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Abdominal fat is increasingly linked to brain health. A total of 10,001 healthy participants were scanned on 1.5T MRI with a short whole-body MR imaging protocol. Deep learning with FastSurfer segmented 96 brain regions. Separate models segmented visceral and subcutaneous abdominal fat. Regression analyses of abdominal fat types and normalized brain volumes were evaluated, controlling for age and sex. Logistic regression models determined the risk of brain total gray and white matter volume loss from the highest quartile of visceral fat and lowest quartile of these brain volumes. This cohort had an average age of 52.9 ± 13.1 years with 52.8% men and 47.2% women. Segmented visceral abdominal fat predicted lower volumes in multiple regions including: total gray matter volume (r = -.44, p<.001), total white matter volume (r =-.41, p<.001), hippocampus (r = -.39, p< .001), frontal cortex (r = -.42, p<.001), temporal lobes (r = -.44, p<.001), parietal lobes (r = -.39, p<.001), occipital lobes (r =-.37, p<.001). Women showed lower brain volumes than men related to increased visceral fat. Visceral fat predicted increased risk for lower total gray matter (age 20-39: OR = 5.9; age 40-59, OR = 5.4; 60-80, OR = 5.1) and low white matter volume: (age 20-39: OR = 3.78; age 40-59, OR = 4.4; 60-80, OR = 5.1). Higher subcutaneous fat is related to brain volume loss. Elevated visceral and subcutaneous fat predicted lower brain volumes and may represent novel modifiable factors in determining brain health.

This research forms a part of the comprehensive Indian Environmental Radiation Monitoring Network program, focusing on the continuous measurement of absorbed dose rate in outdoor air due to natural gamma radiation (cosmic and terrestrial) in Bengaluru, Karnataka, India. Over the course of a decade (2013-2023), data were collected from 41 monitoring locations in the city using permanently field-installed Geiger-Mueller detector-based environmental radiation monitors. This paper presents an analysis of the extensive long-term monitoring results. The mean absorbed gamma dose rate in outdoor air across the monitoring locations ranged from 84 ± 9 to 156 ± 4 nGy.h-1, with a calculated mean value of 124 ± 15 nGy.h-1. The estimated mean annual effective dose due to outdoor natural gamma radiation varied from 0.10 ± 0.01 to 0.19 ± 0.01 mSv.y-1, with an overall mean of 0.15 ± 0.02 mSv.y-1., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Introduction: Low-cost simple tests for preclinical Alzheimer's disease are a research priority. We evaluated whether remote unsupervised webcam recordings of finger-tapping were associated with cognitive performance in older adults., Methods: A total of 404 cognitively-asymptomatic participants (64.6 [6.77] years; 70.8% female) completed 10-second finger-tapping tests (Tasmanian [TAS] Test) and cognitive tests (Cambridge Neuropsychological Test Automated Battery [CANTAB]) online at home. Regression models including hand movement features were compared with null models (comprising age, sex, and education level); change in Akaike Information Criterion greater than 2 (ΔAIC > 2) denoted statistical difference., Results: Hand movement features improved prediction of episodic memory, executive function, and working memory scores (ΔAIC > 2). Dominant hand features outperformed nondominant hand features for episodic memory (ΔAIC = 2.5), executive function (ΔAIC = 4.8), and working memory (ΔAIC = 2.2)., Discussion: This brief webcam test improved prediction of cognitive performance compared to age, sex, and education. Finger-tapping holds potential as a remote language-agnostic screening tool to stratify community cohorts at risk for cognitive decline., Competing Interests: Author disclosures are available in the supporting information., (© 2024 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Background: The potential neuroprotective effects of regular physical activity on brain structure are unclear, despite links between activity and reduced dementia risk., Objective: To investigate the relationships between regular moderate to vigorous physical activity and quantified brain volumes on magnetic resonance neuroimaging., Methods: A total of 10,125 healthy participants underwent whole-body MRI scans, with brain sequences including isotropic MP-RAGE. Three deep learning models analyzed axial, sagittal, and coronal views from the scans. Moderate to vigorous physical activity, defined by activities increasing respiration and pulse rate for at least 10 continuous minutes, was modeled with brain volumes via partial correlations. Analyses adjusted for age, sex, and total intracranial volume, and a 5% Benjamini-Hochberg False Discovery Rate addressed multiple comparisons., Results: Participant average age was 52.98±13.04 years (range 18-97) and 52.3% were biologically male. Of these, 7,606 (75.1%) reported engaging in moderate or vigorous physical activity approximately 4.05±3.43 days per week. Those with vigorous activity were slightly younger (p < 0.00001), and fewer women compared to men engaged in such activities (p = 3.76e-15). Adjusting for age, sex, body mass index, and multiple comparisons, increased days of moderate to vigorous activity correlated with larger normalized brain volumes in multiple regions including: total gray matter (Partial R = 0.05, p = 1.22e-7), white matter (Partial R = 0.06, p = 9.34e-11), hippocampus (Partial R = 0.05, p = 5.96e-7), and frontal, parietal, and occipital lobes (Partial R = 0.04, p≤1.06e-5)., Conclusions: Exercise-related physical activity is associated with increased brain volumes, indicating potential neuroprotective effects.

