 = 10.2 μM) without cytotoxicity. Notably, (–)- hopeaphenol also inhibited two emerging variants of concern originating from the United Kingdom (B.1.1.7) and South Africa (B.1.351) in both cytopathic effect and spike-containing pseudovirus assays with similar (B.1.1.7) or improved (B.1.351) efficacies over the USA- WA1/2020 variant. These results identify (–)-hopeaphenol and related stilbenoid analogues as potent and selective inhibitors of viral entry across multiple SARS-CoV-2 variants including those with increased infectivity and/or reduced susceptibility to existing vaccines.

Importance

SARS-CoV-2 antivirals are needed to supplement existing vaccine efforts and target emerging viral variants with increased infectivity or reduced susceptibility to existing vaccines. Here we show that (–)-hopeaphenol, a naturally-occurring stilbenoid compound, in addition to its analogues vatalbinoside A and vaticanol B, inhibit SARS-CoV-2 by blocking the interaction of the viral spike protein with the cellular ACE2 entry receptor. Importantly, in addition to inhibiting the early USA-WA1/2020 SARS-CoV-2 variant, hopeaphenol also inhibits emerging variants of concern including B.1.1.7 (“United Kingdom variant”) and B.1.351 (“South Africa variant”), with improved efficacy against B.1.351. (–)-Hopeaphenol therefore represents a new antiviral lead against infection from multiple SARS-CoV-2 variants.
Molecular interactions of the M and E integral membrane proteins of SARS-CoV-2
Authors: Monje-Galvan Viviana , Voth Gregory A.
Published: April 2021

Specific lipid-protein interactions are key for cellular processes, and even more so for the replication of pathogens. The COVID-19 pandemic has drastically changed our lives and cause the death of nearly three million people worldwide, as of this writing. SARS-CoV-2 is the virus that causes the disease and has been at the center of scientific research over the past year. Most of the research on the virus is focused on key players during its initial attack and entry into the cellular host; namely the S protein, its glycan shield, and its interactions with the ACE2 receptors of human cells. As cases continue to raise around the globe, and new mutants are identified, there is an urgent need to understand the mechanisms of this virus during different stages of its life cycle. Here, we consider two integral membrane proteins of SARS-CoV-2 known to be important for viral assembly and infectivity. We have used microsecond-long all-atom molecular dynamics to examine the lipid-protein and protein-protein interactions of the membrane (M) and envelope (E) structural proteins of SARS-CoV-2 in a complex membrane model. We contrast the two proposed protein complexes for each of these proteins, and quantify their effect on their local lipid environment. This ongoing work also aims to provide molecular-level understanding of the mechanisms of action of this virus to possibly aid in the design of novel treatments.
Disentangling how multiple traits drive 2 strain frequencies in SIS dynamics with coinfection
Authors: Thao Le Thi Minh , Madec Sten , Gjini Erida
Published: April 2021

A general theory for competitive dynamics among many strains at the epidemiological level is required to understand polymorphisms in virulence, transmissibility, antibiotic resistance and other biological traits of infectious agents. Mathematical coinfection models have addressed specific systems, focusing on the criteria leading to stable coexistence or competitive exclusion, however, due to their complexity and nonlinearity, analytical solutions in coinfection models remain rare. Here we study a 2-strain SIS compartmental model with co-infection/co-colonization, incorporating multiple fitness dimensions under the same framework: variation in transmissibility, duration of carriage, pairwise susceptibilities to coinfection, coinfection duration, and transmission priority effects from mixed coinfection. Taking advantage of a singular perturbation approach, under the assumption of strain similarity, we expose how strain dynamics on a slow timescale are explicitly governed by a replicator equation which encapsulates all traits and their interplay. This allows us to predict explicitly not only the final epidemiological outcome of a given 2-player competition, but moreover, their entire frequency dynamics as a direct function of their relative variation and of strain-transcending global parameters. Based on mutual invasion fitnesses, we analyze and report rigorous results on transition phenomena in the 2-strain system, strongly mediated via coinfection prevalence. We show that coinfection is not always a promoter of coexistence; instead, its effect to favour or prevent polymorphism is non-monotonic and depends on the type and level of phenotypic differentiation between strains. This framework offers a deeper analytical understanding of 2-strain competitive games in coinfection, with theoretical and practical applications in epidemiology, ecology and evolution.
Diversity in somatic DNA repair efficiencies between commercial inbred maize lines and native Central American purple landraces
Authors: Víquez-Zamora Carlos , Castro-Pacheco Sergio , Viñas María , Bolaños-Villegas Pablo
Published: April 2021

