bluuebunny/crossref_metadata_2025 huggingface dataset:
In vitro activity of dalbavancin and other anti-staphylococcal agents against infecting isolates of methicillin-resistant coagulase-negative staphylococci
Authors: Plota Maria , Papadimitriou-Olivgeris Matthaios , Kolonitsiou Fevronia , Tsiata Ekaterini , Spiliopoulou Iris , Assimakopoulos Stelios F. , Marangos Markos
Published: September 2021

Introduction. Dalbavancin was approved in Europe in 2015 for skin and soft tissue infections.

Hypothesis/Gap Statement. Data on methicillin-resistant coagulase-negative staphylococci (MR-CNS) dalbavancin susceptibility are scarce.

Aim. To assess the susceptibility of MR-CNS to dalbavancin and other anti-staphylococcal agents.

Methodology. A total of 443 MR-CNS clinical isolates from patients hospitalized in a Greek university hospital during a 2.5-year period (January 2018 to June 2020) were included. The MICs for vancomycin, teicoplanin, linezolid and daptomycin were investigated by Etest and the MIC for dalbavancin was determined according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines in 196 isolates. The consumption of the aforementioned antimicrobials was calculated.

Results. In total, 51 isolates were resistant to teicoplanin (11.5 %) and 211 (47.6 %) to linezolid; all were susceptible to vancomycin and daptomycin. Among 196 isolates tested, 32 (16.3 %) were resistant to dalbavancin. A significant increase of MIC during the study period was found for vancomycin, teicoplanin and daptomycin, while a decrease in linezolid’s MIC was observed. Dalbavancin’s MIC remained stable. No difference in consumption was observed among the studied anti-staphylococcal agents.

Conclusion. An increase of vancomycin, teicoplanin and daptomycin MICs among MR-CNS was observed, whereas 47.6 % of isolates were non-susceptible to linezolid. Dalbavancin retains excellent potency against MR-CNS, even in the presence of non-susceptibility to other anti-staphylococcal antibiotics.
Flanker: a tool for comparative genomics of gene flanking regions
Authors: Matlock William , Lipworth Samuel , Constantinides Bede , Peto Timothy E. A. , Walker A. Sarah , Crook Derrick , Hopkins Susan , Shaw Liam P. , Stoesser Nicole
Published: September 2021

Analysing the flanking sequences surrounding genes of interest is often highly relevant to understanding the role of mobile genetic elements (MGEs) in horizontal gene transfer, particular for antimicrobial-resistance genes. Here, we present Flanker, a Python package that performs alignment-free clustering of gene flanking sequences in a consistent format, allowing investigation of MGEs without prior knowledge of their structure. These clusters, known as ‘flank patterns’ (FPs), are based on Mash distances, allowing for easy comparison of similarity across sequences. Additionally, Flanker can be flexibly parameterized to fine-tune outputs by characterizing upstream and downstream regions separately, and investigating variable lengths of flanking sequence. We apply Flanker to two recent datasets describing plasmid-associated carriage of important carbapenemase genes (bla
OXA-48 and bla
KPC-2/3) and show that it successfully identifies distinct clusters of FPs, including both known and previously uncharacterized structural variants. For example, Flanker identified four Tn4401 profiles that could not be sufficiently characterized using TETyper or MobileElementFinder, demonstrating the utility of Flanker for flanking-gene characterization. Similarly, using a large (n=226) European isolate dataset, we confirm findings from a previous smaller study demonstrating association between Tn1999.2 and bla
OXA-48 upregulation and demonstrate 17 FPs (compared to the 5 previously identified). More generally, the demonstration in this study that FPs are associated with geographical regions and antibiotic-susceptibility phenotypes suggests that they may be useful as epidemiological markers. Flanker is freely available under an MIT license at https://github.com/wtmatlock/flanker.
A safety survey on pesticide residues in green coffee
beans
Authors: Son Ji-Hee , Oh Moon-Seog , Moon Sun-Ae , Kim Han-Taek , Lee Chang-Hee , Ryu Ji-Eun , Kim A-Ram , Kim Ji-Won , Choi Ok-Kyung
Published: September 2021

We investigated pesticide residues in green coffee beans. Toward this, we
collected 80 samples of green coffee beans and analyzed the presence of 41
different pesticides using a combination of the QuEChERS method and GC-MS/MS and
LC-MS/MS. In the validation study, the values of limit of detection and limit of
quantitation were in the range of 0.0003-0.0031 mg/kg and 0.0009-0.0093 mg/kg,
respectively. The coefficient of determination (R2) was >
0.99. The recovery rate was satisfied except for 2 pesticides at the
concentration level of 0.01 mg/kg, and except for 5 pesticides at the
concentration level of 0.1, 0.5 mg/kg. The pesticide residue detection rate in
the green coffee beans was 18.8% (15 of 80 samples). Pesticide residues were
detected in 11 samples from Brazil, 2 samples from Colombia, 1 sample from
Kenya, and 1 sample from India, all of which were Coffea
arabica. Five kinds of residual pesticides were detected.
Chlorpyrifos is an organophosphorus insecticide, triadimenol is a triazol
fungicide, imidacloprid, thiamethoxam, and clothianidin are neonicotinoid
insecticides. All 15 green coffee beans in which detected pesticide residues
were evaluated at a safe level below the Maximum Residual Limits (MRLs), but
since coffee consumption is increasing day by day, the levels of pesticide
residues in green coffee beans should be monitored continuously.
Evaluation of antioxidant activity and lipid oxidative stability of
roasted buckwheat according to in vitro digestive
system
Authors: Bae Hyun-Gyeong , Kim Seonghyeon , Lee Jae-Cheol , Kim Mi-Ja
Published: September 2021