The Indian Environmental Radiation Monitoring Network continuously monitors the outdoor natural gamma absorbed dose rate in air at different locations throughout India by employing Geiger-Mueller (GM) detector-based field-installed environmental radiation monitors (ERMs). Hyderabad, Telangana, India is known to have high natural background radiation levels due to the presence of high concentrations of primordial radionuclides in its granitic rocks. There are a total of 59 ERMs installed at various locations across Hyderabad. Long-term monitoring data of these locations are presented in this paper. The mean values of outdoor natural gamma absorbed dose rate in air at the monitoring locations were found to vary in the range of 104-258 nGy.h-1 with a mean of 193 ± 40 nGy.h-1. The mean annual effective dose due to outdoor natural gamma radiation was estimated to be 0.24 ± 0.05 mSv.y-1. Analysis of the long-term seasonal variation of outdoor natural gamma absorbed dose rate in air showed that the same was lowest during monsoons., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The Indian Environmental Radiation Monitoring Network continuously monitors, throughout India, the absorbed dose rate in air due to outdoor natural gamma radiation, by using Geiger-Mueller detector-based standalone environmental radiation monitors. The network consists of 546 monitors spread across 91 monitoring locations distributed all over the country. In this paper, the countrywide long-term monitoring results are summarised. The measured mean dose rate of the monitoring locations followed a log-normal distribution and ranged from 50 to 535 nGy.h-1 with a median value of 91 nGy.h-1. Due to outdoor natural gamma radiation, the average annual effective dose was estimated to be 0.11 mSv.y-1., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Although Ipilimumab (anti-CTLA-4) is FDA-approved for stage III/IV melanoma adjuvant treatment, it is not used clinically in first-line therapy, given the superior relapse-free survival (RFS)/toxicity benefits of anti-PD-1 therapy. However, it is important to understand anti-CTLA-4's mechanistic contribution to combination anti-PD-1/CTLA-4 therapy and investigate anti-CTLA-4 therapy for BRAF-wild type melanoma cases reresected after previous adjuvant anti-PD-1 therapy. Our group published that nitric oxide (NO) increased within the immune effector cells among patients with longer RFS after adjuvant ipilimumab, whereas NO increased within the immune suppressor cells among patients with shorter RFS. Herein, we measured the post-translational modifications of STAT1 (nitration-nSTAT1 and phosphorylation-pSTAT1) that are important for regulating its activity via flow cytometry and mass spectrometry approaches. PBMCs were analyzed from 35 patients undergoing adjuvant ipilimumab treatment. Shorter RFS was associated with higher pSTAT1 levels before ( p = 0.007) and after ( p = 0.036) ipilimumab. Ipilimumab-treated patients with high nSTAT1 levels before and after therapy in PBMCs experienced decreased RFS, but the change in nSTAT1 levels before and after ipilimumab therapy was associated with longer RFS ( p = 0.01). The measurement of post-translational modifications in STAT1 may distinguish patients with prolonged RFS from ipilimumab and provide mechanistic insight into responses to ipilimumab combination regimens.

