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Abstract There are 90 independent genome-wide significant genetic risk variants for Parkinson’s disease (PD) but currently only five nominated loci for PD progression. The biology of PD progression is likely to be of central importance in defining mechanisms that can be used to develop new treatments. We studied 6766 PD patients, over 15,340 visits with a mean follow-up of between 4.2 and 15.7 years and carried out genome-wide survival studies for time to a motor progression endpoint, defined by reaching Hoehn and Yahr stage 3 or greater, and death (mortality). There was a robust effect of the APOE ε4 allele on mortality in PD. We also identified a locus within the TBXAS1 gene encoding thromboxane A synthase 1 associated with mortality in PD. We also report 4 independent loci associated with motor progression in or near MORN1, ASNS, PDE5A, and XPO1. Only the non-Gaucher disease causing GBA1 PD risk variant E326K, of the known PD risk variants, was associated with mortality in PD. Further work is needed to understand the links between these genomic variants and the underlying disease biology. However, these may represent new candidates for disease modification in PD.

Abstract The International League Against Epilepsy (ILAE)/International Bureau for Epilepsy (IBE)/World Health Organization (WHO) Global Campaign Against Epilepsy was launched in Geneva and Dublin in the summer of 1997. The second phase of the Campaign was launched by a major event in Geneva, led by WHO Director General Dr. Gro Harlem Brundtland in February 2001. Since then, the Campaign has been gathering momentum around the world culminating in the WHO General Assembly Resolution (WHA 68.20) on Epilepsy in May 2015 supported by 194 countries. Recently, the World Federation of Neurology and other neurological non‐governmental organizations (NGOs) have joined forces with the Epilepsy Campaign, leading to the WHO General Assembly Resolution (WHA 73.10) in May 2022 promoting a 10‐year Intersectoral Global Action Plan (IGAP) for Epilepsy and Other Neurological Disorders. I was privileged to serve as the first Chairperson of the Global Campaign Against Epilepsy and this year all my documents and correspondence relating to the Campaign have been delivered to the Wellcome Collection in London. These are the basis for this detailed account of the origins and early development of the Campaign. I describe the events leading to the birth of the concept, planning for the Campaign, the launch, development, and the achievements of phase one. This first phase focused on awareness raising, education, and involvement, especially within WHO, ILAE, and IBE, including a series of five Regional Public Health meetings and Declarations on Epilepsy. In 1999, the WHO raised the status of the Campaign to the highest level, the first ever for a Non‐Communicable Disease, resulting in the high profile launch of phase two in 2001, paving the way to the continuing global momentum and achievements, including the 2015 and 2022 WHO Resolutions.

The impact of aging on body composition and glucose metabolism is not well established in C57BL/6J mice, despite being a common pre-clinical model for aging and metabolic research. The purpose of this study was to examine the effect of advancing age on body composition, in vivo glucose metabolism, and skeletal muscle AKT expression in young (Y: 4 months old, n = 7), old (O: 17–18 months old, n = 10), and very old (VO: 26–27 month old, n = 9) male C57BL/6J mice. Body composition analysis, assessed by nuclear magnetic resonance, demonstrated O mice had a significantly greater fat mass and body fat percentage when compared to Y and VO mice. Furthermore, VO mice had a significantly greater lean body mass than both O and Y mice. We also found that the VO mice had greater AKT protein levels in skeletal muscle compared to O mice, an observation that explains a portion of the increased lean body mass in VO mice. During glucose tolerance (GT) testing, blood glucose values were significantly lower in the VO mice when compared to the Y and O mice. No age-related differences were observed in insulin tolerance (IT). We also assessed the glucose response to AMPK activation by 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR). The change in blood glucose following AICAR administration was significantly reduced in VO mice compared to Y and AG mice. Our findings indicate that lean body mass and AKT2 protein expression in muscle are significantly increased in VO mice compared to O mice. The increase in AKT2 likely plays a role in the greater lean body mass observed in the oldest of old mice. Finally, despite the increased GT, VO mice appear to be resistant to AMPK-mediated glucose uptake.

Abstract Gaining insight into the genetic regulation of gene expression in human brain is key to the interpretation of genome-wide association studies for major neurological and neuropsychiatric diseases. Expression quantitative trait loci (eQTL) analyses have largely been used to achieve this, providing valuable insights into the genetic regulation of steady-state RNA in human brain, but not distinguishing between molecular processes regulating transcription and stability. RNA quantification within cellular fractions can disentangle these processes in cell types and tissues which are challenging to model in vitro. We investigated the underlying molecular processes driving the genetic regulation of gene expression specific to a cellular fraction using allele-specific expression (ASE). Applying ASE analysis to genomic and transcriptomic data from paired nuclear and cytoplasmic fractions of anterior prefrontal cortex, cerebellar cortex and putamen tissues from 4 post-mortem neuropathologically-confirmed control human brains, we demonstrate that a significant proportion of genetic regulation of gene expression occurs post-transcriptionally in the cytoplasm, with genes undergoing this form of regulation more likely to be synaptic. These findings have implications for understanding the structure of gene expression regulation in human brain, and importantly the interpretation of rapidly growing single-nucleus brain RNA-sequencing and eQTL datasets, where cytoplasm-specific regulatory events could be missed.

Abstract Neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease, are devastating complex diseases resulting in physical and psychological burdens on patients and their families. There have been important efforts to understand their genetic basis leading to the identification of disease risk-associated loci involved in several molecular mechanisms, including immune-related pathways. Regional, in contrast to genome-wide, genetic correlations between pairs of immune and neurodegenerative traits have not been comprehensively explored, but could uncover additional immune-mediated risk-associated loci. Here, we systematically assess the role of the immune system in five neurodegenerative diseases by estimating regional genetic correlations between these diseases and immune-cell-derived single-cell expression quantitative trait loci (sc-eQTLs). We also investigate correlations between diseases and protein levels. We observe significant (FDR

Abstract Recent analyses have found waves of neural activity traveling across entire visual cortical areas in awake animals. These traveling waves modulate the excitability of local networks and perceptual sensitivity. The general computational role of these spatiotemporal patterns in the visual system, however, remains unclear. Here, we hypothesize that traveling waves endow the visual system with the capacity to predict complex and naturalistic inputs. We present a network model whose connections can be rapidly and efficiently trained to predict individual natural movies. After training, a few input frames from a movie trigger complex wave patterns that drive accurate predictions many frames into the future solely from the network’s connections. When the recurrent connections that drive waves are randomly shuffled, both traveling waves and the ability to predict are eliminated. These results suggest traveling waves may play an essential computational role in the visual system by embedding continuous spatiotemporal structures over spatial maps.

