bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clostridioides difficile
-mucus interactions encompass shifts in gene expression, metabolism, and biofilm formation
Authors: Furtado Kathleen L. , Plott Lucas , Markovetz Matthew , Powers Deborah , Wang Hao , Hill David B. , Papin Jason , Allbritton Nancy L. , Tamayo Rita 
Published: June 2024

ABSTRACT

In a healthy colon, the stratified mucus layer serves as a crucial innate immune barrier to protect the epithelium from microbes. Mucins are complex glycoproteins that serve as a nutrient source for resident microflora and can be exploited by pathogens. We aimed to understand how the intestinal pathogen,
Clostridioides difficile
, independently uses or manipulates mucus to its benefit, without contributions from members of the microbiota. Using a 2-D primary human intestinal epithelial cell model to generate physiologic mucus, we assessed
C. difficile-
mucus interactions through growth assays, RNA-Seq, biophysical characterization of mucus, and contextualized metabolic modeling. We found that host-derived mucus promotes
C. difficile
growth both
in vitro
and in an infection model. RNA-Seq revealed significant upregulation of genes related to central metabolism in response to mucus, including genes involved in sugar uptake, the Wood-Ljungdahl pathway, and the glycine cleavage system. In addition, we identified differential expression of genes related to sensing and transcriptional control. Analysis of mutants with deletions in highly upregulated genes reflected the complexity of
C. difficile
-mucus interactions, with potential interplay between sensing and growth. Mucus also stimulated biofilm formation
in vitro
, which may in turn alter the viscoelastic properties of mucus. Context-specific metabolic modeling confirmed differential metabolism and the predicted importance of enzymes related to serine and glycine catabolism with mucus. Subsequent growth experiments supported these findings, indicating mucus is an important source of serine. Our results better define responses of
C. difficile
to human gastrointestinal mucus and highlight flexibility in metabolism that may influence pathogenesis.

IMPORTANCE

Clostridioides difficile
results in upward of 250,000 infections and 12,000 deaths annually in the United States. Community-acquired infections continue to rise, and recurrent disease is common, emphasizing a vital need to understand
C. difficile
pathogenesis.
C. difficile
undoubtedly interacts with colonic mucus, but the extent to which the pathogen can independently respond to and take advantage of this niche has not been explored extensively. Moreover, the metabolic complexity of
C. difficile
remains poorly understood but likely impacts its capacity to grow and persist in the host. Here, we demonstrate that
C. difficile
uses native colonic mucus for growth, indicating
C. difficile
possesses mechanisms to exploit the mucosal niche. Furthermore, mucus induces metabolic shifts and biofilm formation in
C. difficile
, which has potential ramifications for intestinal colonization. Overall, our work is crucial to better understand the dynamics of
C. difficile
-mucus interactions in the context of the human gut.
Genome-wide CRISPRi screens for high-throughput fitness quantification and identification of determinants for dalbavancin susceptibility in
Staphylococcus aureus
Authors: Liu Xue , de Bakker Vincent , Heggenhougen Maria Victoria , Mårli Marita Torrissen , Frøynes Anette Heidal , Salehian Zhian , Porcellato Davide , Morales Angeles Danae , Veening Jan-Willem , Kjos Morten 
Published: June 2024

ABSTRACT

Antibiotic resistance and tolerance remain a major problem for the treatment of staphylococcal infections. Identifying genes that influence antibiotic susceptibility could open the door to novel antimicrobial strategies, including targets for new synergistic drug combinations. Here, we developed a genome-wide CRISPR interference library for
Staphylococcus aureus
, demonstrated its use by quantifying gene fitness in different strains through CRISPRi-seq, and used it to identify genes that modulate susceptibility to the lipoglycopeptide dalbavancin. By exposing the library to sublethal concentrations of dalbavancin using both CRISPRi-seq and direct selection methods, we not only found genes previously reported to be involved in antibiotic susceptibility but also identified genes thus far unknown to affect antibiotic tolerance. Importantly, some of these genes could not have been detected by more conventional transposon-based knockout approaches because they are essential for growth, stressing the complementary value of CRISPRi-based methods. Notably, knockdown of a gene encoding the uncharacterized protein KapB specifically sensitizes the cells to dalbavancin, but not to other antibiotics of the same class, whereas knockdown of the Shikimate pathway showed the opposite effect. The results presented here demonstrate the promise of CRISPRi-seq screens to identify genes and pathways involved in antibiotic susceptibility and pave the way to explore alternative antimicrobial treatments through these insights.