Background: Despite optimal neoadjuvant chemotherapy only 40% of gastric cancer tumours achieve complete or partial treatment response. In the absence of treatment response, neoadjuvant chemotherapy in gastric cancer contributes to adverse events without additional survival benefit compared to adjuvant treatment or surgery alone. Additional strategies and methods are required to optimize the allocation of existing treatment regimens such as FLOT chemotherapy (5-Fluorouracil, Leucovorin, Oxaliplatin and Docetaxel). Predictive biomarkers detected using immunohistochemistry (IHC) methods may provide useful data regarding treatment response., Aim: To investigate the utility of CD4, CD8, Galectin-3 and E-cadherin in predicting neoadjuvant FLOT chemotherapy tumour response in gastric adenocarcinoma., Methods: Forty-three adult patients with gastric adenocarcinoma, of which 18 underwent neoadjuvant chemotherapy, were included in a prospective clinical cohort. Endoscopic biopsies were obtained from gastric cancer and normal adjacent gastric mucosa. Differences in expression of Galectin-3, E-cadherin, CD4 + and CD8 + molecules between tumours with and without treatment response to neoadjuvant chemotherapy were assessed with IHC. Treatment response was graded by clinical pathologists using the Tumour Regression Score according to the College of American Pathologists criteria. Treatment response was defined as complete or near complete tumour response, whereas partial or poor/no response was defined as incomplete. Digital IHC images were annotated and quantitatively assessed using QuPath 0.3.1. Biomarker expression between responsive and incomplete response tumours was assessed using a two-sided Wilcoxon test. Biomarker expression was also compared between normal and cancer tissue and between 15 paired tumour samples before and after chemotherapy. We performed a preliminary multivariate analysis and power analysis to guide future study. Statistical analyses were completed using R 4.1.2., Results: The ratio between CD4 + and CD8 + lymphocytes was significantly greater in treatment responsive tumours (Wilcoxon, P = 0.03). In univariate models, CD4 + /CD8 + ratio was the only biomarker that significantly predicted favourable treatment response (Accuracy 86%, P < 0.001). Using a glmnet multivariate model, high CD4 + /CD8 + ratio and low Galectin-3 expression were the most influential variables in predicting a favourable treatment response. Analyses of paired samples found that FLOT chemotherapy also results in increased expression of CD4 + and CD8 + tumour infiltrating lymphocytes (Paired Wilcoxon, P = 0.002 and P = 0.008, respectively). Our power analysis suggests future study requires at least 35 patients in each treatment response group for CD8 and Galectin-3 molecules, whereas 80 patients in each treatment response group are required to assess CD4 and E-cadherin biomarkers., Conclusion: We demonstrate that an elevated CD4 + /CD8 + Ratio is a promising IHC-based biomarker to predict favourable treatment response to FLOT neoadjuvant chemotherapy in locally advanced gastric cancer., Competing Interests: Conflict-of-interest statement: All authors have no conflicts of interest to disclose., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Tuberculosis, caused by Mycobacterium tuberculosis ( Mtb ), is a serious and devastating infectious disease worldwide. Approximately a quarter of the world population harbors latent Mtb infection without pathological consequences. Exposure of immunocompetent healthy individuals with Mtb does not result in active disease in more than 90% individuals, suggesting a defining role of host immunity to prevent and/or clear early infection. However, innate immune stimulation strategies have been relatively underexplored for the treatment of tuberculosis. In this study, we used cell culture and mouse models to examine the role of a heat-killed form of a non-pathogenic microbe, Caulobacter crescentus (HKCC), in inducing innate immunity and limiting Mtb infection. We also examined the added benefits of a distinct chemo-immunotherapeutic strategy that incorporates concurrent treatments with low doses of a first-line drug isoniazid and HKCC. This therapeutic approach resulted in highly significant reductions in disseminated Mtb in the lungs, liver, and spleen of mice compared to either agent alone. Our studies demonstrate the potential of a novel innate immunotherapeutic strategy with or without antimycobacterial drugs in controlling Mtb infection in mice and open new avenues for the treatment of tuberculosis in humans.

An inadequate supply of fresh tissue is a major limitation of three-dimensional patient-derived gastric organoid research. We propose that tissue procurement for organoid culture could be increased by developing a cold storage shipment protocol for fresh surgical tissues. Sixty stomach specimens from C57BL/6J mice were resected, of which forty-five were stored in Hank's Balanced Salt (HBSS), University of Wisconsin (UW), or Histidine-Tryptophan-Ketoglutarate (HTK) solutions for subsequent organoid culture. Stomachs were dissociated and processed into gastric organoids as fresh tissue or after transport at 4 °C for 24 or 48 h. All gastric organoid cultures were established and maintained for 10 passages. Cold storage for 24 or 48 h did not significantly affect organoid viability. Although cold storage was associated with decreased organoid growth rate, there were no differences in viability, cytotoxic dose response, or LGR5 and TROY stem cell gene expression compared to organoids prepared from fresh tissue. As a proof of concept, six human gastric cancer organoids were established after 24 or 48 h of storage. Patient-derived gastric organoids from mouse and human gastric tissue can be established after 48 h of cold ischemia. Our method, which only requires ice packs, standard shipping containers, and HBSS is feasible and reliable. This method does not affect the reliability of downstream dose-response assays and maintains organoid viability for at least 10 passages. The shipment of fresh tissue for organoid procurement could serve to enhance multicenter collaboration and achieve more elaborate or controlled organoid experimentation.

Lipomas of the oral cavity are uncommon. Here we report a case of 85 year old female presenting with a progressively increasing large growth in the oropharynx which was diagnosed as lipoma on histopathology. The clinicoradiological and histopathological findings are discussed. To the best of our knowledge; this is one of the largest intraoral lipoma reported in India till date. The present case highlights the need to be aware of intraoral lipomas which can present as large growths at this unusual site so as to avoid any unwarranted aggressive surgery., Competing Interests: Conflict of InterestThere are no conflicts of interest., (© Association of Otolaryngologists of India 2021.)

