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1.
Epilepsy Behav ; 158: 109928, 2024 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-38959747

RESUMEN

Temporal encephaloceles (TE) are an under-identified, potentially intervenable cause of epilepsy. This systematic review consolidates the current data to identify the major clinical, neuroimaging, and EEG features and surgical outcomes of epilepsy associated with TE. Literature searches were carried out using MEDLINE, Embase, PsycINFO, Scopus, and Cochrane Library databases from inception to December 7, 2023. Studies were included if they described clinical, neuroimaging, EEG, or surgical data in ≥5 patients with TE and epilepsy. Of 562 studies identified in the search, 24 met the eligibility criteria, reporting 423 unique patients with both epilepsy and TE. Compared to epilepsy patients without TE, those with TE had a higher mean age of seizure onset and were less likely to have a history of febrile seizures. Seizure semiologies were variable, but primarily mirrored temporal lobe onset patterns. Epilepsy patients with TE had a higher likelihood of having clinical or radiographic features of idiopathic intracranial hypertension (IIH) than those without. Brain MRI may show ipsilateral mesial temporal sclerosis (16 %). CT scans of the skull base usually revealed bony defects near the TE (90 %). Brain PET scans primarily showed ipsilateral temporal lobe hypometabolism (80 %), mostly in the anterior temporal lobe (67 %). Scalp EEG mostly lateralized ipsilateral to the implicated TE (92 % seizure onset) and localized to the temporal lobe (96 %). Intracranial EEG revealed seizure onset near the TE (11 of 12 cases including TE-adjacent electrodes) with variable timing of spread to the ipsilateral hippocampus. After surgical treatment of the TE, the rate of Engel I or ILAE 1 outcomes at one year was 75 % for lesionectomy, 85 % for anterior temporal lobectomy (ATL), and 80 % for ATL with amygdalohippocampectomy. Further studies are needed to better elucidate the relationship between IIH, TE, and epilepsy, improve the identification of TE, and optimize surgical interventions.

3.
Schizophr Res ; 271: 246-252, 2024 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-39059248

RESUMEN

Negative symptoms are a source of disability in schizophrenia, but criteria for identifying patients for clinical trials are in flux. Minimum severity for negative symptoms is paired with a definition of minimal psychosis to identify predominant negative symptoms. Two previous successful negative symptoms treatment studies used very different severity and selection criteria. We compared the prevalence of participants meeting those two criteria in a large outpatient sample of participants with schizophrenia. Data from 867 outpatients with schizophrenia who participated in one of four NIMH-funded studies were analyzed. Common data elements included diagnoses, the PANSS, and an assessment of everyday functioning. We compared previous criterion for premoninant negative symptoms based on low levels of agitation and psychosis and different cut-offs for negative symptoms severity. 57 % of the participants met the agitation-based criteria for low scores and 33 % met the psychosis-based criteria. 18 % met total PANSS score ≥ 20 and 8 % met ≥24 prominent negative symptoms criteria. 14 % met low agitation and PANSS≥20 and 2 % met the low psychosis and negative symptoms ≥24 criteria. Participants who met all predominant criteria had more impairments in social functioning (all p < .001, all d > 0.37). Criteria for predominant negative symptoms from previous clinical trials identify widely different numbers of cases, with criteria for negative symptom severity and low symptoms both impacting. All criteria yield the expected profile of relatively specific social deficits. Even in unselected populations who participated in complex research protocols, 14 % meet low- agitation based criteria for predominant negative symptoms and many more participants would be expected to meet criteria with enrichment for the presence of negative symptoms.