An in vitro digestive system simulates the human digestive
tract. This study aimed to evaluate antioxidant activity and oxidative stability
of roasted buckwheat extracts after treatment with an in vitro
digestive system. The buckwheat samples were subjected to the following roasting
conditions: 180°C for 10 min, 180°C for 20 min, 200°C for
10 min, and 200°C for 20 min; ethanol extracts of the buckwheat samples
were prepared after the in vitro digestive system treatment.
Buckwheat samples roasted at 200°C for 10 min showed the highest
in vitro antioxidant activities, including
2,2-diphenyl-1-picrylhydrazyl, 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic
acid) cation radical-scavenging activity, and ferric-reducing antioxidant power.
The total phenolics content of buckwheat roasted at 200°C for 10 min was
13.14 μmol tannic acid equivalent/g extract, while those of the samples
subjected to the other roasting treatments ranged from 7.58 to 9.86 μmol
tannic acid equivalent/g extract. Furthermore, the synthesis of primary and
secondary oxidative products from corn oil containing 1,000 ppm buckwheat
roasted at 200°C for 10 min decreased by 10% and 20%, significantly,
compared to those in the control groups (p<0.05). Overall, the ethanolic
extracts of roasted buckwheat obtained after in vitro digestive
treatment still possessed relatively high in vitro antioxidant
activity. It was found that roasted buckwheat according to in
vitro digestion could be used as an antioxidant material.
Quality characteristics of kombucha made with different mixing
ratios of green tea extract and yuzu juice during fermentation
Authors: Woo Hyo-Gyeong , Lee Chae-Mi , Jeong Jae-Hee , Choi Byung-Kuk , Huh Chang-Ki
Published: September 2021

In this study, the quality characteristics of kombucha according to the mixing
ratio of green tea extract and yuzu juice during fermentation were compared. The
pH of the kombucha decreased as the amount of yuzu juice increased. The
titratable acidity increased in a juice-concentration dependent manner during
fermentation. The reducing sugar content was 1.68% in kombucha made with a
mixture of 70% green tea extract and 30% yuzu juice on the 20th day
of fermentation, showing the lowest reducing sugar content. The alcohol content
did not change until the 10th day of fermentation and increased
slightly thereafter. The number of lactic acid bacteria and the quantity of
yeast were the highest in the samples of kombucha made with a mixture of 70%
green tea extract and 30% yuzu juice. The total polyphenol content was 40.79 mg
TAE/mL in the kombucha made with this combination and this also showed the
highest total flavonoid content of 37.15 mg QE/mL. In addition, the sensory
evaluation results showed the highest preference in all the measured parameters
for kombucha made with a mixture of 70% green tea extract and 30% yuzu
juice.
Antioxidative degradation product from purpurogallin induced by
gamma irradiation
Authors: Jeong Gyeong Han , Kim Tae Hoon
Published: September 2021

Gamma irradiation is a promising technique for improving the quality, safety, and
shelf-life of foods. However, research on radiation-induced systemic degradation
related to changes in the chemical structure and biological activity is still
limited. In this study, radiolytic degradation and antioxidant activity
enhancement of purpurogallin were studied in response to varying dose of gamma
irradiation. Pure purpurogallin in methanol was exposed to gamma rays from 10 to
100 kGy. Purpurogallin reaction mixture was completely degraded when irradiated
with 50 kGy and showed an increased antioxidation activity against
2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis
(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+). It also
exhibited hydroxyl radical scavenging ability. The structure of the newly-formed
simple phenolic compound, pyrogallol (2) from gamma irradiated purpurogallin at
50 kGy was characterized using 1H, 13C, heteronuclear
singles quantum coherence (HSQC), and heteronuclear multiple bond correlation
(HMBC) NMR, and fast atom bombardment mass (FABMS) spectroscopy. Compared to the
parent purpurogallin, the small phenolic molecule (2) exhibited significantly
enhanced antioxidant activity against DPPH, ABTS+, and
hydroxyl radical scavenging activities with SC50 values of
9.5±0.3, 12.6±0.4, and 48.1±0.9 μM, respectively.
These results indicate that degradation of purpurogallin induced by gamma
irradiation might enhance its antioxidant property.
Transiently increased intercommunity regulation characterizes concerted cell phenotypic transition
Authors: Wang Weikang , Ni Ke , Poe Dante , Xing Jianhua
Published: September 2021

Phenotype transition takes place in many biological processes such as differentiation and reprogramming. A fundamental question is how cells coordinate switching of expressions of clusters of genes. Through analyzing single cell RNA sequencing data in the framework of transition path theory, we studied how such a genome-wide expression program switching proceeds in five different cell transition processes. For each process we reconstructed a reaction coordinate describing the transition progression, and inferred the gene regulation network (GRN) along the reaction coordinate. In all processes we observed common pattern that the overall effective number and strength of regulation between different communities increase first and then decrease. The change accompanies with similar change of the GRN frustration, defined as overall conflict between the regulation received by genes and their expression states, and GRN heterogeneity. While studies suggest that biological networks are modularized to contain perturbation effects locally, our analyses reveal a general principle that during a cell phenotypic transition, intercommunity interactions increase to concertedly coordinate global gene expression reprogramming, and canalize to specific cell phenotype as Waddington visioned.
Perilacunar bone tissue exhibits sub-micrometer modulus gradation which depends on the recency of osteocyte bone formation
Authors: Rux Caleb J. , Vahidi Ghazal , Darabi Amir , Cox Lewis M. , Heveran Chelsea M.
Published: September 2021