Abstract Genetic correlation ( $$r_g$$ r g ) between traits can offer valuable insight into underlying shared biological mechanisms. Neurodegenerative diseases overlap neuropathologically and often manifest comorbid neuropsychiatric symptoms. However, global $$r_g$$ r g analyses show minimal $$r_g$$ r g among neurodegenerative and neuropsychiatric diseases. Importantly, local $$r_g$$ r g s can exist in the absence of global relationships. To investigate this possibility, we applied LAVA, a tool for local $$r_g$$ r g analysis, to genome-wide association studies of 3 neurodegenerative diseases (Alzheimer’s disease, Lewy body dementia and Parkinson’s disease) and 3 neuropsychiatric disorders (bipolar disorder, major depressive disorder and schizophrenia). We identified several local $$r_g$$ r g s missed in global analyses, including between (i) all 3 neurodegenerative diseases and schizophrenia and (ii) Alzheimer’s and Parkinson’s disease. For those local $$r_g$$ r g s identified in genomic regions containing disease-implicated genes, such as SNCA, CLU and APOE, incorporation of expression quantitative trait loci identified genes that may drive genetic overlaps between diseases. Collectively, we demonstrate that complex genetic relationships exist among neurodegenerative and neuropsychiatric diseases, highlighting putative pleiotropic genomic regions and genes. These findings imply sharing of pathogenic processes and the potential existence of common therapeutic targets.

Abstract Open science and collaboration are necessary to facilitate the advancement of Parkinson’s disease (PD) research. Hackathons are collaborative events that bring together people with different skill sets and backgrounds to generate resources and creative solutions to problems. These events can be used as training and networking opportunities, thus we coordinated a virtual 3-day hackathon event, during which 49 early-career scientists from 12 countries built tools and pipelines with a focus on PD. Resources were created with the goal of helping scientists accelerate their own research by having access to the necessary code and tools. Each team was allocated one of nine different projects, each with a different goal. These included developing post-genome-wide association studies (GWAS) analysis pipelines, downstream analysis of genetic variation pipelines, and various visualization tools. Hackathons are a valuable approach to inspire creative thinking, supplement training in data science, and foster collaborative scientific relationships, which are foundational practices for early-career researchers. The resources generated can be used to accelerate research on the genetics of PD.

REM-sleep behavior disorder often precedes Parkinson’s disease or dementia. Here, the authors perform a genome-wide association study for REM-sleep behavior disorder, and discover how it potentially affects gene expression in the brain.

Summary: Saccadic eye movements are known to cause saccadic suppression, a temporary reduction in visual sensitivity and visual cortical firing rates. While saccadic suppression has been well characterized at the level of perception and single neurons, relatively little is known about the visual cortical networks governing this phenomenon. Here we examine the effects of saccadic suppression on distinct neural subpopulations within visual area V4. We find subpopulation-specific differences in the magnitude and timing of peri-saccadic modulation. Input-layer neurons show changes in firing rate and inter-neuronal correlations prior to saccade onset, and putative inhibitory interneurons in the input layer elevate their firing rate during saccades. A computational model of this circuit recapitulates our empirical observations and demonstrates that an input-layer-targeting pathway can initiate saccadic suppression by enhancing local inhibitory activity. Collectively, our results provide a mechanistic understanding of how eye movement signaling interacts with cortical circuitry to enforce visual stability.

Humans are thought to be more susceptible to neurodegeneration than equivalently-aged primates. It is not known whether this vulnerability is specific to anatomically-modern humans or shared with other hominids. The contribution of introgressed Neanderthal DNA to neurodegenerative disorders remains uncertain. It is also unclear how common variants associated with neurodegenerative disease risk are maintained by natural selection in the population despite their deleterious effects. In this study, we aimed to quantify the genome-wide contribution of Neanderthal introgression and positive selection to the heritability of complex neurodegenerative disorders to address these questions.We used stratified-linkage disequilibrium score regression to investigate the relationship between five SNP-based signatures of natural selection, reflecting different timepoints of evolution, and genome-wide associated variants of the three most prevalent neurodegenerative disorders: Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's disease.We found no evidence for enrichment of positively-selected SNPs in the heritability of Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's disease, suggesting that common deleterious disease variants are unlikely to be maintained by positive selection. There was no enrichment of Neanderthal introgression in the SNP-heritability of these disorders, suggesting that Neanderthal admixture is unlikely to have contributed to disease risk.These findings provide insight into the origins of neurodegenerative disorders within the evolution of Homo sapiens and addresses a long-standing debate, showing that Neanderthal admixture is unlikely to have contributed to common genetic risk of neurodegeneration in anatomically-modern humans.

The cortical column is one of the fundamental computational circuits in the brain. In order to understand the role neurons in different layers of this circuit play in cortical function it is necessary to identify the boundaries that separate the laminar compartments. While histological approaches can reveal ground truth they are not a practical means of identifying cortical layers in vivo. The gold standard for identifying laminar compartments in electrophysiological recordings is current-source density (CSD) analysis. However, laminar CSD analysis requires averaging across reliably evoked responses that target the input layer in cortex, which may be difficult to generate in less well-studied cortical regions. Further, the analysis can be susceptible to noise on individual channels resulting in errors in assigning laminar boundaries. Here, we have analyzed linear array recordings in multiple cortical areas in both the common marmoset and the rhesus macaque. We describe a pattern of laminar spike–field phase relationships that reliably identifies the transition between input and deep layers in cortical recordings from multiple cortical areas in two different non-human primate species. This measure corresponds well to estimates of the location of the input layer using CSDs, but does not require averaging or specific evoked activity. Laminar identity can be estimated rapidly with as little as a minute of ongoing data and is invariant to many experimental parameters. This method may serve to validate CSD measurements that might otherwise be unreliable or to estimate laminar boundaries when other methods are not practical.

