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1.
bioRxiv ; 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-39005372

ABSTRACT

Dietary restriction of the sulfur-containing amino acids methionine and cysteine (SAAR) improves body composition, enhances insulin sensitivity, and extends lifespan; benefits seen also with endurance exercise. Yet, the impact of SAAR on skeletal muscle remains largely unexplored. Here we demonstrate that one week of SAAR in sedentary, young, male mice increases endurance exercise capacity. Indirect calorimetry showed that SAAR increased lipid oxidation at rest and delayed the onset of carbohydrate utilization during exercise. Transcriptomic analysis revealed increased expression of genes involved in fatty acid catabolism especially in glycolytic muscle following SAAR. These findings were functionally supported by increased fatty acid circulatory turnover flux and muscle ß-oxidation. Reducing lipid uptake from circulation through endothelial cell (EC)-specific CD36 deletion attenuated the running phenotype. Mechanistically, VEGF-signaling inhibition prevented exercise increases following SAAR, without affecting angiogenesis, implicating noncanonical VEGF signaling and EC CD36-dependent fatty acid transport in regulating exercise capacity by influencing muscle substrate availability.

2.
Environ Health ; 23(1): 62, 2024 Jul 05.
Article in English | MEDLINE | ID: mdl-38970053

ABSTRACT

BACKGROUND: Autism spectrum disorder (ASD) is a prevalent and heterogeneous neurodevelopmental disorder. Risk is attributed to genetic and prenatal environmental factors, though the environmental agents are incompletely characterized. METHODS: In Early Autism Risk Longitudinal Investigation (EARLI) and Markers of Autism Risk in Babies Learning Early Signs (MARBLES), two pregnancy cohorts of siblings of children with ASD, urinary metals concentrations during two pregnancy time periods (< 28 weeks and ≥ 28 weeks of gestation) were measured using inductively coupled plasma mass spectrometry. At age three, clinicians assessed ASD with DSM-5 criteria. In an exposure-wide association framework, using multivariable log binomial regression, we examined each metal for association with ASD status, adjusting for gestational age at urine sampling, child sex, age at pregnancy, race/ethnicity and education. We meta-analyzed across the two cohorts. RESULTS: In EARLI (n = 170) 17% of children were diagnosed with ASD, and 44% were classified as having non-neurotypical development (Non-TD). In MARBLES (n = 231), 21% were diagnosed with ASD, and 14% classified as Non-TD. During the first and second trimester period (< 28 weeks), having cadmium concentration over the level of detection was associated with 1.69 (1.08, 2.64) times higher risk of ASD, and 1.29 (0.95, 1.75)times higher risk of Non-TD. A doubling of first and second trimester cesium concentration was marginally associated with 1.89 (0.94, 3.80) times higher risk of ASD, and a doubling of third trimester cesium with 1.69 (0.97, 2.95) times higher risk of ASD. CONCLUSION: Exposure in utero to elevated levels of cadmium and cesium, as measured in urine collected during pregnancy, was associated with increased risk of developing ASD.


Subject(s)
Autism Spectrum Disorder , Metals, Heavy , Prenatal Exposure Delayed Effects , Siblings , Humans , Autism Spectrum Disorder/urine , Autism Spectrum Disorder/epidemiology , Autism Spectrum Disorder/chemically induced , Female , Pregnancy , Metals, Heavy/urine , Metals, Heavy/adverse effects , Prenatal Exposure Delayed Effects/epidemiology , Prenatal Exposure Delayed Effects/chemically induced , Child, Preschool , Longitudinal Studies , Male , Maternal Exposure/adverse effects , Environmental Pollutants/urine , Environmental Pollutants/adverse effects , Cohort Studies
3.
Nutrients ; 16(13)2024 Jun 29.
Article in English | MEDLINE | ID: mdl-38999831

