bluuebunny/crossref_metadata_2025_split huggingface dataset:
New myxobacteria of the
Myxococcaceae
clade produce angiolams with antiparasitic activities
Authors: Walesch Sebastian , Garcia Ronald , Mahmoud Abdelhalim B. , Panter Fabian , Bollenbach Sophie , Mäser Pascal , Kaiser Marcel , Krug Daniel , Müller Rolf 
Published: February 2024

ABSTRACT

In the past century, microbial natural products have proven themselves to be substantial and fruitful sources of anti-infectives. In addition to the well-studied Actinobacteria, understudied bacterial taxa like the Gram-negative myxobacteria have increasingly gained attention in the ongoing search for novel and biologically active natural products. In the course of a regional sampling campaign to source novel myxobacteria, we recently uncovered new myxobacterial strains MCy12716 and MCy12733 belonging to the
Myxococcaceae
clade. Early bioactivity screens of the bacterial extracts revealed the presence of bioactive natural products that were identified as angiolam A and several novel derivatives. Sequencing of the corresponding producer strains allowed the identification of the angiolam biosynthetic gene cluster, which was verified by targeted gene inactivation. Based on bioinformatic analysis of the biosynthetic gene cluster, a concise biosynthesis model was devised to explain angiolam biosynthesis. Importantly, novel angiolam derivatives uncovered in this study named angiolams B, C, and D were found to display promising antiparasitic activities against the malaria pathogen
Plasmodium falciparum
in the 0.3–0.8 µM range.

IMPORTANCE

The COVID-19 pandemic and continuously emerging antimicrobial resistance (AMR) have recently raised awareness about limited treatment options against infectious diseases. However, the shortage of treatment options against protozoal parasitic infections, like malaria, is much more severe, especially for the treatment of so-called neglected tropical diseases. The detection of anti-parasitic bioactivities of angiolams produced by MCy12716 and MCy12733 displays the hidden potential of scarcely studied natural products to have promising biological activities in understudied indications. Furthermore, the improved biological activities of novel angiolam derivatives against
Plasmodium falciparum
and the evaluation of its biosynthesis display the opportunities of the angiolam scaffold on route to treat protozoal parasitic infections as well as possible ways to increase the production of derivatives with improved bioactivities.
Prospective fecal microbiomic biomarkers for chronic wasting disease
Authors: Didier Adam , Bourner Maureen , Kleks Guy , Zolty Avihai , Kumar Brajendra , Nichols Tracy , Durynski Karie , Bender Susan , Gibison Michelle , Murphy Lisa , Ellis Julie C. , Dong Dawei W. , Kashina Anna 
Published: February 2024

ABSTRACT

Chronic wasting disease (CWD) is a naturally occurring prion disease in cervids that has been rapidly proliferating in the United States. Here, we investigated a potential link between CWD infection and gut microbiome by analyzing 50 fecal samples obtained from CWD-positive animals of different sexes from various regions in the USA compared to 50 CWD-negative controls using high throughput sequencing of the 16S ribosomal RNA and targeted metabolomics. Our analysis reveals promising trends in the gut microbiota that could potentially be CWD-dependent, including several bacterial taxa at each rank level, as well as taxa pairs, that can differentiate between CWD-negative and CWD-positive deer. Through machine-learning, these taxa and taxa pairs at each rank level could facilitate identification of around 70% of both the CWD-negative and the CWD-positive samples. Our results provide a potential tool for diagnostics and surveillance of CWD in the wild, as well as conceptual advances in our understanding of the disease.

