bluuebunny/crossref_metadata_2025_split huggingface dataset:
Optimizing
in vitro
spherulation cues in the fungal pathogen
Coccidioides
Authors: Homer Christina M. , Ochoa Elena , Voorhies Mark , Sil Anita 
Published: December 2024

ABSTRACT

Coccidioides
spp. are part of a group of thermally dimorphic fungal pathogens, which grow as filamentous cells (hyphae) in the soil and transform to a different morphology upon inhalation into the host. The
Coccidioides
host form, the spherule, is unique and highly undercharacterized due to both technical and biocontainment challenges. Each spherule arises from an environmental spore (arthroconidium), matures, and develops hundreds of internal endospores, which are released from the spherule upon rupture. Each endospore can then go on to form another spherule in a cycle called spherulation. One of the foremost technical challenges has been reliably growing spherules in culture without the formation of contaminating hyphae and consistently inducing endospore release from spherules. Here, we present optimization of
in vitro
spherule growth and endospore release, by closely controlling starting cell density in the culture, using freshly harvested arthroconidia, and decreasing the concentration of multiple salts in spherulation media. We developed a minimal medium to test spherule growth on various carbon and nitrogen sources. We defined a critical role for the dispersant Tamol in both early spherule formation and prevention of the accumulation of a visible film around spherules. Finally, we examined how the conditions under which arthroconidia are generated influence their transcriptome and subsequent development into spherules, demonstrating that this is an important variable to control when designing spherulation experiments. Together, our data reveal multiple strategies to optimize
in vitro
spherulation growth, enabling characterization of this virulence-relevant morphology.

IMPORTANCE

Coccidioides
spp. are thermally dimorphic fungal pathogens found in the Southwest United States, Mexico, Central America, and South America.
Coccidioides
can infect both immunocompetent and immunocompromised people and can cause a devastating disseminated infection, including meningitis, with 30% mortality despite all currently available treatments. In this work, we tackle one of the current largest technical barriers to studying the fungus
Coccidioides
: reliably growing its host form
in vitro
. Our work is impactful because we have created a set of foundational tools for the burgeoning field of
Coccidioides
pathogenesis research. We have carefully optimized conditions that allow the development of
Coccidioides in vitro
into its pathogenic form. This work will open up many lines of investigation into the molecules that underlie
Coccidioides
pathogenesis.
Systematic identification of secondary bile acid production genes in global microbiome
Authors: Yang Yuwei , Gao Wenxing , Zhu Ruixin , Tao Liwen , Chen Wanning , Zhu Xinyue , Shen Mengping , Xu Tingjun , Zhao Tingting , Zhang Xiaobai , Zhu Lixin , Jiao Na 
Published: December 2024

ABSTRACT

Microbial metabolism of bile acids (BAs) is crucial for maintaining homeostasis in vertebrate hosts and environments. Although certain organisms involved in bile acid metabolism have been identified, a global, comprehensive elucidation of the microbes, metabolic enzymes, and bile acid remains incomplete. To bridge this gap, we employed hidden Markov models to systematically search in a large-scale and high-quality search library comprising 28,813 RefSeq multi-kingdom microbial complete genomes, enabling us to construct a secondary bile acid production gene catalog. This catalog greatly expanded the distribution of secondary bile acid production genes across 11 phyla, encompassing bacteria, archaea, and fungi, and extended to 14 habitats spanning hosts and environmental contexts. Furthermore, we highlighted the associations between secondary bile acids (SBAs) and gastrointestinal and hepatic disorders, including inflammatory bowel disease (IBD), colorectal cancer (CRC), and nonalcoholic fatty liver disease (NAFLD), further elucidating disease-specific alterations in secondary bile acid production genes. Additionally, we proposed the pig as a particularly suitable animal model for investigating secondary bile acid production in humans, given its closely aligned secondary bile acid production gene composition. This gene catalog provides a comprehensive and reliable foundation for future studies on microbial bile acid metabolism, offering new insights into the microbial contributions to health and disease.