IMPORTANCE

Antibiotic resistance is a challenge for treating staphylococcal infections. Identifying genes that affect how antibiotics work could help create new treatments. In our study, we made a CRISPR interference library for
Staphylococcus aureus
and used this to find which genes are critical for growth and also mapped genes that are important for antibiotic sensitivity, focusing on the lipoglycopeptide antibiotic dalbavancin. With this method, we identified genes that altered the sensitivity to dalbavancin upon knockdown, including genes involved in different cellular functions. CRISPRi-seq offers a means to uncover untapped antibiotic targets, including those that conventional screens would disregard due to their essentiality. This paves the way for the discovery of new ways to fight infections.
Treatment modality for aneurysmal subarachnoid hemorrhage and risk of shunt dependent hydrocephalus and mortality: population based study
Authors: Omar Abdelsimar Tan , Diestro Jose Danilo Bengzon , Spears Julian , Patorno Elisabetta 
Published: June 2024

BackgroundHydrocephalus is a significant contributor to morbidity following aneurysmal subarachnoid hemorrhage (aSAH). We aimed to investigate the association between primary treatment modality and the incidence of hydrocephalus requiring CSF diversion, using a target trial approach for causal inference.MethodsThis cohort study used US administrative health claims data (Clinformatics Data Mart) and was conducted among aSAH patients undergoing primary treatment with either clipping or coiling, from January 1, 2004, to February 28, 2023. The primary outcome was hydrocephalus requiring CSF diversion surgery while the secondary outcome was mortality. Multivariable regression and 1:1 propensity score (PS) matching were used for confounder control. Crude and adjusted hazard ratios (HRs) with 95% CIs were calculated.ResultsA total of 5816 patients (mean age 59 years; 72% women) undergoing clipping (n=1794) or coiling (n=4022) were included in the primary cohort. The 1:1 PS matched cohort had 1794 participants per arm. Clipping demonstrated higher hazards of shunt dependent hydrocephalus compared with coiling in both the multivariable Fine–Gray model (HR 1.39, 95% CI 1.19 to 1.62) and the PS matched cohorts (HR 1.39, 95% CI 1.16 to 1.66). Mortality analysis favored clipping in the crude analysis (HR 0.78, 95% CI 0.69 to 0.88) but leaned toward coiling after confounder adjustment (HR 1.13, 95% CI 1.00 to 1.29 in the multivariable model; HR 1.11, 95% CI 0.95 to 1.29 in the PS matched cohort).ConclusionThese findings suggest that coiling is associated with reduced hazards of shunt dependent hydrocephalus following aSAH compared with clipping, and provide valuable insights for shared decision making among clinicians and patients, in the context of conflicting evidence from smaller observational studies.
Early postoperative pain and 30-day complications following major abdominal surgery: a retrospective cohort study
Authors: Helden Esmee van , Kranendonk Josephine , Vermulst Ad , Boer Arjen de , Reuver Philip de , Rosman Camiel , Wilt Johannes de , Laarhoven Kees van , Scheffer Gert Jan , Keijzer Christiaan , Warlé Michiel 
Published: June 2024