Morphology and function of the dorsolateral prefrontal cortex (dlPFC), and corresponding working memory performance, are affected early in the aging process, but nearly half of aged individuals are spared of working memory deficits. Translationally relevant model systems are critical for determining the neurobiological drivers of this variability. The common marmoset (Callithrix jacchus) is advantageous as a model for these investigations because, as a non-human primate, marmosets have a clearly defined dlPFC that enables measurement of prefrontal-dependent cognitive functions, and their short (∼10 year) lifespan facilitates longitudinal studies of aging. Previously, we characterized working memory capacity in a cohort of marmosets that collectively covered the lifespan, and found age-related working memory impairment. We also found a remarkable degree of heterogeneity in performance, similar to that found in humans. Here, we tested the hypothesis that changes to synaptic ultrastructure that affect synaptic efficacy stratify marmosets that age with cognitive impairment from those that age without cognitive impairment. We utilized electron microscopy to visualize synapses in the marmoset dlPFC and measured the sizes of boutons, presynaptic mitochondria, and synapses. We found that coordinated scaling of the sizes of synapses and mitochondria with their associated boutons is essential for intact working memory performance in aged marmosets. Further, lack of synaptic scaling, due to a remarkable failure of synaptic mitochondria to scale with presynaptic boutons, selectively underlies age-related working memory impairment. We posit that this decoupling results in mismatched energy supply and demand, leading to impaired synaptic transmission. We also found that aged marmosets have fewer synapses in dlPFC than young, though the severity of synapse loss did not predict whether aging occurred with or without cognitive impairment. This work identifies a novel mechanism of synapse dysfunction that stratifies marmosets that age with cognitive impairment from those that age without cognitive impairment. The process by which synaptic scaling is regulated is yet unknown and warrants future investigation.

How different oncogenic Akt mutants can affect the response to Akt inhibitors is currently unclear. Here, the authors analyse somatic mutations of Akt1-3 isoforms in several human cancers, investigate their oncogenic effects and therapeutic relevance in vitro and confirm some of their data in a clinical trial testing the AKT inhibitor capivasertib in patients with solid tumors harboring AKT alterations.

Controlling non-native plant invasions that reduce the quality of preferred wetland habitats is a challenge for many wetland managers. Herbicides may be used to control invasions, but it may be difficult to find effective application methods depending on the terrain. Manned aircraft cover large patches, but aerial use is limited by high costs, weather conditions, and overspray concerns. Ground applications target smaller patches, but their effectiveness may be limited by accessibility, labor costs, and applicator health concerns. Considering these difficulties, unmanned aerial systems (UAS) have emerged as a viable alternative for more effectively treating plant invasions. We tested the use of a specialized UAS to control invasive perennial pepperweed (Lepidium latifolium) in Suisun Marsh in northern California, USA. This “spray drone” flew at an altitude of 2–3 m, a speed of 24 kmph, and applied herbicide with a swath width of 6 m. We applied herbicide with the spray drone to treat small patches before they expanded. To delineate invasive patch boundaries, we first flew a survey drone with a 4K resolution camera to detect emerging plants with color imagery and conduct an initial classification analysis. We subsequently visited areas with suspected invasive patches based on the classification, and observers manually confirmed the presence of the invasive species. We then flew the spray drone on transects to treat the patches and examined the results with post-treatment survey drone imagery and plots along ground transects. In total, we sprayed 14 ha of Lepidium across eight sites and found that 87% of the Lepidium was discernibly affected by our herbicide treatment. Furthermore, we measured the overspray, which was substantially less than that reported for other aerial application methods such as helicopter-spraying, and our estimated operational costs were lower. Our results indicated that applying remote-sensing imagery for the identification of invasive species patches and the use of a spray drone for treatment may be an effective means of controlling invasive plants with high precision at a reasonable cost. In the near future, a unified UAS system that both identifies invasive species and then treats them in a single pass should be a promising goal for early detection and rapid response in wetland management.

Fairbrother-Browne and collaborators analyze the relationship between nuclear and mitochondrial gene expression across the human brain and find correlation profiles that are governed by regional patterns. They show that these correlations are disrupted in neurodegenerative diseases, suggesting the relevance of mito-nuclear interactions for normal brain function.

Spontaneous traveling cortical waves shape neural responses. Using a large-scale computational model, the authors show that transmission delays shape locally asynchronous spiking dynamics into traveling waves without inducing correlations and boost responses to external input, as observed in vivo.

Knowledge of genomic features specific to humans may be important for understanding disease. Here the authors demonstrate a potential role for these human-lineage-specific sequences in brain development and neurological disease.

Background: In the clinical setting, it is not common practice to consider a vector bite, such as from a tick or flea, to be a contributing factor to chronic digestive symptoms. This article investigates associations we have observed among symptomatic patients and positive blood tests for vector-borne illness (VBI). Methods: Patients who visited an urban gastroenterology clinic over a 3-year period were retrospectively reviewed. A total of 270 patients presenting with a constellation of digestive symptoms — and who had no apparent digestive pathology and reported no prior diagnosis or treatments for VBI — were analyzed. Before the initial visit, all patients completed a review of systems medical history form, which comprised 19 gastrointestinal (GI) symptoms and 73 non-GI-related symptoms and conditions. Patients were tested for small intestinal bacterial overgrowth (SIBO) by lactulose breath test. VBI (babesiosis, ehrlichiosis, anaplasmosis, bartonellosis, borreliosis) was established using 1 or more of several blood tests. Odds ratio (OR) analysis determined associations between exposure to VBI, SIBO, and presenting symptoms/conditions. Two age groups (≤ 35 years and ≥ 36 years) were studied using Cochran-Mantel-Haenszel stratum-based test. Results: A higher OR (2.03, 95% CI: 1.5–3.6) was found between patients with ≥ 3 digestive symptoms and positive blood tests for ≥ 1 VBI. Five of the 19 GI symptoms were independently associated with VBI-positive samples: food intolerance, indigestion, nausea/vomiting, constipation, and heartburn. A similar association in patients with ≥ 3 non-GI symptoms (OR: 2.83, 95% CI: 1.3–6.4) was observed. Five of the 73 non-GI symptoms/conditions were independently associated with VBI-positive samples: chest pain, shortness of breath, extremity or joint pain, anxiety, and night sweats. Having ≥3 of any digestive or nondigestive symptoms generated significant relative risk of being VBI-positive. Presence of SIBO alone did not identify significant relative risk for a VBI, and age was not a confounder. Conclusions: Findings revealed an association between positive blood tests for vector-borne illness and chronically symptomatic patients regardless of whether symptoms were digestive or nondigestive. The manifestation of 3 or more gastrointestinal and/or extraintestinal symptoms should raise suspicion for a VBI.