ABSTRACT

The interactions of different dietary doses of copper with fructose contribute to the development of metabolic dysfunction-associated steatotic liver disease (MASLD) via the gut-liver axis. The underlying mechanisms remain elusive. The aim of this study was to identify the specific pathways leading to gut barrier dysfunction in the ileum using a proteomics approach in a rat model. Male weanling Sprague Dawley rats were fed diets with adequate copper (CuA), marginal copper (CuM), or supplemented copper (CuS) in the absence or presence of fructose supplementation (CuAF, CuMF, and CuSF) for 4 weeks. Ileum protein was extracted and analyzed with an LC-MS. A total of 2847 differentially expressed proteins (DEPs) were identified and submitted to functional enrichment analysis. As a result, the ileum proteome and signaling pathways that were differentially altered were revealed. Of note, the CuAF is characterized by the enrichment of oxidative phosphorylation and ribosome as analyzed with the KEGG; the CuMF is characterized by an enriched arachidonic acid metabolism pathway; and focal adhesion, the regulation of the actin cytoskeleton, and tight junction were significantly enriched by the CuSF. In conclusion, our proteomics analysis identified the specific pathways in the ileum related to the different dietary doses of copper-fructose interactions, suggesting that distinct mechanisms in the gut are involved in the development of MASLD.


Subject(s)
Copper , Fructose , Ileum , Liver , Proteomics , Rats, Sprague-Dawley , Animals , Fructose/administration & dosage , Fructose/adverse effects , Male , Copper/metabolism , Proteomics/methods , Ileum/metabolism , Ileum/drug effects , Liver/metabolism , Liver/drug effects , Rats , Diet , Proteome/metabolism , Signal Transduction/drug effects , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/etiology , Dietary Supplements
4.
J Cyst Fibros ; 2024 Jul 04.
Article in English | MEDLINE | ID: mdl-38969602

ABSTRACT

BACKGROUND: Effective detection of early lung disease in cystic fibrosis (CF) is critical to understanding early pathogenesis and evaluating early intervention strategies. We aimed to compare ability of several proposed sensitive functional tools to detect early CF lung disease as defined by CT structural disease in school aged children. METHODS: 50 CF subjects (mean±SD 11.2 ± 3.5y, range 5-18y) with early lung disease (FEV1≥70 % predicted: 95.7 ± 11.8 %) performed spirometry, Multiple breath washout (MBW, including trapped gas assessment), oscillometry, cardiopulmonary exercise testing (CPET) and simultaneous spirometer-directed low-dose CT imaging. CT data were analysed using well-evaluated fully quantitative software for bronchiectasis and air trapping (AT). RESULTS: CT bronchiectasis and AT occurred in 24 % and 58 % of patients, respectively. Of the functional tools, MBW detected the highest rates of abnormality: Scond 82 %, MBWTG RV 78 %, LCI 74 %, MBWTG IC 68 % and Sacin 51 %. CPET VO2peak detected slightly higher rates of abnormality (9 %) than spirometry-based FEV1 (2 %). For oscillometry AX (14 %) performed better than Rrs (2 %) whereas Xrs and R5-19 failed to detect any abnormality. LCI and Scond correlated with bronchiectasis (r = 0.55-0.64, p < 0.001) and AT (r = 0.73-0.74, p < 0.001). MBW-assessed trapped gas was detectable in 92 % of subjects and concordant with CT-assessed AT in 74 %. CONCLUSIONS: Significant structural and functional deficits occur in early CF lung disease, as detected by CT and MBW. For MBW, additional utility, beyond that offered by LCI, was suggested for Scond and MBW-assessed gas trapping. Our study reinforces the complementary nature of these tools and the limited utility of conventional oscillometry and CPET in this setting.