Maize is a staple food all over the world. Models for climate change suggest that, in the future, cloud formation might be reduced in the tropics increasing the exposure to Ultraviolet-B (UV-B) radiation, a DNA-damaging agent. UV-B (290 to 320 nm) has been shown to affect yield in maize. In this project we have determined the differences in DNA repair efficiencies between U.S. inbred lines B73 and Mo17, and Central American purple landraces from Guatemala and Costa Rica. Our results from single cell electrophoresis experiments (Comet Assay) suggest that the landrace Pujagua Santa Cruz (P1, Costa Rican) was resistant to damage caused by the radiomimetic agent zeocin (24h/100 micrograms per mL), while landrace Pujagua La Cruz (P2, Costa Rican) was able to repair DNA damage after one hour. On the other hand, line Mo17 (Missouri, USA) was unable to repair the damage, while B73 (Iowa, USA) and the landraces Jocopilas (Guatemalan), Orotina Congo (Costa Rican) and Talamanca (Costa Rican) were partially able to repair DNA damage. High Resolution Melting (HRM) curve analysis of putative homologous DNA repair gene ZeaATM1 showed that both P1 and P2 had differences in the melting temperatures for this gene compared to B73 and Mo17, while P1 showed additional differences in ZeaSOG1, ZeaRAD51 and ZeaBRCA1, suggesting that in this landrace the presence of polymorphisms may be common among key genes for this pathway. Taken together our results suggest that key adaptive differences in DNA repair efficiencies exist between inbred lines and landraces of maize and that some Central America landraces could be used as a valuable pool of alleles for plant breeding aiming to increase tolerance to radiation.
How the footprint of history shapes the evolution of digital organisms
Authors: Bundy Jason N. , Ofria Charles , Lenski Richard E.
Published: April 2021

Gould’s thought experiment of “replaying life’s tape” provides a conceptual framework for experiments that quantify the contributions of adaptation, chance, and history to evolutionary outcomes. For example, we can empirically measure how varying the depth of history in one environment influences subsequent evolution in a new environment. Can this “footprint of history”—the genomic legacy of prior adaptation—grow too deep to overcome? Can it constrain adaptation, even with intense selection in the new environment? We investigated these questions using digital organisms. Specifically, we evolved ten populations from one ancestor under identical conditions. We then replayed evolution from three time points in each population’s history (corresponding to shallow, intermediate, and deep history) in two new environments (one similar and one dissimilar to the prior environment). We measured the contributions of adaptation, chance, and history to the among-lineage variation in fitness and genome length in both new environments. In both environments, variation in genome length depended largely on history and chance, not adaptation, indicating weak selection. By contrast, adaptation, chance, and history all contributed to variation in fitness. Crucially, whether the depth of history affected adaptation depended on the environment. When the ancestral and new environments overlapped, history was as important as adaptation to the fitness achieved in the new environment for the populations with the deepest history. However, when the ancestral and novel environments favored different traits, adaptation overwhelmed even deep history. This experimental design for assessing the influence of the depth of history is promising for both biological and digital systems.
ROR and RYK extracellular region structures suggest that receptor tyrosine kinases have distinct WNT-recognition modes
Authors: Shi Fumin , Mendrola Jeannine M. , Sheetz Joshua B. , Wu Neo , Sommer Anselm , Speer Kelsey F. , Noordermeer Jasprina N. , Kan Zhong-Yuan , Perry Kay , Englander S. Walter , Stayrook Steven E. , Fradkin Lee G. , Lemmon Mark A.
Published: April 2021

SUMMARY

WNTs play key roles in development and disease, by binding both Frizzled (FZD) seven-pass transmembrane receptors and numerous co-receptors that include the ROR and RYK receptor tyrosine kinases (RTKs). We describe crystal structures and WNT-binding characteristics of extracellular regions from the Drosophila ROR and RYK orthologs Nrk (neurospecific receptor tyrosine kinase) and Derailed-2 (Drl-2). RORs bind WNTs though a FZD-related cysteine-rich domain (CRD), and RYKs through a WNT-inhibitory factor (WIF) domain. Our structures suggest that neither the Nrk CRD nor the Drl-2 WIF domain can accommodate the acyl chain typically attached to WNTs. The Nrk CRD contains a deeply buried bound fatty acid, unlikely to be exchangeable with a WNT acyl chain. The Drl-2 WIF domain lacks the lipid-binding site seen in WIF-1. We also show that DWnt-5, which regulates Drosophila ROR and RYK orthologs, lacks an acyl chain. Together with analysis of WNT/receptor interaction sites, these structures provide new insight into how WNTs recruit their RTK co-receptors into signaling complexes.
Metaphloem development in the Arabidopsis root tip
Authors: Graeff Moritz , Hardtke Christian S.
Published: April 2021