Globally, relationships between avian richness and elevation in mountain ecosystems typically reflect one of four well‐documented patterns, but the mechanisms responsible for these patterns are poorly understood. We investigated which pattern best described bird species richness in peatlands of the Upper Bow Basin of the Canadian Rocky Mountains (1300–2000 m a.s.l.) and used a model competition framework to investigate possible mechanisms. Avian richness displayed a plateauing (cubic) relationship in response to increasing elevation (AICc weight = 0.48). Log richness was significantly positively related to log peatland area (R2 = 0.42, p = 0.001); however, and once we accounted for the richness–area relationship (area was not related to elevation (R2 = 0.13, p = 0.083)), the richness–elevation relationship was best described by a negative linear model rather than a cubic model (AICc weight = 0.69, R2 = 0.39). Consequently, we reject the neutral model of the mid‐domain effect and conclude that peatland area and one or more environmental filters are simultaneously driving relationships between avian richness and elevation in Rocky Mountain peatlands. Multicausality likely explains why researchers in different geographies observe inconsistent patterns between richness and elevation: drivers and interactions among drivers may vary spatially. Importantly, Natural Subregion was a stronger predictor of avian species richness than elevation per se (AICc weight = 0.96), suggesting that the responsible environmental filter(s) is relatively homogenous within ecological land classes (e.g. primary productivity) rather than directly variable with elevation (e.g. temperature). The results also lend insight into priorities for future research on richness–elevation patterns in mountain birds.

Regulation of gene expression and splicing are thought to be tissue-specific. Here, the authors obtain genomic and transcriptomic data from putamen and substantia nigra of 117 neurologically healthy human brains and find that splicing eQTLs are enriched for neuron-specific regulatory information.

Background Several studies have demonstrated a patient preference for physicians wearing a white coat associated with improved patient satisfaction. There are few studies on physicians’ perceptions of attire mainly done in the outpatient and surgical specialties. Objective Assess non-surgical physicians’ perception of attire in the hospital and to identify if any difference in the choice of attire amongst generation X and millennial physicians. Methods We surveyed 86 physicians in the hospital with six sets of pictures of commonly worn physician attires in the hospital setting with a two-part questionnaire. Key Results Formal attire with a white coat was found to be most favored, followed by formal without a white coat. Casual attire without a white coat was the least preferred across the surveyed attributes. The results were similar in generation X and millennial physicians. Only 49% concordance was observed with what physicians preferred and what they wore. Conclusion Our study showed that physicians felt wearing a white coat was the best to convey specific attributes like honesty, confidence, professionalism, among others, similar to prior studies done in patients. However, less than half of the physicians surveyed themselves followed the preferred attire.

To understand a visual scene, the brain segregates figures from background by assigning borders to foreground objects. Neurons in primate visual cortex encode which object owns a border (border ownership), but the underlying circuitry is not understood. Here, we used multielectrode probes to record from border ownership-selective units in different layers in macaque visual area V4 to study the laminar organization and timing of border ownership selectivity. We find that border ownership selectivity occurs first in deep layer units, in contrast to spike latency for small stimuli in the classical receptive field. Units on the same penetration typically share the preferred side of border ownership, also across layers, similar to orientation preference. Units are often border ownership-selective for a range of border orientations, where the preferred sides of border ownership are systematically organized in visual space. Together our data reveal a columnar organization of border ownership in V4 where the earliest border ownership signals are not simply inherited from upstream areas, but computed by neurons in deep layers, and may thus be part of signals fed back to upstream cortical areas or the oculomotor system early after stimulus onset. The finding that preferred border ownership is clustered and can cover a wide range of spatially contiguous locations suggests that the asymmetric context integrated by these neurons is provided in a systematically clustered manner, possibly through corticocortical feedback and horizontal connections.

The potential role of proteinase activated receptor 2 (PAR2) in the development of age-related obesity and insulin resistance is not well-understood. To address the hypothesis that deletion of PAR2 might ameliorate age-related obesity and impaired glucose homeostasis, we assessed body composition and insulin action in 18-month-old male PAR2 knockout (PAR2KO-AG), age-matched (AG) and young C57BL6 (YG, 6-month-old) mice. Body composition was measured by magnetic resonance spectroscopy (MRS) and insulin action was assessed by glucose tolerance (GT), insulin tolerance (IT) and AICAR tolerance (AT) testing. AG mice weighed significantly more than YG mice (p = 0.0001) demonstrating age-related obesity. However, PAR2KO-AG mice weighed significantly more than AG mice (p = 0.042), indicating that PAR2 may prevent a portion of age-related obesity. PAR2KO-AG and AG mice had greater fat mass and body fat percentage than YG mice. Similar to body weight, fat mass was greater in PAR2KO-AG mice compared to AG mice (p = 0.045); however, only a trend for greater body fat percentage in PAR2KO-AG compared to AG mice was observed (p = 0.09). No differences existed in lean body mass among the PAR2KO-AG, AG, and YG mice (p = 0.58). With regard to insulin action, the area under the curve (AUC) for GT was lower in PAR2KO-AG compared to AG mice (p = 0.0003) and YG mice (p = 0.001); however, no differences existed for the AUC for IT or AT. Our findings indicate that age-related obesity is not dependent on PAR2 expression.