5.
Cont Lens Anterior Eye ; : 102257, 2024 Jul 04.
Article in English | MEDLINE | ID: mdl-38969607

ABSTRACT

PURPOSE: The current subclassifications of dry eye disease (DED) are aqueous deficient (ADDE) and evaporative (EDE) forms, but there lacks consistency in the clinical characteristics used to define each of these. This study used clinical data to inform cut-off values for the subclassification of ADDE and EDE, to allow more consistent study of the epidemiology of both DED subtypes. METHODS: The study enrolled 261 residents from the UK, extracted from a cohort with demographics representing the population (mean 42.4 ± 18.7 years, 56 % females). The TFOS DEWS II diagnostic criteria were used to identify those with DED. Meibomian gland loss/drop-out (from meibography), lipid layer thickness (LLT - from interferometry graded on the Guillon-Keeler scale), and tear meniscus height (TMH - Keratograph 5M) along with tear evaporation (Delfin Vapometer) were used to characterise the subclassification. The Dry Eye Risk Factor Survey was used to assess risk factors associated with each DED subtype. RESULTS: Compared to individuals who were not diagnosed with DED, EDE was characterized by signs of meibomian gland loss of > 28 %, LLT grade < 3 and tear evaporation > 46 g/m2/h. In contrast, ADDE was best characterized by a reduced TMH < 0.2 mm. Based on these criteria, the prevalence of ADDE was 6.2 %, EDE was 64.2 %, and 11.1 % exhibited features of both ADDE and EDE, with 18.5 % unclassified despite having a DED diagnosis. Contact lens wear and computer use were risk factors for ADDE (p < 0.05), whereas age was a positive risk factor for EDE (p < 0.01). Meibomian gland loss (occurring in 27.9 %) was the most commonly observed sign in EDE. CONCLUSIONS: Data driven-classification of DED confirms that the evaporative form is most prevalent and identified that in a generalisable UK population, ADDE alone occurs only in approximately 1 in 16 cases of DED.

6.
Mil Med ; 2024 Jul 06.
Article in English | MEDLINE | ID: mdl-38970431

ABSTRACT

INTRODUCTION: Veterans and active duty service members are significantly more likely to die by suicide using firearms compared to the general population. Not-secure firearm storage (e.g., keeping guns loaded/in an unlocked location) is associated with greater risk for suicide and a third of veteran firearm owners store at least 1 personal firearm unsecured. Veterans and active duty service members are also significantly more likely to be diagnosed with posttraumatic stress disorder (PTSD) than the general population. Symptoms of PTSD are divided into 4 criteria: reexperiencing, avoidance, negative affect, and hyperarousal. Research has suggested that endorsement of hyperarousal symptoms is positively associated with unsecure firearm storage and that avoidance symptoms might be negatively associated with unsecure storage practices. The present study examined the relationship between self-reported firearm ownership and storage practices among each item from the Primary Care PTSD Screening for DSM-IV-TR (PC-PTSD-IV) to explore associations between PTSD features and firearm ownership and storage. MATERIALS AND METHODS: Participants were recruited from primary care clinics across 5 military installations in the United States as part of a larger study (Mage = 45.4, SD = 16.9). Among participants (n = 2,685), most of our sample identified as male (51.3%) and white (67.3%) with 61.6% currently serving in the military, 16.8% retirees, and 21.6% family members. PTSD symptoms were assessed using the PC-PTSD-IV and a quarter met the clinical threshold for PTSD. Binomial and multinomial logistic regression analyses were used. RESULTS: Among completed responses, 989 (38.1%) people reported owning guns; among gun owners, 386 (39.0%) reported that they were loaded, and 352 (35.6%) reported they were loaded and unlocked. Endorsement of specific items on the PC-PTSD-IV, including those specific to hyperarousal and avoidance, was not significantly associated with storing firearms loaded and/or in nonsecure locations when controlling for military service. Non-responses to items around firearm storage practices were significantly associated with those individuals meeting the clinical threshold for PTSD according to the PC-PTSD-IV and participants currently serving had higher odds of storing at least 1 personal firearm loaded and both loaded and unlocked. CONCLUSIONS: Results from our study highlight similarities and departures from the previous literature on the connection between PTSD and non-secure firearm storage practices. Further research may examine (1) the relation between PTSD symptoms and firearm storage between active duty service members, retirees, and family members and (2) whether non-response to items regarding firearm ownership is systematic.