We evaluated the anti-mycobacterial effect of a flavonoid 5,7-dihydroxy-2-(4-hydroxyphenyl) 4 H -chromen-4-one ( 1 ) and two pyrimidines, 4-hydroxy-2-dimethylamino-5-nitroso-6-aminopyrimidine ( 2 ) and 2-chloro-5- n -nonylpyrimidine ( 3 ) in vitro against Mycobacterium tuberculosis ( M. tuberculosis , H37Ra) and Mycobacterium avium (M. avium) , using a Microplate Alamar Blue Assay (MABA). The effects of the compounds 1 - 3 in combination with first- and second-line anti-TB drugs isoniazid, rifampicin, cycloserine, and clarithromycin on the growth of M. tuberculosis and M. avium were also evaluated in in vitro assays. As a single agent, compounds 1 and 2 exhibited modest activity while compound 3 was the most effective against M. tuberculosis and M. avium . When compounds 1 - 3 were evaluated at lower than 50% of their inhibitory concentrations in a two-drug combination with isoniazid or rifampicin, they showed additive to synergistic interactions. This inhibitory effect was improved when each of the three compounds was tested together in a three-drug combination with two of the first-line anti-TB drugs. Compounds 1 - 3 also demonstrated strong synergistic interaction in combination with cycloserine and clarithromycin in inhibiting the growth of M. tuberculosis and M. avium , respectively. This study demonstrated that compounds 1 - 3 have potential to be developed as effective anti-TB agents with combined use., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Background: Telemedicine video consultations are rapidly increasing globally, accelerated by the COVID-19 pandemic. This presents opportunities to use computer vision technologies to augment clinician visual judgement because video cameras are so ubiquitous in personal devices and new techniques, such as DeepLabCut (DLC) can precisely measure human movement from smartphone videos. However, the accuracy of DLC to track human movements in videos obtained from laptop cameras, which have a much lower FPS, has never been investigated; this is a critical gap because patients use laptops for most telemedicine consultations., Objectives: To determine the validity and reliability of DLC applied to laptop videos to measure finger tapping, a validated test of human movement., Method: Sixteen adults completed finger-tapping tests at 0.5 Hz, 1 Hz, 2 Hz, 3 Hz and at maximal speed. Hand movements were recorded simultaneously by a laptop camera at 30 frames per second (FPS) and by Optotrak, a 3D motion analysis system at 250 FPS. Eight DLC neural network architectures (ResNet50, ResNet101, ResNet152, MobileNetV1, MobileNetV2, EfficientNetB0, EfficientNetB3, EfficientNetB6) were applied to the laptop video and extracted movement features were compared to the ground truth Optotrak motion tracking., Results: Over 96% (529/552) of DLC measures were within +/-0.5 Hz of the Optotrak measures. At tapping frequencies >4 Hz, there was progressive decline in accuracy, attributed to motion blur associated with the laptop camera's low FPS. Computer vision methods hold potential for moving us towards intelligent telemedicine by providing human movement analysis during consultations. However, further developments are required to accurately measure the fastest movements., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The worldwide prevalence of dementia is rapidly rising. Alzheimer's disease (AD), accounts for 70% of cases and has a 10-20-year preclinical period, when brain pathology covertly progresses before cognitive symptoms appear. The 2020 Lancet Commission estimates that 40% of dementia cases could be prevented by modifying lifestyle/medical risk factors. To optimise dementia prevention effectiveness, there is urgent need to identify individuals with preclinical AD for targeted risk reduction. Current preclinical AD tests are too invasive, specialist or costly for population-level assessments. We have developed a new online test, TAS Test, that assesses a range of motor-cognitive functions and has capacity to be delivered at significant scale. TAS Test combines two innovations: using hand movement analysis to detect preclinical AD, and computer-human interface technologies to enable robust 'self-testing' data collection. The aims are to validate TAS Test to [1] identify preclinical AD, and [2] predict risk of cognitive decline and AD dementia., Methods: Aim 1 will be addressed through a cross-sectional study of 500 cognitively healthy older adults, who will complete TAS Test items comprising measures of motor control, processing speed, attention, visuospatial ability, memory and language. TAS Test measures will be compared to a blood-based AD biomarker, phosphorylated tau 181 (p-tau181). Aim 2 will be addressed through a 5-year prospective cohort study of 10,000 older adults. Participants will complete TAS Test annually and subtests of the Cambridge Neuropsychological Test Battery (CANTAB) biennially. 300 participants will undergo in-person clinical assessments. We will use machine learning of motor-cognitive performance on TAS Test to develop an algorithm that classifies preclinical AD risk (p-tau181-defined) and determine the precision to prospectively estimate 5-year risks of cognitive decline and AD., Discussion: This study will establish the precision of TAS Test to identify preclinical AD and estimate risk of cognitive decline and AD. If accurate, TAS Test will provide a low-cost, accessible enrichment strategy to pre-screen individuals for their likelihood of AD pathology prior to more expensive tests such as blood or imaging biomarkers. This would have wide applications in public health initiatives and clinical trials., Trial Registration: ClinicalTrials.gov Identifier: NCT05194787 , 18 January 2022. Retrospectively registered., (© 2022. The Author(s).)