4.
Eur J Intern Med ; 2024 Jul 20.
Artículo en Inglés | MEDLINE | ID: mdl-39034174

RESUMEN

OBJECTIVES: To evaluate whether the timing of initial antibiotic administration in patients with sepsis in hospital affects mortality. METHODS: This systematic review and meta-analysis included studies from inception up to 19 May 2022. Interventional and observational studies including adult human patients with suspected or confirmed sepsis and reported time of antibiotic administration with mortality were included. Data were extracted by two independent reviewers. Summary estimates were calculated by using random-effects model. The primary outcome was mortality. RESULTS: We included 42 studies comprising 190,896 patients with sepsis. Pooled data showed that the OR for patient mortality who received antibiotics ≤1 hr was 0.83 (95 %CI: 0.67 to 1.04) when compared with patients who received antibiotics >1hr. Significant reductions in the risk of death in patients with earlier antibiotic administration were observed in patients ≤3 hrs versus >3 hrs (OR: 0.80, 95 %CI: 0.68 to 0.94) and ≤6 hrs vs 6 hrs (OR: 0.57, 95 %CI: 0.39 to 0.82). CONCLUSIONS: Our findings show an improvement in mortality in sepsis patients with early administration of antibiotics at <3 and <6 hrs. Thus, these results suggest that antibiotics should be administered within 3 hrs of sepsis recognition or ED arrival regardless of the presence or absence of shock.

5.
Genet Med ; : 101211, 2024 Jul 13.
Artículo en Inglés | MEDLINE | ID: mdl-39011766

RESUMEN

PURPOSE: An early genetic diagnosis can guide the time-sensitive treatment of individuals with genetic epilepsies. However, most genetic diagnoses occur long after disease onset. We aimed to identify early clinical features suggestive of genetic diagnoses in individuals with epilepsy through large-scale analysis of full-text electronic medical records (EMR). METHODS: We extracted 89 million time-stamped standardized clinical annotations using Natural Language Processing from 4,572,783 clinical notes from 32,112 individuals with childhood epilepsy, including 1,925 individuals with known or presumed genetic epilepsies. We applied these features to train random forest models to predict SCN1A-related disorders and any genetic diagnosis. RESULTS: We identified 47,774 age-dependent associations of clinical features with genetic etiologies a median of 3.6 years prior to molecular diagnosis. Across all 710 genetic etiologies identified in our cohort, neurodevelopmental differences between 6-9 months increased the likelihood of a later molecular diagnosis fivefold (P<0.0001, 95% CI=3.55-7.42). A later diagnosis of SCN1A-related disorders (AUC=0.91) or an overall positive genetic diagnosis (AUC=0.82) could be reliably predicted using random forest models. CONCLUSION: Clinical features predictive of genetic epilepsies precede molecular diagnoses by up to several years in conditions with known precision treatments. An earlier diagnosis facilitated by automated EMR analysis has the potential for earlier targeted therapeutic strategies in the genetic epilepsies.

6.
JMIR Ment Health ; 11: e59198, 2024 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-38967418

RESUMEN

Background: Paranoia is a spectrum of fear-related experiences that spans diagnostic categories and is influenced by social and cognitive factors. The extent to which social media and other types of media use are associated with paranoia remains unclear. Objective: We aimed to examine associations between media use and paranoia at the within- and between-person levels. Methods: Participants were 409 individuals diagnosed with schizophrenia spectrum or bipolar disorder. Measures included sociodemographic and clinical characteristics at baseline, followed by ecological momentary assessments (EMAs) collected 3 times daily over 30 days. EMA evaluated paranoia and 5 types of media use: social media, television, music, reading or writing, and other internet or computer use. Generalized linear mixed models were used to examine paranoia as a function of each type of media use and vice versa at the within- and between-person levels. Results: Of the 409 participants, the following subgroups reported at least 1 instance of media use: 261 (63.8%) for using social media, 385 (94.1%) for watching TV, 292 (71.4%) for listening to music, 191 (46.7%) for reading or writing, and 280 (68.5%) for other internet or computer use. Gender, ethnoracial groups, educational attainment, and diagnosis of schizophrenia versus bipolar disorder were differentially associated with the likelihood of media use. There was a within-person association between social media use and paranoia: using social media was associated with a subsequent decrease of 5.5% (fold-change 0.945, 95% CI 0.904-0.987) in paranoia. The reverse association, from paranoia to subsequent changes in social media use, was not statistically significant. Other types of media use were not significantly associated with paranoia. Conclusions: This study shows that social media use was associated with a modest decrease in paranoia, perhaps reflecting the clinical benefits of social connection. However, structural disadvantage and individual factors may hamper the accessibility of media activities, and the mental health correlates of media use may further vary as a function of contents and contexts of use.


