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El estudio de la percepción del entorno ha sido un tema central en la literatura de la teoría de la organización, debido a la importancia que tiene para definir sus procesos, formas de gestión y estructuras organizativas que adoptan. Este trabajo tiene como objetivo diseñar y proponer una escala de medición para valorar la percepción gerencial y directiva del entorno en medianas empresas. Se consideraron un conjunto de contribuciones teóricas, empíricas y metodológicas que permitieron identificar el dominio del constructo objeto de estudio y sus indicadores. Presentando los resultados de una de las variables estudiadas en las medianas empresas del estado Lara, Venezuela, con metodología de naturaleza cuantitativa. Se examinaron las propiedades psicométricas de la escala de medición, apoyado con diferentes pruebas estadísticas. Los resultados demuestran que las propiedades psicométricas de la escala son adecuadas según los parámetros de la literatura, por lo que es una referencia útil para futuras investigaciones. Como conclusión, se plantea la necesidad de que los investigadores empleen métodos estadísticos multivariantes, que permitan evaluar la pertinencia y eficacia de los instrumentos de levantamiento de datos, a fin de garantizar tanto la rigurosidad metodológica, como la calidad de los análisis e interpretación de resultados.

Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue malignant tumor. It is more likely to occur in children under 5 years of age and it is most often found in the head and neck. The presentation in the penis is extremely rare. The embryonic variety is the most common histologic subtype. The RMS of the penis is usually a painless mass. In some cases dysuria and priapism can also be present. Treatment is based on surgical resection, che- motherapy and radiation therapy. We describe a 3 year old boy with a 6 month history of a painless enlargement of the penis due to the presence of a mass. On its dorsal aspect measuring 3 x 3 cm with necrotic and ulcerated areas; it did not affect the urethral meatus. On the CT scan a tumor on the left lateral side of the penile shaft was found, with a diameter of 2.8 x 2.5 x 3.3 cm and a 12 cc volume. Surgical resection of the mass was performed. The histopathologic study reported an embryonal type RMS. The patient was treated with chemotherapeutic agents including ifosfamide and doxorubicin, with a favorable outcome.

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María Jesús Hernández Arroyo,1 Salvador Enrique Cabrera Figueroa,2 Rosa Sepúlveda Correa,3 María de la Paz Valverde Merino,1 Alicia Iglesias Gómez,4 Alfonso Domínguez-Gil Hurlé5 On behalf of the Tormes Team 1Pharmacy Service, University Hospital of Salamanca, Salamanca, Spain; 2Pharmacy Institute, University Austral of Chile, Valdivia, Chile; 3Department of Statistics, University of Salamanca, Salamanca, Spain; 4Infectious Disease Service, University Hospital of Salamanca, Salamanca, Spain; 5Department of Pharmacy and Pharmaceutical Technology, University of Salamanca, Salamanca, Spain Background: Antiretroviral treatments (ART) form the basis of adequate clinical control in human immunodeficiency virus-infected patients, and adherence plays a primary role in the grade and duration of the antiviral response. The objectives of this study are: (1) to determine the impact of the implementation of a pharmaceutical care program on improvement of ART adherence and on the immunovirological response of the patients; and (2) to detect possible correlations between different adherence evaluation measurements. Methods: A 60-month long retrospective study was conducted. Adherence measures used were: therapeutic drug monitoring, a simplified medication adherence questionnaire, and antiretroviral dispensation records (DR). The number of interviews and interventions related to adherence made for each patient in yearly periods was related to the changes in the adherence variable (measured with DR) in these same yearly periods. The dates when the laboratory tests were drawn were grouped according to proximity with the study assessment periods (February–May, 2005–2010). Results: A total of 528 patients were included in the study. A significant relationship was observed between the simplified medication adherence questionnaire and DR over the 60-month study period (P < 0.01). Improvement was observed in the mean adherence level (P < 0.001), and there was a considerable decrease in the percentage of patients with CD4+ lymphocytes less than 200 cells/mm3 (P < 0.001). A relationship was found between the number of patients with optimum adherence levels and the time that plasma viral load remained undetected. The number of interviews and interventions performed in each patient in the first 12 months from the onset of the pharmaceutical care program (month 6), was related to a significant increase in adherence during this same time period. Conclusion: The results suggest that the establishment and permanence of a pharmaceutical care program may increase ART adherence, increase permanence time of the patient with undetectable plasma viral loads, and improve patients' lymphocyte count. Keywords: pharmaceutical care, antiretroviral treatment adherence, undetectable PVLs, CD4+ lymphocyte count, adherence measures, HIV/AIDS

Abstract: Pathogenesis of diabetic foot infections include polineuropathy, macro and microvascular disease and neutrophil functional deficit. Endothelium dependent vasodilatation related to Nitric Oxide (NO) production is compromised in diabetics predisposed to foot ulceration. NO is also produced when neutrophils and macrophages are stimulated by cytokines or bacterial lipopolysaccarides through the inducible nitric oxide synthase (iNOS), exerting microbicide activity. Lipid peroxidation reflected by Malondialdehyde (MDA) production, is associated with diabetic microangiopathy development. To compare serum NO and MDA levels in patients with infected and non-infected diabetic foot, 27 type 2 diabetics, 38 to 65 years old were studied, and divided into three groups: 8 control subjects without foot affection (A), 10 with non-infected diabetic foot (B) and 9 with infected diabetic foot (C). NO was determined by diazotization assay and MDA by thiobarbituric acid assay. B and C showed lower NO levels (p = 7.636 x 10-5 and p = 0,006) compared with A group. NO was higher in the infected group than in the non-infected (p = 0,05), nevertheless, the obtained values do not coincide with the expected values considering the big amount of NO produced through iNOS, it suggests another defect of diabetic’s leukocyte. There were no significant differences in MDA between the groups, indicating absence of relevant oxidative stress. Resumen: La patogenia de las infecciones del pie diabético involucra la polineuropatía, la enfermedad macro y microvascular y el déficit funcional de los neutrófilos. La vasodilatación dependiente del endotelio, relacionada con el Óxido Nítrico (NO), está comprometida en diabéticos predispuestos a ulceración del pie. El NO, es producido también por neutrófilos y macrófagos estimulados por citoquinas o lipopolisacáridos bacterianos mediante la sintetasa de NO inducible (iNOS), ejerciendo actividad microbicida. La peroxidación lipídica reflejada por la producción de Malondialdehido (MDA), está implicada en el desarrollo de microangiopatía diabética. Para comparar los niveles séricos de NO y MDA en pacientes con pie diabético con y sin infección, se estudiaron 27 individuos diabéticos tipo 2 con edades entre 38 y 65 años divididos en 3 grupos: 8 controles sin afección de los pies (A), 10 con pie diabético sin infección (B) y 9 con pie diabético infectado (C). El NO fué determinado mediante ensayo de diazotización y el MDA mediante la reacción de Ácido Thiobarbitúrico. ByC mostraron niveles de NO menores (p = 7.636 x 10-5 y p = 0,006) que A. El NO fue mayor en el grupo infectado que en el grupo sin infección (p = 0,05), sin embargo los valores obtenidos no coinciden con lo esperado teniendo en cuenta las grandes cantidades de NO producido mediante la iNOS, sugiriendo un defecto más del leucocito del diabético. No hubo diferencia significativa en el MDA entre los grupos, indicando ausencia de stress oxidativo relevante.

