bluuebunny/crossref_metadata_2025 huggingface dataset:
Microbiome diversity protects against pathogens by nutrient blocking
Authors: Spragge Frances , Bakkeren Erik , Jahn Martin T. , B. N. Araujo Elizete , Pearson Claire F. , Wang Xuedan , Pankhurst Louise , Cunrath Olivier , Foster Kevin R.
Published: December 2023

The human gut microbiome plays an important role in resisting colonization of the host by pathogens, but we lack the ability to predict which communities will be protective. We studied how human gut bacteria influence colonization of two major bacterial pathogens, both in vitro and in gnotobiotic mice. Whereas single species alone had negligible effects, colonization resistance greatly increased with community diversity. Moreover, this community-level resistance rested critically upon certain species being present. We explained these ecological patterns through the collective ability of resistant communities to consume nutrients that overlap with those used by the pathogen. Furthermore, we applied our findings to successfully predict communities that resist a novel target strain. Our work provides a reason why microbiome diversity is beneficial and suggests a route for the rational design of pathogen-resistant communities.
Solar-powered clothes, for the heat and cold
Authors: Huang Xingyi , Li Pengli
Published: December 2023

A wearable device allows the human body to adapt to changes in ambient temperature
Tracing the origin of virulence
Authors: Duchene Sebastian
Published: December 2023

Microbial genomes from ancient chickens uncover the drivers of pathogenicity
Obesity meets its match
Authors: Couzin-Frankel Jennifer
Published: December 2023

Blockbuster weight loss drugs show promise for a wider range of health benefits
Universities uneasy with plan to disclose misconduct findings
Authors: Mervis Jeffrey
Published: December 2023

Transparency could benefit, but some see a threat to privacy
Susceptibility of
Toxoplasma gondii
to autophagy in human cells relies on multiple interacting parasite loci
Authors: Rinkenberger Nicholas , Rosenberg Alex , Radke Joshua B. , Bhushan Jaya , Tomita Tadakimi , Weiss Louis M. , Sibley L. David
Published: December 2023

Autophagy contributes to innate immunity by targeting intracellular pathogens for elimination. Previous studies identified a non-canonical autophagy pathway that controls
Toxoplasma gondii
infection in a strain-dependent manner in interferon gamma-activated human cells. Ubiquitination of unknown targets recruits adaptors and LC3 to the parasitophorous vacuole, leading to membrane envelopment and stunted growth. Vacuoles containing strain types II and III are susceptible, while type I strains of
T. gondii
are largely resistant and hence avoid autophagy-mediated growth restriction. Here we interrogated the genetic differences in LC3 recruitment between a resistant type I (GT1) strain and a susceptible type III (CTG) strain of
T. gondii
. We took advantage of a previous genetic cross between these two strains to determine the LC3 recruitment phenotype of 34 unique progeny clones. Genetic linkage mapping revealed that LC3 recruitment was highly multigenic, depending on two major quantitative trait loci (QTLs) on chromosome II and VIII, as well as three minor contributing loci. Ubiquitin affinity capture followed by mass spectrometry identified several potential targets exposed at the surface of the parasitophorous vacuole, including several candidates within the major QTLs. We tested several candidates and identified the dense granule proteins MAF1 on chromosome II, and MAG1 and PSD1 on chromosome VIII, as being partially responsible for susceptibility to LC3 recruitment. Differential susceptibility is likely due to strain-specific differences in recognition of parasite molecules, rather than actively blocking recognition, thus revealing a new mechanism for cell-autonomous restriction of intracellular pathogens.

IMPORTANCE

Autophagy is a process used by cells to recycle organelles and macromolecules and to eliminate intracellular pathogens. Previous studies have shown that some stains of
Toxoplasma gondii
are resistant to autophagy-dependent growth restriction, while others are highly susceptible. Although it is known that autophagy-mediated control requires activation by interferon gamma, the basis for why parasite strains differ in their susceptibility is unknown. Our findings indicate that susceptibility involves at least five unlinked parasite genes on different chromosomes, including several secretory proteins targeted to the parasite-containing vacuole and exposed to the host cell cytosol. Our findings reveal that susceptibility to autophagy-mediated growth restriction relies on differential recognition of parasite proteins exposed at the host-pathogen interface, thus identifying a new mechanism for cell-autonomous control of intracellular pathogens.
Pathogenic bacteria experience pervasive RNA polymerase backtracking during infection
Authors: Browning Kaitlyn R. , Merrikh Houra
Published: December 2023

Pathogenic bacteria and their eukaryotic hosts are in a constant arms race. Hosts have numerous defense mechanisms, including some that cause DNA damage. How these host defense mechanisms impact molecular transactions along the bacterial chromosome during infection is unclear. This is partially due to the lack of a method that can detect these events in pathogens while they are within host cells. We developed and optimized a system capable of mapping and measuring levels of bacterial proteins associated with the chromosome while they are actively infecting the host (referred to as PIC-seq). Here, we focused on the dynamics of RNA polymerase (RNAP) movement and association with the chromosome in the pathogenic bacterium
Salmonella enterica
as a model system during infection. Using PIC-seq, we found that RNAP association patterns with the chromosome change during infection genome wide, including at regions that encode for key virulence genes. Importantly, we found that infection of a host significantly increases RNAP backtracking on the bacterial chromosome. RNAP backtracking is the most common form of disruption to RNAP progress on the chromosome. Interestingly, we found that genes experiencing backtracking are downregulated. We observed that the resolution of backtracked RNAPs
via
the anti-backtracking factors GreA and GreB is critical for pathogenesis and for regulation of gene expression during infection. Altogether, our findings have important implications for both efficient transcription and stalled RNAP-driven mutagenesis, which can promote antimicrobial resistance and/or hypervirulence. These results suggest that the host can accelerate the evolution of bacterial pathogens, potentially at their own expense.