Asunto(s)
Trastorno Bipolar , Evaluación Ecológica Momentánea , Trastornos Paranoides , Esquizofrenia , Medios de Comunicación Sociales , Humanos , Femenino , Masculino , Trastorno Bipolar/psicología , Trastorno Bipolar/epidemiología , Adulto , Esquizofrenia/epidemiología , Esquizofrenia/diagnóstico , Medios de Comunicación Sociales/estadística & datos numéricos , Persona de Mediana Edad , Trastornos Paranoides/psicología , Trastornos Paranoides/epidemiología
7.
J Biol Chem ; : 107569, 2024 Jul 13.
Artículo en Inglés | MEDLINE | ID: mdl-39009342

RESUMEN

Loss of glycogen myophosphorylase (PYGM) expression results in an inability to break down muscle glycogen, leading to McArdle disease-an autosomal recessive metabolic disorder characterized by exercise intolerance and muscle cramps. While previously considered relatively benign, this condition has recently been associated with pattern dystrophy in the retina, accompanied by variable sight impairment, secondary to retinal pigment epithelial (RPE) cell involvement. However, the pathomechanism of this condition remains unclear. In this study, we generated a PYGM-null induced pluripotent stem cell (iPSC) line, and differentiated it into mature RPE to examine structural and functional defects, along with metabolite release into apical and basal media. Mutant RPE exhibited normal photoreceptor outer segment phagocytosis but displayed elevated glycogen levels, reduced transepithelial resistance, and increased cytokine secretion across the epithelial layer compared to isogenic wildtype controls. Additionally, decreased expression of the visual cycle component, RDH11, encoding 11-cis-retinol dehydrogenase, was observed in PYGM-null RPE. While glycolytic flux and oxidative phosphorylation levels in PYGM-null RPE were near normal, the basal oxygen consumption rate (OCR) was increased. OCR in response to physiological levels of lactate was significantly greater in wildtype compared to PYGM-null RPE. Inefficient lactate utilization by mutant RPE resulted in higher glucose dependence and increased glucose uptake from the apical medium in the presence of lactate, suggesting a reduced capacity to spare glucose for photoreceptor use. Metabolic tracing confirmed slower 13C-lactate utilization by PYGM-null RPE. These findings have key implications for retinal health since they likely underlie the vision impairment in individuals with McArdle disease.

8.
J Fish Biol ; 2024 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-38965998

RESUMEN

Acoustic telemetry has been used to monitor the movement of aquatic animals in a broad range of aquatic environments. Despite their importance, mangrove habitats are understudied for the spatial ecology of elasmobranchs, with acoustic telemetry rarely used inside mangrove habitats. One reason for this may be a general assumption that acoustic signals would not be able to be detected by receivers in such shallow, structurally complex, environments. This study tested whether acoustic receivers can be used inside mangrove habitats to track the movement of sharks and rays. Thirty-eight receivers were deployed in a mangrove system in Pioneer Bay, Orpheus Island, Great Barrier Reef, including inside mangroves, mangrove edges, and adjacent reef flat areas. The detection range and receiver performance metrics, such as code detection efficiency, rejection coefficient, and noise quotient, were examined and tested among habitats. The results highlighted that the signal from transmitters was successfully detected inside mangrove habitats as well as on the adjacent reef flat. The range to detect at least 50% of transmissions was up to 20 m inside mangroves and up to 120 m outside mangroves. The performance metrics of acoustic receivers inside the mangrove habitat were characterized by low background noise, low rejection rates, and reasonably high code detection efficiency. Furthermore, this study tested the application of this method on juvenile blacktip reef shark Carcharhinus melanopterus and mangrove whipray Urogymnus granulatus, and demonstrated that it can be used to successfully track animals inside mangrove habitat. This novel method could reveal further information on how sharks and rays use mangrove habitats.

9.
Nat Mater ; 2024 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-39043927

RESUMEN

Solar energy is the fastest-growing source of electricity generation globally. As deployment increases, photovoltaic (PV) panels need to be produced sustainably. Therefore, the resource utilization rate and the rate at which those resources become available in the environment must be in equilibrium while maintaining the well-being of people and nature. Metal halide perovskite (MHP) semiconductors could revolutionize PV technology due to high efficiency, readily available/accessible materials and low-cost production. Here we outline how MHP-PV panels could scale a sustainable supply chain while appreciably contributing to a global renewable energy transition. We evaluate the critical material concerns, embodied energy, carbon impacts and circular supply chain processes of MHP-PVs. The research community is in an influential position to prioritize research efforts in reliability, recycling and remanufacturing to make MHP-PVs one of the most sustainable energy sources on the market.