BackgroundIncreasing evidence supports a positive relationship between the intensity of early postoperative pain, and the risk of 30-day postoperative complications. Higher pain levels may hamper recovery and contribute to immunosuppression after surgery. This leaves patients at risk of postoperative complications.MethodsOne thousand patients who underwent major abdominal surgery (cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, esophageal, liver, or pancreas surgery) at the Radboud university medical center were randomly selected from eligible patients between 2014 and 2020. Pain scores on day 1, the independent variable of interest, were extracted from the electronic patient files. Outcome measures were 30-day postoperative complications (infectious, non-infectious, total complications and classification according to Clavien-Dindo).ResultsSeven hundred ninety complications occurred in 572 patients within 30 days after surgery, of which 289 (36.7%) were of infectious origin, and 501 (63.4%) complications were non-infectious. The mean duration from the end of surgery to the occurrence of infectious complications was 6.5 days (SD 5.6) and 4.1 days (SD 4.7) for non-infectious complications (p<0.001). Logistic regression analysis revealed that pain scores on postoperative day 1 (POD1) were significantly positively associated with 30-day total complications after surgery (OR=1.132, 95% CI (1.076 to 1.190)), Clavien-Dindo classification (OR=1.131, 95% CI (1.071 to 1.193)), infectious complications (OR=1.126, 95% CI (1.059 to 1.196)), and non-infectious complications (OR=1.079, 95% CI (1.022 to 1.140)).ConclusionsAfter major abdominal surgery, higher postoperative pain scores on day 1 are associated with an increased risk of 30-day postoperative complications. Further studies should pursue whether optimization of perioperative analgesia can improve immune homeostasis, reduce complications after surgery and enhance postoperative recovery.
Structure of anisotropic fuzzy dark matter black holes
Authors: Khan S. , Adeel A. , Yousaf Z. 
Published: June 2024

AbstractBuilding on the Einasto dark matter (DM) density parameterizations, this study explores the possibility of constructing DM black holes (BHs) within the formalism of the Starobinsky gravity model. This approach extends the solutions characterizing the non-commutative mini BHs and introduces DM as the fundamental material constituting the BH. Assuming an anisotropic fluid configuration, we demonstrate the existence of different BH models subject to the values of the Einasto index $$\alpha $$
α
and rescaled mass $$\xi $$
ξ
. To achieve this, we begin by considering a de Sitter-like equation of state (EOS) wherein $$\varepsilon =-P_{r}$$

ε
=
-

P
r

. Interestingly, the resulting BH solution not only shares a similar horizon structure with a Reissner-Nordström BH but also replaces the central singularity with a regular de Sitter core through the mechanism of quadratic $$f(\textrm{R})$$

f
(
R
)

corrections. We further explore the possibility of using a nonlocal EOS instead of the previous one. This alternative approach allows us to construct a fuzzy DM stellar droplet. However, the radial pressure $$P_{r}$$

P
r

remains negative in this case. More precisely, we explore the possibility of these findings informing the existence of moderately massive DM-BHs within the galactic structures. Such objects could have played a role in the early stages of galactic formation. Furthermore, we delve into the intriguing possibility of these moderately massive DM-BHs acting as the central objects within galaxies.
Stellar model with non-zero strange quark mass ($$m_s\ne 0$$) and Mak–Harko density profile admitting observational results
Authors: Roy R. , Goswami K. B. , Saha A. , Hakim A. , Chattopadhyay P. K. 
Published: June 2024

AbstractThis article describes the configuration of strange quark stars composed of three flavour quarks in hydrostatic equilibrium considering the energy density profile of Mak and Harko and non-zero strange quark mass ($$m_s\ne {0}$$

m
s

≠
0

). A suitable stellar model is proposed assuming equation of state of interior matter as modified MIT equation of state in bag model $$p=\frac{1}{3}(\rho -4B_g)$$

p
=

1
3

(
ρ
-
4

B
g

)

, where $$B_g$$

B
g

is known as bag constant, to predict the viability of strange stars. The interior of such compact stars is mainly composed of quarks and electrons to establish charge neutrality condition. We have checked the various stability windows depending on the energy per baryon for different values of bag constant $$B_g$$

B
g

and mass of strange quark $$m_s$$

m
s

. We have studied the effect of non-zero mass of the strange quark ($$m_s$$

m
s

) on the physical properties of the strange star in the context of the modified MIT bag equation of state. We note that the maximum stellar mass decreases with increasing $$m_s$$

m
s

. The model is suitable for predicting the radius, central density and other properties of compact stars having mass $$\le 2.01M_{\odot }$$