7.
Nat Genet ; 2024 Jul 08.
Article in English | MEDLINE | ID: mdl-38977855

ABSTRACT

The African BioGenome Project (AfricaBP) Open Institute for Genomics and Bioinformatics aims to overcome barriers to capacity building through its distributed African regional workshops and prioritizes the exchange of grassroots knowledge and innovation in biodiversity genomics and bioinformatics. In 2023, we implemented 28 workshops on biodiversity genomics and bioinformatics, covering 11 African countries across the 5 African geographical regions. These regional workshops trained 408 African scientists in hands-on molecular biology, genomics and bioinformatics techniques as well as the ethical, legal and social issues associated with acquiring genetic resources. Here, we discuss the implementation of transformative strategies, such as expanding the regional workshop model of AfricaBP to involve multiple countries, institutions and partners, including the proposed creation of an African digital database with sequence information relating to both biodiversity and agriculture. This will ultimately help create a critical mass of skilled genomics and bioinformatics scientists across Africa.

8.
bioRxiv ; 2024 Jun 28.
Article in English | MEDLINE | ID: mdl-38979312

ABSTRACT

Sweet's syndrome is a poorly understood inflammatory skin disease characterized by neutrophil infiltration to the dermis. Single-nucleus and bulk transcriptomics of archival clinical samples of Sweet's syndrome revealed a prominent interferon signature in Sweet's syndrome skin that was reduced in tissue from other neutrophilic dermatoses. This signature was observed in different subsets of cells, including fibroblasts that expressed interferon-induced genes. Functionally, this response was supported by analysis of cultured primary human dermal fibroblasts that were observed to highly express neutrophil chemokines in response to activation by type I interferon. Furthermore, single-molecule resolution spatial transcriptomics of skin in Sweet's syndrome identified positionally distinct immune acting fibroblasts that included a CXCL1+ subset proximal to neutrophils and a CXCL12+ subset distal to the neutrophilic infiltrate. This study defines the cellular landscape of neutrophilic dermatoses and suggests dermal immune acting fibroblasts play a role in the pathogenesis of Sweet's syndrome through recognition of type I interferons.

9.
Nat Commun ; 15(1): 5028, 2024 Jun 12.
Article in English | MEDLINE | ID: mdl-38866748

ABSTRACT

Cholesterol-dependent cytolysins (CDCs) comprise a large family of pore-forming toxins produced by Gram-positive bacteria, which are used to attack eukaryotic cells. Here, we functionally characterize a family of 2-component CDC-like (CDCL) toxins produced by the Gram-negative Bacteroidota that form pores by a mechanism only described for the mammalian complement membrane attack complex (MAC). We further show that the Bacteroides CDCLs are not eukaryotic cell toxins like the CDCs, but instead bind to and are proteolytically activated on the surface of closely related species, resulting in pore formation and cell death. The CDCL-producing Bacteroides is protected from the effects of its own CDCL by the presence of a surface lipoprotein that blocks CDCL pore formation. These studies suggest a prevalent mode of bacterial antagonism by a family of two-component CDCLs that function like mammalian MAC and that are wide-spread in the gut microbiota of diverse human populations.


Subject(s)
Complement Membrane Attack Complex , Humans , Complement Membrane Attack Complex/metabolism , Bacteroides/genetics , Bacteroides/metabolism , Bacterial Toxins/metabolism , Bacterial Toxins/genetics , Cytotoxins/metabolism , Gastrointestinal Microbiome , Bacterial Proteins/metabolism , Bacterial Proteins/genetics , Complement System Proteins/metabolism , Complement System Proteins/immunology , Animals , Eukaryotic Cells/metabolism
10.
Front Physiol ; 15: 1394707, 2024.
Article in English | MEDLINE | ID: mdl-38827993