La alabanza de la monarquía resalta de modo significativo en la trayectoria literaria de Sor Juana desde su primer poema publicado preconventualmente hasta un texto mencionado (aún no encontrado) en la Fama póstuma. El doble montaje de sus siete loas a los monarcas –escenificación virreinal y publicación en España– está estrechamente vinculado a la ubicación de los virreyes dentro de la política de la corte madrileña.

We report a case of cutaneous infection caused by Phialemonium curvatum GAMS et COOKE, 1983, after bone marrow transplantation. The genus Phialemonium was created by GAMS & MCGINNIS in 1983 including three new species: Ph. obovatum, Ph. curvatum and Ph. dimorphosporum, and represents an intermediate genus between Acremonium and Phialophora. Nowadays, the genus Phialemonium is considered to be a pheoid fungus which may cause the eventual lesions observed in pheo- and hyalohyphomycosis. Species of this genus have been described as opportunistic agents in humans and animals, mainly as a result of immunosuppression. In the present case, the patient had multiple myeloma and received an allogenic bone marrow transplant from his HLA-compatible brother. Two months after transplantation, he developed purplish and painful nodular lesions on the right ankle. Some of these lesions drained spontaneously and apparently hyaline mycelial filaments were observed, whose culture was initially identified as Acremonium sp. Subsequent studies showed that the fungus was Phialemonium curvatum. The infection was treated with amphotericin B, followed by ketoconazole. The patient was submitted to surgical debridement followed by two skin grafts to repair the bloody area. The duration of the treatment was 4 months and secondary prophylaxis with ketoconazole alone was maintained for one additional month. No recurrence was observed after discontinuation of treatment. The authors comment on the pathogenicity of the genus Phialemonium.

La agitación psicomotriz en un paciente adulto hospitalizado es una de las situaciones más estresantes con las que se puede encontrar el personal de enfermería en su trabajo diario. El conocer su manejo, las intervenciones a realizar y el proporcionar en todo momento la seguridad del paciente y la de los profesionales que estén implicados constituye la primera pauta de actuación. Debemos recordar que la agitación psicomotriz no es sólo característica de los enfermos mentales, hay causas orgánicas que pueden ocasionar estos estados de alteración. Por lo que el conocimiento de estas causas pueden prevenir o minimizar futuras complicaciones. Con este artículo se pretender guiar al personal de enfermería que trabajan en las plantas de hospitalización en el cuidado de estos pacientes y elaborar unas recomendaciones básicas y pautas de actuación para la creación de unos planes estandarizados para estos enfermos. Para ello se utilizará la taxonomía enfermera NANDA, NIC, NOC.

Abstract An immune response (IR) index to identify cows with high (H) and low (L) antibody-mediated immune responses (AMIR) had been previously devised. High AMIR associated with decreased mastitis and improved response to vaccination. Measurement of cell-mediated immune response (CMIR) was not included in the index; therefore various antigen/adjuvant combinations were evaluated as inducers of DTH to be added to the IR-index. The Bacillus Calmette Guérin (BCG)-induced/purified protein derivative (PPD)-elicited tuberculin skin test is a reliable measure of DTH; however, its use to identify livestock with high CMIR may be confounded due to previous exposure to Mycobacteria tuberculosis. DTH to BCG/PPD was therefore compared with that induced by Mycobacteria phlei (saprophyte) and its derivative phlein as the test antigen. Antibody to OVA was also evaluated. The results indicated that BCG/PPD and M. phlei/phlein induced similar DTH, but cross reaction to PPD was evident following induction of DTH using M. phlei making it a less than ideal alternative for testing livestock. Nonetheless, cows could be ranked for both AMIR and CMIR. RNA from two cows with the highest and lowest IR ranks was then used to probe a human 1.7 kD microarray to determine the ability of a human array to provide information on bovine genes associated with H and L.

Abstract Background Although most HTLV infections in Spain have been found in native intravenous drug users carrying HTLV-2, the large immigration flows from Latin America and Sub-Saharan Africa in recent years may have changed the prevalence and distribution of HTLV-1 and HTLV-2 infections, and hypothetically open the opportunity for introducing HTLV-3 or HTLV-4 in Spain. To assess the current seroprevalence of HTLV infection in Spain a national multicenter, cross-sectional, study was conducted in June 2009. Results A total of 6,460 consecutive outpatients attending 16 hospitals were examined. Overall, 12% were immigrants, and their main origin was Latin America (4.9%), Africa (3.6%) and other European countries (2.8%). Nine individuals were seroreactive for HTLV antibodies (overall prevalence, 0.14%). Evidence of HTLV-1 infection was confirmed by Western blot in 4 subjects (prevalence 0.06%) while HTLV-2 infection was found in 5 (prevalence 0.08%). Infection with HTLV types 1, 2, 3 and 4 was discarded by Western blot and specific PCR assays in another two specimens initially reactive in the enzyme immunoassay. All but one HTLV-1 cases were Latin-Americans while all persons with HTLV-2 infection were native Spaniards. Conclusions The overall prevalence of HTLV infections in Spain remains low, with no evidence of HTLV-3 or HTLV-4 infections so far.

Abstract Background As concern about youth obesity continues to mount, there is increasing consideration of widespread policy changes to support improved nutritional and enhanced physical activity offerings in schools. A critical element in the success of such programs may be to involve students as spokespeople for the program. Making such a public commitment to healthy lifestyle program targets (improved nutrition and enhanced physical activity) may potentiate healthy behavior changes among such students and provide a model for their peers. This paper examines whether student's "public commitment"--voluntary participation as a peer communicator or in student-generated media opportunities--in a school-based intervention to prevent diabetes and reduce obesity predicted improved study outcomes including reduced obesity and improved health behaviors. Methods Secondary analysis of data from a 3-year randomized controlled trial conducted in 42 middle schools examining the impact of a multi-component school-based program on body mass index (BMI) and student health behaviors. A total of 4603 students were assessed at the beginning of sixth grade and the end of eighth grade. Process evaluation data were collected throughout the course of the intervention. All analyses were adjusted for students' baseline values. For this paper, the students in the schools randomized to receive the intervention were further divided into two groups: those who participated in public commitment activities and those who did not. Students from comparable schools randomized to the assessment condition constituted the control group. Results We found a lower percentage of obesity (greater than or equal to the 95th percentile for BMI) at the end of the study among the group participating in public commitment activities compared to the control group (21.5% vs. 26.6%, p = 0.02). The difference in obesity rates at the end of the study was even greater among the subgroup of students who were overweight or obese at baseline; 44.6% for the "public commitment" group, versus 53.2% for the control group (p = 0.01). There was no difference in obesity rates between the group not participating in public commitment activities and the control group (26.4% vs. 26.6%). Conclusions Participating in public commitment activities during the HEALTHY study may have potentiated the changes promoted by the behavioral, nutrition, and physical activity intervention components. Trial Registration ClinicalTrials.gov number, NCT00458029