IMPORTANCE
Bile acid metabolism is an important function in both host and environmental microorganisms. The existing functional annotations from single source pose limitations on cross-habitat analysis. Our construction of a systematic secondary bile acid production gene catalog encompassing numerous high-quality reference sequences propelled research on bile acid metabolism in the global microbiome, holding significance for the concept of One Health. We further highlighted the potential of the microbiota-secondary bile acid axis as a target for the treatment of hepatic and intestinal diseases, as well as the varying feasibility of using animal models for studying human bile acid metabolism. This gene catalog offers a solid groundwork for investigating microbial bile acid metabolism across different compartments, including humans, animals, plants, and environments, shedding light on the contributions of microorganisms to One Health.
In vivo
interspecies dissemination of IncM2-type
bla
NDM-1
carrying plasmid
Authors: Lurie-Weinberger Mor N. , Bychenko-Banyas Darya , Mor Meirav , Laviad-Shitrit Sivan , Kaplan Ella , Rakovitsky Nadya , Keren-Paz Alona , Ben-Zvi Chaim , Carmeli Yehuda 
Published: December 2024

ABSTRACT

The gastrointestinal tract is a unique ecological niche with a high abundance of various Enterobacterales in close proximity. This allows the exchange of mobile genetic elements that carry resistance determinants. In the hospital setting, resistant organisms are prevalent and selective antibiotic pressure is high, providing a supportive platform for interspecies dissemination of resistance. Seven New Delhi metallo-beta-lactamase(NDM) positive and one NDM-negative bacteria were sent for WGS followed by bioinformatics analysis. Here, we describe three separate cases of patients simultaneously colonized by two NDM producing-species (
Escherichia coli
and
Klebsiella pneumoniae
), in which we documented interspecies dissemination of the
bla
NDM-1
by an 87,450 bp IncM2 type multi-drug resistance plasmid (here named pNCICAN_NDM-01_21-il). This plasmid was found to be highly conjugative. Our results underline the risk of interspecies horizontal plasmid dissemination. Such events may cause the emergence of high-risk clones, as well as lead to under-recognized multi-species outbreaks.

IMPORTANCE
Conjugative, carbapenemase-carrying multidrug-resistant plasmids that can move between species of clinically relevant Enterobacterales pose a great risk to patients’ health, especially when they spread inside a medical institution. Yet, most institutions monitor bacteria according to species and are at risk of missing plasmid-driven outbreaks. Thus, this work indicates that plasmid surveillance is an important tool for infection control.
Protease shaving of
Mycobacterium tuberculosis
facilitates vaccine antigen discovery and delivery of novel cargoes to the Mtb surface
Authors: Lepe Bianca A. , Zheng Christine R. , Leddy Owen K. , Allsup Benjamin L. , Solomon Sydney L. , Bryson Bryan D. 
Published: December 2024

ABSTRACT

Tuberculosis (TB) is the leading cause of infectious disease death and lacks a vaccine capable of protecting adults from pulmonary TB. The bacterial surface is a critical interface that shapes host-pathogen interactions. Several knowledge gaps persist in our understanding of
Mycobacterium tuberculosis
(Mtb)-host interactions that may be addressed by an improved understanding of the Mtb surface proteome, including the identification of novel vaccine targets as well as developing new approaches to interrogate host-pathogen interactions. Here, we sought to expand our understanding of the Mtb surface proteome in service of these knowledge gaps by adapting protease shaving protocols for multiplexed quantitative mass spectrometry. Pairing quantitative mass spectrometry with the construction of validation strains, we revealed several novel Mtb proteins on the Mtb surface largely derived from the PE/PPE class of Mtb proteins, including PPE18, a component of a leading Mtb vaccine candidate. We next exploited the localization of PPE18 to decorate the Mtb surface with heterologous proteins. Together, these studies reveal potential novel targets for new Mtb vaccines as well as facilitate new approaches to study difficult-to-study cellular compartments during bacterial growth and infection.

IMPORTANCE

The surface of a bacterial pathogen is a critical interface between the bacterium and the immune system. A better understanding of this interface would facilitate the discovery of new vaccine targets, new virulence proteins, and enable new technologies that modify the bacterial surface. In this study, we established a multiplexed and quantitative biochemical strategy to study the surface of
Mycobacterium tuberculosis
(Mtb) and identified new vaccine targets. We furthermore established design rules for new technologies aimed at modifying the composition of the bacterial surface. Specifically, we achieved a biological milestone that has not been rigorously reported previously, which is the successful modification of the Mtb surface with a non-native protein.
The impact of tobacco smoking and smoking cessation on lung cancer and stroke incidence among people with HIV on antiretroviral therapy in South Africa: a simulation modeling study
Authors: D’Couto Helen , Thielking Acadia M , Sewpaul Ronel , Levy Douglas E , Rigotti Nancy A , Chrysanthopoulou Stavroula A , Siedner Mark J , Freedberg Kenneth A , Wood Robin , Hyle Emily P , Reddy Krishna P 
Published: December 2024