Abstract Hawai'i's endangered waterbirds have experienced epizootics caused by ingestion of prey that accumulated a botulinum neurotoxin produced by the anaerobic bacterium Clostridium botulinum (avian botulism; Type C). Waterbird carcasses, necrophagous flies, and their larvae initiate and spread avian botulism, a food‐borne paralytic disease lethal to waterbirds. Each new carcass has potential to develop toxin‐accumulating necrophagous vectors amplifying outbreaks and killing hundreds of endangered waterbirds. Early carcass removal is an effective mitigation strategy for preventing avian intoxication, toxin concentration in necrophagous and secondary food webs, and reducing the magnitude of epizootics. However, rapid detection of carcasses can be problematic and labor intensive. Therefore, we tested a new method using scent detection canines for avian botulism surveillance on Kaua'i Island. During operational surveillance and a randomized double‐blind field trial, trained detector canines with experienced field handlers improved carcass detection probability, especially in dense vegetation. Detector canines could be combined with conventional surveillance to optimize search strategies for carcass removal and are a useful tool to reduce risks of the initiation and propagation of avian botulism.

Abstract Determining parameters that govern pathogen transmission (such as the force of infection, FOI), and pathogen impacts on morbidity and mortality, is exceptionally challenging for wildlife. Vital parameters can vary, for example across host populations, between sexes and within an individual's lifetime. Feline immunodeficiency virus (FIV) is a lentivirus affecting domestic and wild cat species, forming species‐specific viral–host associations. FIV infection is common in populations of puma (Puma concolor), yet uncertainty remains over transmission parameters and the significance of FIV infection for puma mortality. In this study, the age‐specific FOI of FIV in pumas was estimated from prevalence data, and the evidence for disease‐associated mortality was assessed. We fitted candidate models to FIV prevalence data and adopted a maximum likelihood method to estimate parameter values in each model. The models with the best fit were determined to infer the most likely FOI curves. We applied this strategy for female and male pumas from California, Colorado, and Florida. When splitting the data by sex and area, our FOI modeling revealed no evidence of disease‐associated mortality in any population. Both sex and location were found to influence the FOI, which was generally higher for male pumas than for females. For female pumas at all sites, and male pumas from California and Colorado, the FOI did not vary with puma age, implying FIV transmission can happen throughout life; this result supports the idea that transmission can occur from mothers to cubs and also throughout adult life. For Florida males, the FOI was a decreasing function of puma age, indicating an increased risk of infection in the early years, and a decreased risk at older ages. This research provides critical insight into pathogen transmission and impact in a secretive and solitary carnivore. Our findings shed light on the debate on whether FIV causes mortality in wild felids like puma, and our approach may be adopted for other diseases and species. The methodology we present can be used for identifying likely transmission routes of a pathogen and also estimating any disease‐associated mortality, both of which can be difficult to establish for wildlife diseases in particular.

Abstract Background The unique physicochemical properties of multi-walled carbon nanotubes (MWCNT) have led to many industrial applications. Due to their low density and small size, MWCNT are easily aerosolized in the workplace making respiratory exposures likely in workers. The International Agency for Research on Cancer designated the pristine Mitsui-7 MWCNT (MWCNT-7) as a Group 2B carcinogen, but there was insufficient data to classify all other MWCNT. Previously, MWCNT exposed to high temperature (MWCNT-HT) or synthesized with nitrogen (MWCNT-ND) have been found to elicit attenuated toxicity; however, their genotoxic and carcinogenic potential are not known. Our aim was to measure the genotoxicity of MWCNT-7 compared to these two physicochemically-altered MWCNTs in human lung epithelial cells (BEAS-2B & SAEC). Results Dose-dependent partitioning of individual nanotubes in the cell nuclei was observed for each MWCNT material and was greatest for MWCNT-7. Exposure to each MWCNT led to significantly increased mitotic aberrations with multi- and monopolar spindle morphologies and fragmented centrosomes. Quantitative analysis of the spindle pole demonstrated significantly increased centrosome fragmentation from 0.024–2.4 μg/mL of each MWCNT. Significant aneuploidy was measured in a dose-response from each MWCNT-7, HT, and ND; the highest dose of 24 μg/mL produced 67, 61, and 55%, respectively. Chromosome analysis demonstrated significantly increased centromere fragmentation and translocations from each MWCNT at each dose. Following 24 h of exposure to MWCNT-7, ND and/or HT in BEAS-2B a significant arrest in the G1/S phase in the cell cycle occurred, whereas the MWCNT-ND also induced a G2 arrest. Primary SAEC exposed for 24 h to each MWCNT elicited a significantly greater arrest in the G1 and G2 phases. However, SAEC arrested in the G1/S phase after 72 h of exposure. Lastly, a significant increase in clonal growth was observed one month after exposure to 0.024 μg/mL MWCNT-HT & ND. Conclusions Although MWCNT-HT & ND cause a lower incidence of genotoxicity, all three MWCNTs cause the same type of mitotic and chromosomal disruptions. Chromosomal fragmentation and translocations have not been observed with other nanomaterials. Because in vitro genotoxicity is correlated with in vivo genotoxic response, these studies in primary human lung cells may predict the genotoxic potency in exposed human populations.

Gene co-expression networks are a powerful type of analysis to construct gene groupings based on transcriptomic profiling. Co-expression networks make it possible to discover modules of genes whose mRNA levels are highly correlated across samples. Subsequent annotation of modules often reveals biological functions and/or evidence of cellular specificity for cell types implicated in the tissue being studied. There are multiple ways to perform such analyses with weighted gene co-expression network analysis (WGCNA) amongst one of the most widely used R packages. While managing a few network models can be done manually, it is often more advantageous to study a wider set of models derived from multiple independently generated transcriptomic data sets (e.g., multiple networks built from many transcriptomic sources). However, there is no software tool available that allows this to be easily achieved. Furthermore, the visual nature of co-expression networks in combination with the coding skills required to explore networks, makes the construction of a web-based platform for their management highly desirable. Here, we present the CoExp Web application, a user-friendly online tool that allows the exploitation of the full collection of 109 co-expression networks provided by the CoExpNets suite of R packages. We describe the usage of CoExp, including its contents and the functionality available through the family of CoExpNets packages. All the tools presented, including the web front- and back-ends are available for the research community so any research group can build its own suite of networks and make them accessible through their own CoExp Web application. Therefore, this paper is of interest to both researchers wishing to annotate their genes of interest across different brain network models and specialists interested in the creation of GCNs looking for a tool to appropriately manage, use, publish, and share their networks in a consistent and productive manner.