IMPORTANCE

Eukaryotic hosts have defense mechanisms that may disrupt molecular transactions along the pathogen’s chromosome through excessive DNA damage. Given that DNA damage stalls RNA polymerase (RNAP) thereby increasing mutagenesis, investigating how host defense mechanisms impact the movement of the transcription machinery on the pathogen chromosome is crucial. Using a new methodology we developed, we elucidated the dynamics of RNAP movement and association with the chromosome in the pathogenic bacterium
Salmonella enterica
during infection. We found that dynamics of RNAP movement on the chromosome change significantly during infection genome-wide, including at regions that encode for key virulence genes. In particular, we found that there is pervasive RNAP backtracking on the bacterial chromosome during infections and that anti-backtracking factors are critical for pathogenesis. Altogether, our results suggest that, interestingly, the host environment can promote the development of antimicrobial resistance and hypervirulence as stalled RNAPs can accelerate evolution through increased mutagenesis.
The most exposed regions of SARS-CoV-2 structural proteins are subject to strong positive selection and gene overlap may locally modify this behavior
Authors: Rubio Alejandro , de Toro Maria , Pérez-Pulido Antonio J.
Published: December 2023

The SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic that emerged in 2019 has been an unprecedented event in international science, as it has been possible to sequence millions of genomes, tracking their evolution very closely. This has enabled various types of secondary analyses of these genomes, including the measurement of their sequence selection pressure. In this work, we have been able to measure the selective pressure of all the described SARS-CoV-2 genes, even analyzed by sequence regions, and we show how this type of analysis allows us to separate the genes between those subject to positive selection (usually those that code for surface proteins or those exposed to the host immune system) and those subject to negative selection because they require greater conservation of their structure and function. We have also seen that when another gene with an overlapping reading frame appears within a gene sequence, the overlapping sequence between the two genes evolves under a stronger purifying selection than the average of the non-overlapping regions of the main gene. We propose this type of analysis as a useful tool for locating and analyzing all the genes of a viral genome when an adequate number of sequences are available.

IMPORTANCE

We have analyzed the selection pressure of all severe acute respiratory syndrome coronavirus 2 genes by means of the nonsynonymous (Ka) to synonymous (Ks) substitution rate. We found that protein-coding genes are exposed to strong positive selection, especially in the regions of interaction with other molecules (host receptor and genome of the virus itself). However, overlapping coding regions are more protected and show negative selection. This suggests that this measure could be used to study viral gene function as well as overlapping genes.
Transmission of antimicrobial resistance in the gut microbiome of gregarious cockroaches: the importance of interaction between antibiotic exposed and non-exposed populations
Authors: Bogri Amalia , Jensen Emilie Egholm Bruun , Borchert Asbjørn Vedel , Brinch Christian , Otani Saria , Aarestrup Frank M.
Published: December 2023

Antimicrobial resistance (AMR) is a major global health concern, further complicated by its spread via the microbiome bacterial members. While mathematical models discuss AMR transmission through the symbiotic microbiome, experimental studies are scarce. Herein, we used a gregarious cockroach,
Pycnoscelus surinamensis,
as an
in vivo
animal model for AMR transmission investigations. We explored whether the effect of antimicrobial treatment is detectable with metagenomic sequencing, and whether AMR genes can be spread and established in unchallenged (not treated with antibiotics) individuals following contact with treated donors, and under various frequencies of interaction. Gut and soil substrate microbiomes were investigated by metagenomic sequencing for bacterial community composition and resistome profiling. We found that tetracycline treatment altered the treated gut microbiome by decreasing bacterial diversity and increasing the abundance of tetracycline resistance genes. Untreated cockroaches that interacted with treated donors also had elevated tetracycline resistance. The levels of resistance differed depending on the magnitude and frequency of donor transfer. Additionally, treated donors showed signs of microbiome recovery due to their interaction with the untreated ones. Similar patterns were also recorded in the soil substrate microbiomes. Our results shed light on how interacting microbiomes facilitate AMR gene transmission to previously unchallenged hosts, a dynamic influenced by the interaction frequencies, using an
in vivo
model to validate theoretical AMR transmission models.