IMPORTANCE
This is a comprehensive study that tests the connection between the composition of the gut microbiome in deer in response to chronic wasting disease (CWD). We analyzed 50 fecal samples obtained from CWD-positive animals compared to 50 CWD-negative controls to identify CWD-dependent changes in the gut microbiome, matched with the analysis of fecal metabolites. Our results show promising trends suggesting that fecal microbial composition can directly correspond to CWD disease status. These results point to the microbial composition of the feces as a potential tool for diagnostics and surveillance of CWD in the wild, including non-invasive CWD detection in asymptomatic deer and deer habitats, and enable conceptual advances in our understanding of the disease.
A CRISPR/LbCas12a-based method for detection of bacterial fruit blotch pathogens in watermelon
Authors: Wang Zelu , Cheng Wenhui , Dong Zhiyu , Yao Xiamei , Deng Xu , Ou Chun 
Published: February 2024

ABSTRACT

Acidovorax citrulli
is the main pathogen causing bacterial fruit blotch, which seriously threatens the global watermelon industry. At present, rapid, sensitive, and low-cost detection methods are urgently needed. The established CRISPR/LbCas12a visual detection method can specifically detect
A. citrulli
and does not cross-react with other pathogenic bacteria such as
Erwinia tracheiphila
,
Pseudomonas syringae
, and
Xanthomonas campestris
. The sensitivity of this method for genomic DNA detection is as low as 0.7 copies/μL, which is higher than conventional PCR and real-time PCR. In addition, this method only takes 2.5 h from DNA extraction to quantitative detection and does not require complex operation and sample treatment. Additionally, the technique was applied to test real watermelon seed samples for
A. citrulli
, and the results were contrasted with those of real-time fluorescence quantitative PCR and conventional PCR. The high sensitivity and specificity have broad application prospects in the rapid detection of bacterial fruit blotch bacterial pathogens of watermelon.

IMPORTANCE

Bacterial fruit blotch,
Acidovorax citrulli
, is an important seed-borne bacterial disease of watermelon, melon, and other cucurbits. The lack of rapid, sensitive, and reliable pathogen detection methods has hampered research on fruit spot disease prevention and control. Here, we demonstrate the CRISPR/Cas12a system to analyze aspects of the specificity and sensitivity of
A. citrulli
and to test actual watermelon seed samples. The results showed that the CRISPR/Cas12a-based free-amplification method for detecting bacterial fruit blotch pathogens of watermelons was specific for
A. citrulli
target genes and 100-fold more sensitive than conventional PCR with quantitative real-time PCR. This method provides a new technical tool for the detection of
A. citrulli
.
Atypia detected during breast screening and subsequent development of cancer: observational analysis of the Sloane atypia prospective cohort in England
Authors: Freeman Karoline , Jenkinson David , Clements Karen , Wallis Matthew G , Pinder Sarah E , Provenzano Elena , Stobart Hilary , Stallard Nigel , Kearins Olive , Sharma Nisha , Shaaban Abeer , Kirwan Cliona Clare , Hilton Bridget , Thompson Alastair M , Taylor-Phillips Sian 
Published: February 2024

Abstract

Objective
To explore how the number and type of breast cancers developed after screen detected atypia compare with the anticipated 11.3 cancers detected per 1000 women screened within one three year screening round in the United Kingdom.

Design
Observational analysis of the Sloane atypia prospective cohort in England.

Setting
Atypia diagnoses through the English NHS breast screening programme reported to the Sloane cohort study. This cohort is linked to the English Cancer Registry and the Mortality and Birth Information System for information on subsequent breast cancer and mortality.

Participants
3238 women diagnosed as having epithelial atypia between 1 April 2003 and 30 June 2018.

Main outcome measures
Number and type of invasive breast cancers detected at one, three, and six years after atypia diagnosis by atypia type, age, and year of diagnosis.

Results

There was a fourfold increase in detection of atypia after the introduction of digital mammography between 2010 (n=119) and 2015 (n=502). During 19 088 person years of follow-up after atypia diagnosis (until December 2018), 141 women developed breast cancer. Cumulative incidence of cancer per 1000 women with atypia was 0.95 (95% confidence interval 0.28 to 2.69), 14.2 (10.3 to 19.1), and 45.0 (36.3 to 55.1) at one, three, and six years after atypia diagnosis, respectively. Women with atypia detected more recently have lower rates of subsequent cancers detected within three years (6.0 invasive cancers per 1000 women (95% confidence interval 3.1 to 10.9) in 2013-18
v
24.3 (13.7 to 40.1) in 2003-07, and 24.6 (14.9 to 38.3) in 2008-12). Grade, size, and nodal involvement of subsequent invasive cancers were similar to those of cancers detected in the general screening population, with equal numbers of ipsilateral and contralateral cancers.