ABSTRACT

In numerous medical conditions, including pregnancy, gravity and posture interact to impact physiology and pathophysiology. Recent investigations, for example, pertaining to maternal sleeping posture during the third trimester and possible impact on fetal growth and stillbirth risk highlight the importance and potential clinical implications of the subject. In this review, we provide an extensive discussion of the impact of maternal posture on fetal physiology from conception to the postpartum period in human pregnancy. We conducted a systematic literature search of the MEDLINE database and identified 242 studies from 1991 through 2021, inclusive, that met our inclusion criteria. Herein, we provide a synthesis of the resulting literature. In the first section of the review, we group the results by the impact of maternal posture at rest on the cervix, uterus, placenta, umbilical cord, amniotic fluid, and fetus. In the second section of the review, we address the impact on fetal-related outcomes of maternal posture during various maternal activities (e.g., sleep, work, exercise), medical procedures (e.g., fertility, imaging, surgery), and labor and birth. We present the published literature, highlight gaps and discrepancies, and suggest future research opportunities and clinical practice changes. In sum, we anticipate that this review will shed light on the impact of maternal posture on fetal physiology in a manner that lends utility to researchers and clinicians who are working to improve maternal, fetal, and child health.

11.
Inj Prev ; 2024 Jun 06.
Article in English | MEDLINE | ID: mdl-38844337

ABSTRACT

BACKGROUND: Veteran suicide remains a significant issue, as 17.5 Veterans die by suicide each day. The US Department of Veteran Affairs (VA) has implemented a robust suicide prevention program within its integrated behavioural health system. Further, the VA has increasingly contributed to suicide prevention in community settings, where a large proportion of Veterans receive health care and social services. One component integral to preventing suicide among Veterans receiving community services is ensuring that organisations are equipped with the latest evidence-based Veteran-specific suicide prevention strategies. METHODS: The Patient Safety Center of Inquiry-Suicide Prevention Collaborative piloted a Veteran suicide prevention learning collaborative in the Denver/Colorado Springs, CO region, spanning 16 months as a multimodal initiative to integrate community organisations and assist them in implementing Veteran suicide prevention strategies used within VA. Agencies completed social network analysis surveys at baseline (T1), year 1 (T2) and 16 months (T3) to examine social networks, partnerships and collaborations among community organisations and the VA over time. RESULTS: The quantity of learning collaborative relationships increased from 30 at T1 to 41 at T3 while the quality of relationships deepened over time from awareness and cooperative to more coordinated and integrated. CONCLUSION: Improvement in relationship quantity and quality facilitates community organisation engagement in collaborating to strengthen their Veteran suicide prevention programming. Learning collaboratives work with the individual organisation for intraorganisational facilitation of implementing suicide prevention strategies and engage and enhance interorganisational partnerships. This multimodal intervention can engage community organisations and provide a stronger safety net for Veterans at risk for suicide.

12.
Biomedicines ; 12(6)2024 May 31.
Article in English | MEDLINE | ID: mdl-38927434

ABSTRACT

BACKGROUND: Virtually the entire spectrum of liver disease is observed in association with type 2 diabetes mellitus (T2DM); indeed, T2DM is now the most common cause of liver disease in the U.S. We conducted a pilot study to investigate the relevance of increased microbial translocation and systemic inflammation in the development of liver injury in patients with T2DM. METHODS: Patients with T2DM (n = 17) and non-diabetic controls (NDC; n = 11) aged 25-80 yrs. participated in this study. Serum levels of endotoxin, calprotectin, soluble CD14 and CD163, and several inflammatory cytokines were measured. In addition to standard liver injury markers, ALT and AST, novel serum markers of liver injury, keratin 18 (K-18) M30 (apoptosis-associated caspase-cleaved keratin 18), and M65 (soluble keratin 18) were evaluated. Statistical analyses were performed using the Mann-Whitney test to assess differences between study groups. Pearson's correlation analysis was performed to determine the strength of association between two variables using GraphPad Prism 9.5.0 software. RESULTS: Patients with T2DM had significantly higher levels of sCD14 in comparison to NDC, suggesting an increase in gut permeability, microbial translocation, and monocyte/macrophage activation. Importantly, relevant to the ensuing inflammatory responses, the increase in sCD14 in patients with T2DM was accompanied by a significant increase in sCD163, a marker of hepatic Kupffer cell activation and inflammation. Further, a positive correlation was observed between sCD163 and endotoxin and sCD14 in T2DM patients but not in NDC. In association with these changes, keratin 18 (K-18)-based serum markers (M65 and M30) that reflect hepatocyte death were significantly higher in the T2DM group indicating ongoing liver injury. Notably, both M65 and M30 levels correlated with sCD14 and sCD163, suggesting that immune cell activation and hepatic inflammation may be linked to the development of liver injury in T2DM. CONCLUSIONS: These findings suggest that the pathogenic changes in the gut-liver axis, marked by increased microbial translocation, may be a major component in the etiology of hepatocyte inflammation and injury in patients with T2DM. However, larger longitudinal studies, including histological evidence, are needed to confirm these observations.