The phloem transport network is a major evolutionary innovation that enabled plants to dominate terrestrial ecosystems. In the growth apices, the meristems, apical stem cells continuously produce early, so-called protophloem. This is easily observed in Arabidopsis root meristems, where the differentiation of individual protophloem sieve element precursors into interconnected, conducting sieve tubes is laid out in a spatio-temporal gradient. The mature protophloem eventually collapses as the neighboring metaphloem takes over its function further distal from the stem cell niche. Compared to protophloem, metaphloem ontogenesis is poorly characterized, primarily because its visualization is challenging. Here we describe an improved protocol to investigate metaphloem development in Arabidopsis root tips in combination with a set of new molecular markers. We found that mature metaphloem sieve elements are only observed in the late post-meristematic root although their specification is initiated as soon as protophloem sieve elements enucleate. Moreover, unlike protophloem sieve elements, metaphloem sieve elements only differentiate once they have fully elongated. Finally, our results suggest that metaphloem differentiation is not directly controlled by protophloem-derived cues but rather follows a distinct, robust developmental trajectory.

Summary statement

Metaphloem sieve element differentiation in Arabidopsis roots follows a robust developmental trajectory.
WITHDRAWN: Molecular Dynamics guided Brownian tomography of apoferritin in liquid water
Authors: Gutierrez Silvia Acosta , De Pace Cesare , Ing Gabriel , Marchello Gabriele , Wilkinson Neil , Garvasio Francesco L. , Ruiz Pérez Lorena , Battaglia Giuseppe
Published: April 2021

Withdrawal Statement

The authors have withdrawn their manuscript owing to a mistake in one of the proteins used for the data used to generate Fig.1, where we believed we used the apoferritin but instead used the ferritin proteins. Therefore, the authors do not wish this work to be cited as a reference for the project. If you have any questions, please get in touch with the corresponding author.
A somatic piRNA pathway regulates epithelial-to-mesenchymal transition of chick neural crest cells
Authors: Galton Riley , Fejes-Toth Katalin , Bronner Marianne E.
Published: April 2021

In the metazoan germline, Piwi proteins play an essential regulatory role in maintenance of stemness and self-renewal by piRNA-mediated repression of transposable elements. To date, the activity of Piwi proteins and the piRNA pathway in vertebrates was believed to be confined to the gonads. Our results reveal expression of Piwil1 in a vertebrate somatic cell type, the neural crest–a migratory embryonic stem cell population. We show that Piwil1 is expressed at low levels throughout chick neural crest development, peaking just before neural crest cells undergo an epithelial-to-mesenchymal transition to leave the neural tube and migrate into the periphery. Importantly, loss of Piwil1 impedes neural crest emigration. Small RNA sequencing reveals somatic piRNAs with sequence signatures of an active ping pong loop. Coupled with Piwil1 knockout RNA-seq, our data suggest that Piwil1 regulates expression of the transposon derived gene ERNI in the chick dorsal neural tube, which in turn suppresses Sox2 expression to precisely control the timing of neural crest specification and emigration. Our work provides mechanistic insight into a novel function of the piRNA pathway as a regulator of somatic development in vertebrates.
A new crystal form of GABARAPL2
Authors: Scicluna Kristen , Dewson Grant , Czabotar Peter E. , Birkinshaw Richard W.
Published: April 2021

The Atg8 protein family comprises the GABA type A receptor-associated proteins (GABARAPs) and microtubule-associated protein 1 light chains 3 (MAP1LC3s) that are essential mediators of autophagy. The LC3-interacting region (LIR) motifs of autophagy receptors and adaptors bind Atg8 proteins to promote autophagosome formation, cargo recruitment, and autophagosome closure and fusion to lysosomes. A crystal structure of human GABARAPL2 has been published [PDB entry 4co7; Ma et al. (2015), Biochemistry, 54, 5469–5479]. This was crystallized in space group P21 with a monoclinic angle of 90° and shows a pseudomerohedral twinning pathology. This article reports a new, untwinned GABARAPL2 crystal form, also in space group P21, but with a 98° monoclinic angle. No major conformational differences were observed between the structures. In the structure described here, the C-terminal Phe117 binds into the LIR docking site (LDS) of a neighbouring molecule within the asymmetric unit, as observed in the previously reported structure. This crystal contact blocks the LDS for co-crystallization with ligands. Phe117 of GABARAPL2 is normally removed during biological processing by Atg4 family proteases. These data indicate that to establish interactions with the LIR, Phe117 should be removed to eliminate the crystal contact and liberate the LDS for co-crystallization with LIR peptides.
Antibacterial potential of selected phytomolecules: An experimental study
Authors: Jhanji Rishabh , Singh Arti , Kumar Anoop
Published: April 2021