Osteocytes are capable of resorbing and replacing bone local to the lacunar-canalicular system (LCS remodeling). However, the impacts of these processes on perilacunar bone quality are not understood. It is well established that aging is associated with reduced whole-bone fracture resistance, reduced osteocyte viability, and truncated LCS geometries, but it remains unclear if aging changes perilacunar bone quality. In this study, we employed atomic force microscopy (AFM) to quantify sub-micrometer gradations from 2D maps surrounding osteocyte lacunae in young (5 mo) and aged (22 mo) female mice. AFM-mapped lacunae were also imaged with confocal laser scanning microscopy to determine which osteocytes had recently deposited bone as determined by the presence of fluorochrome labels. These assays allowed us to quantify gradations in nanoscale mechanical properties of bone-forming/non-bone-forming osteocytes in young and aged mice. This study reports for the first time that there are sub-micrometer gradations in modulus surrounding lacunae and that these gradations are dependent upon recent osteocyte bone formation. Perilacunar bone adjacent to bone-forming osteocytes demonstrated lower peak and bulk modulus values when compared to bone near non-bone-forming osteocytes from the same mouse. Bone-forming osteocytes also showed increased perilacunar modulus variability. Age reduced lacunar size but did not significant effect modulus gradation or variability. In general, lacunar morphology was not a strong predictor of modulus gradation patterns. These findings support the idea that lacunar-canalicular remodeling activity changes the material properties of surrounding bone tissue on a sub-micrometer scale. Therefore, conditions that affect osteocyte health have the potential to impact bone quality.

GRAPHICAL ABSTRACT
Chromosomal instability mediates immune exclusion and response to cytotoxic chemotherapy in colorectal liver metastases
Authors: Martinez Carlos A , Spurr Liam F , Iyer Soumya C , Pugh Sian A , Bridgewater John A , Primrose John N , Domingo Enric , Maughan Timothy S , D’Angelica Michael I , Talamonti Mark , Posner Mitchell C , Connell Philip P , Weichselbaum Ralph R , Pitroda Sean P
Published: September 2021

The genomic drivers of immune exclusion in colorectal cancer liver metastases (CRCLM) remain poorly understood. Chromosomal instability (CIN), resulting in aneuploidy and genomic rearrangements, is the central pathway of mismatch repair-proficient colorectal cancer pathogenesis; however, it is unknown whether CIN impacts the outcomes of patients with limited spread of CRCLM treated with curative intent cytotoxic chemotherapy and surgery. Herein, we examined the relationship between CIN and the molecular subtypes of CRCLM, immune signaling, treatment sensitivity, and patient outcomes in three independent CRCLM patient cohorts. We established that a previously developed 70-gene CIN signature (CIN70) is a reliable measure of CIN, encompassing features of both aneuploidy and cellular proliferation. We demonstrated that tumors with the canonical subtype of CRCLM exhibit elevated levels of CIN and aneuploidy. Genomically unstable tumors were associated with an immune-depleted tumor microenvironment, and patients with genomically unstable tumors were at increased risk for disease progression in adverse metastatic sites, resulting in poor progression-free and overall survival. However, high-CIN tumors were particularly susceptible to DNA-damaging chemotherapies, including topoisomerase inhibitors, as well as radiation therapy. Treatment with genotoxic agents depleted CIN-rich cell populations, which resulted in a concomitant increase in intratumoral CD8+ T-cells in patients with primary rectal, breast, and bladder cancer. Taken together, we propose a mechanistic explanation for why cytotoxic chemotherapy can augment anti-tumor immunity and improve outcomes in patients with genomically unstable cancers.
Sexual dimorphism and the effect of wild introgressions on recombination in cassava (Manihot esculenta Crantz) breeding germplasm
Authors: Chan Ariel W. , Villwock Seren S. , Williams Amy L. , Jannink Jean-Luc
Published: September 2021

Recombination has essential functions in meiosis, evolution, and breeding. The frequency and distribution of crossovers dictate the generation of new allele combinations and can vary across species and between sexes. Here, we examine recombination landscapes across the 18 chromosomes of cassava (Manihot esculenta Crantz) with respect to male and female meioses and known introgressions from the wild relative Manihot glaziovii. We used SHAPEIT2 and duoHMM to infer crossovers from genotyping-by-sequencing (GBS) data and a validated multi-generational pedigree from the International Institute of Tropical Agriculture (IITA) cassava breeding germplasm consisting of 7,020 informative meioses. We then constructed new genetic maps and compared them to an existing map previously constructed by the International Cassava Genetic Map Consortium (ICGMC). We observed higher recombination rates in females compared to males, and lower recombination rates in M. glaziovii introgression segments on chromosomes 1 and 4, with suppressed recombination along the entire length of the chromosome in the case of the chromosome 4 introgression. Finally, we discuss hypothesized mechanisms underlying our observations of heterochiasmy and crossover suppression and discuss the broader implications for plant breeding.
On the Origin of Feces: Fungal diversity, distribution, and conservation implications from feces of small mammals
Authors: Bradshaw Alexander J , Autumn Kendra , Rickart Eric , Dentinger Bryn T.M.
Published: September 2021