IMPORTANCE

Antimicrobial resistance is a rising threat to human and animal health. The spread of resistance through the transmission of the symbiotic gut microbiome is of concern and has been explored in theoretical modeling studies. In this study, we employ gregarious insect populations to examine the emergence and transmission of antimicrobial resistance
in vivo
and validate modeling hypotheses. We find that antimicrobial treatment increases the levels of resistance in treated populations. Most importantly, we show that resistance increased in untreated populations after interacting with the treated ones. The level of resistance transmission was affected by the magnitude and frequency of population mixing. Our results highlight the importance of microbial transmission in the spread of antimicrobial resistance.
High prevalence and genetic diversity of
Treponema paraluisleporidarum
isolates in European lagomorphs
Authors: Knauf Sascha , Hisgen Linda , Ågren Erik O. , Barlow Alexander M. , Faehndrich Marcus , Voigt Ulrich , Fischer Luisa , Grillová Linda , Hallmaier-Wacker Luisa K. , Kik Marja J. L. , Klink Jana C. , Křenová Jitka , Lavazza Antonio , Lüert Simone , Nováková Markéta , Čejková Darina , Pacioni Carlo , Trogu Tiziana , Šmajs David , Roos Christian
Published: December 2023

The bacterium
Treponema paraluisleporidarum
causes syphilis in lagomorphs. In a set of 1,095 samples from four species—European brown hare, mountain hare, Corsican hare, and European rabbit—we tested for infection and genotyped the strains that infect wild lagomorphs. Samples originate from Sweden, the Netherlands, the United Kingdom, Germany, the Czech Republic, and Italy. The phylogenetic analyses of two informative gene targets (
tp0488
and
tp0548
) showed high genetic diversity among the lagomorph-infecting treponemes. More specifically, we found a high number of nucleotide variants and various short repeat units in the
tp0548
locus that have not been described for human syphilis and primate yaws causing
Treponema pallidum
. While the functional aspect of these short repeat units remains subject to ongoing investigations, it likely enables the pathogen to better survive in its lagomorph host. Our data did not support any geographic clustering, which is equally reflected in the host population genetics as shown by mitochondrial genome data corresponding to the sampled lagomorph populations. This is unexpected and in contrast with what has been shown for nonhuman primate infection with
T. pallidum
. In the future, the combination of multi-locus sequence typing and whole genome data from modern and ancient samples from a wide geographic range and multiple lagomorph species will contribute to a better understanding of the epidemiology and evolutionary path of lagomorph-infecting treponemes. In conclusion, our current study demonstrates widespread infection and a high genetic variation of the syphilis-causing pathogen in a higher number of positively PCR-tested European lagomorphs (
n
= 302/1,095).

IMPORTANCE

Syphilis is an ancient disease of humans and lagomorphs caused by two distinct but genetically closely related bacteria (>98% sequence identity based on the whole genome) of the genus
Treponema
. While human syphilis is well studied, little is known about the disease in the lagomorph host. Yet, comparative studies are needed to understand mechanisms in host–pathogen coevolution in treponematoses. Importantly,
Treponema paraluisleporidarum
–infected hare populations provide ample opportunity to study the syphilis-causing pathogen in a naturally infected model population without antibiotic treatment, data that cannot be obtained from syphilis infection in humans. We provide data on genetic diversity and are able to highlight various types of repetitions in one of the two hypervariable regions at the
tp0548
locus that have not been described in the human syphilis-causing sister bacterium
Treponema pallidum
subsp.
pallidum
.
A. castellanii
and
P. aeruginosa
mutually exacerbate damage to corneal cells during coinfection
Authors: Chen Chun-Hsien , Liao Chen-Chieh , Wang Yu-Jen , Huang Fu-Chin , Lin Wei-Chen
Published: December 2023

Microorganisms that are involved in microbial invasion keratitis infiltrate the cornea and cause eye pain. Despite the administration of antimicrobial treatment, patients with amoebic keratitis develop bacterial coinfections.
Pseudomonas aeruginosa
infection accounts for 50% of the reported bacterial coinfections in these patients. However, the role of pathogenic bacteria in amoeba-induced corneal damage remains unclear. In our current study, we conducted assays to examine cytopathic effects and observed increased corneal cell damage in the group with secondary
P. aeruginosa
infections. Imaging revealed that the presence of
A. castellanii
enhanced the accumulation of
P. aeruginosa
in areas of cell monolayer leakage. We demonstrated that treatment of
P. aeruginosa
with amoeba-soluble antigen resulted in higher adhesion ability, increased biofilm formation, and more severe corneal cell damage. Overall, this research significantly contributes to our understanding of the risk of
P. aeruginosa
coinfection in the progression of Acanthamoeba keratitis.

IMPORTANCE

At the National Cheng Kung University Hospital, numerous cases of amoebic keratitis had been identified with concurrent bacterial infections. Among these bacterial coinfections,
Pseudomonas aeruginosa
accounted for 50% of the reported cases. However, the impact of pathogenic bacteria on amoeba-induced corneal damage remains unclear. In our study, we successfully demonstrated that
P. aeruginosa
accumulated on the
Acanthamoeba castellanii
surface and caused more severe corneal damage. We also indicated that the exposure of
P. aeruginosa
to amoeba-soluble antigens enhanced its adhesion ability, promoted biofilm formation, and led to more severe corneal cell damage. These findings significantly contributed to our understanding of the risk associated with
P. aeruginosa
coinfection in the progression of amoeba keratitis.
Mycobiomes of two distinct clades of ambrosia gall midges (Diptera: Cecidomyiidae) are species-specific in larvae but similar in nutritive mycelia
Authors: Pyszko Petr , Šigutová Hana , Kolařík Miroslav , Kostovčík Martin , Ševčík Jan , Šigut Martin , Višňovská Denisa , Drozd Pavel
Published: December 2023