Antibiotic resistance is a snowballing international threat. Some of the antibiotics have lost their effectiveness due to overuse and underuse. Thus, there is an urgent need to tackle this global challenge, either by inhibiting the resistance mechanisms or by the development of new chemical entities. Thus, in the current study, the antibacterial activity of selected phytomolecules was investigated against bacterial strains, alone and in combination, with standard drugs. The antibacterial potential of these phytomolecules was explored using in vitro assays (microtiter assay, bacterial growth kinetics, percentage retardation of growth, and antimicrobial synergy study) and in vivo studies (zebrafish infection model). In vitro and in vivo studies have shown promising antibacterial effects against, both, Gram‐positive and Gram‐negative bacteria. Moreover, a cell viability assay also indicated the cytoprotective effect of these phytomolecules in combination with standard antibiotics (SABX). Thus, these phytomolecules could be a promising broad‐spectrum antibacterial agent in combination with standard antibiotics.
Multi‐dimensionality as a path forward in plant‐soil feedback research
Authors: J. Gundale Michael , Kardol Paul
Published: April 2021

Feedback between plants and their associated soil biota is an important driver of plant distribution, abundance and community composition with consequences for ecosystem functioning. The field of plant‐soil feedback (PSF) research has become an integral subdiscipline of terrestrial ecosystem ecology, and in recent decades has rapidly evolved by deepening and broadening its scope.

We review the major developments in the field, discuss methodological considerations and present a way forward for new approaches to PSF research that will lead to a more generalized and predictive understanding of PSFs. We illustrate that the field of PSF research has pursued multiple dimensions, including temporal scales, biogeographic perspectives, environmental context and the level of biological resolution.

Plant‐soil feedbacks have been related to successional species turnover, but our inferences are often constrained by experimental time‐scales, and anthropogenic impacts can alter or disrupt the temporal interactions between plants and soil biota. Plant‐soil feedbacks also have been used to explain spatial patterns of plant recruitment, coexistence and diversity, and have increasingly been linked to the patterns of spread and abundance of non‐native and invasive plants.

In recent years, more consideration also has been given to the sensitivity of PSF to environmental context, in particularly to gradients of resource availability and changing climatic conditions (including extreme events). Here, of particular interest are the differential responses of mutualistic and antagonistic soil biota. How plants interact with different groups of soil biota has further been predicted from species' phylogenetic relatedness and increasingly also from plant chemical and morphological shoot, root and litter traits.

Synthesis. In moving the field forward, future PSF research should take a multidimensional approach by explicitly considering cross‐connections between dimensions, including, for example, spatio‐temporal variation in resource availability, and trait–environment relationships across taxonomic and functional groups of plants and soil organisms. This forward movement will be accelerated by further methodological advances utilizing new types of experiments in the laboratory and in the field, as well as establishing global collaborative networks.
Multiresidue determination of antibiotics in ready‐to‐eat duck eggs marketed through e‐commerce stores in China and subsequent assessment of dietary risks to consumers
Authors: Ji Xiaofeng , Xu Yan , Wang Jianmei , Lyu Wentao , Li Rui , Tan Simin , Xiao Yingping , Tang Biao , Yang Hua , Qian Mingrong
Published: April 2021