Abstract Background Theoretically, increased levels of physical activity self-efficacy (PASE) should lead to increased physical activity, but few studies have reported this effect among youth. This failure may be at least partially attributable to measurement limitations. In this study, Item Response Modeling (IRM) was used to develop new physical activity and sedentary behavior change self-efficacy scales. The validity of the new scales was compared with accelerometer assessments of physical activity and sedentary behavior. Methods New PASE and sedentary behavior change (TV viewing, computer video game use, and telephone use) self-efficacy items were developed. The scales were completed by 714, 6th grade students in seven US cities. A limited number of participants (83) also wore an accelerometer for five days and provided at least 3 full days of complete data. The new scales were analyzed using Classical Test Theory (CTT) and IRM; a reduced set of items was produced with IRM and correlated with accelerometer counts per minute and minutes of sedentary, light and moderate to vigorous activity per day after school. Results The PASE items discriminated between high and low levels of PASE. Full and reduced scales were weakly correlated (r = 0.18) with accelerometer counts per minute after school for boys, with comparable associations for girls. Weaker correlations were observed between PASE and minutes of moderate to vigorous activity (r = 0.09 – 0.11). The uni-dimensionality of the sedentary scales was established by both exploratory factor analysis and the fit of items to the underlying variable and reliability was assessed across the length of the underlying variable with some limitations. The reduced sedentary behavior scales had poor reliability. The full scales were moderately correlated with light intensity physical activity after school (r = 0.17 to 0.33) and sedentary behavior (r = -0.29 to -0.12) among the boys, but not for girls. Conclusion New physical activity and sedentary behavior change self-efficacy scales have fewer items than classical test theory derived alternatives and have reasonable validity for boys, but more work is needed to develop comparable scales for girls. Fitting the items to a underlying variable could be useful in tailoring interventions to this scale.

This article describes a study to identify perspectives of Latin American nursing professors and leaders about the research competencies needed by students with different levels of academic preparation (bachelor's, master's, and doctoral). The sample included 42 nurses from eight Latin American countries who wrote narrative comments on a questionnaire sent by e-mail. The responses were analyzed by a process of content analysis. The participants identified differences that should be emphasized in the different academic levels. The findings could be used to develop educational programs to prepare nurse researchers. [ABSTRACT FROM AUTHOR]

Introduction: Veterans are at risk for mental and physical health problems but may not seek traditional health care services. Wellness-based interventions, including exercise and nutrition, have been associated with improvements in physical and mental health among this population. This study explores the acceptability, feasibility, and efficacy of a 3-month health and fitness program for veterans., Materials and Methods: Participants in 2 time-based cohorts from 2019 to 2023 (cohort 1: n = 261; cohort 2: n = 256) were cleared by a physician to participate. Participants then completed a fitness test and self-reported surveys (e.g., quality of life, sleep, and pain) before and after the 3-month program. Participants were recruited to participate at one of three sites: Boston, MA Fort Myers, FL, or Tampa, FL. The 3-month program consisted of weekly, supervised group fitness and one-on-one sessions, nutritional consultations, yoga, and other wellness activities. Primary program outcomes were measured by fitness assessments, self-report surveys, program completion, and program satisfaction. Fitness assessments included measures of weight, body mass index, grip strength, waist to hip ratio, body fat, lean mass, fat mass, heart rate, and blood pressure (BP). Self-report measures included quality of life, depression, loneliness, sleep quality, pain intensity, and pain interference., Results: In cohort 1, significant improvements were found for measures of weight (P = .01), left-handed grip strength (P < .01), body fat percent (P < .01), and quality of life (P < .01). In cohort 2, significant improvements were found for measures of waist:hip ratio (P = .02), right and left-handed grip strength (P < .01), body mass index (P = .02), body fat percent (P < .01), and quality of life (P = .02). For both cohorts, pain intensity (cohort 1: P = .01, cohort 2: P < .001) and pain interference (cohort 1: P = .02, cohort 2: P < .001) increased significantly., Conclusions: These data suggest that a 3-month health and fitness program for veterans is acceptable and feasible and may improve physical and mental health outcomes. Considerations for program retention and assessment completion are discussed., (© The Association of Military Surgeons of the United States 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Alzheimer's disease (AD) not only affects cognition and neuropathology, but several other facets capable of negatively impacting quality of life and potentially driving impairments, including altered gut microbiome (GMB) composition and metabolism. Aged (20 + mo) female TgF344-AD and wildtype rats were cognitively characterized on several tasks incorporating several cognitive domains, including task acquisition, object recognition memory, anxiety-like behaviors, and spatial navigation. Additionally, metabolic phenotyping, GMB sequencing throughout the intestinal tract (duodenum, jejunum, ileum, colon, and feces), neuropathological burden assessment and marker gene functional abundance predictions (PICRUSt2) were conducted. TgF344-AD rats demonstrated significant cognitive impairment in multiple domains, as well as regionally specific GMB dysbiosis. Relationships between peripheral factors were investigated using Canonical Correspondence Analysis (CCA), revealing correlations between GMB changes and both cognitive and metabolic factors. Moreover, communities of gut microbes contributing to essential metabolic pathways were significantly altered in TgF344-AD rats. These data indicate dysbiosis may affect cognitive outcomes in AD through alterations in metabolism-related enzymatic pathways that are necessary for proper brain function. Moreover, these changes were mostly observed in intestinal segments required for carbohydrate digestion, not fecal samples. These data support the targeting of intestinal and microbiome health for the treatment of AD., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Introduction: Age-related cognitive decline has been linked to distinct patterns of cellular dysfunction in the prelimbic cortex (PL) and the CA3 subregion of the hippocampus. Because higher cognitive functions require both structures, selectively targeting a neurobiological change in one region, at the expense of the other, is not likely to restore normal behavior in older animals. One change with age that both the PL and CA3 share, however, is a reduced ability to utilize glucose, which can produce aberrant neural activity patterns., Methods: The current study used a ketogenic diet (KD) intervention, which reduces the brain's reliance on glucose, and has been shown to improve cognition, as a metabolic treatment for restoring neural ensemble dynamics in aged rats. Expression of the immediate-early genes Arc and Homer 1a were used to quantify the neural ensembles that were active in the home cage prior to behavior, during a working memory/biconditional association task, and a continuous spatial alternation task., Results: Aged rats on the control diet had increased activity in CA3 and less ensemble overlap in PL between different task conditions than did the young animals. In the PL, the KD was associated with increased activation of neurons in the superficial cortical layers, establishing a clear link between dietary macronutrient content and frontal cortical activity. The KD did not lead to any significant changes in CA3 activity., Discussion: These observations suggest that the availability of ketone bodies may permit the engagement of compensatory mechanisms in the frontal cortices that produce better cognitive outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Hernandez, Barrett, Lubke, Maurer and Burke.)