Abstract Obesity, insulin resistance, and poor metabolic profile are hallmarks of a high‐fat diet (HFD), highlighting the need to understand underlying mechanisms. Therefore, we sought to determine the effect of succinic acid (SA) on metabolism in high‐fat diet (HFD)‐induced obesity. Animals were randomly assigned to either low‐fat diet (LFD) or a high‐fat diet (HFD). Mice consumed their respective diets for 4.5 months and then assigned to the following groups: (LFD)+vehicle, LFD + SA (0.75 mg/ml), HFD + vehicle, or HFD + SA. Body weight (BW), food, and water intake, were tracked weekly. After 6 weeks, insulin, glucose, and pyruvate tolerance tests were completed, and spontaneous physical activity was assessed. Epididymal white adipose tissue (EWAT) mass and in vitro measurements of oxidative skeletal muscle (soleus) respiration were obtained. Expectedly, the HFD increased BW and EWAT mass, and reduced glucose and insulin tolerance. SA significantly reduced EWAT mass, more so in HFD (p .05). A significant (p

Abstract Obesity and aging are linked to inflammation and increased risk of chronic disease. Telomeres are the endcaps of chromosomes that are regulated by telomerase, the enzyme that elongates telomeres, as well as a protein complex known as shelterin. Telomere dysfunction is associated with inflammation, aging, and disease. However, the effect of high‐fat diet (HFD) induced obesity and advancing age on the shelterin complex and telomerase in adipose tissue is unknown. The present study investigated the effects of obesity and aging on C57BL/6J mice adipose tissue mRNA expression of shelterin complex genes. Young (YG) mice (3 mo) were randomly assigned to be fed either a high‐fat diet (YG + HFD; 60% kcal from fat) or a low‐fat diet (YG + LFD; 10% kcal from fat). A subset of mice were aged until 16 months. Body weight and epididymal white adipose tissue (EWAT) weight increased with age or a HFD. There was a trend for increased Terf2 expression, as expression was increased in HFD + YG by ~47% and aged mice by ~80%. Pot1b expression was increased in aged mice by ~35%–60% compared to YG, independent of diet. mTert, the gene that codes for the catalytic subunit of telomerase, was significantly elevated in aged mice. Changes in telomere associated gene expression was accompanied by changes in expression of inflammatory markers Mcp1 and Tnfα. These findings suggest obesity and age impact expression of shelterin complex and telomerase related genes in adipose, perhaps altering telomere function in adipose tissue thereby increasing inflammation and risk of chronic disease.

Parkinson’s dementia is a common and devastating part of Parkinson’s disease. Whilst timing and severity vary, dementia in Parkinson’s is often preceded by visual dysfunction. White matter changes, representing axonal loss, occur early in the disease process. Clarifying which white matter connections are affected in Parkinson’s with visual dysfunction and why specific connections are vulnerable will provide important mechanistic insights. Here, we use diffusion tractography in 100 Parkinson’s patients (33 low visual performers) and 34 controls to identify patterns of connectivity loss in Parkinson’s with visual dysfunction. We examine the relationship between regional transcription and connectivity loss, using the Allen Institute for Brain Science transcriptome atlas. We show that interhemispheric connections are preferentially affected in Parkinson’s low visual performers. Interhemispheric connection loss was associated with downweighted genes related to the smoothened signalling pathway (enriched in glutamatergic neurons) and upweighted metabolic genes. Risk genes for Parkinson’s but not Alzheimer’s or Dementia with Lewy bodies were over-represented in upweighted genes associated with interhemispheric connection loss. Our findings suggest selective vulnerability in Parkinson’s patients at highest risk of dementia (those with visual dysfunction), where differences in gene expression and metabolic dysfunction, affecting longer connections with higher metabolic burden, drive connectivity loss.

Small intestinal bacterial overgrowth (SIBO) is a condition of increased microbial load in the small intestine. The microbes feed on dietary carbohydrates and starches via fermentation, leading to gas production, inflammation and damage to the lining of the small intestine. Clinical presentation is varied, including abdominal pain, bloating, malabsorption and systemic symptoms. SIBO is associated with many challenging and chronic conditions such as fibromyalgia, chronic fatigue and chronic pain syndromes, and has been shown to be a causative factor in two out of three cases of irritable bowel syndrome. Symptoms improve with antimicrobial treatment, but recurrence is common. Many providers may not be aware of SIBO. This narrative review highlights a clinical case and the most recent literature regarding SIBO, including history, clinical presentation, prevalence, pathophysiology, diagnostic workup, treatment and prevention. Integrative medicine approaches, including diet, supplements and manual therapies, are also reviewed. SIBO can be a challenging condition and requires an integrative, patient-centered approach. Further studies are needed to guide clinicians in the workup and treatment of SIBO.

Mitochondrial dysfunction plays a significant role in neurodegenerative disease including ataxias and other movement disorders, particularly those marked by progressive degeneration in the cerebellum. In this study, we investigate the role of mitochondrial oxidative phosphorylation (OXPHOS) deficits in cerebellar tissue of a Purkinje cell-driven spinocerebellar ataxia type 1 (SCA1) mouse. Using RNA sequencing transcriptomics, OXPHOS complex assembly analysis and oxygen consumption assays, we report that in the presence of mutant polyglutamine-expanded ataxin-1, SCA1 mice display deficits in cerebellar OXPHOS complex I (NADH-coenzyme Q oxidoreductase). Complex I genes are upregulated at the time of symptom onset and upregulation persists into late stage disease; yet, functional assembly of complex I macromolecules are diminished and oxygen respiration through complex I is reduced. Acute treatment of postsymptomatic SCA1 mice with succinic acid, a complex II (succinate dehydrogenase) electron donor to bypass complex I dysfunction, ameliorated cerebellar OXPHOS dysfunction, reduced cerebellar pathology and improved motor behavior. Thus, exploration of mitochondrial dysfunction and its role in neurodegenerative ataxias, and warrants further investigation.