10.
Age Ageing ; 53(7)2024 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-39058917

RESUMEN

BACKGROUND: Visual impairment (VI) is associated with dementia and other neuropsychiatric outcomes, but previous studies have not considered genetic sources of confounding or effect modification. METHODS: We analysed data from the Health and Retirement Study, an ongoing nationally representative survey of older US adults, a subset of whom underwent genetic testing from 2006 to 2012 (n = 13 465). Using discrete time proportional hazards models and generalised estimating equations, we measured the association between VI and dementia, depression and hallucinations adjusting for demographics and comorbidities, ancestry-specific principal components and polygenic risk scores (PRS) for Alzheimer's disease, major depressive disorder or schizophrenia. Effect modification was assessed using VI-PRS interaction terms and stratified analyses. RESULTS: VI was associated with dementia, depression and hallucinations after adjusting polygenic risk and other confounders. There was no VI-PRS interaction for dementia or depression. However, the association between VI and hallucinations varied by genetic risk of schizophrenia. Within the bottom four quintiles of schizophrenia PRS, VI was not associated with hallucinations among White (OR 1.16, 95% CI: 0.87-1.55) or Black participants (OR 0.96, 95% CI: 0.49-1.89). In contrast, VI was strongly associated with hallucinations among White (OR 2.08, 95% CI: 1.17-3.71) and Black (OR 10.63, 95% CI: 1.74-65.03) participants in the top quintile of schizophrenia PRS. CONCLUSIONS: The association between VI and neuropsychiatric outcomes is not explained by shared genetic risk factors, and there is a significant interaction between VI and polygenic risk of hallucinations in older adults.


Asunto(s)
Demencia , Predisposición Genética a la Enfermedad , Alucinaciones , Trastornos Psicóticos , Trastornos de la Visión , Humanos , Masculino , Femenino , Anciano , Demencia/genética , Demencia/epidemiología , Demencia/psicología , Demencia/diagnóstico , Factores de Riesgo , Estados Unidos/epidemiología , Trastornos de la Visión/genética , Trastornos de la Visión/epidemiología , Trastornos de la Visión/psicología , Alucinaciones/genética , Alucinaciones/epidemiología , Alucinaciones/psicología , Alucinaciones/diagnóstico , Trastornos Psicóticos/genética , Trastornos Psicóticos/epidemiología , Trastornos Psicóticos/psicología , Herencia Multifactorial , Medición de Riesgo , Factores de Edad , Persona de Mediana Edad , Anciano de 80 o más Años , Esquizofrenia/genética , Esquizofrenia/epidemiología
11.
Int J Obes (Lond) ; 2024 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-38849462

RESUMEN

BACKGROUND: Preliminary data suggests that obesity might hasten the decline in mRNA vaccine-induced immunity against SARS-CoV-2. However, whether this renders individuals with obesity more susceptible to long COVID symptoms post-vaccination remains uncertain. Given sleep's critical role in immunity, exploring the associations between obesity, probable long COVID symptoms, and sleep disturbances is essential. METHODS: We analyzed data from a survey of 5919 adults aged 18 to 89, all of whom received two SARS-CoV-2 mRNA vaccinations. Participants were categorized into normal weight, overweight, and obesity groups based on ethnicity-specific BMI cutoffs. The probability of long COVID was evaluated using the Post-Acute Sequelae of SARS-CoV-2 (PASC) score, as our survey did not permit confirmation of acute SARS-CoV-2 infection through methods such as antibody testing. Additionally, sleep patterns were assessed through questionnaires. RESULTS: Participants with obesity exhibited a significantly higher adjusted odds ratio (OR) of having a PASC score of 12 or higher, indicative of probable long COVID in our study, compared to those with normal weight (OR: 1.55, 95% CI: 1.05, 2.28). No significant difference was observed for overweight individuals (OR: 0.92 [95% CI: 0.63, 1.33]). Both obesity and probable long COVID were associated with increased odds of experiencing a heightened sleep burden, such as the presence of obstructive sleep apnea or insomnia (P < 0.001). However, no significant interaction between BMI and probable long COVID status was found. CONCLUSIONS: Even post-vaccination, individuals with obesity may encounter a heightened risk of experiencing prolonged COVID-19 symptoms. However, confirming our observations necessitates comprehensive studies incorporating rigorous COVID infection testing, such as antibody assays - unavailable in our anonymous survey. Additionally, it is noteworthy that the correlation between probable long COVID and sleep disturbances appears to be independent of BMI.