13.
J Multidiscip Healthc ; 17: 2903-2910, 2024.
Article in English | MEDLINE | ID: mdl-38911613

ABSTRACT

Lower extremity peripheral artery disease (PAD) is a common atherosclerotic cardiovascular disease (ASCVD) involving the aortoiliac, femoropopliteal, and infrapopliteal arterial segments. PAD remains a largely underdiagnosed and undertreated condition. The ankle-brachial index (ABI) is a simple and widely available test that is key detection tool in the diagnosis of PAD and is prognostic for mortality and morbidity. The cardiovascular (CV) team is a diverse array of health care clinicians (eg, nurses, nurse practitioners, physician assistants/associates, pharmacists, podiatrists) who have the qualifications and skills to be able to recognize when patients are at risk for PAD and perform an ABI. It is critical that the healthcare community recognize the critical role the CV team could play in improving outcomes and reducing disparities for patients with PAD.

14.
Emerg Med Clin North Am ; 42(3): 695-709, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38925783

ABSTRACT

The safety and health of individuals who may be exposed to the spaceflight environment are first and foremost cared for through prevention. This environment, which encompasses microgravity, radiation, and alternobaric factors, can have physiologic impacts on every human system. Available medical care and resources in the spaceflight environment are currently limited by mass and volume constraints, with available medical resources thereby focusing on a patient's stabilization and evacuation. An understanding of the spaceflight environment and its possible effects is crucial for the treatment of individuals prior to, during, and after spaceflight.


Subject(s)
Space Flight , Weightlessness , Humans , Weightlessness/adverse effects , Aerospace Medicine , Astronauts
15.
Microsc Microanal ; 30(3): 574-593, 2024 Jul 04.
Article in English | MEDLINE | ID: mdl-38838186

ABSTRACT

Ossa cordis, bones located within the heart trigones, are often classified as heterotopic or ectopic bones. Despite their high prevalence in cattle and some other bovids, little is known about their structure or development. Scanning electron microscopy, X-ray microtomography, gross dissections, and measurements showed the anatomical locations, prevalence, shapes, and measurements of the cardiac bones in both Egyptian Baladi cattle and Holstein-Friesians. All cattle (n = 12) had an Ossa cordis dextrum (average = 50.70 × 20.91 × 5.40 mm). Additionally, 80% Egyptian Baladi and 57% Holstein-Friesian had a smaller Ossa cordis sinistrum (average = 24.94 × 12.75 × 4.12 mm). Egyptian Baladi Ossa cordis were smaller than observed in Holstein-Friesians. Energy-dispersive X-ray analysis showed the elemental constitution (carbon, oxygen, calcium, nitrogen, phosphorus, sodium, and magnesium) of Ossa cordis and Cartilago cordis. These imaging techniques, plus four histological stains (hematoxylin and eosin, Crossman's trichrome, Alcian blue with Van Gieson, and Sirius Red) and microscopy, demonstrated osteoblasts, osteocytes, osteoclasts, astrocytes, blood vessels, bone marrow, lamellar and woven bone, cortical bone, trabeculations with pores and canaliculi, and fibrous components including collagen in the Ossa cordis dextrum and sinistrum. Hyaline cartilage and fibrocartilage (chondrocytes and cartilage matrix) were found within and surrounding the Ossa cordis. These findings were additionally compared against other cattle breeds and species.