Fungi are extremely diverse, but only a small fraction of the total estimated species have been characterized. Often, the extent of diversity and distribution of fungal communities is difficult or near impossible to assess. This is due to the fact that many Fungi are cryptic and persist predominantly hidden within substrates such as soil or plant material. This is particularly true for hypogeous sporocarps, including truffles, which are extremely difficult to survey in a systematic manner. However, fungi with hypogeous sporocarps have evolved traits that make them highly attractive to animals, such as small mammals, which ingest and disperse fungal spores through defecation. Here, samples of feces from 138 small mammals collected in the western United States were assessed for total fungal diversity using a dual-index metabarcoding, high-throughput Illumina sequencing approach. Our findings exhibit many identifications within Agaricomycetidae, with 65 of the 138 samples containing sequences belonging to several species of the hypogeous truffle genus Rhizopogon. Metadata, such as geospatial coordinates, for each captured small mammal can be used as a proxy for the presence or absence of Rhizopogon species identified in their feces. Utilizing these proxy data, along with publicly available data on observation and occurrence from data repositories such as GBIF and MycoPortal, it is possible to augment our current knowledge of the extent of occurrence and area of occupancy of cryptic hypogeous fungi without direct observation, further enhancing our ability to assess their conservation status.
Chronic THC vapor inhalation rescues hyperalgesia in rats with chronic inflammation and produces sex-specific alterations in midbrain neuronal activity
Authors: Kelley Leslie K. , Lightfoot Savannah H.M. , Hill Matthew N. , Gilpin Nicholas W. , Middleton Jason W.
Published: September 2021

Abstract

In an effort to reduce reliance on opioids for the treatment of pain in the clinic, ongoing work is testing the utility of cannabinoid drugs as a potential alternative for treatment of chronic pain. We tested chronic THC vapor inhalation effects on thermal nociception and mechanical sensitivity, as well as midbrain (i.e., ventrolateral periaqueductal gray [vlPAG]) neuronal function, in adult male and female Wistar rats with chronic inflammatory pain (CFA treatment). We report that chronic THC vapor inhalation rescues both thermal hyperalgesia and mechanical hypersensitivity in males treated with CFA, but only thermal hyperalgesia in CFA females. Most of the anti-hyperalgesic effects of chronic THC vapor were still observable 24 hours after cessation of the last THC exposure. We also report that chronic THC vapor inhalation modulates intrinsic and synaptic properties of vlPAG neurons, including reductions in action potential firing rate and spontaneous inhibitory synaptic transmission in males, and that these effects occur specifically in neurons that respond to current input with a “delayed” firing phenotype. Treatment with CFA led to increased firing rate and increased sIPSC amplitude in vlPAG neurons of female rats, and chronic THC vapor rescued sIPSC amplitudes to control levels – these effects were specific to vlPAG neurons categorized as having an “onset” firing phenotype. Ongoing work is exploring sex-specific mechanisms (e.g., CB1 receptor) of THC vapor rescue effects in the vlPAG of rats treated with CFA, and further exploring the vlPAG cell types impacted by CFA treatment and chronic THC vapor inhalation.

Significance Statement

Many adults in the U.S. with pain self-medicate with THC and cannabis, and many humans use e-cigarette type devices filled with cannabis extracts to self-administer THC and other constituents of the marijuana plant. Until recently, most rodent studies of THC effects on brain and behavior have used injection procedures and male rats. Here, we tested the effect of chronic THC vapor inhalation on pain-related behaviors and midbrain neural circuit function in adult male and female Wistar rats. As predicted, chronic THC vapor inhalation rescued chronic inflammatory pain effects on behavior and midbrain neuronal function.
Cooperative Allostery and Structural Dynamics of Streptavidin at Cryogenic- and Ambient-temperature
Authors: Ayan Esra , Yuksel Busra , Destan Ebru , Ertem Fatma Betul , Yildirim Gunseli , Eren Meryem , Yefanov Oleksandr M. , Barty Anton , Tolstikova Alexandra , Ketawala Gihan K. , Botha Sabine , Dao E. Han , Hayes Brandon , Liang Mengning , Seaberg Matthew H. , Hunter Mark S. , Batyuk Alex , Mariani Valerio , Su Zhen , Poitevin Frederic , Yoon Chun Hong , Kupitz Christopher , Cohen Aina , Doukov Tzanko , Sierra Raymond G. , Dağ Çağdaş , DeMirci Hasan
Published: September 2021

Multimeric protein assemblies are abundant in nature. Streptavidin is an attractive protein that provides a paradigm system to investigate the intra- and intermolecular interactions of multimeric protein complexes. Also, it offers a versatile tool for biotechnological applications. Here, we present two apo-streptavidin structures, the first one is an ambient temperature Serial Femtosecond X-ray crystal (Apo-SFX) structure at 1.7 Å resolution and the second one is a cryogenic crystal structure (Apo-Cryo) at 1.1 Å resolution. These structures are mostly in agreement with previous structural data. Combined with computational analysis, these structures provide invaluable information about structural dynamics of apo streptavidin. Collectively, these data further reveal a novel cooperative allostery of streptavidin which binds to substrate via water molecules that provide a polar interaction network and mimics the substrate biotin which displays one of the strongest affinities found in nature.
UCHL1 facilitates aggregates clearance and enhances neural stem cell activation in spinal cord injury
Authors: Ding Lu , Chu Weiwei , Xia Yu , Shi Ming , Li Tian , Zhou Feng-Quan , Deng David Y.B.
Published: September 2021