The aviation industry has seen dramatic growth over the decades till the recent disruption due to the COVID-19 pandemic. Moreover, long-haul routes with a distance of more than 4000 km are common for major airlines worldwide. Therefore, aircraft cabin noise assessment is essential, especially in long-haul flights, for passenger and flight crew health wellness. In this paper, the cabin noise of five wide-body aircraft, namely Airbus A330-300ER, A350-900, A380-800, and Boeing B777-200ER and B787-900, was recorded using a calibrated in-house developed smartphone application. The sound pressure levels of in-cabin noise have been measured on two different decibel scales, namely, A-weighted [dB(A)] and C-weighted scales [dB(C)]. The sound pressure levels of Airbus A380-800 were lowest among selected models, while the in-cabin pressure level values of Airbus A350-900 were maximum. However, the difference in decibel levels between the aircraft is minimal as it is within 3 dB., 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., (© 2022 Elsevier Ltd. All rights reserved.)

Background & Objective: With populations aging, the number of people with dementia worldwide is expected to triple to 152 million by 2050. Seventy percent of cases are due to Alzheimer's disease (AD) pathology and there is a 10-20 year 'pre-clinical' period before significant cognitive decline occurs. We urgently need, cost effective, objective biomarkers to detect AD, and other dementias, at an early stage. Risk factor modification could prevent 40% of cases and drug trials would have greater chances of success if participants are recruited at an earlier stage. Currently, detection of dementia is largely by pen and paper cognitive tests but these are time consuming and insensitive to the pre-clinical phase. Specialist brain scans and body fluid biomarkers can detect the earliest stages of dementia but are too invasive or expensive for widespread use. With the advancement of technology, Artificial Intelligence (AI) shows promising results in assisting with detection of early-stage dementia. This scoping review aims to summarise the current capabilities of AI-aided digital biomarkers to aid in early detection of dementia, and also discusses potential future research directions., Methods & Materials: In this scoping review, we used PubMed and IEEE Xplore to identify relevant papers. The resulting records were further filtered to retrieve articles published within five years and written in English. Duplicates were removed, titles and abstracts were screened and full texts were reviewed., Results: After an initial yield of 1,463 records, 1,444 records were screened after removal of duplication. A further 771 records were excluded after screening titles and abstracts, and 496 were excluded after full text review. The final yield was 177 studies. Records were grouped into different artificial intelligence based tests: (a) computerized cognitive tests (b) movement tests (c) speech, conversion, and language tests and (d) computer-assisted interpretation of brain scans., Conclusions: In general, AI techniques enhance the performance of dementia screening tests because more features can be retrieved from a single test, there are less errors due to subjective judgements and AI shifts the automation of dementia screening to a higher level. Compared with traditional cognitive tests, AI-based computerized cognitive tests improve the discrimination sensitivity by around 4% and specificity by around 3%. In terms of speech, conversation and language tests, combining both acoustic features and linguistic features achieve the best result with accuracy around 94%. Deep learning techniques applied in brain scan analysis achieves around 92% accuracy. Movement tests and setting smart environments to capture daily life behaviours are two potential future directions that may help discriminate dementia from normal aging. AI-based smart environments and multi-modal tests are promising future directions to improve detection of dementia in the earliest stages., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aims: Visual triggers have long been recognized clinically to stimulate urgency urinary incontinence (UUI). Current pathophysiology recognizes the importance of cortical control over micturition but there is no standardized methodology for clinicians to study the impact of visual triggers. Our aim was to develop an imaging protocol able to characterize the brain's response to personalized visual triggers, providing a methodology for evaluation on connectivity within the brain in patients with visually triggered urinary urgency., Methods: A magnetic resonance imaging (MRI) methodology specific for urologic use was developed. A 3T-Elition Scanner was first used to acquire static structural images. These images were then used to define approximately 200 brain regions of interest (ROI) using a validated brain atlas. Then, real-time functional MRI (fMRI) scans were conducted during natural bladder filling, where study subjects were shown randomized block sequences of visual stimuli comprised of both subject-specific trigger images and neutral images. The fMRI scan data were merged to identify key ROI underlying UUI., Results: Dynamic fMRI scans were conducted in 10 subjects, 4 with trigger-induced UUI, 2 with trigger-induced urgency, and 4 with no urgency or leakage to visual triggers. No subjects with UUI history lost continence during imaging, but all four subjects reported sensations of urgency in response to their own subject-specific trigger images. The ROI identified were the periaqueductal gray, anterior cingulate gyrus, pons, and prefrontal cortex. We found increased activity in the prefrontal cortex and limbic system ROI in response to subject-specific visual triggers of UUI., Conclusions: This information provides proof of principle for further exploration of subject-specific trigger image evaluation using fMRI to explore causation in patients with UUI., (© 2021 Wiley Periodicals LLC.)