In this work, the occurrence of 34 common antibiotic (15 sulfonamides and 19 quinolones) residues were evaluated in 236 ready‐to‐eat duck eggs (salted and preserved duck eggs) marketed through e‐commerce stores by ultra‐performance liquid chromatography coupled to tandem mass spectrometry, and subsequent dietary risk assessments for Chinese consumers were conducted. Among violated positives in duck egg samples, 11 analytes were found including sulfamethazine, sulfaquinoxaline, sulfamethoxazole, sulfadiazine, sulfamonomethoxine, ciprofloxacin, enrofloxacin, ofloxacin, flumequine, sarafloxacin, and nalidixic acid. A higher number of antibiotics were detected in salted duck eggs (five sulfonamides and six quinolones) than in preserved duck eggs (one sulfonamide and two quinolones). The maximum contamination of sulfonamides and quniolones was 448.0 µg/kg (sulfaquinoxaline) and 563.7 µg/kg (enrofloxacin) in salted duck eggs, respectively. Dietary exposure was evaluated through the estimated daily intake (EDI) of risky antibiotics (sulfamethazine, ciprofloxacin, and enrofloxacin) and hazard quotients (HQs). The results showed that EDIs and HQs were in the range of 0.0004 to 0.0099 µg/kg bw/day and 0.0009 to 0.1594%, respectively. The risk was low since HQs obtained were less than 100%. However, a special attention should be paid to ready‐to‐eat duck egg products high percentile consumers with the prosperity of e‐commerce market in China.

Practical Application

The present analytical method could be used for multiresidue determination of antibiotics in ready‐to‐eat duck eggs, and dietary risk assessments of risky antibiotics provided a support for the work of regulatory bodies to conduct surveillance programs regarding food safety evaluation of ready‐to‐eat foods.
Anti‐hepatic fibrosis effects of AD‐2 affecting the Raf–MEK signaling pathway and inflammatory factors in thioacetamide‐induced liver injury
Authors: Li Tao , Su GuangYue , Zhao YuQing
Published: April 2021

25‐Hydroxylprotopanaxadiol‐3β, 12β, 20‐triol (25‐OH‐PPD or AD‐2) belongs to dammarane ginsenoside, and is commonly obtained from the acidic hydrolysate of total ginsensides of Panax ginseng. This study investigated the potential mechanism of AD‐2 toward improving thioacetamide (TAA)‐induced hepatic fibrosis in mice. Mice were divided into seven groups: control group, TAA model group, TAA + AD‐2 (5, 10, and 20 mg/kg) groups, TAA + silymarin (100 mg/kg) group, and TAA + Fu Fang Biejia (FFBj; 300 mg/kg) group. All mice were treated to intraperitoneal TAA injection to establish a hepatic fibrosis model, and drugs were administered orally. The mechanism and related pathways underlying the AD‐2‐mediated action against hepatic fibrosis were explored by Western blotting and immunohistochemical staining. After AD‐2 treatment, the expression levels of Lipin‐1, SREBP1, and F4/80 significantly decreased, meanwhile the protein expressions levels of IL1β, IL1R1, IL18, Bax, Bid, Bcl‐2, and cFlips also decreased. Furthermore, AD‐2 inhibited RAF and MEK pathways. The results demonstrate that AD‐2 can alleviate hepatic fibrosis. The mechanism is likely related to the regulation of lipid accumulation, inflammatory response, apoptosis pathway, and Raf–MEK signaling pathways, which provide a basis for clinical research for the treatment of hepatic fibrosis.

Practical Application

Ginsenoside is one of the main active ingredients of ginseng, and can alleviate the symptoms of various diseases, for example, hepatic fibrosis. This paper mainly used Western blotting to explore its possible mechanism of action. The goal was to provide a reference for the development of traditional Chinese medicines for hepatic fibrosis.
Improvement of serum lipid parameters in consumers of Mexican Wagyu‐Cross beef: A randomized controlled trial
Authors: Vela‐Vásquez Diana A. , Sifuentes‐Rincón Ana M. , Delgado‐Enciso Ivan , Delgado‐Enciso Osiris G. , Ordaz‐Pichardo Cynthia , Arellano‐Vera Williams , Treviño‐Alvarado Víctor
Published: April 2021