Oral transmucosal administration, where drugs are absorbed directly through the non-keratinized, lining mucosa of the mouth, represents a solution to drug delivery with several advantages. Oral mucosal equivalents (OME) developed as 3D in vitro models are of great interest since they express the correct cell differentiation and tissue architecture, simulating the in vivo conditions better than monolayer cultures or animal tissues. The aim of this work was to develop OME to be used as a membrane for drug permeation studies. We developed both full-thickness (i.e., connective plus epithelial tissue) and split-thickness (i.e., only epithelial tissue) OME using non-tumor-derived human keratinocytes OKF6 TERT-2 obtained from the floor of the mouth. All the OME developed here presented similar transepithelial electrical resistance (TEER) values, comparable to the commercial EpiOral™. Using eletriptan hydrobromide as a model drug, we found that the full-thickness OME had similar drug flux to EpiOral™ (28.8 vs. 29.6 µg/cm 2 /h), suggesting that the model had the same permeation barrier properties. Furthermore, full-thickness OME showed an increase in ceramide content together with a decrease in phospholipids in comparison to the monolayer culture, indicating that lipid differentiation occurred due to the tissue-engineering protocols. The split-thickness mucosal model resulted in 4-5 cell layers with basal cells still undergoing mitosis. The optimum period at the air-liquid interface for this model was twenty-one days; after longer times, signs of apoptosis appeared. Following the 3R principles, we found that the addition of Ca 2+ , retinoic acid, linoleic acid, epidermal growth factor and bovine pituitary extract was important but not sufficient to fully replace the fetal bovine serum. Finally, the OME models presented here offer a longer shelf-life than the pre-existing models, which paves the way for the further investigation of broader pharmaceutical applications (i.e., long-term drug exposure, effect on the keratinocytes' differentiation and inflammatory conditions, etc.).

Angiotensin (1-7) [Ang (1-7)] is an active heptapeptide of the noncanonical arm of the renin-angiotensin system that modulates molecular signaling pathways associated with vascular and cellular inflammation, vasoconstriction, and fibrosis. Preclinical evidence suggests that Ang (1-7) is a promising therapeutic target that may ameliorate physical and cognitive function in late life. However, treatment pharmacodynamics limits its clinical applicability. Therefore, this study explored the underlying mechanisms altered by a genetically modified probiotic (GMP) that expresses Ang (1-7) combined with and without exercise training in an aging male rat model as a potential adjunct strategy to exercise training to counteract the decline of physical and cognitive function. We evaluated cross-tissue (prefrontal cortex, hippocampus, colon, liver, and skeletal muscle) multi-omics responses. After 12 wk of intervention, the 16S mRNA microbiome analysis revealed a main effect of probiotic treatment within- and between groups. The probiotic treatment enhanced α diversity (Inverse Simpson ( F [2,56] = 4.44; P = 0.02); Shannon-Wiener ( F [2,56] = 4.27; P = 0.02)) and β-diversity ( F [2,56] = 2.66; P = 0.01) among rats receiving our GMP. The analysis of microbes' composition revealed three genera altered by our GMP ( Enterorhabdus , Muribaculaceae unclassified , and Faecalitalea ). The mRNA multi-tissue data analysis showed that our combined intervention upregulated neuroremodeling pathways on prefrontal cortex (i.e., 140 genes), inflammation gene expression in the liver (i.e., 63 genes), and circadian rhythm signaling on skeletal muscle. Finally, the integrative network analysis detected different communities of tightly (| r | > 0.8 and P < 0.05) correlated metabolites, genera , and genes in these tissues. NEW & NOTEWORTHY This manuscript uses a multiomics approach (i.e., microbiome, metabolomics, and transcriptomics) to explore the underlying mechanisms driven by a genetically modified probiotic (GMP) designed to express angiotensin (1-7) combined with moderate exercise training in an aged male rat model. After 12 wk of intervention, our findings suggest that our GMP enhanced gut microbial diversity while exercise training altered the transcriptional response in relevant neuroremodeling genes, inflammation, and circadian rhythm signaling pathways in an aging animal model.

Approximately 60-70 million people suffer from traumatic brain injury (TBI) each year. Animal models continue to be paramount in understanding mechanisms of cellular dysfunction and testing new treatments for TBI. Enhancing the translational potential of novel interventions therefore necessitates testing pre-clinical intervention strategies with clinically relevant cognitive assays. This study used a unilateral parietal lobe controlled cortical impact (CCI) model of TBI and tested rats on a touchscreen-based Paired Associates Learning (PAL) task, which is part of the Cambridge Neuropsychological Test Automated Battery. In humans, the PAL task has been used to assess cognitive deficits in the ability to form stimulus-location associations in a multitude of disease states, including TBI. Although the use of PAL in animal models could be important for understanding the clinical severity of cognitive impairment post-injury and throughout intervention, to date, the extent to which a rat model of TBI produces deficits in PAL task performance has not yet been reported. This study details the behavioral consequences of the CCI injury model with a Trial-by-Trial analysis of PAL performance that enables behavioral strategy use to be inferred. Following behavior, the extent of the injury was quantified with histology and staining for the presence of glial fibrillary acid protein and ionized calcium-binding adapter molecule 1. Rats that received unilateral CCI were impaired on the PAL task and showed more aberrant response-driven behavior. The magnitude of PAL impairment was also correlated with Iba1 staining in the thalamus. These observations suggest that PAL could be useful for pre-clinical assessments of novel interventions for treating TBI., Competing Interests: Conflict of interest Authors report no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Declining health, gut dysbiosis, and cognitive impairments are hallmarks of advanced age. While caloric restriction is known to robustly extend the healthspan and alter gut microbiome composition, it is difficult maintain. Time-restricted feeding or changes in dietary macronutrient composition could be feasible alternatives for enhancing late life cognitive and physical health that are easier to comply with for extended periods of time. To investigate this possibility, 8-month-old rats were placed on time-restricted feeding with a ketogenic or micronutrient- and calorically matched control diet for 13 months. A third group of rats was permitted to eat standard chow ad libitum during this time. At 22 months, all rats were tested on a biconditional association task and fecal samples were collected for microbiome composition analysis. Regardless of dietary composition, time-restricted-fed rats had better cognitive performance than ad libitum-fed rats. This observation could not be accounted for by differences in motivation, procedural or sensorimotor impairments. Additionally, there were significant differences in gut microbiome diversity and composition between all diet conditions. Allobaculum abundance was associated with cognitive task performance, indicating a link between gut health and cognitive outcomes in aged subjects. Overall, time restricted feeding had the largest influence on cognitive performance in aged rats., Competing Interests: The authors declare no conflict of interest.

