Chronic Drinking During Adolescence Predisposes the Adult Rat for Continued Heavy Drinking: Neurotrophin and Behavioral Adaptation after Long-Term, Continuous Ethanol Exposure

Previous research has found that adolescent ethanol (EtOH) exposure alters drug seeking behaviors, cognition and neuroplasticity. Using male Sprague Dawley rats, differences in spatial working memory, non-spatial discrimination learning and behavioral flexibility were explored as a function of age at the onset (mid-adolescent vs. adult) of chronic EtOH exposure (CET). Concentrations of mature brain-derived neurotrophic factor (mBDNF) and betanerve growth factor (beta-NGF) in the prefrontal cortex and hippocampus were also assessed at different time-points: during CET, following acute abstinence (48-hrs), and after protracted abstinence (6-8 wks). Our results revealed that an adolescent onset of CET leads to increased EtOH consumption that persisted into adulthood. In both adult and adolescent onset CET groups, there were significant long-term reductions in prefrontal cortical mBDNF and beta-NGF levels. However, only adult onset CET rats displayed decreased hippocampal BDNF levels. Spatial memory, assessed by spontaneous alternation and delayed alternation, was not significantly affected by CET as a function of age of drinking onset, but higher blood-EtOH levels were correlated with lower spontaneous alternation scores. Regardless of the age of onset, EtOH exposed rats were impaired on non-spatial discrimination learning and displayed inflexible behavioral patterns upon reversal learning. Our results indicate that adolescent EtOH exposure changes long-term consumption patterns producing behavioral and neural dysfunctions that persist across the lifespan

Modes of Acetylcholine Signaling in the Prefrontal Cortex: Implications for Cholinergic Dysfunction and Disorders

The forebrain cholinergic system is an important mediator of arousal, attention, memory, and other cognitive processes. Cholinergic signaling is typically divided into two patterns, tonic signaling, which involves sustained changes in ambient acetylcholine (ACh) tone over seconds to minutes, and phasic signaling, which involves fast changing, spatially specific release of ACh on a millisecond timescale. There is evidence to suggest unique functional roles for both types of signaling in the prefrontal cortex: phasic release of ACh is thought to be necessary for attentional processes, as well as cue detection, while tonic signaling is thought to be involved in regulating global arousal states and has been shown to increase with general cognitive demand. The differences between these two types of signaling may originate from electrophysiological properties of cholinergic cell types, distinct muscarinic and nicotinic receptor utilization and/or expression, and/or differential hydrolysis of ACh by acetylcholinesterase. This review will summarize the current views on the functional role of each type of signaling, while the contributions of ACh receptors, hydrolysis, and basal forebrain anatomy are examined. Additionally, the implications of these factors in ACh signaling will be examined in terms of cholinergic circuit dysfunction that occurs in neurodegenerative diseases

Winning and losing: differences in reward and punishment sensitivity between smokers and nonsmokers

Background: Smokers show increased brain activation in reward processing regions in response to smoking-related cues, yet few studies have examined secondary rewards not associated with smoking (i.e., money). Inconsistencies exist in the studies that do examine secondary rewards with some studies showing increased brain activation in reward processing brain regions, while others show decreased activation or no difference in activation between smokers and nonsmokers. Aims: The goal of the current study is to see if smokers process the evaluation and delivery of equally salient real world rewards similarly or differently than nonsmokers. Methods: The current study employed functional magnetic resonance imaging (fMRI) to examine brain responses in smokers and nonsmokers during the evaluation and delivery of monetary gains and losses. Results: In comparison to nonsmokers, smokers showed increased activation in the ventromedial prefrontal cortex to the evaluation of anticipated monetary losses and the brain response. Moreover, smokers compared to nonsmokers showed decreased activation in the inferior frontal gyrus to the delivery of expected monetary gains. Brain activations to both the evaluation of anticipated monetary losses and the delivery of expected monetary gains correlated with increased self-reported smoking craving to relieve negative withdrawal symptoms and craving related to positive aspects of smoking, respectively. Discussion: Together these results indicate that smokers are hyperresponsive to the evaluation of anticipated punishment and hyporesponsive to the delivery of expected rewards. Although further research is needed, this hypersensitivity to punishments coupled with increased craving may negatively impact quit attempts as smokers anticipate the negative withdrawal symptoms associated with quitting

Branching principles of animal and plant networks identified by combining extensive data, machine learning, and modeling

Branching in vascular networks and in overall organismic form is one of the most common and ancient features of multicellular plants, fungi, and animals. By combining machine-learning techniques with new theory that relates vascular form to metabolic function, we enable novel classification of diverse branching networks--mouse lung, human head and torso, angiosperm and gymnosperm plants. We find that ratios of limb radii--which dictate essential biologic functions related to resource transport and supply--are best at distinguishing branching networks. We also show how variation in vascular and branching geometry persists despite observing a convergent relationship across organisms for how metabolic rate depends on body mass.Comment: 55 pages, 8 figures, 8 table