≤
2.01

M
⊙

, such as $$4U~1820-30$$

4
U

1820
-
30

, $$PSR~J1614-2230$$

P
S
R

J
1614
-
2230

etc, which are supposed to be strange stars. The radius of few recently observed compact stars are predicted in our model and they are found to be compatible with the value as predicted from observation. The model is found to be suitable in view of all the necessary criterion along with fulfilment of stability of the stellar configuration as well as stable in view of small radial perturbations.
Understanding Benign Breast Disease and Subsequent Breast Cancer in Hispanic White Females: A Step Closer to Evidence-Based Management
Authors: Lohani Kush R. , Nibbe Andrea M. , Vierkant Robert A. , Pacheco-Spann Laura M. , Seymour Lisa R. , Vachon Celine M. , Sherman Mark E. , Winham Stacey J. , Degnim Amy C. , Hill Deirdre A. 
Published: June 2024

Abstract

Introduction:
Although Hispanic White (HW) females have a lower incidence of breast cancer than non-Hispanic White (NHW) females, breast cancer risk is unclear for HW females after benign breast disease (BBD).

Methods:
We compared BBD characteristics and subsequent breast cancer risk among HW and NHW females in New Mexico using a population-based collection of benign breast biopsies (1996–2007). BBD was categorized as nonproliferative disease (NPD), proliferative disease without atypia (PDWA), or atypical hyperplasia (AH). Breast cancer risk was assessed as absolute risk (AR) using cumulative incidence and RR by comparing the number of breast cancer events in BBDs to non-BBD.

Results:
This study included 3,684 HW and 6,587 NHW females with BBD. HW females had similar proportions of NPD (58.6% vs. 54.3%), PDWA (21.4% vs. 23.5%), and AH (3.6% vs. 3.3%) as NHW females. Breast cancer risk among all females with BBD was higher than population-based expected rates (RR, 1.87) and was similar for HW and NHW subgroups (RR = 1.99 vs. 1.84). As expected, breast cancer risk increased with increasing BBD severity, both overall [RR, 1.81 (NPD), 1.85 (PDWA), and 3.10 (AH)] and in the HW and NHW subgroups. Adjusted AR of breast cancer at 5 years also increased with the severity of BBD (HW vs. NHW; NPD: 1.4% vs. 2.1%; PDWA: 1.5% vs. 2.7%; AH: 6% vs. 4.8%).

Conclusions:
We found similar breast cancer RRs and ARs in HW and NHW. Risk counseling should ensure that HW females receive breast cancer clinical management warranted by their similar absolute risks.

Impact:
The present population-based provides evidence for the clinical management of HW females with BBD for the prevention of breast cancer.
IRE1α Mediates the Hypertrophic Growth of Cardiomyocytes Through Facilitating the Formation of Initiation Complex to Promote the Translation of TOP-Motif Transcripts
Authors: Li Chao , Li Shiqian , Zhang Guangyu , Li Qinfeng , Song Weidan , Wang Xiaoding , Cook Jane A. , van der Stoel Miesje , Wright Bradley W. , Altamirano Francisco , Niewold Erica L. , Han Jungsoo , Kimble Garrett , Zhang Pengfei , Luo Xiang , Urra Hery , May Herman I. , Ferdous Anwarul , Sun Xue-Nan , Deng Yingfeng , Ikonen Elina , Hetz Claudio , Kaufman Randal J. , Zhang Kezhong , Gillette Thomas G. , Scherer Philipp E. , Hill Joseph A. , Chen Jin , Wang Zhao V. 
Published: June 2024

BACKGROUND:
Cardiomyocyte growth is coupled with active protein synthesis, which is one of the basic biological processes in living cells. However, it is unclear whether the unfolded protein response transducers and effectors directly take part in the control of protein synthesis. The connection between critical functions of the unfolded protein response in cellular physiology and requirements of multiple processes for cell growth prompted us to investigate the role of the unfolded protein response in cell growth and underlying molecular mechanisms.