Activation of endogenous neural stem cells (NSCs) is critically important for the adult neurogenesis. However, NSC activation is extremely limited after spinal cord injury (SCI). Recent evidence suggests that accumulation of protein aggregates impedes quiescent NSC activation. Here, we found ubiquitin c-terminal hydrolase l-1 (UCHL1), an important deubiquitinating enzyme, functioned to facilitate NSC activation by clearing protein aggregations through ubiquitin-proteasome approach. Upregulation of UCHL1 enhanced NSC proliferation in the spinal cord after injury. Based on protein microarray analysis of SCI cerebrospinal fluid, it is further revealed that C3+neurotoxic reactive astrocytes negatively regulated UCHL1 and aggresome clearance through C3/C3aR signaling, resulting in reduced capacity of NSC to activate. Furthermore, blockade of reactive astrocytes or C3/C3aR pathway led to enhanced NSC activation post-SCI. Together, this study elucidated a mechanism regulating NSC activation in the adult spinal cord involving the UCHL1-proteasome approach, which may provide potential molecular targets for NSC fate regulation.
Combinatorial aspects of the Löwenstein avoidance rule. Part I: the independence polynomial
Authors: Moreira de Oliveira Jr Montauban , Eon Jean-Guillaume
Published: September 2021

According to Löwenstein's rule, Al–O–Al bridges are forbidden in the aluminosilicate framework of zeolites. A graph-theoretical interpretation of the rule, based on the concept of independent sets, was proposed earlier. It was shown that one can apply the vector method to the associated periodic net and define a maximal Al/(Al+Si) ratio for any aluminosilicate framework following the rule; this ratio was called the independence ratio of the net. According to this method, the determination of the independence ratio of a periodic net requires finding a subgroup of the translation group of the net for which the quotient graph and a fundamental transversal have the same independence ratio. This article and a companion paper deal with practical issues regarding the calculation of the independence ratio of mainly 2-periodic nets and the determination of site distributions realizing this ratio. The first paper describes a calculation technique based on propositional calculus and introduces a multivariate polynomial, called the independence polynomial. This polynomial can be calculated in an automatic way and provides the list of all maximal independent sets of the graph, hence also the value of its independence ratio. Some properties of this polynomial are discussed; the independence polynomials of some simple graphs, such as short paths or cycles, are determined as examples of calculation techniques. The method is also applied to the determination of the independence ratio of the 2-periodic net dhc.
Structural and catalytic characterization of Blastochloris viridis and Pseudomonas aeruginosa homospermidine synthases supports the essential role of cation–π interaction
Authors: Helfrich F. , Scheidig Axel J.
Published: September 2021

Polyamines influence medically relevant processes in the opportunistic pathogen Pseudomonas aeruginosa, including virulence, biofilm formation and susceptibility to antibiotics. Although homospermidine synthase (HSS) is part of the polyamine metabolism in various strains of P. aeruginosa, neither its role nor its structure has been examined so far. The reaction mechanism of the nicotinamide adenine dinucleotide (NAD+)-dependent bacterial HSS has previously been characterized based on crystal structures of Blastochloris viridis HSS (BvHSS). This study presents the crystal structure of P. aeruginosa HSS (PaHSS) in complex with its substrate putrescine. A high structural similarity between PaHSS and BvHSS with conservation of the catalytically relevant residues is demonstrated, qualifying BvHSS as a model for mechanistic studies of PaHSS. Following this strategy, crystal structures of single-residue variants of BvHSS are presented together with activity assays of PaHSS, BvHSS and BvHSS variants. For efficient homospermidine production, acidic residues are required at the entrance to the binding pocket (`ionic slide') and near the active site (`inner amino site') to attract and bind the substrate putrescine via salt bridges. The tryptophan residue at the active site stabilizes cationic reaction components by cation–π interaction, as inferred from the interaction geometry between putrescine and the indole ring plane. Exchange of this tryptophan for other amino acids suggests a distinct catalytic requirement for an aromatic interaction partner with a highly negative electrostatic potential. These findings substantiate the structural and mechanistic knowledge on bacterial HSS, a potential target for antibiotic design.
Does sport media raise her name? Examining intersectional representation in media narratives
Authors: Isard Risa F. , Melton E. Nicole
Published: September 2021

Purpose

The purpose of this research was to examine the role of intersectionality (multiple marginalized identities) in narratives used within online media coverage of women's sports. The authors adopted an intersectionality lens and drew from sports media literature to explore the representation of Black athletes in women's sport.

Design/methodology/approach

The authors conducted a quantitative content analysis of online articles from ESPN, CBS Sports and Sports Illustrated from the 2020 WNBA Season. The authors coded the number of times an athlete was mentioned in an article, the athlete's race, publicly disclosed sexual orientation and gender expression. The authors used hierarchical regression to examine the relationship between an athlete's social identities and frequency of media mentions.