Conclusions
Many atypia could represent risk factors rather than precursors of invasive cancer requiring surgery in the short term. Women with atypia detected more recently have lower rates of subsequent cancers detected, which might be associated with changes to mammography and biopsy techniques identifying forms of atypia that are more likely to represent overdiagnosis. Annual mammography in the short term after atypia diagnosis might not be beneficial. More evidence is needed about longer term risks.
Large overlap in neutrophil transcriptome between lupus and COVID-19 with limited lupus-specific gene expression
Authors: Najjar Rayan , Rogel Noga , Pineda Jose Mario Bello , Wang Xiaoxing , Tran Megan , Bays Alison , Mustelin Tomas 
Published: February 2024

ObjectivesTo illuminate the poorly understood aetiology of SLE by comparing the gene expression profile of SLE neutrophils with that of neutrophils from patients infected by SARS-CoV-2, a disease (COVID-19) with well-defined antigens and a similar type I interferon response.MethodsRNA sequencing of neutrophils from patients with SLE (n=15) and healthy controls (n=12) was analysed for differential gene expression and modulated pathways. The same analyses were performed on a similar neutrophil dataset from patients with SARS-CoV-2 infection (n=30) and healthy controls (n=8). Next, we carried out comparative analyses to identify common and unique transcriptional changes between the two disease contexts, emphasising genes regulated in opposite directions.ResultsWe identified 372 differentially expressed genes in SLE neutrophils compared with healthy donor neutrophils (≥2 fold, p<0.05), 181 of which were concordant with transcriptional changes in SARS-CoV-2-infected individuals compared with their respective healthy controls. In contrast, 118 genes demonstrated statistically significant alterations exclusive to SLE, including 28 genes that were differentially expressed in opposite directions in the two diseases.ConclusionsThe substantial overlap between neutrophil responses in SLE and COVID-19 suggests that the unknown cause of SLE is functionally similar to a viral infection and drives a similar immune activation and type I interferon response. Conversely, the genes regulated in the opposite direction represent responses unique to SLE. These include tyrosylprotein sulfotransferase-1 and nucleic acid deaminases of the APOBEC family, which can catalyse cytosine-to-uridine editing of both RNA and DNA, and other RNA-modifying enzymes.
Initiation patterns of anticoagulants for atrial fibrillation among older UK adults with and without chronic kidney disease, 2010–2020
Authors: Liaw Julia , Liaw Deborah , Dave Chintan 
Published: February 2024

BackgroundThere is a paucity of data on the initiation patterns of anticoagulants among older atrial fibrillation patients with and without chronic kidney disease (CKD).Setting and methodsWe used the UK Clinical Practice Research Datalink (2010–2020) to conduct a retrospective cohort study to evaluate anticoagulant initiation patterns for older adults (≥65 years) with CKD (N=18 421) and without CKD (N=41 901), categorised by severity of CKD: stages 3a, 3b and 4, and initiation dose by respective direct oral anticoagulant (DOAC).ResultsOver the study period, warfarin initiations sharply declined and were replaced by DOACs regardless of CKD status or stage. By 2020, patients with CKD were modestly more likely (8.8% difference) to initiate apixaban compared with those without CKD (58.8% vs 50.0%; p<0.01). Among patients with CKD, those with stages 3a and 3b CKD had higher apixaban initiations compared with stage 4 CKD (56.9% and 64.6% vs 52.9%, respectively; p<0.01). Conversely, patients with stage 4 CKD were over three times more likely to initiate warfarin (14.7%) compared with those with stage 3a (2.6%) and 3b (4.0%) CKD (p<0.01). Throughout the study period, there was a rise in the proportion of patients initiating the higher 10 mg daily dose for apixaban, with an increase of 20.6% (from 64.3% in 2013 to 84.9% in 2020; p value for trend <0.01) among patients without CKD, and 21.8% (53.1% to 74.9%; p<0.01), 24.4% (18.8% to 43.2%; p<0.01) and 18.5% (0.0% to 18.2%; p<0.01) among patients with stages 3a, 3b and 4 CKD, respectively.Conclusions and relevanceInitiation of DOACs increased regardless of CKD status and stage, although with a reduced magnitude in severe CKD. Apixaban emerged as the preferred agent, with a secular trend towards the higher initiation dose in all subgroups. These findings illuminate evolving trends and priorities in anticoagulant preferences among patients with and without CKD.
Overcoming Diverse Undesired Effects in Recommender Systems: A Deontological Approach
Authors: G. Duran Paula , Gilabert Pere , Seguí Santi , Vitrià Jordi 
Published: February 2024