Ambrosia gall midges (AGMs) are mostly host plant-specific. In their galls, they harbor fungal symbionts on which they feed. Therefore, they represent unique steps in the evolution of the gall-forming Cecidomyiidae (Diptera). Gall-associated fungi have been studied predominantly by cultivations, and potential larval endosymbionts have been completely neglected. Using ITS2 rRNA metabarcoding, we characterized the mycobiomes of individual gall compartments (gall surface, gall interior, and larva) of six species from two phylogenetically separated tribes (Asphondyliini and Lasiopterini). Compared to the gall surface and interior, the larvae harbored significantly higher fungal richness and taxonomic diversity, and a larger pool of indicator taxa. Larval mycobiome composition was more species-specific; however, the fungal genera
Fusarium
,
Filobasidium
,
Tilletiopsis
,
Alternaria
, and
Aureobasidium
were indicator taxa shared among species. Overall, the larvae harbored 29% of unique taxa that can play a functional role in the host (e.g., initiation of gall development or selection of the mycelia composition). The mycobiome of the gall interior was assembled least stochastically, and its composition was the least species-specific, being dominated by
Botryosphaeria dothidea
(except for
Lasioptera arundinis
). Therefore, the interior of ambrosia galls offers a unique environment that supports the growth of similar fungi, regardless of the host plant species and the phylogenetic distance between the AGM tribes. Our study illustrates a range of fungal microorganisms indicative of individual gall compartments, but their potential function, especially in larvae, remains to be solved.

IMPORTANCE

Ambrosia gall midges are endophagous insect herbivores whose larvae live enclosed within a single gall for their entire development period. They may exhibit phytomycetophagy, a remarkable feeding mode that involves the consumption of plant biomass and mycelia of their cultivated gall symbionts. Thus, AGMs are ideal model organisms for studying the role of microorganisms in the evolution of host specificity in insects. However, compared to other fungus-farming insects, insect–fungus mutualism in AGMs has been neglected. Our study is the first to use DNA metabarcoding to characterize the complete mycobiome of the entire system of the gall-forming insects as we profiled gall surfaces, nutritive mycelia, and larvae. Interestingly, larval mycobiomes were significantly different from their nutritive mycelia, although
Botryosphaeria dothidea
dominated the nutritive mycelia, regardless of the evolutionary separation of the tribes studied. Therefore, we confirmed a long-time hypothesized paradigm for the important evolutionary association of this fungus with AGMs.
An Approach to Constructing Explicit Estimators in Nonlinear Regression
Authors: Linke Yu. Yu. , Borisov I. S.
Published: December 2023

We consider the problem of constructing explicit consistent estimators of finite-dimensional
parameters of nonlinear regression models using various nonparametric kernel estimators.
Chronic kidney disease and its predictors among highly active antiretroviral therapy naïve and experienced HIV-infected individuals at the selected hospitals, Southwest Ethiopia: a comparative cross-sectional study
Authors: Belay Alemayehu Sayih , Manaye Gizachew Ayele , Kebede Kindie Mitiku , Abateneh Dejene Derseh , Debebe Shibihon
Published: December 2023

Objective

This study aimed to determine the prevalence of chronic kidney disease (CKD) and its predictors among highly active antiretroviral therapy (HAART) naïve and experienced HIV-infected individuals.

Method and analysis

Hospital-based comparative cross-sectional study design was used at Mizan-Tepi University Teaching Hospital, Bonga General Hospital and Tepi General Hospital. A total of 616 naïve and experienced HIV-infected individuals participated. A systematic random sampling and consecutive sampling methods were applied to select the HAART experienced and naïve HIV-infected individuals, respectively. Descriptive statistics were used for all study variables. Independent t-test and logistic regression analysis were performed to compare the mean between naïve and experienced patients and to identify its predictor variables considering a <0.05 and 95% CI, respectively.

Results

A total of 616 HIV-positive respondents were enrolled in this study. The prevalence of CKD was 41 (29.3%) of 140 and 78 (16.4%) of 476 HAART-naïve and HAART-experienced HIV patients, respectively. Rural residency, being anaemic, being hypertensive, having had a family history of kidney disease and stage IV current WHO) clinical stage were independent risk factors of CKD among naïve HIV patients, whereas, rural residency, utilisation of drinking water per day below the recommended amount, being anaemic, being hypertensive, stage IV current WHO clinical stage and obesity were predictors of CKD among experienced HIV patients. Statistically significant difference was observed between HAART naïve and HAART experienced participants with regard to the mean glomerular filtration rate level (t=−3.987, 95% CI −18.29 to −6.22).

Conclusion

CKD was higher among HAART-naïve than HAART-experienced study participants. Therefore, early initiation of antiretroviral therapy (ART) drugs, modification of lifestyles to decrease obesity and early detection and treatment of comorbidities such as anaemia and hypertension may have profound effects in reducing CKD and increasing patients’ quality of life.
HER2 and HLA-A*02 dual CAR-T cells utilize LOH in a NOT logic gate to address on-target off-tumor toxicity
Authors: Bassan David , Weinberger Leehee , Yi Jason , Kim Tanya , Weist Michael R , Adams Gregor B , Foord Orit , Chaim Neta , Tabak Sarit , Bujanover Nir , Lopesco Yael , Vucci Kristina , Schnair Caitlin , Levy-Knafo Limor , Kendall Richard L , Calzone Frank J , Sharbi-Yunger Adi
Published: December 2023

Background

One of the major challenges in chimeric antigen receptor (CAR)-T cell therapy for solid tumors is the potential for on-target off-tumor toxicity due to the expression of CAR tumor antigens in essential tissues and organs. Here, we describe a dual CAR NOT gate incorporating an inhibitory CAR (iCAR) recognizing HLA-A*02 (“A2”) that enables effective treatment with a potent HER2 activating CAR (aCAR) in the context of A2 loss of heterozygosity (LOH).