Findings

Within mainstream online sport media, Black WNBA athletes receive less media attention than white WNBA athletes. Black athletes who do not present in traditionally feminine ways receive the least amount of media attention, while white athletes have the freedom to express their gender in a variety of ways and still capture media interest. Within league press releases, however, there is no difference in media mentions based on race, sexual orientation or gender expression.

Practical implications

The findings in this research are important for sport media professionals who write stories and player-activists who are pursuing racial justice. Outlets should commit to antiracist storytelling practices. Players, player agents and players' associations—all of whom have shown their power to create change for a more equitable industry and society—should also advocate for and organize around practices that create more equitable media coverage.

Originality/value

This study is one of the few empirical investigations of women's professional sport that examines the influence of intersecting social identities.
Pessary or surgery for a symptomatic pelvic organ prolapse: the PEOPLE study, a multicentre prospective cohort study
Authors: van der Vaart LR , Vollebregt A , Milani AL , Lagro‐Janssen AL , Duijnhoven RG , Roovers J‐PWR , Van der Vaart CH
Published: September 2021

Objective

To compare the 24‐month efficacy of pessary or surgery as the primary treatment for symptomatic pelvic organ prolapse (POP).

Design

Multicentre prospective comparative cohort study.

Setting

Twenty‐two Dutch hospitals.

Population

Women referred with symptomatic POP of stage ≥2 and moderate‐to‐severe POP symptoms.

Methods

The primary outcome was subjective improvement at the 24‐month follow‐up according to the Patient Global Impression of Improvement (PGI‐I) scale. Secondary outcomes included improvement in prolapse‐related symptoms measured with the Pelvic Floor Distress Inventory (PFDI‐20), improvement in subjective severeness of symptoms according to the Patient Global Impression of Severity (PGI‐S) scale and crossover between therapies. The primary safety outcome was the occurrence of adverse events.

Main outcome measure

PGI‐I at 24 months.

Results

We included 539 women, with 335 women (62.2%) in the pessary arm and 204 women (37.8%) in the surgery arm. After 24 months, subjective improvement was reported by 134 women (83.8%) in the surgery group compared with 180 women (74.4%) in the pessary group (risk difference 9.4%, 95% CI 1.4–17.3%, P < 0.01). Seventy‐nine women (23.6%) switched from pessary to surgery and 22 women (10.8%) in the surgery group underwent additional treatment. Both groups showed a significant reduction in bothersome POP symptoms (P ≤ 0.01) and a reduction in the perceived severity of symptoms (P ≤ 0.001) compared with the baseline.

Conclusions

Significantly more women in the surgery group reported a subjective improvement after 24 months. Both therapies, however, showed a clinically significant improvement of prolapse symptoms.

Tweetable abstract

Pessary treatment and vaginal surgery are both efficacious in reducing the presence and severity of prolapse symptoms, although the chance of significant improvement is higher following surgery.
T‐cell subsets in the skin and their role in inflammatory skin disorders
Authors: Kortekaas Krohn Inge , Aerts Joeri L. , Breckpot Karine , Goyvaerts Cleo , Knol Edward , Van Wijk Femke , Gutermuth Jan
Published: September 2021

T lymphocytes (T cells) are major players of the adaptive immune response. Naive T cells are primed in the presence of cytokines, leading to polarization into distinct T‐cell subsets with specific functions. These subsets are classified based on their T‐cell receptor profile, expression of transcription factors, surface cytokine and chemokine receptors, and their cytokine production, which together determine their specific function. This review provides an overview of the various T‐cell subsets and their function in several inflammatory skin disorders ranging from allergic inflammation to skin tumors. Moreover, we highlight similarities of T‐cell responses across different skin disorders, demonstrating the presence of similar and opposing functions for the different T‐cell subsets. Finally, we discuss the effects of currently available and promising therapeutic approaches to harness T cells in inflammatory skin diseases for which efficacy next to unwanted side effects provide new insights into the pathophysiology of skin disorders.
Review article: therapeutic aspects of bile acid signalling in the gut‐liver axis
Authors: Simbrunner Benedikt , Trauner Michael , Reiberger Thomas
Published: September 2021

Background

Bile acids are important endocrine modulators of intestinal and hepatic signalling cascades orchestrating critical pathophysiological processes in various liver diseases. Increasing knowledge on bile acid signalling has stimulated the development of synthetic ligands of nuclear bile acid receptors and other bile acid analogues.

Aim

This review summarises important aspects of bile acid‐mediated crosstalk between the gut and the liver (“gut‐liver axis”) as well as recent findings from experimental and clinical studies.

Methods

We performed a literature review on bile acid signalling, and therapeutic applications in chronic liver disease.

Results

Intestinal and hepatic bile acid signalling pathways maintain bile acid homeostasis. Perturbations of bile acid‐mediated gut‐liver crosstalk dysregulate transcriptional networks involved in inflammation, fibrosis and endothelial dysfunction. Bile acids induce enterohepatic feedback signalling by the release of intestinal hormones, and regulate enterohepatic circulation. Importantly, bile acid signalling plays a central role in maintaining intestinal barrier integrity and antibacterial defense, which is particularly relevant in cirrhosis, where bacterial translocation has a profound impact on disease progression. The nuclear bile acid farnesoid X receptor (FXR) is a central intersection in bile acid signalling and has emerged as a relevant therapeutic target.