Fear-based disorders such as post-traumatic stress disorder (PTSD) steepen age-related cognitive decline and double the risk for developing Alzheimer's disease (AD). Because of the seemingly hyperactive properties of fear memories, PTSD symptoms can worsen with age. Perturbations in the synaptic circuitry supporting fear memory extinction are key neural substrates of PTSD. The basolateral amygdala (BLA) is a medial temporal lobe structure that is critical in the encoding, consolidation, and retrieval of fear memories. As little is known about fear extinction memory and BLA synaptic dysfunction within the context of aging and AD, the goal of this study was to investigate how fear extinction memory deficits and basal amygdaloid nucleus (BA) synaptic dysfunction differentially associate in nonpathologic aging and AD in the TgF344AD (TgAD) rat model of AD. Young, middle-aged, and older-aged WT and TgAD rats were trained on a delay fear conditioning and extinction procedure before ex vivo extracellular field potential recording experiments in the BA. Relative to young WT rats, long-term extinction memory was impaired, and in general, was associated with a hyperexcitable BA and impaired LTP in TgAD rats at all ages. In contrast, long-term extinction memory was impaired in aged WT rats and was associated with impaired LTP but not BA hyperexcitability. Interestingly, the middle-aged TgAD rats showed intact short-term extinction and BA LTP, which is suggestive of a compensatory mechanism, whereas differential neural recruitment in older-aged WT rats may have facilitated short-term extinction. As such, associations between fear extinction memory and amygdala deficits in nonpathologic aging and AD are dissociable., (Copyright © 2022 Hernandez et al.)

Both ketogenic diets (KD) and time-restricted feeding (TRF) regimens have the ability to influence several parameters of physical health, including gut microbiome composition and circulating cytokine concentration. Moreover, both of these dietary interventions prevent common impairments associated with the aging process. However, significantly altering macronutrient intake, which is required for a KD, may be unappealing to individuals and decrease compliance to dietary treatments. In contrast to a KD, TRF allows individuals to continue eating the foods they are used to, and only requires a change in the time of day at which they eat. Therefore, we investigated both a KD and a diet with a more Western-like macronutrient profile in the context of TRF, and compared both diets to animals allowed access to standard chow ad libitum in young adult and aged rats. While limited effects on cytokine levels were observed, both methods of microbiome analysis (16S sequencing and metagenomics) indicate that TRF and KDs significantly altered the gut microbiome in aged rats. These changes were largely dependent on changes to feeding paradigm (TRF vs. ad libitum) alone regardless of macronutrient content for many gut microbiota, but there were also macronutrient-specific changes. Specifically, functional analysis indicates significant differences in several pathways, including those involved in the tricarboxylic acid (TCA) cycle, carbohydrate metabolism and neurodegenerative disease. These data indicate that age- and disease-related gut dysbiosis may be ameliorated through the use of TRF with both standard diets and KDs.

Background: The majority of research to understand the risk factors of nonsyndromic orofacial clefts (NSOFCs) has been conducted in high-income populations. Although patients with NSOFCs in low- and middle-income countries (LMICs) are at the highest risk of not receiving care, global health infrastructure allows innovative partnerships to explore the etiologic mechanisms of cleft and targets for prevention unique to these populations., Methods: The International Family Study (IFS) is an ongoing case-control study with supplemental parental trio data designed to examine genetic, environmental, lifestyle, and sociodemographic risk factors for NSOFCs in 8 LMICs (through August 2020). Interview and biological samples are collected for each family. The interview includes demographics, family history of cleft, diet and water sources, maternal pregnancy history, and other lifestyle and environmental factors., Results: Seven of 8 countries are currently summarized (2012-2017) for a total of 2955 case and 2774 control families with 11 946 unique biological samples from Vietnam, Philippines, Honduras, Madagascar, Morocco, Democratic Republic of the Congo, and Nicaragua. The phenotype distribution was 1641 (55.5%) cases with cleft lip and palate, 782 (26.5%) with cleft lip (CL), and 432 (14.6%) with cleft palate (CP)., Discussion: The International Family Study is the largest case set of NSOFCs with an associated biobank in LMICs currently assembled. The biobank, family, and case-control study now include samples from 8 LMICs where local health care infrastructure cannot address the surgical burden of cleft or investigate causal mechanisms. The International Family Study can be a source of information and may collaborate with local public health institutions regarding education and interventions to potentially prevent NSOFCs.