Methods

A CAR-T cell screen was conducted to identify inhibitory domains derived from natural immune receptors (iDomains) to be used in a NOT gate, to kill A2−HER2+lung cancer cell lines but spare A2+HER2+lung cancer cell-lines with high specificity. The extensive analysis of lead candidates included T-cell activation and killing, assays of reversibility and durability in sequential challenges, target cell specificity in mixed 3D spheroids and 2D cultures, and the characterization of CAR expression level and cell-trafficking.

Results

A leukocyte immunoglobulin-like receptor B1 (LIR1) iDomain iCAR was identified as most effective in regulating the cytotoxicity of a second generation HER2 aCAR. Target transfer experiments demonstrated that the ‘on’ and ‘off’ cell state of the LIR1 NOT gate CAR-T cell is both durable and reversible. Protection required iCAR signaling and was associated with reduced aCAR and iCAR surface expression. iCAR regulation was sufficient to generate high target specificity in a 3D adjacent spheroid assay designed to model the interface between clonal A2 LOH foci and normal tissue. However, we observed significant bystander killing of A2+cells in admix culture through aCAR dependent and independent mechanisms. LIR1 NOT gate CAR-T cells conferred protection against H1703-A2+tumors and high efficacy against H1703-A2−tumors in-vivo. We observed that the iCAR is inactive in A2+donors due to cis-binding, but Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) knockout of HLA-A fully restored iCAR activity.

Conclusions

We have preclinically validated an iCAR NOT gate technology broadly applicable for targeting HER2 expression in the context of A2 LOH. This approach is designed to prevent off tumor toxicity while allowing highly potent antitumor activity.
Multimorbidity of cardiovascular disease subtypes in a prospective cohort of 1.2 million UK women
Authors: Suh Jae Won , Floud Sarah , Reeves Gillian K , Cairns Benjamin J , Wright F Lucy
Published: December 2023

Objective

Cardiovascular multimorbidity (CVM) is the co-occurrence of multiple cardiovascular disease subtypes (CVDs) in one person. Because common patterns and incidence of CVM are not well-described, particularly in women, we conducted a descriptive study of CVM in the Million Women Study, a large population-based cohort of women.

Methods

UK women aged 50–64 years were followed up using hospital admissions and mortality records for an average of 19 years. CVM was defined as having ≥2 of 19 selected CVDs. The age-specific cumulative incidence of CVM between age 60 and 80 years was estimated. The numbers and proportions of individual, pairs and other combinations of CVDs that comprised incident CVM were calculated. For each individual CVD subtype, age-standardised proportions of the counts of other co-occurring CVDs were estimated.

Results

The age-specific likelihood of having CVM nearly doubled every 5 years between age 60 and 80 years. Among 1.2 million women without CVD at study baseline, 16% (n=196 651) had incident CVM by the end of follow-up. Around half of all women with CVM had a diagnosis of ischaemic heart disease (n=102 536) or atrial fibrillation (n=96 022), almost a third had heart failure (n=72 186) and a fifth had stroke (n=40 442). The pair of CVDs with the highest age-adjusted incidence was ischaemic heart disease and atrial fibrillation (18.95 per 10 000 person-years). Over 60% of individuals with any given CVD subtype also had other CVDs, after age standardisation.

Conclusions

CVM is common. The majority of women with any specific CVD subtype eventually develop at least one other. Clinical and public health guidelines for CVD management should acknowledge this high likelihood of CVM.
Adult congenital heart disease training in Europe: current status, disparities and potential solutions
Authors: McMahon Colin J , Voges Inga , Jenkins Petra , Brida Margarita , van der Bosch Annemien E , Dellborg Mikael , Heying Ruth , Stein Jörg I , Georgiev Borislav , Mesihovic-Dinarevic Senka , Prokšelj Katja , Oskarsson Gylfi , Frogoudaki Alexandra , Karagöz Tevfik , Jossif Antonis , Doros Gabriela , Nielsen Dorte , Jalanko Mikko , Sanchez Perez Inmaculada , Alvares Sílvia , Estensen Mette-Elise , Petropoulos Andreas , Tagen Raili , Gumbienė Lina , Michel-Behnke Ina , Olejnik Peter , Clift Paul F , Sendzikaite Skaiste , Albert-Brotons Dimpna C , Rhodes Mark , Pitkänen Olli , Bassareo Pier Paolo , Gatzoulis Michael A , Walsh Kevin , Milanesi Ornella , Ladouceur Magalie , Chessa Massimo , Budts Werner
Published: December 2023

Objectives

This study aimed to determine the status of training of adult congenital heart disease (ACHD) cardiologists in Europe.

Methods

A questionnaire was sent to ACHD cardiologists from 34 European countries.

Results

Representatives from 31 of 34 countries (91%) responded. ACHD cardiology was recognised by the respective ministry of Health in two countries (7%) as a subspecialty. Two countries (7%) have formally recognised ACHD training programmes, 15 (48%) have informal (neither accredited nor certified) training and 14 (45%) have very limited or no programme. Twenty-five countries (81%) described training ACHD doctors ‘on the job’. The median number of ACHD centres per country was 4 (range 0–28), median number of ACHD surgical centres was 3 (0–26) and the median number of ACHD training centres was 2 (range 0–28). An established exit examination in ACHD was conducted in only one country (3%) and formal certification provided by two countries (7%). ACHD cardiologist number versus gross domestic product Pearson correlation coefficient=0.789 (p<0.001).