12.
Conserv Biol ; : e14311, 2024 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-38853694

RESUMEN

Conducting conservation research and establishing protected areas (PAs) based on research results are critical to biodiversity conservation. However, the effect of research and PAs on conservation of threatened species has rarely been evaluated simultaneously. We collected data on PAs from 2000 for 2021 and determined the number of publications on global primates (published from 1950 to 2021) to assess the effect of PAs, research, and biological and socioeconomic factors on the current International Union for Conservation of Nature endangered status and change in status. We used the MCMCglmm package to conduct a phylogenetic comparative analysis to control the phylogenetic relationship of primate species. The status of 24.6% (82 of 333) of species assessed at least twice declined. Only the black lion tamarin (Leontopithecus chrysopygus) had an improved status. Species with status declines mostly occurred on the south coast of West Africa and in Madagascar. PAs covered 22.1% of each species' range. Forest loss in PAs (5.5%) was significantly lower than forest loss within 5 km outside PAs (13.8%), suggesting PAs effectively mitigated forest loss. Both the median number of total publications and conservation publications on critically endangered species were higher than those of other categories. Models showed that PA coverage and number of publications or conservation-focused publications were not related to current status or change in status over time. A decline in status was not related to creation of PAs or increase of research since the last assessment. Our results suggest that current PAs and research are not reversing the extinction crisis of global primates. Doing more conservation-oriented research, strengthening management of current PAs, and expanding PAs will be needed to protect primates globally.


Efectos de la cobertura e investigación de áreas protegidas sobre el estado de conservación de los primates a nivel mundial Resumen La investigación para la conservación y la creación de áreas protegidas (AP) con base en sus resultados son de suma importancia para conservar la biodiversidad. Sin embargo, pocas veces se ha analizado de forma simultánea el efecto de la investigación y las AP sobre la conservación de especies amenazadas. Recolectamos datos sobre las AP entre el 2000 y el 2021 y determinamos el número de artículos sobre primates publicados entre 1950 y 2021 para evaluar el efecto de las AP, la investigación y los factores biológicos y socioeconómicos sobre el estado actual de en peligro y de cambio de estatus de la Unión Internacional para la Conservación de la Naturaleza. Usamos el paquete MCMCglmm para realizar un estudio filogenético comparativo para analizar la relación filogenética del estado de las especies y del cambio de estatus de primates. El estatus del 24.6% (82 de 333) de las especies analizadas declinó al menos dos veces. Solamente el tití leoncito (Leontopithecus chrysopygus) tuvo una mejoraría en su estado. Las especies con declinación en su estado se ubicaron principalmente en la costa sur del Oeste de África y en Madagascar. Las AP cubrieron el 22.1% de la distribución de cada especie. La pérdida de bosques en las AP (5.5%) fue mucho menor que la pérdida dentro de los primeros 5 km fuera de las AP (13.8%), lo que sugiere que las AP mitigan eficientemente la pérdida de bosque. Tanto el número medio de publicaciones totales como el de publicaciones sobre la conservación de especies en peligro crítico fue mayor que aquellos de cualquier otra categoría. Los modelos mostraron que la cobertura de AP y el número de publicaciones o de publicaciones enfocadas en la conservación no estaban relacionados con el estado actual o el cambio de estado. La declinación del estado no estuvo relacionada con la creación de AP o el incremento en la investigación desde nuestro último análisis. Nuestros resultados sugieren que la investigación y las AP actuales no están revirtiendo la crisis mundial de extinción de primates. Para proteger a los primates se necesitará realizar más investigación orientada a la conservación, fortalecer el manejo actual de las AP, así como expandirlas.