While neurodegenerative diseases can strike at any age, the majority of afflicted individuals are diagnosed at older ages. Due to the important impact of age in disease diagnosis, the field of neuroscience could greatly benefit from the many of the theories and ideas from the biology of aging-now commonly referred as geroscience. As discussed in our complementary perspective on the topic, there is often a "silo-ing" between geroscientists who work on understanding the mechanisms underlying aging and neuroscientists who are studying neurodegenerative diseases. While there have been some strong collaborations between the biology of aging and neuroscientists, there is still great potential for enhanced collaborative effort between the 2 fields. To this end, here, we review the state of the geroscience field, discuss how neuroscience could benefit from thinking from a geroscience perspective, and close with a brief discussion on some of the "missing links" between geroscience and neuroscience and how to remedy them. Notably, we have a corresponding, concurrent review from the neuroscience perspective. Our overall goal is to "bridge the gap" between geroscience and neuroscience such that more efficient, reproducible research with translational potential can be conducted., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Neuroscience has a rich history of studies focusing on neurobiology of aging. However, much of the aging studies in neuroscience occur outside of the gerosciences. The goal of this primer is 2-fold: first, to briefly highlight some of the history of aging neurobiology and second, to introduce to geroscientists the broad spectrum of methodological approaches neuroscientists use to study the neurobiology of aging. This primer is accompanied by a corresponding geroscience primer, as well as a perspective on the current challenges and triumphs of the current divide across these 2 fields. This series of manuscripts is intended to foster enhanced collaborations between neuroscientists and geroscientists with the intent of strengthening the field of cognitive aging through inclusion of parameters from both areas of expertise., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Blocking the major cat allergen, Fel d 1, with mAbs was effective in preventing an acute cat allergic response., Objectives: This study sought to extend the allergen-specific antibody approach and demonstrate that a combination of mAbs targeting Bet v 1, the immunodominant and most abundant allergenic protein in birch pollen, can prevent the birch allergic response., Methods: Bet v 1-specific mAbs, REGN5713, REGN5714, and REGN5715, were isolated using the VelocImmune platform. Surface plasmon resonance, x-ray crystallography, and cryo-electron microscopy determined binding kinetics and structural data. Inhibition of IgE-binding, basophil activation, and mast cell degranulation were assessed via blocking ELISA, flow cytometry, and the passive cutaneous anaphylaxis mouse model., Results: REGN5713, REGN5714, and REGN5715 bind with high affinity and noncompetitively to Bet v 1. A cocktail of all 3 antibodies, REGN5713/14/15, blocks IgE binding to Bet v 1 and inhibits Bet v 1- and birch pollen extract-induced basophil activation ex vivo and mast cell degranulation in vivo. Crystal structures of the complex of Bet v 1 with immunoglobulin antigen-binding fragments of REGN5713 or REGN5715 show distinct interaction sites on Bet v 1. Cryo-electron microscopy reveals a planar and roughly symmetrical complex formed by REGN5713/14/15 bound to Bet v 1., Conclusions: These data confirm the immunodominance of Bet v 1 in birch allergy and demonstrate blockade of the birch allergic response with REGN5713/14/15. Structural analyses show simultaneous binding of REGN5713, REGN5714, and REGN5715 with substantial areas of Bet v 1 exposed, suggesting that targeting specific epitopes is sufficient to block the allergic response., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Monoclonal antibodies against SARS-CoV-2 are a clinically validated therapeutic option against COVID-19. Because rapidly emerging virus mutants are becoming the next major concern in the fight against the global pandemic, it is imperative that these therapeutic treatments provide coverage against circulating variants and do not contribute to development of treatment-induced emergent resistance. To this end, we investigated the sequence diversity of the spike protein and monitored emergence of virus variants in SARS-COV-2 isolates found in COVID-19 patients treated with the two-antibody combination REGEN-COV, as well as in preclinical in vitro studies using single, dual, or triple antibody combinations, and in hamster in vivo studies using REGEN-COV or single monoclonal antibody treatments. Our study demonstrates that the combination of non-competing antibodies in REGEN-COV provides protection against all current SARS-CoV-2 variants of concern/interest and also protects against emergence of new variants and their potential seeding into the population in a clinical setting., Competing Interests: Declaration of interests Regeneron authors own options and/or stock of the company. This work has been described in one or more pending provisional patent applications. G.S.A., G.H., D.M.W., L.L., N.S., A.J.M., G.D.Y., and C.A.K. are officers of Regeneron., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Increasing life expectancies are unfortunately accompanied by increased prevalence of Alzheimer's disease (AD). Regrettably, there are no current therapeutic options capable of preventing or treating AD. We review here data indicating that AD is accompanied by gut dysbiosis and impaired renin angiotensin system (RAS) function. Therefore, we propose the potential utility of an intervention targeting both the gut microbiome and RAS as both are heavily involved in proper CNS function. One potential approach which our group is currently exploring is the use of genetically-modified probiotics (GMPs) to deliver therapeutic compounds. In this review, we specifically highlight the potential utility of utilizing a GMP to deliver Angiotensin (1-7), a beneficial component of the renin-angiotensin system with relevant functions in circulation as well as locally in the gut and brain., Competing Interests: Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Prefrontal cortical and medial temporal lobe connectivity is critical for higher cognitive functions that decline in older adults. Likewise, these cortical areas are among the first to show anatomical, functional, and biochemical alterations in advanced age. The prelimbic subregion of the prefrontal cortex and the perirhinal cortex of the medial temporal lobe are densely reciprocally connected and well-characterized as undergoing age-related neurobiological changes that correlate with behavioral impairment. Despite this fact, it remains to be determined how changes within these brain regions manifest as alterations in their functional connectivity. In our previous work, we observed an increased probability of age-related dysfunction for perirhinal cortical neurons that projected to the prefrontal cortex in old rats compared to neurons that were not identified as projection neurons. The current study was designed to investigate the extent to which aged prelimbic cortical neurons also had altered patterns of Arc expression during behavior, and if this was more evident in those cells that had long-range projections to the perirhinal cortex. The expression patterns of the immediate-early gene Arc were quantified in behaviorally characterized rats that also received the retrograde tracer cholera toxin B (CTB) in the perirhinal cortex to identify projection neurons to this region. As in our previous work, the current study found that CTB+ cells were more active than those that did not have the tracer. Moreover, there were age-related reductions in prelimbic cortical neuron Arc expression that correlated with a reduced ability of aged rats to multitask. Unlike the perirhinal cortex, however, the age-related reduction in Arc expression was equally likely in CTB+ and CTB- negative cells. Thus, the selective vulnerability of neurons with long-range projections to dysfunction in old age may be a unique feature of the perirhinal cortex. Together, these observations identify a mechanism involving prelimbic-perirhinal cortical circuit disruption in cognitive aging., (Copyright © 2020 Hernandez, Truckenbrod, Barrett, Lubke, Clark and Burke.)

Introduction : Dual-task walking is common in daily life but becomes more difficult with aging. Little is known about the neurobiological mechanisms affecting competing cognitive demands. Translational studies with human and animal models are needed to address this gap. This pilot study investigated the feasibility of implementing a novel cross-species dual-task model in humans and rats and aimed to establish preliminary evidence that the model induces a dual-task cost. Methods : Young and older humans and rats performed an object discrimination task (OD), a baseline task of typical walking (baseline), an alternation turning task on a Figure 8 walking course (Alt), and a dual-task combining object discrimination with the alternation task (AltOD). Primary behavioral assessments including walking speed and correct selections for object discrimination and turning direction. In humans, left prefrontal cortex activity was measured with functional near-infrared spectroscopy (fNIRS). Results : Human subjects generally performed well on all tasks, but the older adults exhibited a trend for a slowing of walking speed immediately before the turning decision for Alt and AltOD compared to baseline. Older adults also had heightened prefrontal activity relative to young adults for the Alt and AltOD tasks. Older rodents required more training than young rodents to learn the alternation task. When tested on AltOD with and without a 15-s delay between trials, older rodents exhibited a substantial performance deficit for the delayed version on the initial day of testing. Old rats, however, did not show a significant slowing in walking speed with increasing task demand, as was evident in the young rats. Discussion : This study demonstrates the feasibility and challenges associated with implementing a cross-species dual-task model. While there was preliminary evidence of dual-task cost in both humans and rats, the magnitude of effects was small and not consistent across species. This is likely due to the relative ease of each task in humans and the walking component in rats not being sufficiently challenging. Future versions of this test should make the cognitive tasks more challenging and the motor task in rats more complex., (Copyright © 2020 Hernandez, Winesett, Federico, Williams, Burke and Clark.)

Inclusion of female subjects in preclinical biomedical research is imperative for understanding mechanisms of age-related cognitive decline, as more than half of individuals older than 65 are female. In rodents, however, few behavioral and physical assessments have been conducted in both sexes within the same study. The current article documents data obtained from young and aged rats of both sexes that performed a battery of cognitive and physical assessments to examine for potential interactions between sex and age. Physical performance was measured with a rotarod test of motor coordination, assessment of maximum grip strength, and swim speed. While females outperformed males in rotarod and grip strength, there was also an age-dependent decline in physical performance in both sexes. Cognitive assessments included the Morris watermaze test of hippocampal dependent spatial memory and a biconditional association task with a working memory (WM) component, both of which were not significantly different across sex. Notably, a cognitive dual task that simultaneously tests working memory (WM) and biconditional association task (BAT) acquisition has previously been shown to be more sensitive to age-related cognitive decline than the watermaze in male rats, which is replicated here in both female and male rats. Furthermore, young and aged females (<27 months) spent a similar percent of time in each estrus cycle phase and phase did not influence WM/BAT performance. Future studies utilizing similar behavioral paradigms to examine the neurobiology of cognitive aging should be representative of the human population they intend to model through the inclusion of female subjects. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