Subject(s)
Microscopy, Electron, Scanning , X-Ray Microtomography , Animals , Cattle , Spectrometry, X-Ray Emission , Bone and Bones/ultrastructure
17.
Nature ; 630(8017): 744-751, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38867042

ABSTRACT

DNA base damage is a major source of oncogenic mutations1. Such damage can produce strand-phased mutation patterns and multiallelic variation through the process of lesion segregation2. Here we exploited these properties to reveal how strand-asymmetric processes, such as replication and transcription, shape DNA damage and repair. Despite distinct mechanisms of leading and lagging strand replication3,4, we observe identical fidelity and damage tolerance for both strands. For small alkylation adducts of DNA, our results support a model in which the same translesion polymerase is recruited on-the-fly to both replication strands, starkly contrasting the strand asymmetric tolerance of bulky UV-induced adducts5. The accumulation of multiple distinct mutations at the site of persistent lesions provides the means to quantify the relative efficiency of repair processes genome wide and at single-base resolution. At multiple scales, we show DNA damage-induced mutations are largely shaped by the influence of DNA accessibility on repair efficiency, rather than gradients of DNA damage. Finally, we reveal specific genomic conditions that can actively drive oncogenic mutagenesis by corrupting the fidelity of nucleotide excision repair. These results provide insight into how strand-asymmetric mechanisms underlie the formation, tolerance and repair of DNA damage, thereby shaping cancer genome evolution.


Subject(s)
DNA Damage , DNA Repair , DNA-Directed DNA Polymerase , DNA , Mutagenesis , Mutation , Animals , Humans , Mice , Alkylation/radiation effects , Cell Line , DNA/chemistry , DNA/genetics , DNA/metabolism , DNA/radiation effects , DNA Adducts/chemistry , DNA Adducts/genetics , DNA Adducts/metabolism , DNA Adducts/radiation effects , DNA Damage/genetics , DNA Damage/radiation effects , DNA Repair/genetics , DNA Repair/physiology , DNA Replication , DNA-Directed DNA Polymerase/metabolism , Mutagenesis/genetics , Mutagenesis/radiation effects , Mutation/genetics , Mutation/radiation effects , Neoplasms/genetics , Transcription, Genetic , Ultraviolet Rays/adverse effects
18.
Cancer Cell ; 42(7): 1185-1201.e14, 2024 Jul 08.
Article in English | MEDLINE | ID: mdl-38906156

ABSTRACT

Multiple myeloma (MM) is an incurable plasma cell malignancy that exploits transcriptional networks driven by IRF4. We employ a multi-omics approach to discover IRF4 vulnerabilities, integrating functional genomics screening, spatial proteomics, and global chromatin mapping. ARID1A, a member of the SWI/SNF chromatin remodeling complex, is required for IRF4 expression and functionally associates with IRF4 protein on chromatin. Deleting Arid1a in activated murine B cells disrupts IRF4-dependent transcriptional networks and blocks plasma cell differentiation. Targeting SWI/SNF activity leads to rapid loss of IRF4-target gene expression and quenches global amplification of oncogenic gene expression by MYC, resulting in profound toxicity to MM cells. Notably, MM patients with aggressive disease bear the signature of SWI/SNF activity, and SMARCA2/4 inhibitors remain effective in immunomodulatory drug (IMiD)-resistant MM cells. Moreover, combinations of SWI/SNF and MEK inhibitors demonstrate synergistic toxicity to MM cells, providing a promising strategy for relapsed/refractory disease.


Subject(s)
DNA-Binding Proteins , Interferon Regulatory Factors , Multiple Myeloma , Plasma Cells , Transcription Factors , Multiple Myeloma/drug therapy , Multiple Myeloma/pathology , Multiple Myeloma/genetics , Multiple Myeloma/metabolism , Interferon Regulatory Factors/metabolism , Interferon Regulatory Factors/genetics , Animals , Transcription Factors/metabolism , Transcription Factors/genetics , Humans , Mice , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/genetics , Plasma Cells/drug effects , Plasma Cells/metabolism , Plasma Cells/pathology , Gene Expression Regulation, Neoplastic/drug effects , Cell Line, Tumor , Cell Differentiation/drug effects
19.
J Arthroplasty ; 2024 Jun 17.
Article in English | MEDLINE | ID: mdl-38897263