13.
JMIR Med Educ ; 10: e54071, 2024 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-38889065

RESUMEN

Background: Health care professionals must learn continuously as a core part of their work. As the rate of knowledge production in biomedicine increases, better support for health care professionals' continuous learning is needed. In health systems, feedback is pervasive and is widely considered to be essential for learning that drives improvement. Clinical quality dashboards are one widely deployed approach to delivering feedback, but engagement with these systems is commonly low, reflecting a limited understanding of how to improve the effectiveness of feedback about health care. When coaches and facilitators deliver feedback for improving performance, they aim to be responsive to the recipient's motivations, information needs, and preferences. However, such functionality is largely missing from dashboards and feedback reports. Precision feedback is the delivery of high-value, motivating performance information that is prioritized based on its motivational potential for a specific recipient, including their needs and preferences. Anesthesia care offers a clinical domain with high-quality performance data and an abundance of evidence-based quality metrics. Objective: The objective of this study is to explore anesthesia provider preferences for precision feedback. Methods: We developed a test set of precision feedback messages with balanced characteristics across 4 performance scenarios. We created an experimental design to expose participants to contrasting message versions. We recruited anesthesia providers and elicited their preferences through analysis of the content of preferred messages. Participants additionally rated their perceived benefit of preferred messages to clinical practice on a 5-point Likert scale. Results: We elicited preferences and feedback message benefit ratings from 35 participants. Preferences were diverse across participants but largely consistent within participants. Participants' preferences were consistent for message temporality (α=.85) and display format (α=.80). Ratings of participants' perceived benefit to clinical practice of preferred messages were high (mean rating 4.27, SD 0.77). Conclusions: Health care professionals exhibited diverse yet internally consistent preferences for precision feedback across a set of performance scenarios, while also giving messages high ratings of perceived benefit. A "one-size-fits-most approach" to performance feedback delivery would not appear to satisfy these preferences. Precision feedback systems may hold potential to improve support for health care professionals' continuous learning by accommodating feedback preferences.


Asunto(s)
Retroalimentación , Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Encuestas y Cuestionarios , Personal de Salud/psicología , Mejoramiento de la Calidad
14.
Biol Psychol ; 191: 108826, 2024 Jun 09.
Artículo en Inglés | MEDLINE | ID: mdl-38862067

RESUMEN

Studies of COMT Val158Met suggest that the neural circuitry subserving inhibitory control may be modulated by this functional polymorphism altering cortical dopamine availability, thus giving rise to heritable differences in behaviors. Using an anatomically-constrained magnetoencephalography method and stratifying the sample by COMT genotype, from a larger sample of 153 subjects, we examined the spatial and temporal dynamics of beta oscillations during motor execution and inhibition in 21 healthy Met158/Met158 (high dopamine) or 21 Val158/Val158 (low dopamine) genotype individuals during a Go/NoGo paradigm. While task performance was unaffected, Met158 homozygotes demonstrated an overall increase in beta power across regions essential for inhibitory control during early motor preparation (∼100 ms latency), suggestive of a global motor "pause" on behavior. This increase was especially evident on Go trials with slow response speed and was absent during inhibition failures. Such a pause could underlie the tendency of Met158 allele carriers to be more cautious and inhibited. In contrast, Val158 homozygotes exhibited a beta drop during early motor preparation, indicative of high response readiness. This decrease was associated with measures of behavioral disinhibition and consistent with greater extraversion and impulsivity observed in Val homozygotes. These results provide mechanistic insight into genetically-determined interindividual differences of inhibitory control with higher cortical dopamine associated with momentary response hesitation, and lower dopamine leading to motor impulsivity.

15.
Nature ; 630(8017): 744-751, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38867042

RESUMEN

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.