IntroductionWith declining HIV-related mortality, over 20% of people with HIV (PWH) in South Africa are now over age 50 years, and tobacco-related non-communicable disease burden is increasing. We quantified the impact of smoking and smoking cessation on lung cancer and stroke incidence among PWH in South Africa.MethodsUsing a microsimulation model, we simulated 18 cohorts of initially virologically suppressed PWH over their lifetime, categorised by sex, initial age (35 years/45 years/55 years) and smoking status (current/former/never). Smoking status remains constant throughout the simulation; individuals with former smoking status quit at model start. PWH can disengage from HIV care and experience virological rebound. We modelled the relative risk of lung cancer for females (males) with current versus never smoking status as 16.69 (15.83), and for females (males) with former versus never smoking status as 1.99–8.80 (1.90–6.18), depending on age at cessation. Corresponding modelled relative risks of stroke were 1.79 (1.54) for current versus never smoking, and 1.00–1.29 (1.00–1.12) for former versus never smoking. We varied HIV-related and smoking-related parameters in sensitivity analyses.ResultsModelled female (male) PWH who stop smoking at age 45 years experience 61.3% (70.9%) and 35.6% (18.6%) lower cumulative lung cancer and stroke incidence over 25 years compared with people who continue smoking. The proportion alive and lung cancer-free or alive and stroke-free over 25 years would increase by 10.4 (9.5) or 10.5 (8.5) percentage points. In sensitivity analysis, smoking and smoking cessation have a greater impact on lung cancer and stroke cumulative incidence if competing HIV-related mortality risks are lower or if PWH experience higher lung cancer and stroke risk compared with people without HIV apart from smoking.ConclusionSmoking cessation could substantially reduce lung cancer and stroke risk among PWH in South Africa. To reduce the rising non-communicable disease burden among PWH, smoking cessation should become part of routine care of PWH.
Clinical study of a micro-implantable pulse generator for the treatment of peripheral neuropathic pain: 3-month and 6-month results from the COMFORT-randomised controlled trial
Authors: Hatheway John , Hersel Alexander , Song Jonathan , Engle Mitchell , Gutierrez Genaro , Khemlani Vishal , Kapural Leonardo , Moore Gregory , Ajakwe Reginald , Trainor Drew , Hah Jennifer , Staats Peter S , Lynch Paul , Makous James , Heit Gary , Kottalgi Shilpa , Desai Mehul J 
Published: December 2024

BackgroundWe report the results from the first large, postmarket, multicentre, randomised controlled trial (RCT) evaluating peripheral nerve stimulation (PNS) for the treatment of chronic peripheral pain with a micro-implantable pulse generator (micro-IPG).MethodsSubjects meeting eligibility were randomised (2:1) to either the active arm receiving PNS and conventional medical management (CMM) or the control arm receiving CMM alone. Treatments were limited to the following areas: lower back, shoulder, knee and foot/ankle.ResultsAt 6 months, the active arm achieved an 88% responder rate with a 70% average reduction in pain. At the 3-month primary endpoint, the active arm achieved an 84% responder rate with an average pain reduction of 67% compared with the control arm, which achieved a 3% responder rate with an average pain reduction of 6%. Both responder rate and pain reduction in the active arm were significantly better than in the control arm (p<0.001). A majority of patient-reported outcomes also reached statistical significance. There have been no reports of pocket pain and no serious adverse device effects. 81% of subjects found the external wearable component of the PNS system to be comfortable.ConclusionsThis study successfully reached its primary endpoint—the active arm achieved a statistically significant superior responder rate as compared with the control arm at 3 months. These RCT results demonstrated that PNS, with this micro-IPG, is efficacious and safe. This ongoing study will follow subjects for 3 years, the results of which will be reported as they become available.
The effects of morning versus evening high-intensity interval exercise on the magnitude of the morning blood pressure surge
Authors: Bommarito Julian C. , Millar Philip J. 
Published: December 2024