Conclusion

Formal or accredited training in ACHD is rare among European countries. Many countries have very limited or no training and resort to ‘train people on the job’. Few countries provide either an exit examination or certification. Efforts to harmonise training and establish standards in exit examination and certification may improve training and consequently promote the alignment of high-quality patient care.
Long-lasting improvement of refractory antisynthetase syndrome with tocilizumab: a report of two cases
Authors: Baumann Benvenuti Fleur , Dudler Jean
Published: December 2023

No standardised and universal treatment is available for antisynthetase syndrome. In particular, there is an unmet need for a single efficient treatment acting on its various manifestations, including interstitial lung disease, myositis and polyarthritis.

We describe the cases of two patients with multiple and severe manifestations, including joint, muscular and lung involvement, both refractory to various treatments, including rituximab, who demonstrated significant improvement of all their manifestations, including joint, muscular and lung diseases on tocilizumab. The response was also long-lasting, with both patients still being in full remission after >10 years of treatment.

Our experience shows that interleukin-6 inhibition could be a very effective treatment option in antisynthetase syndrome, with efficacy on a wide spectrum of manifestations.
GAME-THEORETICAL MODEL OF COVID-19 VACCINATION IN THE ENDEMIC EQUILIBRIUM
Authors: MARQUEZ RENEE MARIA ARGANA , MINAS MARIA SEANNA CABERO , SANTOS JORDAN VANCE TAITANO , YOON KANGSAN , CAMPO VINCE NICOLAS S. , OH HYUNJU , RYCHTÁŘ JAN , TAYLOR DEWEY
Published: December 2023

An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), epi-centred in Hubei Province of the People’s Republic of China, quickly spread worldwide and caused COVID-19 pandemic. It infected hundreds of millions of people and caused millions of deaths. In this paper, we develop a compartmental ODE model of COVID-19 transmission. We consider a possibility of breakthrough infections after the vaccination and account for both symptomatic and asymptomatic infections and transmissions. We also incorporate game theory to study the optimal vaccination decisions from the individuals’ perspective. We show that vaccination alone is unlikely to eliminate COVID-19. To achieve herd immunity, the individuals would have to receive a dose of a vaccine more frequently than once every 3 months. It is therefore crucial to adhere to various guidelines, such as quarantine, isolate and wear a mask if tested positive for COVID-19.
Community Engaged Researchers and Designers: How We Work and What We Need
Authors: Amidon Timothy R. , Moore Kristen R. , Simmons Michele
Published: December 2023

This introductory essay describes the need for clarity and openness surrounding community-engaged research projects, which comprise expertise, efforts, and experiences that often fail to make their way into traditional research accounts and articles.
Making Graduate Student CER Practices Visible: Navigating the Double-Binds of Identities, Space, and Time
Authors: Allison Lydia , Maggio Christopher , Kalim Salma , Schoettler Megan
Published: December 2023

In this dialogue, four recently commenced PhD students discuss and thus expound upon how their community-engaged research shaped their methodologies and vice versa. The four authors explain how they each individually overcame the double-binds of identities, space, and time associated with graduate school and community partnerships. They conclude by detailing how, in overcoming these double-binds, they were able to enact community-engaged practices not only tied to their respective methodologies but also focused on equity and social justice.
Hi-PART: Going Beyond Graph Pooling with Hierarchical Partition Tree for Graph-Level Representation Learning
Authors: Ren Yuyang , Zhang Haonan , Fu Luoyi , Liang Shiyu , Zhou Lei , Wang Xinbing , Cao Xinde , Long Fei , Zhou Chenghu
Published: December 2023

Graph pooling refers to the operation that maps a set of node representations into a compact form for graph-level representation learning. However, existing graph pooling methods are limited by the power of the Weisfeiler–Lehman (WL) test in the performance of graph discrimination. In addition, these methods often suffer from hard adaptability to hyper-parameters and training instability. To address these issues, we propose Hi-PART, a simple yet effective graph neural network (GNN) framework with
Hi
erarchical
Par
tition
T
ree (HPT). In HPT, each layer is a partition of the graph with different levels of granularities that are going toward a finer grain from top to bottom. Such an exquisite structure allows us to quantify the graph structure information contained in HPT with the aid of structural information theory. Algorithmically, by employing GNNs to summarize node features into the graph feature based on HPT’s hierarchical structure, Hi-PART is able to adequately leverage the graph structure information and provably goes beyond the power of the WL test. Due to the separation of HPT optimization from graph representation learning, Hi-PART involves the height of HPT as the only extra hyper-parameter and enjoys higher training stability. Empirical results on graph classification benchmarks validate the superior expressive power and generalization ability of Hi-PART compared with state-of-the-art graph pooling approaches.
A combination of β-hydroxybutyrate and citrate ameliorates disease progression in a rat model of polycystic kidney disease
Authors: Torres Jacob A. , Holznecht Nickolas , Asplund David A. , Amarlkhagva Tselmeg , Kroes Bradley C. , Rebello Juliette , Agrawal Shagun , Weimbs Thomas
Published: December 2023