Obesity is a major public health problem that is highly associated with insulin resistance and type 2 diabetes, two conditions associated with circadian disruption. To date, dieting is one of the only interventions that result in substantial weight loss, but restricting caloric intake is difficult to maintain long-term. The use of artificial sweeteners, particularly in individuals that consume sugar sweetened beverages (energy drinks, soda), can reduce caloric intake and possibly facilitate weight loss. The purpose of the present study was to examine the effects of the artificial sweetener, rebaudioside A (Reb-A), on circadian rhythms, in vivo insulin action, and the susceptibility to diet-induced obesity. Six month old male C57BL/6 mice were assigned to a control or Reb-A (0.1% Reb-A supplemented drinking water) group for six months. Circadian wheel running rhythms, body weight, caloric intake, insulin action, and susceptibility to diet-induced obesity were assessed. Time of peak physical activity under a 12:12 light-dark (LD) cycle, mean activity levels, and circadian period in constant dark were not significantly different in mice that consumed Reb-A supplemented water compared to normal drinking water, indicating that circadian rhythms and biological clock function were unaltered. Although wheel running significantly reduced body weight in both Reb-A and control mice (P = 0.0001), consuming Reb-A supplemented water did not alter the changes in body weight following wheel running (P = 0.916). In vivo insulin action, as assessed by glucose, insulin, and pyruvate tolerance tests, was not different between mice that consumed Reb-A treated water compared to normal drinking water. Finally, Reb-A does not appear to change the susceptibility to diet-induced obesity as both groups of mice gained similar amounts of body weight when placed on a high fat diet. Our results indicate that consuming Reb-A supplemented water does not promote circadian disruption, insulin resistance, or obesity.

The superoxide dismutase mimetic manganese [III] tetrakis [5,10,15,20]-benzoic acid porphyrin (MnTBAP) is a potent antioxidant compound that has been shown to limit weight gain during short-term high fat feeding without preventing insulin resistance. However, whether MnTBAP has therapeutic potential to treat pre-existing obesity and insulin resistance remains unknown. To investigate this, mice were treated with MnTBAP or vehicle during the last five weeks of a 24-week high fat diet (HFD) regimen. MnTBAP treatment significantly decreased body weight and reduced white adipose tissue (WAT) mass in mice fed a HFD and a low fat diet (LFD). The reduction in adiposity was associated with decreased caloric intake without significantly altering energy expenditure, indicating that MnTBAP decreases adiposity in part by modulating energy balance. MnTBAP treatment also improved insulin action in HFD-fed mice, a physiologic response that was associated with increased protein kinase B (PKB) phosphorylation and expression in muscle and WAT. Since MnTBAP is a metalloporphyrin molecule, we hypothesized that its ability to promote weight loss and improve insulin sensitivity was regulated by heme oxygenase-1 (HO-1), in a similar fashion as cobalt protoporphyrins. Despite MnTBAP treatment increasing HO-1 expression, administration of the potent HO-1 inhibitor tin mesoporphyrin (SnMP) did not block the ability of MnTBAP to alter caloric intake, adiposity, or insulin action, suggesting that MnTBAP influences these metabolic processes independent of HO-1. These data demonstrate that MnTBAP can ameliorate pre-existing obesity and improve insulin action by reducing caloric intake and increasing PKB phosphorylation and expression.

Cidea and Cidec play an important role in regulating triglyceride storage in liver and adipose tissue. It is not known if the Cidea and Cidec genes respond to a high fat diet (HFD) or exercise training, two interventions that alter lipid storage. The purpose of the present study was to determine the effect of a HFD and voluntary wheel running (WR) on Cidea and Cidec mRNA and protein expression in adipose tissue and liver of mice. A HFD promoted a significant increase in Cidea and Cidec mRNA levels in adipose tissue and liver. The increase in Cidea and Cidec mRNAs in adipose tissue and liver in response to a HFD was prevented by WR. Similar to the changes in Cidea mRNA, Cidea protein levels in adipose tissue significantly increased in response to a HFD, a process that was, again, prevented by WR. However, in adipose tissue the changes in Cidec mRNA did not correspond to the changes in Cidec protein levels, as a HFD decreased Cidec protein abundance. Interestingly, in adipose tissue Cidea protein expression was significantly related to body weight (R=.725), epididymal adipose tissue (EWAT) mass (R=.475) and insulin resistance (R=.706), whereas Cidec protein expression was inversely related to body weight (R=-.787), EWAT mass (R=-.706), and insulin resistance (R=-.679). Similar to adipose tissue, Cidea protein expression in liver was significantly related to body weight (R=.660), EWAT mass (R=.468), and insulin resistance (R=.599); however, unlike adipose tissue, Cidec protein levels in liver were not related to body weight or EWAT mass and only moderately associated with insulin resistance (R=-.422, P=0.051). Overall, our findings indicate that Cidea is highly associated with adiposity and insulin resistance, whereas Cidec is related to insulin sensitivity. The present study suggests that Cide proteins might play an important functional role in the development of obesity, hepatic steatosis, as well as the pathogenesis of type 2 diabetes.

More than 18 million seabirds nest on 58 Pacific islands protected within vast U.S. Marine National Monuments (1.9 million km2). However, most of these seabird colonies are on low-elevation islands and sea-level rise (SLR) and accompanying high-water perturbations are predicted to escalate with climate change. To understand how SLR may impact protected islands and insular biodiversity, we modeled inundation and wave-driven flooding of a globally important seabird rookery in the subtropical Pacific. We acquired new high-resolution Digital Elevation Models (DEMs) and used the Delft3D wave model and ArcGIS to model wave heights and inundation for a range of SLR scenarios (+0.5, +1.0, +1.5, and +2.0 m) at Midway Atoll. Next, we classified vegetation to delineate habitat exposure to inundation and identified how breeding phenology, colony synchrony, and life history traits affect species-specific sensitivity. We identified 3 of 13 species as highly vulnerable to SLR in the Hawaiian Islands and quantified their atoll-wide distribution (Laysan albatross, Phoebastria immutabilis; black-footed albatross, P. nigripes; and Bonin petrel, Pterodroma hypoleuca). Our models of wave-driven flooding forecast nest losses up to 10% greater than passive inundation models at +1.0 m SLR. At projections of + 2.0 m SLR, approximately 60% of albatross and 44% of Bonin petrel nests were overwashed displacing more than 616,400 breeding albatrosses and petrels. Habitat loss due to passive SLR may decrease the carrying capacity of some islands to support seabird colonies, while sudden high-water events directly reduce survival and reproduction. This is the first study to simulate wave-driven flooding and the combined impacts of SLR, groundwater rise, and storm waves on seabird colonies. Our results highlight the need for early climate change planning and restoration of higher elevation seabird refugia to prevent low-lying protected islands from becoming ecological traps in the face of rising sea levels.