Blood pressure (BP) follows a circadian rhythm, dipping during sleep and surging in the morning. A larger morning BP surge is an independent predictor of cardiovascular events. Acute exercise can produce sustained periods of post-exercise hypotension that last up to 24 h; however, the timing of exercise (morning vs. evening) may influence this response. Whether the timing of exercise influences the morning BP surge remains unknown. The current study investigated the effects of a bout of high-intensity interval exercise (HIIE) performed in the morning versus evening on the magnitude of the morning BP surge in young healthy adults. Twenty-six young, otherwise healthy adults (23 ± 4 years; 15 females) completed a randomized crossover trial where, on different days, they completed a no exercise control visit or performed either morning (0800–1000 h) or evening (1700–1900 h) HIIE. Following each visit, ambulatory BP was assessed in 30 min intervals for 24 hrs. HIIE at either time did not alter the magnitude of the morning BP surge compared to control values (control: 22 ± 5 mmHg; morning exercise: 20 ± 8 mmHg; evening exercise: 22 ± 10 mmHg, P = 0.40) or when grouped separately by sex (visit × sex P = 0.42). A positive correlation existed between Morningness-Eveningness Questionnaire score and the change in nighttime BP following both exercise times (both r = 0.42 and P = 0.04). These findings suggest that HIIE does not attenuate the morning BP surge in young healthy adults and that chronotype can predict nighttime BP responses following HIIE, irrespective of exercise time of day. This study was registered on ClinicalTrials.gov (NCT06702930).
TONE: A CHIME/FRB Outrigger Pathfinder for Localizations of Fast Radio Bursts using Very Long Baseline Interferometry
Authors: Sanghavi Pranav , Leung Calvin , Bandura Kevin , Cassanelli Tomas , Kaczmarek Jane , Kaspi Victoria M. , Khairy Kholoud , Lanman Adam , Lazda Mattias , Masui Kiyoshi W. , Mena-Parra Juan , Michilli Daniele , Pen Ue-Li , Peterson Jeffrey B. , Rahman Mubdi , Shah Vishwangi 
Published: December 2024

The sensitivity and field of view of the Canadian Hydrogen Intensity Mapping Experiment (CHIME) has enabled its fast radio burst (FRB) backend to detect thousands of FRBs. However, the low angular resolution of CHIME prevents it from localizing most FRBs to their host galaxies. Very long baseline interferometry (VLBI) can readily provide the subarcsecond resolution needed to localize many FRBs to their hosts. Thus, we developed TONE: an interferometric array of eight 6-m dishes to serve as a pathfinder for the CHIME/FRB Outriggers project, which will use wide field-of-view cylinders to determine the sky positions for a large sample of FRBs, revealing their positions within their host galaxies to subarcsecond precision. In the meantime, TONE’s [Formula: see text] [Formula: see text]km baseline with CHIME proves to be an excellent testbed for the development and characterization of single-pulse VLBI techniques at the time of discovery. This work describes the TONE instrument, its sensitivity, and its astrometric precision in single-pulse VLBI. We believe that our astrometric errors are dominated by uncertainties in the clock measurements which build up between successive Crab pulsar calibrations which happen every [Formula: see text] [Formula: see text]h; the wider fields-of-view and higher sensitivity of the Outriggers will provide opportunities for higher-cadence calibration. At present, CHIME-TONE localizations of the Crab pulsar yield systematic one-dimensional localization errors of [Formula: see text] [Formula: see text]asec — considerably better than the resolution achievable with seeing limited followup observations in the optical/near-infrared from the ground.
Geological storage of CO
2
in Hungary: the overview of storage potential and the role of natural occurrences
Authors: Falus Gy. , Cseresznyés D. , Szamosfalvi Á. , Szabó-Krausz Zs. , Szabó Cs. , Király Cs. 
Published: December 2024

The Pannonian basin system, shared by seven Central-Eastern European countries, is one of the most prospective areas of onshore CO
2
geological storage in Europe. In the Hungarian part of the Pannonian basin system, the storage could be realized in depleted hydrocarbon reservoirs and saline aquifers comprising dominantly Upper Miocene basin-filling sediments. The estimated overall potential for CO
2
storage exceeds 10
3
Mt in the case of the Hungarian part of the Pannonian basin system. The depleted hydrocarbon reservoirs correspond to this potential with limited, but well-defined capacities. However, saline aquifers represent large but indefinite capacities in the region. Furthermore, the accessibility of hydrocarbon fields is geographically limited in contrast to saline aquifers, which are regionally widespread in the Pannonian basin system. Structures that developed in the basin-filling Late Miocene strata may also have been CO
2
rich or pure CO
2
-containing natural reservoirs. These natural laboratories represent a unique opportunity to study long-term processes taking place in the reservoir–CO
2
system and can be used to predict physical and chemical processes that are characteristic for the subsurface development during and after CO
2
injection in depleted hydrocarbon or saline aquifer reservoir.
New Stochastic Sensors for Simultaneous Determination of Ochratoxin A, and of Aflatoxins B1 and M1 in Food and Biological Samples
Authors: Stefan-van Staden Raluca-Ioana , Ion Cristina Bianca , van Staden Jacobus (Koos) Frederick , Cioates Negut Catalina , Ilie-Mihai Ruxandra-Maria 
Published: December 2024