Combining β-hydroxybutyrate (BHB) and citrate effectively slows and prevents cyst formation and expansion in young Cy/+ rats using less BHB and citrate than when used alone, demonstrating synergy. In adult rats, the combination causes a partial reversal of existing disease, reducing cyst number and cystic area, preserving glomerular health, and decreasing markers of kidney injury. Our results suggest a safe and feasible strategy for supporting kidney health in polycystic kidney disease (PKD) using a combination of BHB and citrate.
Fast and slow muscle fiber transcriptome dynamics with lifelong endurance exercise
Authors: Raue Ulrika , Begue Gwenaelle , Minchev Kiril , Jemiolo Bozena , Gries Kevin J. , Chambers Toby , Rubenstein Aliza , Zaslavsky Elena , Sealfon Stuart C. , Trappe Todd , Trappe Scott
Published: December 2023

This study provides the first insights into fast and slow muscle fiber transcriptome dynamics with lifelong endurance exercise. The fast fibers were more responsive to exercise with divergent transcriptome signatures among young exercisers (growth and metabolic), lifelong exercisers (metabolic), and old healthy nonexercisers (stress). Only lifelong exercisers had a biological response in slow fibers (metabolic). These data provide novel insights into fast and slow muscle fiber health at the molecular level with age and exercise.
Upper airway imaging and function in obstructive sleep apnea in people with and without HIV
Authors: Darquenne Chantal , Theilmann Rebecca J. , Rivoalen Ines , DeYoung Pamela N. , Orr Jeremy E. , Malhotra Atul , Hicks Charles B. , Owens Robert L.
Published: December 2023

Obstructive sleep apnea is common in people living with human immunodeficiency virus (HIV), but the underlying mechanisms are unclear. We did not find differences in upper airway morphology using magnetic resonance imaging (MRI) during wake and natural sleep between people living with HIV (PLWH) with obstructive sleep apnea (OSA) and age, gender, and body mass index (BMI)-matched people with OSA but without HIV. Nor were there differences in tongue volume or changes in airway size during inspiration and expiration. MRI-derived anatomy was correlated with measures of airway collapse.
In Situ and Real-Time Monitoring of Doping Levels by Reflectance Anisotropy Spectroscopy (RAS) during Molecular Beam Epitaxial (MBE) Growth of III/V Semiconductors
Authors: Fouckhardt Henning , Richter Johannes , Doering Christoph , Strassner Johannes
Published: December 2023

Reflectance anisotropy/difference spectroscopy (RAS/RDS) had been developed for monitoring epitaxial semiconductor growth, especially for the metal-organic chemical vapor deposition (MOCVD) of III/V semiconductors. But RAS is also well suited for the control of III/V growth with molecular beam epitaxy (MBE). Although the work on RAS has already started at least three decades ago, the potential of this in situ and real-time monitoring technique, especially for doping control, is not well known yet. Experimental results are given here on the identification of doping types and concentration during MBE growth, exemplarily for GaAs and AlGaAs. Especially, the dependence of the majority charge carrier concentration (i.e., the doping concentration) on the RAS signal difference between the nondoping and doping cases is addressed here.
Mathematical Modeling of Giardiasis Transmission Dynamics with Control Strategies in the Presence of Carriers
Authors: Liana Yustina A. , Chuma Furaha Michael
Published: December 2023

Giardiasis is among the ignored zoonotic illnesses accorded by the World Health Organization that is caused by Giardia duodenalis. The disease is ignored regardless of the harm it causes to people and other creatures. In this paper, a mathematical model for giardiasis illness transmission is formed, which considers sickness carriers and control measures such as screening, treatment, and sanitation of the environment around people. In the assessment, the basic reproduction number,

R

0

, which is used for analyzing the local stability of the equilibria is determined using the state-of-the-art next-generation matrix, while the Metzler constancy speculation is used to show the overall adequacy of the global stability of the equilibrium point free from the disease. In addition, a Lyapunov function has been used to study the stability of the endemic equilibrium point. The assessment of parameters is performed to explore the limits that significantly influence the transmission components of the disease disorders using the normalizing sensitivity index method. The result revealed that the recruitment rate is the most sensitive limit to the reproduction number. The environment-human interaction parameter is the second influential factor in the transmission of giardiasis in the community. In the same manner, the outcomes recommend that carriers assume an expected part in the rate of giardiasis subsequently; disregarding them could risk endeavors to control the pestilence. Besides, the mathematical recreation of the model shows that a mix of each of the three interventions fundamentally affects the control of giardiasis. In this way, we advise implementing the strategies simultaneously in endemic areas to effectively stop the spread of the giardiasis disease in humans.
Decision-Making Based on Spherical Linear Diophantine Fuzzy Rough Aggregation Operators and EDAS Method
Authors: Qiyas Muhammad , Khan Neelam , Naeem Muhammad , Okyere Samuel
Published: December 2023