Early studies in mouse neurodevelopment led to the discovery of the RE1 Silencing Transcription Factor (REST) and its role as a master repressor of neuronal gene expression. Recently, REST was reported to also repress neuronal genes in the human adult brain. These genes were found to be involved in pro-apoptotic pathways; and their repression, associated with increased REST levels during aging, were found to be neuroprotective and conserved across species. However, direct genome-wide REST binding profiles for REST in adult brain have not been identified for any species. Here, we apply this approach to mouse and human hippocampus. We find an expansion of REST binding sites in the human hippocampus that are lacking in both mouse hippocampus and other human non-neuronal cell types. The unique human REST binding sites are associated with genes involved in innate immunity processes and inflammation signaling which, on the basis of histology and recent public transcriptomic analyses, suggest that these new target genes are repressed in glia. We propose that the increases in REST expression in mid-adulthood presage the beginning of brain aging, and that human REST function has evolved to protect the longevity and function of both neurons and glia in human brain. SIGNIFICANCE STATEMENT The RE1 Silencing Transcription Factor (REST) repressor has served historically as a model for gene regulation during mouse neurogenesis. Recent studies of REST have also suggested a conserved role for REST repressor function across lower species during aging. However, direct genome-wide studies for REST have been lacking for human brain. Here, we perform the first genome-wide analysis of REST binding in both human and mouse hippocampus. The majority of REST-occupied genes in human hippocampus are distinct from those in mouse. Further, the REST-associated genes unique to human hippocampus represent a new set related to innate immunity and inflammation, where their gene dysregulation has been implicated in aging-related neuropathology, such as Alzheimer's disease., (Copyright © 2021 the authors.)

With the increasing prevalence of neurodegenerative diseases, including Parkinson's disease, hand tremor detection has become a popular research topic because it helps with the diagnosis and tracking of disease progression. Conventional hand tremor detection algorithms involved wearable sensors. A non-invasive hand tremor detection algorithm using videos as input is desirable but the existing video-based algorithms are sensitive to environmental conditions. An algorithm, with the capability of detecting hand tremor from videos with a cluttered background, would allow the videos recorded in a non-research environment to be used. Clinicians and researchers could use videos collected from patients and participants in their own home environment or standard clinical settings. Neural network based machine learning architectures provide high accuracy classification results in related fields including hand gesture recognition and body movement detection systems. We thus investigated the accuracy of advanced neural network architectures to automatically detect hand tremor in videos with a cluttered background. We examined configurations with different sets of features and neural network based classification models. We compared the performance of different combinations of features and classification models and then selected the combination which provided the highest accuracy of hand tremor detection. We used cross validation to test the accuracy of the trained model predictions. The highest classification accuracy for automatically detecting tremor (vs non tremor) was 80.6% and this was obtained using Convolutional Neural Network-Long Short-Term Memory and features based on measures of frequency and amplitude change., Competing Interests: Conflict of interestAll the authors declared that they have no conflict of interest., (© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2021.)

Background: Activating vestibular afferents via galvanic vestibular stimulation (GVS) has been recently shown to have a number of complex motor effects in Parkinson's disease (PD), but the basis of these improvements is unclear. The evaluation of network-level connectivity changes may provide us with greater insights into the mechanisms of GVS efficacy., Objective: To test the effects of different GVS stimuli on brain subnetwork interactions in both health control (HC) and PD groups using fMRI., Methods: FMRI data were collected for all participants at baseline (resting state) and under noisy, 1 Hz sinusoidal, and 70-200 Hz multisine GVS. All stimuli were given below sensory threshold, blinding subjects to stimulation. The subnetworks of 15 healthy controls and 27 PD subjects (on medication) were identified in their native space, and their subnetwork interactions were estimated by nonnegative canonical correlation analysis. We then determined if the inferred subnetwork interaction changes were affected by disease and stimulus type and if the stimulus-dependent GVS effects were influenced by demographic features., Results: At baseline, interactions with the visual-cerebellar network were significantly decreased in the PD group. Sinusoidal and multisine GVS improved (i.e., made values approaching those seen in HC) subnetwork interactions more effectively than noisy GVS stimuli overall. Worsening disease severity, apathy, depression, impaired cognitive function, and increasing age all limited the beneficial effects of GVS., Conclusions: Vestibular stimulation has widespread system-level brain influences and can improve subnetwork interactions in PD in a stimulus-dependent manner, with the magnitude of such effects associating with demographics and disease status., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Aiping Liu et al.)