Three stochastic sensors based on a nanographene/ferric oxide nanoparticles matrix modified with maltodextrins I (DE 4.0–7.0), II (DE 13.0–17.0), and III (DE 16.5–19.5) can simultaneously determine mycotoxins like aflatoxin B1 (AFB1), M1 (AFM1), and OTA in coffee, milk, grape juice, and biological samples like whole blood, saliva, urine, and breast milk. The sensors’ response properties were established at two pH levels to suit sample native pH values. At pH 3.00, the sensor based on MDIII had the highest sensitivity (3.57 × 108 s−1 mol−1 l) for OTA assay, while the sensor based on MDI had the widest working concentration range (1 × 10–18–1 × 10–5 mol l−1). The sensor based on MDIII had the highest sensitivity (1.45 × 1010 s−1 mol−1 l) for AFB1 assay. At pH 7.40, the sensor based on MDII had the highest sensitivity (7.73 × 1010 s−1 mol−1 l) for OTA assay, while the sensor based on MDIII had the widest working concentration range (1 × 10–18–1 × 10–3 mol l−1). For AFB1, the sensor based on MDIII had the highest sensitivity (4.66 × 1011 s−1 mol−1 l) and the wider working concentration range (1 × 10–16–1 × 10–10 mol l−1). The recovery results (greater than 97.00%, RSD values below 1.00%) showed that the approach can simultaneously analyse the three mycotoxins in food and biological samples.
Olaparib and Radiotherapy Induce Type I Interferon– and CD8+ T Cell–Dependent Sensitization to Immunotherapy in Pancreatic Cancer
Authors: Valvo Victoria M. , Zhang Qiang , Jiang Long , Holcomb Erin A. , Pearson Ashley N. , Edmunds Anna G. , Faulkner Hailey G. , James Jadyn G. , Tate Akshay , Huber Amanda K. , Wang Zhuwen , Guo Yupei , Karnak David , Parsels Leslie A. , Parsels Joshua D. , Lei Yu L. , Rehemtulla Alnawaz , Lin Heng , Carpenter Eileen S. , Wahl Daniel R. , Sahai Vaibhav , Lawrence Theodore S. , Green Michael D. , Morgan Meredith A. 
Published: December 2024

Abstract
PARP inhibitors sensitize pancreatic ductal adenocarcinoma (PDAC) to radiation by inducing DNA damage and replication stress. These mechanisms also have the potential to enhance radiation-induced type I interferon (T1IFN)–mediated antitumoral immune responses. We hypothesized that the PARP inhibitor olaparib would also potentiate radiation-induced T1IFN to promote antitumor immune responses and sensitization of otherwise resistant PDAC to immunotherapy. To test this hypothesis, we assessed the effects of olaparib and radiation on T1IFN production and sensitivity to αPD-L1 immunotherapy, as well as on the tumor microenvironment by single-cell RNA sequencing. We found that olaparib enhanced T1IFN production after radiation and had superior therapeutic efficacy in immunocompetent models. Olaparib and radiation treatment sensitized PDAC tumors to αPD-L1, resulting in decreased tumor burden and a 33% complete response rate. Combination treatment provided durable immune responses as shown by tumor rejection upon tumor rechallenge of previously cured mice. Furthermore, single-cell RNA sequencing analysis revealed that combination treatment induced an immunogenic tumor microenvironment characterized by interferon (IFN) responses in both PDAC and myeloid cell populations, macrophage polarization, and increased CD8+ terminal effector T-cell frequency and activity, findings which were confirmed by IHC and flow cytometry. Furthermore, CD8+ T cells and T1IFN signaling were required for therapeutic efficacy as host depletion of CD8+ T cells or the T1IFN receptor diminished treatment responses. Overall, our results indicate that olaparib enhances radiation-induced T1IFN-mediated immune signaling and subsequently an adaptive immune response, thus sensitizing pancreatic cancer to αPD-L1 therapy, supporting an ongoing clinical trial of this therapy in patients with PDAC.