In today’s digital landscape, recommender systems have gained ubiquity as a means of directing users toward personalized products, services, and content. However, despite their widespread adoption and a long track of research, these systems are not immune to shortcomings. A significant challenge faced by recommender systems is the presence of biases, which produces various undesirable effects, prominently the popularity bias. This bias hampers the diversity of recommended items, thus restricting users’ exposure to less popular or niche content. Furthermore, this issue is compounded when multiple stakeholders are considered, requiring the balance of multiple, potentially conflicting objectives.
In this article, we present a new approach to address a wide range of undesired consequences in recommender systems that involve various stakeholders. Instead of adopting a consequentialist perspective that aims to mitigate the repercussions of a recommendation policy, we propose a deontological approach centered around a minimal set of ethical principles. More precisely, we introduce two distinct principles aimed at avoiding overconfidence in predictions and accurately modeling the genuine interests of users. The proposed approach circumvents the need for defining a multi-objective system, which has been identified as one of the main limitations when developing complex recommenders. Through extensive experimentation, we show the efficacy of our approach in mitigating the adverse impact of the recommender from both user and item perspectives, ultimately enhancing various beyond accuracy metrics. This study underscores the significance of responsible and equitable recommendations and proposes a strategy that can be easily deployed in real-world scenarios.
Risk Factors for Ovarian Cancer by BRCA Status: A Collaborative Case-Only Analysis
Authors: Gersekowski Kate , Na Renhua , Alsop Kathryn , Delahunty Rachel , Goode Ellen L. , Cunningham Julie M. , Winham Stacey J. , Pharoah Paul D.P. , Song Honglin , Webb Penelope M. 
Published: February 2024

Abstract

Background:
Women with an inherited pathogenic variant in BRCA1 or BRCA2 have a greatly increased risk of developing ovarian cancer, but the importance of behavioral factors is less clear. We used a case-only design to compare the magnitude of associations with established reproductive, hormonal, and lifestyle risk factors between BRCA mutation carriers and noncarriers.

Methods:
We pooled data from five studies from the Ovarian Cancer Association Consortium including 637 BRCA carriers and 4,289 noncarriers. Covariate-adjusted generalized linear mixed models were used to estimate interaction risk ratios (IRR) and 95% confidence intervals (CI), with BRCA (carrier vs. noncarrier) as the response variable.

Results:
IRRs were above 1.0 for known protective factors including ever being pregnant (IRR = 1.29, 95% CI; 1.00–1.67) and ever using the oral contraceptive pill (1.30, 95% CI; 1.07–1.60), suggesting the protective effects of these factors may be reduced in carriers compared with noncarriers. Conversely, the IRRs for risk factors including endometriosis and menopausal hormone therapy were below 1.0, suggesting weaker positive associations among BRCA carriers. In contrast, associations with lifestyle factors including smoking, physical inactivity, body mass index, and aspirin use did not appear to differ by BRCA status.

Conclusions:
Our results suggest that associations with hormonal and reproductive factors are generally weaker for those with a pathogenic BRCA variant than those without, while associations with modifiable lifestyle factors are similar for carriers and noncarriers.