Individuals with Parkinson's disease often experience postural instability, a debilitating and largely treatment-resistant symptom. A better understanding of the neural substrates contributing to postural instability could lead to more effective treatments. Constraints of current functional neuroimaging techniques, such as the horizontal orientation of most MRI scanners (forcing participants to lie supine), complicates investigating cortical and subcortical activation patterns and connectivity networks involved in healthy and parkinsonian balance control. In this cross-sectional study, we utilized a newly-validated MRI-compatible balance simulator (based on an inverted pendulum) that enabled participants to perform balance-relevant tasks while supine in the scanner. We utilized functional MRI to explore effective connectivity underlying static and dynamic balance control in healthy older adults (n = 17) and individuals with Parkinson's disease while on medication (n = 17). Participants performed four tasks within the scanner with eyes closed: resting, proprioceptive tracking of passive ankle movement, static balancing of the simulator, and dynamic responses to random perturbations of the simulator. All analyses were done in the participant's native space without spatial transformation to a common template. Effective connectivity between 57 regions of interest was computed using a Bayesian Network learning approach with false discovery rate set to 5%. The first 12 principal components of the connection weights, binomial logistic regression, and cross-validation were used to create 4 separate models: contrasting static balancing vs {rest, proprioception} and dynamic balancing vs {rest, proprioception} for both controls and individuals with Parkinson's disease. In order to directly compare relevant connections between controls and individuals with Parkinson's disease, we used connections relevant for predicting a task in either controls or individuals with Parkinson's disease in logistic regression with Least Absolute Shrinkage and Selection Operator regularization. During dynamic balancing, we observed decreased connectivity between different motor areas and increased connectivity from the brainstem to several cortical and subcortical areas in controls, while individuals with Parkinson's disease showed increased connectivity associated with motor and parietal areas, and decreased connectivity from brainstem to other subcortical areas. No significant models were found for static balancing in either group. Our results support the notion that dynamic balance control in individuals with Parkinson's disease relies more on cortical motor areas compared to healthy older adults, who show a preference of subcortical control during dynamic balancing., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Anti-PD-1 based immune therapies are thought to be dependent on antigen processing and presentation mechanisms. To characterize the immune-dependent mechanisms that predispose stage III/IV melanoma patients to respond to anti-PD-1 therapies, we performed a multi-omics study consisting of expression proteomics and targeted immune-oncology-based mRNA sequencing. Formalin-fixed paraffin-embedded tissue samples were obtained from stage III/IV patients with melanoma prior to anti-PD-1 therapy. The patients were first stratified into poor and good responders based on whether their tumors had or had not progressed while on anti-PD-1 therapy for 1 year. We identified 263 protein/gene candidates that displayed differential expression, of which 223 were identified via proteomics and 40 via targeted-mRNA analyses. The downstream analyses of expression profiles using MetaCore software demonstrated an enrichment of immune system pathways involved in antigen processing/presentation and cytokine production/signaling. Pathway analyses showed interferon (IFN)-γ-mediated signaling via NF-κB and JAK/STAT pathways to affect immune processes in a cell-specific manner and to interact with the inducible nitric oxide synthase. We review these findings within the context of available literature on the efficacy of anti-PD-1 therapy. The comparison of good and poor responders, using efficacy of PD-1-based therapy at 1 year, elucidated the role of antigen presentation in mediating response or resistance to anti-PD-1 blockade.

Using computer-vision and image processing techniques, we aim to identify specific visual cues as induced by facial movements made during monosyllabic speech production. The method is named ADFAC: Automatic Detection of Facial Articulatory Cues. Four facial points of interest were detected automatically to represent head, eyebrow and lip movements: nose tip (proxy for head movement), medial point of left eyebrow, and midpoints of the upper and lower lips. The detected points were then automatically tracked in the subsequent video frames. Critical features such as the distance, velocity, and acceleration describing local facial movements with respect to the resting face of each speaker were extracted from the positional profiles of each tracked point. In this work, a variant of random forest is proposed to determine which facial features are significant in classifying speech sound categories. The method takes in both video and audio as input and extracts features from any video with a plain or simple background. The method is implemented in MATLAB and scripts are made available on GitHub for easy access.•Using innovative computer-vision and image processing techniques to automatically detect and track keypoints on the face during speech production in videos, thus allowing more natural articulation than previous sensor-based approaches.•Measuring multi-dimensional and dynamic facial movements by extracting time-related, distance-related and kinematics-related features in speech production.•Adopting the novel random forest classification approach to determine and rank the significance of facial features toward accurate speech sound categorization., 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., (© 2020 The Authors. Published by Elsevier B.V.)