Asunto(s)
Daño del ADN , Reparación del ADN , ADN Polimerasa Dirigida por ADN , ADN , Mutagénesis , Mutación , Animales , Humanos , Ratones , Alquilación/efectos de la radiación , Línea Celular , ADN/química , ADN/genética , ADN/metabolismo , ADN/efectos de la radiación , Aductos de ADN/química , Aductos de ADN/genética , Aductos de ADN/metabolismo , Aductos de ADN/efectos de la radiación , Daño del ADN/genética , Daño del ADN/efectos de la radiación , Reparación del ADN/genética , Reparación del ADN/fisiología , Replicación del ADN , ADN Polimerasa Dirigida por ADN/metabolismo , Mutagénesis/genética , Mutagénesis/efectos de la radiación , Mutación/genética , Mutación/efectos de la radiación , Neoplasias/genética , Transcripción Genética , Rayos Ultravioleta/efectos adversos
16.
Environ Sci Technol ; 58(26): 11718-11726, 2024 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-38889109

RESUMEN

Mountaintop removal coal mining is a source of downstream pollution. Here, we show that mountaintop removal coal mining also pollutes ecosystems downwind. We sampled regional snowpack near the end of winter along a transect of sites located 3-60 km downwind of coal mining in the Elk River valley of British Columbia, Canada. Vast quantities of polycyclic aromatic compounds (PACs), a toxic class of organic contaminants, are emitted and transported atmospherically far from emission sources. Summed PAC (ΣPAC) snowpack concentrations ranged from 29-94,866 ng/L. Snowpack ΣPAC loads, which account for variable snowpack depth, ranged from <10 µg/m2 at sites >50 km southeast of the mines to >1000 µg/m2 at sites in the Elk River valley near mining operations, with one site >15,000 µg/m2. Outside of the Elk River valley, snowpack ΣPAC loads exhibited a clear spatial pattern decreasing away from the mines. The compositional fingerprint of this PAC pollution matches closely with Elk River valley coal. Beyond our study region, modeling results suggest a depositional footprint extending across western Canada and the northwestern United States. These findings carry important implications for receiving ecosystems and for communities located close to mountaintop removal coal mines exposed to air pollution elevated in PACs.


Asunto(s)
Minas de Carbón , Nieve , Colombia Británica , Hidrocarburos Policíclicos Aromáticos/análisis , Monitoreo del Ambiente
18.
J Biomed Mater Res B Appl Biomater ; 112(7): e35438, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38923755

RESUMEN

Volumetric muscle loss (VML) injury causes irreversible deficits in muscle mass and function, often resulting in permanent disability. The current standard of care is physical therapy, but it is limited in mitigating functional deficits. We have previously optimized a rehabilitation technique using electrically stimulated eccentric contraction training (EST) that improved muscle mass, strength, and size in VML-injured rats. A biosponge scaffold composed of extracellular matrix proteins has previously enhanced muscle function postVML. This study aimed to determine whether combining a regenerative therapy (i.e., biosponge) with a novel rehabilitation technique (i.e., EST) could enhance recovery in a rat model of VML. A VML defect was created by removing ~20% of muscle mass from the tibialis anterior muscle in adult male Lewis rats. Experimental groups included VML-injured rats treated with biosponge with EST or biosponge alone (n = 6/group). EST was implemented 2 weeks postinjury at 150 Hz and was continued for 4 weeks. A linear increase in eccentric torque over 4 weeks showed the adaptability of the VML-injured muscle to EST. Combining biosponge with EST improved peak isometric torque by ~52% compared with biosponge treatment alone at 6 weeks postinjury. Application of EST increased MyoD gene expression and the percentage of large (>2000 µm2) type 2B myofibers but reduced fibrotic tissue deposition in VML-injured muscles. Together, these changes may provide the basis for improved torque production. This study demonstrates the potential for combined regenerative and rehabilitative therapy to improve muscle recovery following VML.


Asunto(s)
Músculo Esquelético , Ratas Endogámicas Lew , Animales , Masculino , Ratas , Músculo Esquelético/lesiones , Músculo Esquelético/metabolismo , Regeneración , Modelos Animales de Enfermedad , Terapia por Estimulación Eléctrica , Contracción Muscular , Enfermedades Musculares/patología , Enfermedades Musculares/rehabilitación
19.
Mil Med ; 2024 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-38739491