Conclusions

Experimental evidence suggests that bile acid signalling improves the intestinal barrier and protects against bacterial translocation in cirrhosis. FXR agonists have displayed efficacy for the treatment of cholestatic and metabolic liver disease in randomised controlled clinical trials. However, similar effects remain to be shown in advanced liver disease, particularly in patients with decompensated cirrhosis.
Free‐of‐charge medicine schemes in the NHS: A local and regional drug and therapeutic committee's experience
Authors: O'Callaghan Simon , Ferner Robin E. , Barron Andrew , Saxby Katherine , Sofat Reecha
Published: September 2021

Introduction

Free‐of‐charge (FoC) medicine schemes are increasingly available and allow access to investigational treatments outside clinical trials or in advance of licensing or NHS commissioning.

Methods

We retrospectively reviewed FoC medicine schemes evaluated between 2013 and 2019 by a single NHS trust and a regional drug and therapeutics committee (DTC). The details of each locally reviewed FoC scheme, and any nationally available Medicines and Healthcare products Regulatory Agency Early Access to Medicines Scheme (MHRA EAMS) in the same period, were recorded and categorised.

Results

Most FoC schemes (95%) allowed access to medicines intended to address an unmet clinical need. Over 7 years, 90% were company‐FoC schemes and 10% were MHRA EAMS that were locally reviewed. Phase 3 clinical trial data were available for 44% of FoC schemes, 37% had phase 2 data and 19% were supported only by phase 1 data, retrospective observational studies or preclinical data. Utilisation of company‐FoC schemes increased on average by 50% per year, while MHRA EAMS schemes showed little growth.

Conclusion

Company‐FoC medicine schemes are increasingly common. This may indicate a preference for pharmaceutical companies to independently co‐ordinate schemes. Motivations for company‐FoC schemes remain unclear and many provide access to treatments that are yet to be evaluated in appropriately conducted clinical trials, and whose efficacy and risk of harm remain uncertain. There is no standardisation of this practice and there is no regulatory oversight. Moreover, no standardised data collection framework is in place that could demonstrate the utility of such programmes in addressing unmet clinical need or to allow generation of further evidence.
Doppler ultrasound to assess the pharmacodynamic effects of splanchnic vasoactive compounds
Authors: Marynissen Heleen , Lodeweyckx Thomas , Bielen Didier , de Hoon Jan
Published: September 2021

Aims

In search of noninvasive biomarkers to assess the pharmacodynamic effects of portal pressure‐lowering drugs, the reproducibility of flow measurements in the superior mesenteric artery was evaluated using Doppler ultrasound.

Methods

A reproducibility study was conducted in 15 healthy male volunteers (18–50 y). Eight ultrasound measurements were performed for each subject: 2 observers each conducted 2 measurements during 2 separate visits. The following flow parameters were captured: peak systolic velocity (PSV), end diastolic velocity (EDV), pulsatility index (PI), volume flow (VF) and vessel diameter. Reproducibility was assessed by the intraclass correlation coefficient.

Results

Results are presented as intraclass correlation coefficient [95% confidence interval]. The flow parameters PSV, EDV, PI and VF correlated excellently within observer during visit 1 (0.888 [0.748–0.953], 0.910 [0.793–0.962], 0.844 [0.656–0.933] and 0.916 [0.857–0.951], respectively) and visit 2 (0.925 [0.829–0.968], 0.942 [0.863–0.976], 0.883 [0.719–0.954] and 0.915 [0.855–0.951], respectively). Measurements conducted during 2 separate visits by 1 observer correlated well to excellently for PSV, EDV, PI and VF (0.756 [0.552–0.875], 0.836 [0.694–0.916], 0.807 [0.631–0.904] and 0.839 [0.783–0.882], respectively). Measurements conducted by 2 distinct observers correlated well to excellently for PSV, EDV and VF during visit 1 (0.813 [0.584–0.922], 0.884 [0.597–0.945] and 0.786 [0.575–0.899], respectively) and visit 2 (0.779 [0.498–0.912], 0.861 [0.672–0.945], 0.810 [0.553–0.926], respectively). Vessel diameter measurements were poorly reproducible.

Conclusion

Doppler ultrasound is a reproducible method for flow measurements in the superior mesenteric artery in a standardized group of healthy volunteers. Therefore, it is a promising technique to assess pharmacodynamic effects of splanchnic vasoactive compounds in early clinical drug development.
Policing and Autocratisation in Bolivarian Venezuela
Authors: Tremaria Stiven
Published: September 2021

This article aims to identify and analyse the mechanisms and manifestations through which the Venezuelan police have undergone a gradual and incremental counter‐reform in the scope of the autocratisation process of the political regime from Chávez to Maduro. It is argued that police counter‐reform has operated through three mechanisms: politicisation, militarisation and informalisation of policing, whose manifestations have become more pronounced when a deepening of autocratisation has taken place
SDHC phaeochromocytoma and paraganglioma: A UK‐wide case series
Authors: Williams Sophie T. , Chatzikyriakou Prodromos , Carroll Paul V. , McGowan Barbara M. , Velusamy Anand , White Gemma , Obholzer Rupert , Akker Scott , Tufton Nicola , Casey Ruth T. , Maher Eamonn R. , Park Soo‐Mi , Porteous Mary , Dyer Rebecca , Tan Tricia , Wernig Florian , Brady Angela F. , Kosicka‐Slawinska Monika , Whitelaw Benjamin C. , Dorkins Huw , Lalloo Fiona , Brennan Paul , Carlow Joseph , Martin Richard , Mitchell Anna L. , Harrison Rachel , Hawkes Lara , Newell‐Price John , Kelsall Alan , Igbokwe Rebecca , Adlard Julian , Schirwani Schaida , Davidson Rosemarie , Morrison Patrick J. , Chung Teng‐Teng , Bowles Christopher , Izatt Louise
Published: September 2021

Objective

Phaeochromocytomas and paragangliomas (PPGL) are rare, but strongly heritable tumours. Variants in succinate dehydrogenase (SDH) subunits are identified in approximately 25% of cases. However, clinical and genetic information of patients with SDHC variants are underreported.