Impact:
Advice to maintain a healthy weight, be physically active, and refrain from smoking will therefore benefit BRCA carriers as well as noncarriers.
Abstract A027: Targeting MYC-induced reprogramming of mitochondrial metabolism in breast cancer
Authors: Anttila Johanna M. , Savelius Mariel , Nicorici Daniel , Awadhpersad Ryan , Munne Pauliina M. , Id Linda , Tervonen Topi A. , Jackson Christopher , Nieminen Anni I. , Klefström Juha 
Published: February 2024

Abstract
Oncogenic MYC is frequently overexpressed in breast cancer, and its overexpression is associated with aggressiveness and unfavorable prognosis of breast cancer. MYC overexpression promotes tumor growth by stimulating cell cycle progression and rewiring metabolism – creating cancer vulnerabilities that can be therapeutically targeted via synthetic lethal strategies. A large part of our current understanding of the MYC overexpression biology and related synthetic lethal pathways is based on findings in various inducible MYC overexpression systems, which demonstrate the acute effects of MYC activation but may poorly represent long-term MYC overexpression status in real cancers. Here we classified 15 triple-negative breast cancer (TNBC) cell lines according to both MYC target gene set expression and MYC protein expression into MYC-high and MYC-low categories and explored the MYC-high status-coupled therapeutic responses and cancer-relevant metabolic changes. We show that mitochondrial respiration inhibiting biguanide drug metformin inhibits cell proliferation and generates senescence-like features in MYC-high TNBC cells. Furthermore, high-resolution respirometry experiments show that MYC-high TNBC cells have higher mitochondrial respiration rates than MYC-low TNBC cells, a phenotype not explained by a higher number of mitochondria. Also, targeting mitochondrial respiration with small molecule inhibitors specifically reduces proliferation in MYC-high TNBC cells and sensitizes them to apoptosis – indicating that MYC-high TNBC cells have higher dependency on mitochondrial respiration than the MYC-low cells. Targeted metabolomic flux experiments demonstrate that small molecule inhibitors of mitochondrial respiration rewire TCA cycle, resulting in suppression of MYC-driven glutamine anaplerosis, which offers a possible explanation for the apoptotic sensitization. In conclusion, our findings provide new insight into the long-term MYC overexpression-associated metabolic changes – highlighting mitochondrial respiration as a potential target for the development of MYC-dependent synthetic lethal strategies against breast cancer.
Citation Format: Johanna M. Anttila, Mariel Savelius, Daniel Nicorici, Ryan Awadhpersad, Pauliina M. Munne, Linda Id, Topi A. Tervonen, Christopher Jackson, Anni I. Nieminen, Juha Klefström. Targeting MYC-induced reprogramming of mitochondrial metabolism in breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A027.
Abstract A082: Stretching towards relief: The Kent-Collins protocol for radiation-induced eustachian tube dysfunction
Authors: Kent Matthew E , Colllins Patrick J , Aizer Ayal A 
Published: February 2024

Abstract
Background: Eustachian tube dysfunction is a common side effect of radiotherapy for head and neck cancers or brain tumors, although few effective treatments exist. The Kent-Collins Protocol represents a novel therapeutic option for post-radiotherapy Eustachian tube dysfunction. Case Presentation: The Kent-Collins Protocol was employed in one patient with Eustachian tube dysfunction following fractionated stereotactic radiotherapy for HER-2 positive breast cancer with cerebral metastases. The Kent-Collins Protocol provided relief of symptoms (conductive hearing loss, aural fullness, and otalgia) for a range of 5 to 45 minutes. The protocol could be repeated when symptoms returned to provide additional relief. The patient also reported psychological benefit from this protocol, knowing the hearing loss was reversible and not likely to be permanent. Conclusions: This case demonstrates the potential of The Kent-Collins Protocol for the treatment of post-radiotherapy Eustachian tube dysfunction. The protocol is effective, inexpensive, easy to teach, and safe, offering an alternative to invasive therapies currently in existence.
Citation Format: Matthew E Kent, Patrick J Colllins, Ayal A Aizer. Stretching towards relief: The Kent-Collins protocol for radiation-induced eustachian tube dysfunction [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A082.