Beef is considered an excellent source of high‐quality protein and micronutrients. The high saturated fatty acid (SFA) composition of beef has been associated with cardiovascular diseases; however, this is a controversial issue because at present, no evidence has scientifically proven such an association. Wagyu cattle have been used as an option to generate high‐quality fatty acids (FAs) in beef and have been crossed with local beef cattle (Wagyu‐Cross). In Mexico, Wagyu‐Cross is marketed assuming the same quality as purebred Wagyu meat without scientific support. This study aimed to determine whether the differences in the FA composition of Wagyu‐Cross and commercial beef affected lipid metabolism in frequent consumers of beef. The study is a randomized, controlled, double‐blinded phase IV clinical trial. Thirty‐four volunteers completed treatments in which 120 g ground beef was consumed 3 days per week for 2 weeks. Volunteers were randomized to the “A” (commercial meat) or “B” (Wagyu‐Cross meat) groups. The beef fat content was 87% higher, the SFA content was 2.3% lower, and the monounsaturated fatty acid (MUFA) C18:1 n‐9 concentrations were higher in Wagyu‐Cross beef than in commercial beef. The B group exhibited a significantly larger change from baseline in the serum lipid profile in total cholesterol (TC) (−4.7% versus +6.9%), low‐density lipoprotein (LDL) (−4.1% versus +10.0%), nonhigh‐density lipoprotein (non‐HDL) (−6.1% versus +4.9%), and the ratio of three atherogenic indexes—TC/HDL (−3.5% versus +6.4%), LDL/HDL (−2.8% versus +14.6%), and non‐HDL/HDL (−4.7% versus +9.3%)—than the A group. This result confirms that meat FA composition is a key point for redirecting cattle breeding strategies and promotes beef as a healthful protein source.

Practical Application

Here, we found new evidence based on a clinical trial that beef with a favorable fatty acid composition (i.e., monounsaturated fatty acid and polyunsaturated fatty acid content) is a key factor in improving parameters associated with consumer health. This information will support the design of cattle breeding strategies as an option to promote beef consumption as a healthier protein source and create opportunities for the development of the functional food industry.
Quantitative proteomics provides an insight into germination‐related proteins in the obligate biotrophic plant pathogen Spongospora subterranea
Authors: Balotf Sadegh , Wilson Richard , Tegg Robert S. , Nichols David S. , Wilson Calum R.
Published: April 2021

The soil‐borne and obligate plant‐associated nature of S. subterranea has hindered a detailed study of this pathogen and in particular, the regulatory pathways driving the germination of S. subterranea remain unknown. To better understand the mechanisms that control the transition from dormancy to germination, protein profiles between dormant and germination stimulant‐treated resting spores were compared using label‐free quantitative proteomics. Among the ~680 proteins identified 20 proteins were found to be differentially expressed during the germination of S. subterranea resting spores. Elongation factor Tu, histones (H2A and H15), proteasome and DJ‐1_PfpI, involved in transcription and translation, were upregulated during the germination of resting spores. Downregulation of both actin and beta‐tubulin proteins occurred in the germinating spores, indicating that the changes in the cell wall cytoskeleton may be necessary for the morphological changes during the germination of the resting spore in S. subterranea. Our findings provide new approaches for the study of these and similar recalcitrant micro‐organisms provide the first insights into the basic protein components of S. subterranea spores. A better understanding of S. subterranea biology may lead to the development of novel approaches for the management of persistent soil inoculum.
Tail risk in the fossil fuel industry: an option implied analysis around the unburnable carbon news
Authors: Neudorfer Pablo
Published: April 2021

This paper studies the option implied tail risk in the oil and gas industry around the unburnable carbon news of April 2009. It was arguably the first science news amplified by the media that stated that the value of the oil and gas industry is stranded. After controlling for the level of proved fossil fuel reserves and the return drop on the event day, I find that large and small companies are perceived as equally exposed to carbon risk. However, the risk persists only in some oil and gas firms. As expected, the level of fossil fuel reserves increases risk.
The frequency and effects of distractions in operating theatres
Authors: Roberts Emilie R. , Hider Phillip N. , Wells Jonathan M. , Beasley Spencer W.
Published: April 2021

Background

Operating theatres (OTs) are complex environments where team members complete difficult tasks under stress. Distractions in these environments can lead to errors that compromise patient safety. A range of potential distractions exist in OTs and previous research suggests they are common. This study assesses the nature, frequency and impact of distracting events in the OT at a tertiary New Zealand hospital.

Methods

Prospective observational study of the frequency, type and impact of OT distractions during a 3‐month period. Two observational methods – the frequency of door openings and a validated tool – were used to categorize OT distractions for a range of acute and elective, paediatric and adult surgical procedures according to their cause and effect.

Results

There were 57 procedures (2037 intraoperative minutes) observed. During this time, 721 door openings and 1152 other distracting events were recorded. On average, either a door opening or other distracting event was recorded 56 times per hour of intraoperative time. The frequency of distractions did not vary in relation to acute versus elective or paediatric versus adult procedures but were more common in the morning. Communication unrelated to the case was the most common distracting event: these and equipment issues had the greatest effect on the entire surgical team, usually by causing some interruption to operative flow.