Nerve Growth Factor Is Responsible for Exercise-Induced Recovery of Septohippocampal Cholinergic Structure and Function

Exercise has been shown to improve or rescue cognitive functioning in both humans and rodents, and the augmented actions of neurotrophins within the hippocampus and associated regions play a significant role in the improved neural plasticity. The septohippocampal circuit is modified by exercise. Beyond an enhancement of spatial working memory and a rescue of hippocampal activity-dependent acetylcholine (ACh) efflux, the re-emergence of the cholinergic/nestin neuronal phenotype within the medial septum/diagonal band (MS/dB) is observed following exercise (Hall and Savage, 2016). To determine which neurotrophin, brain-derived neurotrophic factor (BDNF) or nerve growth factor (NGF), is critical for exercise-induced cholinergic improvements, control and amnestic rats had either NGF or BDNF sequestered by TrkA-IgG or TrkB-IgG coated microbeads placed within the dorsal hippocampus. Hippocampal ACh release within the hippocampus during spontaneous alternation was measured and MS/dB cholinergic neuronal phenotypes were assessed. Sequestering NGF, but not BDNF, abolished the exercise-induced recovery of spatial working memory and ACh efflux. Furthermore, the re-emergence of the cholinergic/nestin neuronal phenotype within the MS/dB following exercise was also selectively dependent on the actions of NGF. Thus, exercise-induced enhancement of NGF within the septohippocampal pathway represents a key avenue for aiding failing septo-hippocampal functioning and therefore has significant potential for the recovery of memory and cognition in several neurological disorders

Exercise leads to sex-specific recovery of behavior and pathological AD markers following adolescent ethanol exposure in the TgF344-AD model

IntroductionHuman epidemiological studies suggest that heavy alcohol consumption may lead to earlier onset of Alzheimer’s Disease (AD), especially in individuals with a genetic predisposition for AD. Alcohol-related brain damage (ARBD) during a critical developmental timepoint, such as adolescence, interacts with AD-related pathologies to accelerate disease progression later in life. The current study investigates if voluntary exercise in mid-adulthood can recover memory deficits caused by the interactions between adolescence ethanol exposure and AD-transgenes.MethodsMale and female TgF344-AD and wildtype F344 rats were exposed to an intragastric gavage of water (control) or 5 g/kg of 20% ethanol (adolescent intermittent ethanol; AIE) for a 2 day on/off schedule throughout adolescence (PD27-57). At 6 months old, rats either remained in their home cage (stationary) or were placed in a voluntary wheel running apparatus for 4 weeks and then underwent several behavioral tests. The number of cholinergic neurons in the basal forebrain and measure of neurogenesis in the hippocampus were assessed.ResultsVoluntary wheel running recovers spatial working memory deficits selectively in female TgF344-AD rats exposed to AIE and improves pattern separation impairment seen in control TgF344-AD female rats. There were sex-dependent effects on brain pathology: Exercise improves the integration of recently born neurons in AIE-exposed TgF344-AD female rats. Exercise led to a decrease in amyloid burden in the hippocampus and entorhinal cortex, but only in male AIE-exposed TgF344-AD rats. Although the number of basal forebrain cholinergic neurons was not affected by AD-transgenes in either sex, AIE did reduce the number of basal forebrain cholinergic neurons in female rats.DiscussionThese data provide support that even after symptom onset, AIE and AD related cognitive decline and associated neuropathologies can be rescued with exercise in unique sex-specific ways

Telomere Length and the Risk of Cutaneous Malignant Melanoma in Melanoma-Prone Families with and without CDKN2A Mutations

Introduction: Recent evidence suggests a link between constitutional telomere length (TL) and cancer risk. Previous studies have suggested that longer telomeres were associated with an increased risk of melanoma and larger size and number of nevi. The goal of this study was to examine whether TL modified the risk of melanoma in melanoma-prone families with and without CDKN2A germline mutations. Materials and Methods We measured TL in blood DNA in 119 cutaneous malignant melanoma (CMM) cases and 208 unaffected individuals. We also genotyped 13 tagging SNPs in TERT. Results: We found that longer telomeres were associated with an increased risk of CMM (adjusted OR = 2.81, 95% CI = 1.02–7.72, P = 0.04). The association of longer TL with CMM risk was seen in CDKN2A- cases but not in CDKN2A+ cases. Among CMM cases, the presence of solar injury was associated with shorter telomeres (P = 0.002). One SNP in TERT, rs2735940, was significantly associated with TL (P = 0.002) after Bonferroni correction. Discussion Our findings suggest that TL regulation could be variable by CDKN2A mutation status, sun exposure, and pigmentation phenotype. Therefore, TL measurement alone may not be a good marker for predicting CMM risk

Informing trait-based ecology by assessing remotely sensed functional diversity across a broad tropical temperature gradient