RESUMEN

INTRODUCTION: The U.S. Military Veterans aged 65 and older comprise an estimated 43% of the 22 million living Veterans in the United States. Veterans have high rates of physical, psychiatric, and social challenges, but it is not known whether Veteran status confers additional risk for cognitive or functional impairments in later life. Thus, this investigation specifically compared older Veterans with their non-Veteran peers in cognitive functioning and performance-based functional capacity. MATERIALS AND METHODS: Participants (N = 110; 29 Veterans and 81 non-Veterans) were part of a larger longitudinal study on biopsychosocial functioning in independently living older adult residents of a Continuing Care Senior Housing Community. The University of California San Diego Institutional Review Board approved the study and all participants provided written informed consent. Participants provided demographic and mental health information and were administered a comprehensive neuropsychological battery. Functional capacity was assessed using the UCSD Performance-Based Skills Assessment-Brief (UPSA-B), which uses financial and communication role-plays to assess everyday functioning skills. Neuropsychological scores were appropriately normed prior to analysis. Multivariate Analyses of Variances with post hoc t-tests and an Analysis of Covariance were used to examine neuropsychological and functional capacity differences, respectively, between Veterans and non-Veterans. RESULTS: Veterans did not differ from non-Veterans in educational attainment (16.4 years versus 15.5 years, P = 0.110), but they were significantly older (mean age 86.9 years ± 5.7, versus 81.74 years ± 6.53; P < 0.001) and were more likely to be male (X2 [1, N = 110] = 62.39, P < 0.001). Thus, though neuropsychological norms already accounted for demographic differences in our participants, age and sex were controlled in the Analysis of Covariance predicting UPSA-B score from Veteran status. Results suggested that, compared to non-Veterans, Veterans had significantly worse performance in the list learning portion of a test of verbal memory (Hopkins Verbal Learning Test-Revised, Total Recall; t = 2.56, P = 0.012, d = 0.56). Veterans and non-Veterans did not significantly differ in performance on the delayed recall portion of the verbal learning test and did not differ on a cognitive screening test (Montreal Cognitive Assessment) or on measures of premorbid intellectual functioning (Wide Range Achievement Test-4 Reading), language (Boston Naming Test, Verbal Fluency), visual memory (Brief Visuospatial Memory Test-Revised), attention/working memory (WAIS-IV Digit Span), processing speed (WAIS-IV Digit Symbol Coding), executive function (Delis-Kaplan Executive Function System Trails and Color-Word Test), or functional capacity (UPSA-B). Because our examination of multiple outcomes might have inflated Type I error, we performed a post hoc adjustment of P values using Benjamini-Hochberg procedures and the group difference in verbal learning remained significant. CONCLUSIONS: Despite largely similar function in most domains, Veterans performed significantly more poorly in verbal list learning than their non-Veteran peers. Additional attention should be given to the understanding, assessment, and possible treatment of learning and memory differences in older Veterans, as this may be an area in which Veteran status confers additional risk or vulnerability to decline. This is the first study to compare objective neuropsychological and functional performance between older (age 65+) US Veterans and non-Veterans.

20.
Nat Ecol Evol ; 8(6): 1118-1128, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38769434

RESUMEN

Many shark populations are in decline around the world, with severe ecological and economic consequences. Fisheries management and marine protected areas (MPAs) have both been heralded as solutions. However, the effectiveness of MPAs alone is questionable, particularly for globally threatened sharks and rays ('elasmobranchs'), with little known about how fisheries management and MPAs interact to conserve these species. Here we use a dedicated global survey of coral reef elasmobranchs to assess 66 fully protected areas embedded within a range of fisheries management regimes across 36 countries. We show that conservation benefits were primarily for reef-associated sharks, which were twice as abundant in fully protected areas compared with areas open to fishing. Conservation benefits were greatest in large protected areas that incorporate distinct reefs. However, the same benefits were not evident for rays or wide-ranging sharks that are both economically and ecologically important while also threatened with extinction. We show that conservation benefits from fully protected areas are close to doubled when embedded within areas of effective fisheries management, highlighting the importance of a mixed management approach of both effective fisheries management and well-designed fully protected areas to conserve tropical elasmobranch assemblages globally.


Asunto(s)
Conservación de los Recursos Naturales , Arrecifes de Coral , Explotaciones Pesqueras , Tiburones , Rajidae , Animales , Conservación de los Recursos Naturales/métodos
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