Conclusion

Distractions in OTs were common, occurring nearly every minute. Most were trivial, but some had the potential to disrupt the operative procedure and result in patient harm. Reducing distractions in surgery could reduce patient harm and improve resource use.
Development of a new pharmacokinetic model for target‐concentration controlled infusion of cefoxitin as a prophylactic antibiotic in colorectal surgical patients
Authors: Kim Kyung Mi , Kim Sung‐Hoon , Yun Ho‐Yong , Jung Jiwon , Bang Ji‐Yeon , Lee Eun‐Kyung , Choi Byung‐Moon , Noh Gyu‐Jeong
Published: April 2021

Aims

There are several limitations to the existing method of administering cefoxitin as a prophylactic antibiotic, and the limitations may be overcome by applying the target‐concentration controlled infusion (TCI) method. Population pharmacokinetic parameters are required to administer cefoxitin by the TCI method. The aim of this study was to construct a new pharmacokinetic model of cefoxitin for the TCI method in colorectal surgical patients.

Methods

In patients undergoing colorectal surgery, 2 g of cefoxitin was dissolved in 50 mL of saline and administered for 10 minutes prior to skin incision. Arterial blood samples were obtained at preset intervals to measure the total and free plasma concentrations of cefoxitin. Population pharmacokinetic analysis was performed using NONMEM software (ICON Development Solutions, Dublin, Ireland). Additionally, stochastic simulation was used to indirectly evaluate the effectiveness of the two administration methods (standard method vs TCI).

Results

In total, 297 plasma concentration measurements from 31 patients were used to characterize the pharmacokinetics of cefoxitin. A three‐compartment mammillary model described the pharmacokinetics of cefoxitin. Body weight and creatinine clearance were significant covariates for clearance. The stochastic simulation showed that when compared with the standard method, the TCI method has a significantly higher fraction of time that the free concentration of cefoxitin is maintained above the minimum inhibitory concentration (P < .001).

Conclusions

TCI has the potential to become a new infusion method for patient‐tailored dosing in surgical patients. To administer cefoxitin via TCI in clinical practice, the newly constructed pharmacokinetic model should undergo proper external validation.
The evolving role of allogeneic haematopoietic cell transplantation in the era of chimaeric antigen receptor T‐cell therapy
Authors: Dholaria Bhagirathbhai , Savani Bipin N. , Huang Xiao‐Jun , Nagler Arnon , Perales Miguel‐Angel , Mohty Mohamad
Published: April 2021

Chimaeric antigen receptor T‐cell (CAR T) therapy has revolutionized the management of many haematological malignancies. It is associated with impressive disease responses in relapsed or refractory high‐grade B‐cell non‐Hodgkin lymphoma (B‐NHL) and acute lymphoblastic leukaemia (B‐ALL) with durable remissions in a subset of patients. Historically, haematopoietic cell transplantation (HCT) has been the standard consolidation strategy for many of these patients who are now being treated with CAR T. Relapses are frequent after CD19 CAR T therapy in B‐ALL and consolidation with allogeneic HCT (allo‐HCT) may improve survival of patients with high‐risk disease. There appears to be a clear difference in B‐ALL outcomes between paediatric and adult patients, with the latter having a much higher risk of relapse after CAR T therapy. Late relapses are infrequent in patients with B‐NHL and consolidation with allo‐HCT may not be needed in patients who achieve a complete remission after CAR T therapy. Future registry‐based and prospective studies will hopefully provide the needed data in the future to risk‐stratify the recipients of CAR T therapy. Meanwhile, we provide guidance on patient selection and practical issues with performing allo‐HCT after CAR T therapy.
Quality of life improvement in children with attention‐deficit hyperactivity disorder reduces family's strain: A structural equation model approach
Authors: Rocco Ilaria , Bonati Maurizio , Corso Barbara , Minicuci Nadia
Published: April 2021

Objectives

The objective of the study is to analyse how the quality of life of children diagnosed with attention‐deficit/hyperactivity disorder (ADHD) impacts the relationship between disease severity and family burden.

Method

The data collected by a longitudinal, observational study involving 1478 children with ADHD residing in 10 European countries (aged 6 to 18 years) were analysed to evaluate the relationships between ADHD severity, the children's quality of life and family burden.

Results

The disorder's severity directly and indirectly affected the children's health‐related quality of life (HRQoL) and family burden. The degree of family burden was modulated by the children's HRQoL.