Spatially continuous data on functional diversity will improve our ability to predict global change impacts on ecosystem properties. We applied methods that combine imaging spectroscopy and foliar traits to estimate remotelysensed functional diversity in tropical forests across an Amazon-to-Andes elevation gradient (215 to 3537 m). We evaluated the scale dependency of community assembly processes and examined whether tropical forest productivitycould be predicted by remotely sensed functional diversity. Functional richness of the community decreased withincreasing elevation. Scale-dependent signals of trait convergence, consistent with environmental filtering, play animportant role in explaining the range of trait variation within each site and along elevation. Single- and multitraitremotely sensed measures of functional diversity were important predictors of variation in rates of net and grossprimary productivity. Our findings highlight the potential of remotely sensed functional diversity to inform trait-based ecology and trait diversity-ecosystem function linkages in hyperdiverse tropical forests.Fil: Durán, Sandra M.. University of Arizona; Estados UnidosFil: Martin, Roberta E.. Arizona State University; Estados UnidosFil: Díaz, Sandra Myrna. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Maitner, Brian S.. Arizona State University; Estados UnidosFil: Malhi, Yadvinder. University of Oxford; Reino UnidoFil: Salinas, Norma. University of Oxford; Reino Unido. Pontificia Universidad Católica de Perú; PerúFil: Shenkin, Alexander. University of Oxford; Reino UnidoFil: Silman, Miles R.. Wake Forest University; Estados UnidosFil: Wieczynski, Daniel J.. University of Oxford; Reino UnidoFil: Asner, Gregory P.. Arizona State University; Estados UnidosFil: Bentley, Lisa Patrick. Sonoma State University; Estados UnidosFil: Savage, Van M.. University of California; Estados UnidosFil: Enquist, Brian J.. Arizona State University; Estados Unido

Accuracy of upper respiratory tract samples to diagnose Mycobacterium tuberculosis: a systematic review and meta-analysis

Background: Pulmonary tuberculosis due to Mycobacterium tuberculosis can be challenging to diagnose when sputum samples cannot be obtained, which is especially problematic in children and older people. We systematically appraised the performance characteristics and diagnostic accuracy of upper respiratory tract sampling for diagnosing active pulmonary tuberculosis. Methods: In this systematic review and meta-analysis, we searched MEDLINE, Cinahl, Web of Science, Global Health, and Global Health Archive databases for studies published between database inception and Dec 6, 2022 that reported on the accuracy of upper respiratory tract sampling for tuberculosis diagnosis compared with microbiological testing of sputum or gastric aspirate reference standard. We included studies that evaluated the accuracy of upper respiratory tract sampling (laryngeal swabs, nasopharyngeal aspirate, oral swabs, saliva, mouth wash, nasal swabs, plaque samples, and nasopharyngeal swabs) to be tested for microbiological diagnosis of tuberculous (by culture and nucleic acid amplification tests) compared with a reference standard using either sputum or gastric lavage for a microbiological test. We included cohort, case-control, cross-sectional, and randomised controlled studies that recruited participants from any community or clinical setting. We excluded post-mortem studies. We used a random-effects meta-analysis with a bivariate hierarchical model to estimate pooled sensitivity, specificity, and diagnostics odds ratio (DOR; odds of a positive test with disease relative to without), stratified by sampling method. We assessed bias using QUADAS-2 criteria. This study is registered with PROSPERO (CRD42021262392). Findings: We screened 10 159 titles for inclusion, reviewed 274 full texts, and included 71, comprising 119 test comparisons published between May 13, 1933, and Dec 19, 2022, in the systematic review (53 in the meta-analysis). For laryngeal swabs, pooled sensitivity was 57·8% (95% CI 50·5–65·0), specificity was 93·8% (88·4–96·8), and DOR was 20·7 (11·1–38·8). Nasopharyngeal aspirate sensitivity was 65·2% (52·0–76·4), specificity was 97·9% (96·0–99·0), and DOR was 91·0 (37·8–218·8). Oral swabs sensitivity was 56·7% (44·3–68·2), specificity was 91·3% (CI 81·0–96·3), and DOR was 13·8 (5·6–34·0). Substantial heterogeneity in diagnostic accuracy was found, probably due to differences in reference and index standards. Interpretation: Upper respiratory tract sampling holds promise to expand access to tuberculosis diagnosis. Exploring historical methods using modern microbiological techniques might further increase options for alternative sample types. Prospective studies are needed to optimise accuracy and utility of sampling methods in clinical practice. Funding: UK Medical Research Council, Wellcome, and UK Foreign, Commonwealth and Development Office

The Physics of LIGO

In the spring term of 1994, I organized a course at Caltech on the The Physics of LIGO (i.e., the physics of the Laser Interferometer Gravitational Wave Observatory). The course consisted of eighteen 1.5-hour-long tutorial lectures, delivered by members of the LIGO team and others, and it was aimed at advanced undergraduates and graduate students in physics, applied physics and in engineering and applied sciences and also at interested postdoctoral fellows, research staff, and faculty