The identification of genes undergoing genetic or epigenetic alterations and contributing to the development of cancer is critical to our understanding of the molecular mechanisms of carcinogenesis. A new approach in identifying alterations of genes that might be relevant to the process of tumor development was used in this study by examining the gene expression profile in human lung cancer cells exposed to 5-aza-2'deoxycytidine (5-aza-dC). A cDNA array analysis was carried out on 5-aza-dC-treated and untreated non small cell lung cancer (NSCLC) cell line NCI-H522. Sixteen and 14 genes were upregulated and downregulated, respectively, by 5-aza-dC treatment. Among them, downregulation of tyrosine protein kinase ABL2 (ABL2) gene and upregulation of hint/protein kinase C inhibitor 1 (Hint/PKCI-1), DVL1, TIMP-1, and TRP-1 genes were found in expanded observations in two or three of five 5-aza-dC-treated NSCLC cell lines. Among these genes, we found that cDNA transfer of Hint/PKCI-1 resulted in a significant in vitro growth inhibition in two cell lines exhibiting 5-aza-dC-induced upregulation of Hint/PKCI-1 and significantly reduced in vivo tumorigenicity of one NSCLC cell line. Hint/PKCI-1, which is the only other characterized human histidine triad (HIT) nucleotide-binding protein in addition to tumor-suppressor gene FHIT, might be involved in lung carcinogenesis.

Influenza A virus infections are widespread in swine herds across the world. Influenza negatively affects swine health and production, and represents a significant threat to public health due to the risk of zoonotic infections. Swine herds can act as reservoirs for potentially pandemic influenza strains. In this study, we develop mathematical models based on experimental data, representing typical breeding and wean-to-finish swine farms. These models are used to explore and describe the dynamics of influenza infection at the farm level, which are at present not well understood. In addition, we use the models to assess the effectiveness of vaccination strategies currently employed by swine producers, testing both homologous and heterologous vaccines. An important finding is that following an influenza outbreak in a breeding herd, our model predicts a persistently high level of infectious piglets. Sensitivity analysis indicates that this finding is robust to changes in both transmission rates and farm size. Vaccination does not eliminate influenza throughout the breeding farm population. In the wean-to-finish herd, influenza infection may persist in the population only if recovered individuals become susceptible to infection again. A homologous vaccine administered to the entire wean-to-finish population after the loss of maternal antibodies eliminates influenza, but a vaccine that only induces partial protection (heterologous vaccine) has little effect on influenza infection levels. Our results have important implications for the control of influenza in swine herds, which is crucial in order to reduce both losses for swine producers and the risk to public health.

Dorsal stream areas provide motion information used by the oculomotor system to generate pursuit eye movements. Neurons in these areas saturate at low levels of luminance contrast. We therefore hypothesized that during the early phase of pursuit, eye velocity would exhibit an oculomotor gain function that saturates at low luminance contrast. To test this, we recorded eye movements in two macaques trained to saccade to an aperture in which a pattern of dots moved left or right. Shortly after the end of the saccade, the eyes followed the direction of motion with an oculomotor gain that increased with contrast before saturating. The addition of a second pattern of dots, moving in the opposite direction and superimposed on the first, resulted in a rightward shift of the contrast-dependent oculomotor gain function. The magnitude of this shift increased with the contrast of the second pattern of dots. Motion was nulled when the two patterns were equal in contrast. Next, we varied contrast over time. Contrast differences that disappeared before saccade onset biased post-saccadic eye movements at short latency. Changes in contrast occurring during or after saccade termination did not influence eye movements for approximately 150 ms. Earlier studies found that eye movements can be explained by a vector average computation when both targets are equal in contrast. We suggest that this averaging computation may reflect a special case of divisive normalization, yielding saturating contrast response functions that shift to the right with opposed motion, averaging motions when targets are equated in contrast.

Background Exposure to secondhand smoke is an important preventable cause of illness and death. A Smoke-Free Paso del Norte Coalition in El Paso, Texas, led a drive to introduce an ordinance to protect nonsmoking persons from the health effects of secondhand smoke in public places. The ordinance was introduced in April 2001 and was passed on June 26, 2001. Context El Paso is the fifth largest city in Texas and the largest border city in the United States. It is the 10th poorest city in the United States; 37% of its residents do not have health insurance. Seventy-eight percent of El Pasos residents are Hispanic/Latino. A large percentage of El Pasos restaurant and bar workers are recent immigrants from Mexico. Methods Campaign activities included a letter-writing campaign to the El Paso Times, petition gathering, community outreach education, meetings with city council members, print and television advertising, a proactive media advocacy campaign, and a youth rally. Consequences One month after the ordinance went into effect, an opinion poll found solid support for the new ordinance. Another survey conducted in December 2002 also found a 22% decline in adult smoking, from 22.1% in 1996 to 17.3% at the time of the survey. Interpretation The El Paso campaign is an example of a successful grassroots campaign. El Pasos campaign relied on direct organizing to identify, recruit, and mobilize supporters, and involved relatively little paid media or paid advocacy efforts. These lessons are transferable to other communities, and the El Paso coalition serves as a model for developing a diverse, representative coalition in a predominantly Mexican American community.

In this paper we argue that to a great extent noun class agreement in Swahili is based on inflectional features. Yet where inflectional features are not present, a derivational feature of inherent noun class controls agreement. Swahili, then, is seen as having a dual noun class system in which agreement is controlled by a hierarchical set of features ranging from inflectional to derivational. The evidence from Swahili indicates that Anderson's [1982] claim that inflectional morphology alone is relevant to syntax may be too strong and supports a weaker version admitting some interaction of derivational morphology with syntax.

A task force of scientists is searching for effective whitefly controls.

Changes in production practices, as well as insecticides, should help control destructive budworm populations that have developed in late-season cotton.