Conclusions

One of the primary causes of the stress experienced by parents of children with ADHD is their perception of the child's reduced HRQoL and not the symptom severity itself. Efforts to minimize symptom severity cannot alone reduce family burden.
Prenatal Neighborhood Ethnocultural Context and the Mental Health of Mothers and Children in Low‐Income Mexican American Families
Authors: Curci Sarah G. , Luecken Linda J. , Perez Marisol , White Rebecca M.B.
Published: April 2021

Socioeconomically disadvantaged neighborhoods increase the risk for poor mental health among residents, yet protective factors may operate alongside risk. This study evaluated the influence of the prenatal neighborhood ethnocultural context on child behavior problems and maternal depressive symptoms. Prenatal maternal role expectations, prenatal culture‐specific stress, and postpartum depression (PPD) symptoms were evaluated as mediators. Participants included 322 low‐income, Mexican American mother‐child dyads. Women (Mage = 27.8) reported on proposed mediators, maternal depressive symptoms, and child behavior problems at 4.5 years. Neighborhood Latinx concentration was obtained from census data. Higher Latinx concentration predicted fewer maternal depressive symptoms and child behavior problems, mediated through role expectations and PPD symptoms. Results suggest prenatal neighborhood context to impact later maternal and child mental health.
Epidemiology and outcome of status epilepticus in children: a Scottish population cohort study
Authors: Mitchell Clodagh , Chatterton Dickson Libby , Ramsay Ailidh , Mesalles‐Naranjo Oscar , Leonard Paul , Brand Celia , Mclellan Ailsa , Shetty Jay
Published: April 2021

Aim

To describe the epidemiology and outcomes of convulsive status epilepticus (CSE) since the introduction of buccal midazolam and the change in International League Against Epilepsy definition of CSE to include seizures of at least 5 minutes.

Method

All children presenting to paediatric emergency departments with CSE (2011–2017) in Lothian, Scotland, were identified. Data, collated from electronic health records, included patient demographics, clinical characteristics, acute seizure management, and adverse outcomes (for example admission to intensive care).

Results

Six hundred and sixty‐five children were admitted with CSE who had 1228 seizure episodes (381 males, 284 females; median age 3y 8mo; age range 0–20y 11mo). CSE accounted for 0.38% (95% confidence interval 0.34–0.42) of annual attendances at emergency departments. Annual prevalence was 0.8 per 1000 children aged 0 to 14 years. Thirty‐four per cent of children had recurrent CSE. Sixty‐nine per cent of seizures lasted 5 to 29 minutes (median duration 10min). Buccal midazolam was given to 30% of children with CSE and had no effect on need for ventilatory support. Seventy per cent of children with CSE required hospital admission. Four per cent resulted in adverse outcome and there were only two deaths. Recurrent seizures, longer duration, and unprovoked seizures increased the odds of adverse outcome.

Interpretation

Adverse outcomes have decreased and the use of buccal midazolam is promising. Identifying high‐risk groups provides an opportunity for early intervention. These data form the basis for an extensive evaluation of acute seizure management and monitoring long‐term outcomes.

What this paper adds

The annual prevalence of convulsive status epilepticus in Lothian, Scotland, was 0.8 per 1000 children.

There was a decrease in case‐fatality proportion from 3–9% to 0.2%.

Use of buccal midazolam has increased, with no increase in adverse outcomes.
Weight and alternative measures for nutrition assessment in children with cerebral palsy
Authors: Stevenson Richard D
Published: April 2021

This commentary is on the original article by Ruiz Brunner et al. on pages 860–865 of this issue.
A pilot study of a yoga intervention for the treatment of anxiety in young people with early psychosis
Authors: McGuire Declan , Shannon Annabelle , Somaiya Janaki , Brown Ellie , O'Donoghue Brian
Published: April 2021

Background

Anxiety is common in young people with early psychosis and treatment options for this co‐morbidity remain limited. Yoga is a promising adjunct intervention that has been shown to reduce anxiety for adults with schizophrenia, therefore this pilot study evaluated the acceptability and potential effectiveness of yoga for anxiety in early psychosis.

Methods

A prospective single arm pilot study of a yoga intervention was conducted within an Early Intervention for psychosis service. Rates of attendance, as well as symptoms of anxiety pre and post yoga session were measured.

Results

A total of 14 young people participated in the study and over 70% attended half or more of the yoga sessions offered. Significant transient reduction in state anxiety after a single session of yoga was observed (p < 0.01).

Conclusions

Yoga was found to be an acceptable and potentially effective adjunctive treatment for anxiety in early psychosis and the results warrant further clinical trials.