ABSTRACT

BACKGROUND: Outpatient primary total knee arthroplasty (TKA) has been well-established as a safe and effective procedure; however, the safety of outpatient revision TKA remains unclear. Therefore, this study utilized a large database to compare outcomes between outpatient and inpatient revision TKA. METHODS: An all-payor database was queried to identify patients undergoing revision TKA from 2010 to 2022. Patients who had diagnosis codes related to periprosthetic joint infection (PJI) were excluded. Outpatient surgery was defined as a length of stay < 24 hours. Cohorts were matched by age, sex, Elixhauser Comorbidity Index, comorbidities (diabetes, obesity, tobacco use), components revised (1-versus 2-component), and revision etiology. Medical complications at 90 days and surgical complications at 1 and 2 years postoperatively were evaluated through multivariate logistic regression. A total of 4,342 aseptic revision TKAs were included. RESULTS: No differences in patient characteristics, procedure type, or revision etiologies were seen between groups. The outpatient cohort had a lower risk of PJI (odds ratio (OR): 0.547, 95% confidence interval (CI): 0.337 to 0.869; P = .012), wound dehiscence (OR: 0.393, 95% CI: 0.225 to 0.658; P < .001), transfusion (OR: 0.241, 95% CI: 0.055 to 0.750; P = .027), reoperation (OR: 0.508, 95% CI: 0.305 to 0.822; P = .007), and any complication (OR: 0.696, 95% CI: 0.584 to 0.829; P < .001) at 90 days postoperatively. At 1 year and 2 years postoperatively, outpatient revision TKA patients had a lower incidence of revision for PJI (OR: 0.332, 95% CI: 0.131 to 0.743; P = .011 and OR: 0.446, 95% CI; 0.217 to 0.859; P = .020, respectively) and all-cause revision (OR: 0.518, 95% CI: 0.377 to 0.706; P < .001 and OR: 0.548, 95% CI: 0.422 to 0.712; P < .001, respectively). CONCLUSIONS: Our findings suggest that revision TKA can be safely performed on an outpatient basis in appropriately selected patients who do not have an increased risk of adverse events relative to inpatient revision TKA. However, we could not ascertain case complexity in either cohort, and despite controlling for several potential confounders, other less tangible differences could exist between groups.

20.
Evol Appl ; 17(6): e13728, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38884021

ABSTRACT

Given the multitude of challenges Earth is facing, sustainability science is of key importance to our continued existence. Evolution is the fundamental biological process underlying the origin of all biodiversity. This phylogenetic diversity fosters the resilience of ecosystems to environmental change, and provides numerous resources to society, and options for the future. Genetic diversity within species is also key to the ability of populations to evolve and adapt to environmental change. Yet, the value of evolutionary processes and the consequences of their impairment have not generally been considered in sustainability research. We argue that biological evolution is important for sustainability and that the concepts, theory, data, and methodological approaches used in evolutionary biology can, in crucial ways, contribute to achieving the UN Sustainable Development Goals (SDGs). We discuss how evolutionary principles are relevant to understanding, maintaining, and improving Nature Contributions to People (NCP) and how they contribute to the SDGs. We highlight specific applications of evolution, evolutionary theory, and evolutionary biology's diverse toolbox, grouped into four major routes through which evolution and evolutionary insights can impact sustainability. We argue that information on both within-species evolutionary potential and among-species phylogenetic diversity is necessary to predict population, community, and ecosystem responses to global change and to make informed decisions on sustainable production, health, and well-being. We provide examples of how evolutionary insights and the tools developed by evolutionary biology can not only inspire and enhance progress on the trajectory to sustainability, but also highlight some obstacles that hitherto seem to have impeded an efficient uptake of evolutionary insights in sustainability research and actions to sustain SDGs. We call for enhanced collaboration between sustainability science and evolutionary biology to understand how integrating these disciplines can help achieve the sustainable future envisioned by the UN SDGs.

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