As the number of individuals living beyond the age of 65 is rapidly increasing, so is the need to develop strategies to combat the age-related cognitive decline that may threaten independent living. Although the link between altered neuronal signaling and age-related cognitive impairments is not completely understood, it is evident that declining cognitive abilities are at least partially due to synaptic dysfunction. Aging is accompanied by well-documented changes in both excitatory and inhibitory synaptic signaling across species. Age-related synaptic alterations are not uniform across the brain, however, with different regions showing unique patterns of vulnerability in advanced age. In the hippocampus, increased activity within the CA3 subregion has been observed across species, and this can be reversed with anti-epileptic medication. In contrast to CA3, the dentate gyrus shows reduced activity with age and declining metabolic activity. Ketogenic diets have been shown to decrease seizure incidence and severity in epilepsy, improve metabolic function in diabetes type II, and improve cognitive function in aged rats. This link between neuronal activity and metabolism suggests that metabolic interventions may be able to ameliorate synaptic signaling deficits accompanying advanced age. We therefore investigated the ability of a dietary regimen capable of inducing nutritional ketosis and improving cognition to alter synapse-related gene expression across the dentate gyrus, CA3 and CA1 subregions of the hippocampus. Following 12 weeks of a ketogenic or calorie-matched standard diet, RTq-PCR was used to quantify expression levels of excitatory and inhibitory synaptic signaling genes within CA1, CA3 and dentate gyrus. While there were no age or diet-related changes in CA1 gene expression, expression levels were significantly altered within CA3 by age and within the dentate gyrus by diet for several genes involved in presynaptic glutamate regulation and postsynaptic excitation and plasticity. These data demonstrate subregion-specific alterations in synaptic signaling with age and the potential for a ketogenic diet to alter these processes in dissociable ways across different brain structures that are uniquely vulnerable in older animals., (Copyright © 2019 Hernandez, Hernandez, Truckenbrod, Campos, McQuail, Bizon and Burke.)

Age-related cognitive decline has been linked to a diverse set of neurobiological mechanisms, including bidirectional changes in proteins critical for neuron function. Importantly, these alterations are not uniform across the brain. For example, the hippocampus (HPC) and prefrontal cortex (PFC) show distinct patterns of dysfunction in advanced age. Because higher cognitive functions require large-scale interactions across prefrontal cortical and hippocampal networks, selectively targeting an alteration within one region may not broadly restore function to improve cognition. One mechanism for decline that the PFC and HPC share, however, is a reduced ability to utilize glucose for energy metabolism. Although this suggests that therapeutic strategies bypassing the need for neuronal glycolysis may be beneficial for treating cognitive aging, this approach has not been empirically tested. Thus, the current study used a ketogenic diet (KD) as a global metabolic strategy for improving brain function in young and aged rats. After 12 weeks, rats were trained to perform a spatial alternation task through an asymmetrical maze, in which one arm was closed and the other was open. Both young and aged KD-fed rats showed resilience against the anxiogenic open arm, training to alternation criterion performance faster than control animals. Following alternation testing, rats were trained to perform a cognitive dual task that required working memory while simultaneously performing a bi-conditional association task (WM/BAT), which requires PFC-HPC interactions. All KD-fed rats also demonstrated improved performance on WM/BAT. At the completion of behavioral testing, tissue punches were collected from the PFC for biochemical analysis. KD-fed rats had biochemical alterations within PFC that were dissociable from previous results in the HPC. Specifically, MCT1 and MCT4, which transport ketone bodies, were significantly increased in KD-fed rats compared to controls. GLUT1, which transports glucose across the blood brain barrier, was decreased in KD-fed rats. Contrary to previous observations within the HPC, the vesicular glutamate transporter (VGLUT1) did not change with age or diet within the PFC. The vesicular GABA transporter (VGAT), however, was increased within PFC similar to HPC. These data suggest that KDs could be optimal for enhancing large-scale network function that is critical for higher cognition.

The link between age-related cellular changes within brain regions and larger scale neuronal ensemble dynamics critical for cognition has not been fully elucidated. The present study measured neuron activity within medial prefrontal cortex (PFC), perirhinal cortex (PER), and hippocampal subregion CA1 of young and aged rats by labeling expression of the immediate-early gene Arc. The proportion of cells expressing Arc was quantified at baseline and after a behavior that requires these regions. In addition, PER and CA1 projection neurons to PFC were identified with retrograde labeling. Within CA1, no age-related differences in neuronal activity were observed in the entire neuron population or within CA1 pyramidal cells that project to PFC. Although behavior was comparable across age groups, behaviorally driven Arc expression was higher in the deep layers of both PER and PFC and lower in the superficial layers of these regions. Moreover, age-related changes in activity levels were most evident within PER cells that project to PFC. These data suggest that the PER-PFC circuit is particularly vulnerable in advanced age., (Copyright © 2018 Elsevier Inc. All rights reserved.)

This study aimed to analyze the links between the production of biopolitics for breastfeeding and social development discourses after the post-war period, with a view towards problematizing the nature/culture dichotomy by which breastfeeding is often operationalized. The study adopts an anthropological perspective to compare biopolitics for breastfeeding with the changes in developmentalist discourses. The analysis of global movements by these biopolitics helped explain how a network of distinct entities (e.g., government agencies, multilateral bodies, international development agencies, and nongovernmental organizations) have shaped breastfeeding over time in keeping with the prevailing developmentalist discourses and practices. Initially, the developmentalist discourse focused on industrialization and modernization, and breastfeeding was not the focus of public policies. In the 1970s and 1980s, when the developmentalist discourse shifted the focus to child malnutrition and infant mortality, the first global biopolitics for breastfeeding were launched, and breastfeeding practice began to be operationalized as a means to fight these health problems. Meanwhile, the contemporary social development discourse also evokes a process of individual development. Simultaneously, biopolitics for breastfeeding rely on various technologies for this purpose. The conclusion is that developmentalist discourses act as a sociocultural reference by which breastfeeding is operationalized, and thus that breastfeeding is not only a natural process, but also a political, economic, and social one.

Nutritional ketosis is induced by high fat/low carbohydrate dietary regimens, which produce high levels of circulating ketone bodies, shifting metabolism away from glucose utilization. While ketogenic diets (KD) were initially introduced to suppress seizures, they are garnering attention for their potential to treat a myriad of neurodegenerative and metabolic disorders that are associated with advanced age. The feasibility and physiological impact of implementing a long-term KD in old animals, however, has not been systematically examined. In this study, young and aged rats consumed a calorically- and nutritionally-matched KD or control diet for 12 weeks. All KD-fed rats maintained higher levels of BHB and lower levels of glucose relative to controls. However, it took the aged rats longer to reach asymptotic levels of BHB compared to young animals. Moreover, KD-fed rats had significantly less visceral white and brown adipose tissue than controls without a loss of lean mass. Interestingly, the KD led to significant alterations in protein levels of hippocampal transporters for monocarboxylates, glucose, and vesicular glutamate and gamma-aminobutyric acid. Most notably, the age-related decline in vesicular glutamate transporter expression was reversed by the KD. These data demonstrate the feasibility and potential benefits of KDs for treating age-associated neural dysfunction.