METHODS:
Cardiomyocyte-specific inositol-requiring enzyme 1α (IRE1α) knockout and overexpression mouse models were generated to explore its function in vivo. Neonatal rat ventricular myocytes were isolated and cultured to evaluate the role of IRE1α in cardiomyocyte growth in vitro. Mass spectrometry was conducted to identify novel interacting proteins of IRE1α. Ribosome sequencing and polysome profiling were performed to determine the molecular basis for the function of IRE1α in translational control.

RESULTS:
We show that IRE1α is required for cell growth in neonatal rat ventricular myocytes under prohypertrophy treatment and in HEK293 cells in response to serum stimulation. At the molecular level, IRE1α directly interacts with eIF4G and eIF3, 2 critical components of the translation initiation complex. We demonstrate that IRE1α facilitates the formation of the translation initiation complex around the endoplasmic reticulum and preferentially initiates the translation of transcripts with 5’ terminal oligopyrimidine motifs. We then reveal that IRE1α plays an important role in determining the selectivity and translation of these transcripts. We next show that IRE1α stimulates the translation of epidermal growth factor receptor through an unannotated terminal oligopyrimidine motif in its 5’ untranslated region. We further demonstrate a physiological role of IRE1α-governed protein translation by showing that IRE1α is essential for cardiomyocyte growth and cardiac functional maintenance under hemodynamic stress in vivo.

CONCLUSIONS:
These studies suggest a noncanonical, essential role of IRE1α in orchestrating protein synthesis, which may have important implications in cardiac hypertrophy in response to pressure overload and general cell growth under other physiological and pathological conditions.
High-Intensity Aphasia Intervention Is Minimally Fatiguing in Chronic Aphasia: An Analysis of Participant Self-Ratings From a Large Randomized Controlled Trial
Authors: Pierce John E. , Cavanaugh Robert , Harvey Sam , Dickey Michael Walsh , Nickels Lyndsey , Copland David , Togher Leanne , Godecke Erin , Meinzer Marcus , Rai Tapan , Cadilhac Dominique A. , Kim Joosup , Hurley Melanie , Foster Abby M. , Carragher Marcella , Wilcox Cassie , Rose Miranda L. 
Published: June 2024

BACKGROUND:
High-intensity therapy is recommended in current treatment guidelines for chronic poststroke aphasia. Yet, little is known about fatigue levels induced by treatment, which could interfere with rehabilitation outcomes. We analyzed fatigue experienced by people with chronic aphasia (>6 months) during high-dose interventions at 2 intensities.

METHODS:
A retrospective observational analysis was conducted on self-rated fatigue levels of people with chronic aphasia (N=173) collected during a previously published large randomized controlled trial of 2 treatments: constraint-induced aphasia therapy plus and multi-modality aphasia therapy. Interventions were administered at a higher intensity (30 hours over 2 weeks) or lower intensity (30 hours over 5 weeks). Participants rated their fatigue on an 11-point scale before and after each day of therapy. Data were analyzed using Bayesian ordinal multilevel models. Specifically, we considered changes in self-rated participant fatigue across a therapy day and over the intervention period.

RESULTS:
Data from 144 participants was analyzed. Participants were English speakers from Australia or New Zealand (mean age, 62 [range, 18–88] years) with 102 men and 42 women. Most had mild (n=115) or moderate (n=52) poststroke aphasia. Median ratings of the level of fatigue by people with aphasia were low (1 on a 0–10-point scale) at the beginning of the day. Ratings increased slightly (+1.0) each day after intervention, with marginally lower increases in the lower intensity schedule. There was no evidence of accumulating fatigue over the 2- or 5-week interventions.

CONCLUSIONS:
Findings suggest that intensive intervention was not associated with large increases in fatigue for people with chronic aphasia enrolled in the COMPARE trial (Constraint-Induced or Multimodality Personalised Aphasia Rehabilitation). Fatigue did not change across the course of the intervention. This study provides evidence that intensive treatment was minimally fatiguing for stroke survivors with chronic aphasia, suggesting that fatigue is not a barrier to high-intensity treatment.