Design

This retrospective case series collated data from 18 UK Genetics and Endocrinology departments.

Patients

Both asymptomatic and disease‐affected patients with confirmed SDHC germline variants are included.

Measurements

Clinical data including tumour type and location, surveillance outcomes and interventions, SDHC genetic variant assessment, interpretation, and tumour risk calculation.

Results

We report 91 SDHC cases, 46 probands and 45 non‐probands. Fifty‐one cases were disease‐affected. Median age at genetic diagnosis was 43 years (range: 11–79). Twenty‐four SDHC germline variants were identified including six novel variants. Head and neck paraganglioma (HNPGL, n = 30, 65.2%), extra‐adrenal paraganglioma (EAPGL, n = 13, 28.2%) and phaeochromocytomas (PCC) (n = 3, 6.5%) were present. One case had multiple PPGLs. Malignant disease was reported in 19.6% (9/46). Eight cases had non‐PPGL SDHC‐associated tumours, six gastrointestinal stromal tumours (GIST) and two renal cell cancers (RCC). Cumulative tumour risk (95% CI) at age 60 years was 0.94 (CI: 0.79–0.99) in probands, and 0.16 (CI: 0–0.31) in non‐probands, respectively.

Conclusions

This study describes the largest cohort of 91 SDHC patients worldwide. We confirm disease‐affected SDHC variant cases develop isolated HNPGL disease in nearly 2/3 of patients, EAPGL and PCC in 1/3, with an increased risk of GIST and RCC. One fifth developed malignant disease, requiring comprehensive lifelong tumour screening and surveillance.
The impact of sensorimotor impairments on developing hand representation: an insight from neonatal brachial plexus palsy
Authors: Bird Laura‐Ashleigh
Published: September 2021

This commentary is on the original article by Van der Looven et al. on pages 183–191 of this issue.
Lachnospira is a signature of antihistamine efficacy in chronic spontaneous urticaria
Authors: Liu Runqiu , Peng Cong , Jing Danrong , Xiao Yangjian , Zhu Wu , Zhao Shuang , Zhang Jianglin , Chen Xiang , Li Jie
Published: September 2021

Chronic spontaneous urticaria (CSU) is a mast cell‐driven disease with many advances in its aetiology and pathogenesis over the past years. The main treatment of CSU is oral second‐generation antihistamines. However, only an average of 50% of CSU patients responded adequately to conventional or quadruple doses of non‐sedative antihistamines. Meanwhile, gut microbiota can affect the efficacy of drugs. The purpose of this study was to investigate the relationship between gut microbiota and the efficacy of antihistamines in patients with CSU. The patients with CSU were divided into responders and non‐responders according to the efficacy of antihistamine monotherapy. The gut microbiota of faecal samples from 15 responders and 15 non‐responders was detected by 16S rDNA sequencing, and the differential bacterial species between the two groups were verified by quantitative polymerase chain reaction (qPCR). Additional faecal samples from 30 responders and 30 non‐responders were used as an extended cohort to further verify the above differential bacterial species by qPCR. Lachnospiraceae and its subordinate taxa were found to be the main differences in gut microbiota between responders and non‐responders. The abundance of Lachnospira in responders was higher than that in non‐responders. Lachnospira exhibits moderate diagnostic value in evaluating the efficacy of antihistamine. Lachnospira is a signature for predicting the efficacy of antihistamine in patients with CSU.
Systematic fatigue spectrum editing by fast wavelet transform and genetic algorithm
Authors: Mohseni Mohamad , Santhanam Sridhar , Williams Jesse , Thakker Ash , Nataraj C.
Published: September 2021

Fatigue testing is critical in order to establish the service life of load‐bearing components and structures. The extensive time associated with full fatigue spectrum testing can lead to prohibitive costs. A significant need exists for a fatigue load spectrum editing methodology, based on the mechanics of fatigue, that produces load spectra that can replicate service damage in laboratory testing and can lead to compressed testing times and reduced costs. In this work, a wavelet genetic (WAVEGEN) algorithm is developed to edit fatigue loading spectra using wavelet analysis to greatly reduce the length of a spectrum while retaining the same damage accumulation characteristics. In addition, an optimization protocol using a genetic algorithm is included within this process to automatically select the best wavelet editing parameters. The algorithm is designed to identify the most suitable wavelet type, filter, and level to optimally edit a given fatigue spectrum and ensure equivalence between edited and unedited spectra from a damage perspective. The algorithm was applied to two well‐known aircraft fatigue spectra: Fighter Aircraft Loading Standard for Fatigue evaluation (FALSTAFF) and Transport Wing Standard (TWIST). The proposed approach has demonstrated that both spectra can be compressed significantly even while ensuring equivalence from a damage perspective.