Obesity is associated with non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Obesity and metabolic abnormalities resulting in low-grade inflammation can increase the risk of developing NASH and HCC. NASH, a risk factor for HCC, is characterized by increased inflammation, lipid accumulation, and liver injury. Obesogenic proteins modulate signaling pathways that induce physiological changes including lipogenesis, ROS, and inflammation. Silibinin, a polyphenol in milk thistle seed, has been shown to have anti-inflammatory properties. Studies have yet to determine whether silibinin can be used to dissect the obesity-cancer link to delay progression of liver cancer. Using an in vitro model, sera from obese (OB), overweight (OW), or normal weight (NW) males (based on BMI) were used to determine the efficacy of silibinin to reduce the pro-tumorigenic properties of obesity. HepG2 cells were exposed to OB, OW, NW ± silibinin and tested for growth, ROS, lipogenesis, MMP-9, invasion and protein expression. Silibinin suppressed obesity-induced growth, ROS, lipogenesis, MMP-9, and cell invasion. These physiological changes corresponded with decreased FASN, IL-6, IL-1B, and phosphorylated Erk. We describe the differential effect of sera from OB, OW, and NW males on characteristics relevant for liver cancer and the potential use of silibinin to mitigate these effects.

Age-related memory deficits correlate with dysfunction in the CA3 subregion of the hippocampus, which includes both hyperactivity and overly rigid activity patterns. While changes in intrinsic membrane currents and interneuron alterations are involved in this process, it is not known whether alterations in afferent input to CA3 also contribute. Neurons in layer II of the lateral entorhinal cortex (LEC) project directly to CA3 through the perforant path, but no data are available regarding the effects of advanced age on LEC activity and whether these activity patterns update in response to environmental change. Furthermore, it is not known the extent to which age-related deficits in sensory discrimination relate to the inability of aged CA3 neurons to update in response to new environments. Young and aged rats were pre-characterized on a LEGO © object discrimination task, comparable to behavioral tests in humans in which CA3 hyperactivity has been linked to impairments. The cellular compartment analysis of temporal activity with fluorescence in situ hybridization for the immediate-early gene Arc was then used to identify the principal cell populations that were active during two distinct epochs of random foraging in different environments. This approach enabled the extent to which rats could discriminate two similar objects to be related to the ability of CA3 neurons to update across different environments. In both young and aged rats, there were animals that performed poorly on the LEGO object discrimination task. In the aged rats only, however, the poor performers had a higher percent of CA3 neurons that were active during random foraging in a novel environment, but this is not related to the ability of CA3 neurons to remap when the environment changed. Afferent neurons to CA3 in LEC, as identified with the retrograde tracer choleratoxin B (CTB), also showed a higher percentage of cells that were positive for Arc mRNA in aged poor performing rats. This suggests that LEC contributes to the hyperactivity seen in CA3 of aged animals with object discrimination deficits and age-related cognitive decline may be the consequence of dysfunction endemic to the larger network.

While several studies have investigated maternal exposures as risk factors for oral clefts, few have examined paternal factors. We conducted an international multi-centered case-control study to better understand paternal risk exposures for oral clefts (cases = 392 and controls = 234). Participants were recruited from local hospitals and oral cleft repair surgical missions in Vietnam, the Philippines, Honduras, and Morocco. Questionnaires were administered to fathers and mothers separately to elicit risk factor and family history data. Associations between paternal exposures and risk of clefts were assessed using logistic regression adjusting for potential confounders. A father's personal/family history of clefts was associated with significantly increased risk (adjusted OR: 4.77; 95% CI: 2.41-9.45). No other significant associations were identified for other suspected risk factors, including education (none/primary school v. university adjusted OR: 1.29; 95% CI: 0.74-2.24), advanced paternal age (5-year adjusted OR: 0.98; 95% CI: 0.84-1.16), or pre-pregnancy tobacco use (adjusted OR: 0.96; 95% CI: 0.67-1.37). Although sample size was limited, significantly decreased risks were observed for fathers with selected occupations. Further research is needed to investigate paternal environmental exposures as cleft risk factors.

The ability to use information from the physical world to update behavioral strategies is critical for survival across species. The prefrontal cortex (PFC) supports behavioral flexibility; however, exactly how this brain structure interacts with sensory association cortical areas to facilitate the adaptation of response selection remains unknown. Given the role of the perirhinal cortex (PER) in higher-order perception and associative memory, the current study evaluated whether PFC-PER circuits are critical for the ability to perform biconditional object discriminations when the rule for selecting the rewarded object shifted depending on the animal's spatial location in a 2-arm maze. Following acquisition to criterion performance on an object-place paired association task, pharmacological blockade of communication between the PFC and PER significantly disrupted performance. Specifically, the PFC-PER disconnection caused rats to regress to a response bias of selecting an object on a particular side regardless of its identity. Importantly, the PFC-PER disconnection did not interfere with the capacity to perform object-only or location-only discriminations, which do not require the animal to update a response rule across trials. These findings are consistent with a critical role for PFC-PER circuits in rule shifting and the effective updating of a response rule across spatial locations., (Published by Elsevier Inc.)

Mutations in the MATR3 gene encoding the nucleotide binding protein Matrin 3 have recently been identified as causing a subset of familial amyotrophic lateral sclerosis (fALS) and more rarely causing distal myopathy. Translating the identification of MATR3 mutations into an understanding of disease pathogenesis and the creation of mouse models requires a complete understanding of normal Matrin 3 levels and distribution in vivo. Consequently, we examined the levels of murine Matrin 3 in body tissues and regions of the central nervous system (CNS). We observed a significant degree of variability in Matrin 3 protein levels among different tissues of adult animals, with the highest levels found in reproductive organs and the lowest in muscle. Within the adult CNS, Matrin 3 levels were lowest in spinal cord. Further, we found that Matrin 3 declines significantly in CNS through early development and young adulthood before stabilizing. As previously reported, antibodies to Matrin 3 primarily stain nuclei, but the intensity of staining was not uniform in all nuclei. The low levels of Matrin 3 in spinal cord and muscle could mean that that these tissues are particularly vulnerable to alterations in Matrin 3 function. Our study is the first to characterize endogenous Matrin 3 in rodents across the lifespan, providing the groundwork for deciphering disease mechanisms and developing mouse models of MATR3-linked ALS. J. Comp. Neurol. 524:2740-2752, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Age-associated cognitive decline can reduce an individual's quality of life. As no single neurobiological deficit can account for the wide spectrum of behavioral impairments observed in old age, it is critical to develop an understanding of how interactions between different brain regions change over the life span. The performance of young and aged animals on behaviors that require the hippocampus and cortical regions to interact, however, has not been well characterized. Specifically, the ability to link a spatial location with specific features of a stimulus, such as object identity, relies on the hippocampus, perirhinal and prefrontal cortices. Although aging is associated with dysfunction in each of these brain regions, behavioral measures of functional change within the hippocampus, perirhinal and prefrontal cortices in individual animals are often not correlated. Thus, how dysfunction of a single brain region within this circuit, such as the hippocampus, impacts behaviors that require communication with the perirhinal and prefrontal cortices remains unknown. To address this question, young and aged rats were tested on the interregion dependent object-place paired association task, as well as a hippocampal-dependent test of spatial reference memory. This particular cohort of aged rats did not show deficits on the hippocampal-dependent task, but were significantly impaired at acquiring object-place associations relative to young. These data suggest that behaviors requiring functional connectivity across different regions of the memory network may be particularly sensitive to aging, and can be used to develop models that will clarify the impact of systems-level dysfunction in the elderly., ((c) 2015 APA, all rights reserved).)