In everyday life, decision-making is a difficult task fraught with ambiguity and uncertainty. Many researchers and scholars have suggested numerous fuzzy set theories to resolve these ambiguities and uncertainties. The EDAS method (evaluation based on distance from average answer) is extremely beneficial in decision-making situations. In multi-attribute group decision-making (MAGDM) situations, this is especially true when there are more competing criteria. In this paper, we introduce the concept of spherical linear diophantine fuzzy rough sets (SLDFRSs). We develop basic operational laws and a number of propose aggregation operators. Furthermore, the necessary and desired features of SLDFRS are explored. This study proposes a new technique known as the spherical linear diophantine fuzzy rough set EDAS (SLDFRS-EDAS) method to deal with these uncertainties in the MAGDM problem. A MAGDM technique is intended to evaluate the emergency system based on the newly introduced operators. Furthermore, a comparison study of the activity and applicability of the suggested approach with earlier procedures is used to validate its viability and applicability.
Resilience in the Depths: First Example of Fin Regeneration in a Silky Shark (Carcharhinus falciformis) following Traumatic Injury
Authors: Black Chelsea
Published: December 2023

Tissue regeneration and wound healing remain extremely understudied in elasmobranchs as many wounds are recorded through one-off opportunistic observations with an inability for long-term monitoring of individuals. This study demonstrates partial fin regeneration of a silky shark (Carcharhinus falciformis) almost one year after a traumatic injury that resulted in a 20.8% loss of the first dorsal fin. The shark was photographed 332 days after the recorded injury with a newly shaped dorsal fin that had healed to 87% of the original size. Photographs provided by divers allowed for accurate measurements of fin growth, confirming an approximate 10.7% increase in fin area, indicative of tissue regeneration. Wound healing rate was calculated to conclude that the initial wound reached complete closure by day 42, which is analogous with other elasmobranch healing rates. Prior to this study, only one other record of dorsal fin regeneration had been documented in a whale shark. This provides the first evidence of dorsal fin regeneration in a silky shark and contributes to the limited studies of wound healing rates in sharks. This newfound insight into tissue regeneration and wound healing underscores the importance of further research to understand how they respond to traumatic injury in the face of mounting environmental challenges, both natural and anthropogenic. Additionally, this study exemplifies the power of collaboration between researchers and the public, including photographers and divers, to expand the scope of research studies and bridge the gap between science and society.
Community Science Strategies Reveal Distributional Patterns of Treponeme-Associated Hoof Disease in Washington Elk (Cervus canadensis)
Authors: Winter Steven N. , Fernández María del Pilar , Clancey Erin , Garrison Kyle , Mansfield Kristin , Wild Margaret A.
Published: December 2023

Treponeme-associated hoof disease (TAHD) is an emerging disease of conservation concern in elk (Cervus canadensis) in the Northwest USA. Elk with TAHD exhibit characteristic hoof lesions that are often accompanied by lameness and limping. The gold standard approach traditionally used for infectious disease surveillance is laboratory confirmation, which for TAHD is a histologic examination of abnormal elk hooves submitted by wildlife agencies. Diagnostic evaluation affords certainty in confirming TAHD; however, these examinations are also labor and resource intensive, and therefore, not conducive to the collection of sufficient data for epidemiologic investigations. In response, two community science (CS) surveillance strategies have been implemented in Washington State: public observations of limping elk from a web-based reporting tool and hunter reports of hoof abnormalities on harvested elk. Surveillance using CS strategies can be implemented widely and may be useful for describing broad distributional patterns of TAHD, despite their unknown relationship to laboratory-confirmed cases. We described and compared the spatial–temporal distribution of TAHD in western Washington game management units (GMU) using the two CS strategies to assess congruences and discrepancies between observed patterns. We used spatial scan statistics to identify possible core-affected and newly emerging areas at the GMU level. Lastly, we contrasted CS observations against confirmed case data to examine possible delays in TAHD detection and co-occurrence among surveillance strategies. We found public observations of limping elk often predated TAHD confirmations in GMUs by several years, while hunter-reported abnormalities predated confirmations in GMUs by several months. High co-occurrence between the presence of apparent and confirmed cases under different surveillance strategies further supports the use of CS sources. This study capitalizes on wide-reaching CS data to provide new and complementary epidemiological information that can help guide future surveillance, management, and research efforts for this novel elk hoof disease.
Allicin-Mediated Cell Cycle Regulation Reverses Taxol Resistance in NSCLC: Molecular Insights and Therapeutic Potentia
Authors: Gao Xudong , Santhanam Ramesh kumar , Huang Zeng , Liu Mingyue , Hou Shanbo , Song Aigang , Ren Tianshu , Zhao Qingchun
Published: December 2023

The clinical efficacy of non-small-cell lung cancer (NSCLC) treatment is significantly hindered by Taxol resistance, demanding the exploration of novel approaches to overcome this challenge. Natural products, renowned for their diverse anticancer potential, offer hope, with allicin emerging as a captivating contender. However, the intricate role and underlying mechanisms of allicin in NSCLC Taxol resistance remain largely unexplored. In this extensive investigation, we delve into the impact of allicin on Taxol resistance, meticulously examining both in vitro and in vivo scenarios. Remarkably, allicin effectively curbs the proliferation and migration of A549/Taxol cells while inducing apoptosis. Unraveling the regulatory potential of genes like CDK1 in the cell cycle pathway, allicin demonstrated the ability to arrest cells in the G2/M phase, thus disrupting the cell cycle and heightening Taxol sensitivity. Strikingly, when combined with Taxol, allicin showed the ability to promote Taxol to inhibit tumor growth and reduce lung nodules in tumor-bearing mice, all without significant toxicity. Importantly, allicin’s prowess in reversing Taxol resistance via cell cycle regulation sheds light on its potential as a resistance-reversing agent in NSCLC, marking a vital milestone in the quest for natural source therapies.