Robust, effective treatments for Parkinson's freezing of gait remain elusive. Our previous study revealed beneficial effects of high-frequency rTMS over the supplementary motor area. The present study aims to explore the neural mechanisms of rTMS treatments utilizing novel exploratory multivariate approaches. We first conducted a resting-state functional MRI study with a group of 40 Parkinson's disease patients with freezing of gait, 31 without freezing of gait, and 30 normal controls. A subset of 30 patients with freezing of gait ( verum group: N  = 20; sham group: N  = 10) who participated the aforementioned rTMS study underwent another scan after the treatments. Using the baseline scans, the imaging biomarkers for freezing of gait and Parkinson's disease were developed by contrasting the connectivity profiles of patients with freezing of gait to those without freezing of gait and normal controls, respectively. These two biomarkers were then interrogated to assess the rTMS effects on connectivity patterns. Results showed that the freezing of gait biomarker was negatively correlated with Freezing of Gait Questionnaire score ( r  = -0.6723, p  < 0.0001); while the Parkinson's disease biomarker was negatively correlated with MDS-UPDRS motor score ( r  = -0.7281, p  < 0.0001). After the rTMS treatment, both the freezing of gait biomarker (0.326 ± 0.125 vs. 0.486 ± 0.193, p  = 0.0071) and Parkinson's disease biomarker (0.313 ± 0.126 vs. 0.379 ± 0.155, p  = 0.0378) were significantly improved in the verum group; whereas no significant biomarker changes were found in the sham group. Our findings indicate that high-frequency rTMS over the supplementary motor area confers the beneficial effect jointly through normalizing abnormal brain functional connectivity patterns specifically associated with freezing of gait, in addition to normalizing overall disrupted connectivity patterns seen in Parkinson's disease., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2020.)

Phenotyping of immune cell subsets in clinical trials is limited to well-defined phenotypes, due to technological limitations of reporting flow cytometry multi-dimensional phenotyping data. We developed a multi-dimensional phenotyping analysis tool and applied it to detect nitric oxide (NO) levels in peripheral blood immune cells before and after adjuvant ipilimumab co-administration with a peptide vaccine in melanoma patients. We analyzed inhibitory and stimulatory markers for immune cell phenotypes that were felt to be important in the NO analysis. The pipeline allows visualization of immune cell phenotypes without knowledge of clustering techniques and to categorize cells by association with relapse-free survival (RFS). Using this analysis, we uncovered the potential for a dichotomous role of NO as a pro- and anti-melanoma factor. NO was found in subsets of immune-suppressor cells associated with shorter-term (≤ 1 year) RFS, whereas NO was also present in immune-stimulatory effector cells obtained from patients with significant longer-term (> 1 year) RFS. These studies provide insights into the cell-specific immunomodulatory role of NO. The methods presented herein can be applied to monitor the pro- and anti-tumor effects of a variety of immune-based therapeutics in cancer patients. Clinical Trial Registration Number: NCT00084656 (https://clinicaltrials.gov/ct2/show/NCT00084656)., (Copyright © 2020 Garg, Ott, Mostofa, Chen, Chen, Kroeger, Cao, Mailloux, Agrawal, Schaible, Sarnaik, Weber, Berglund, Mulé and Markowitz.)

Introduction: Freezing of gait (FOG) contributes to falls in Parkinson's disease (PD), but robust, effective treatments remain elusive. There is evidence indicating that the supplementary motor area (SMA) plays an important role in the pathogenesis of FOG and may therefore be a potential neuromodulation target. The present study explored the clinical efficacy of high-frequency repetitive transcranial magnetic stimulation (rTMS) over the SMA on FOG in PD patients., Methods: A group of 30 PD patients with FOG were enrolled in a randomized, double-blind, sham-controlled trial. Patients were randomly allocated 2:1 to receive ten sessions of either real (N = 20) or sham (N = 10) 10 Hz rTMS over SMA. The patients were assessed at baseline (T 0 ), after the 5th (T 1 ) and 10th (T 2 ) sessions, and then 2 weeks (T 3 ) and 4 weeks (T 4 ) after the last session. The primary clinical outcome was the Freezing of Gait Questionnaire score (FOGQ), with the Movement Disorder Society-Unified Parkinson's Disease Rating Scale motor scores (MDS-UPDRS III) and Timed Up and Go test as secondary clinical outcomes. All the assessments were carried out at the "ON" state., Results: With a four week's follow-up, there were significant interaction effects in the FOGQ (effect of group*time, p = 0.04), MDS-UPDRS III (p = 0.02) and several gait variables (total duration, p < 0.01; cadence, p = 0.04; turn duration, p = 0.01; and turn to sit duration, p = 0.02). Post-hoc analyses revealed a significantly decreased FOGQ score at T 2 and T 4 , and significant improvements of MDS-UPDRS III and gait variables at T 1 , T 2 , T 3 and T 4 in the rTMS group. No significant improvements were found in the sham group., Conclusion: High-frequency rTMS over SMA may ultimately serve as an add-on therapy for alleviating FOG in PD patients., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Fog computing aims to support applications requiring low latency and high scalability by using resources at the edge level. In general, fog computing comprises several autonomous mobile or static devices that share their idle resources to run different services. The providers of these devices also need to be compensated based on their device usage. In any fog-based resource-allocation problem, both cost and performance need to be considered for generating an efficient resource-allocation plan. Estimating the cost of using fog devices prior to the resource allocation helps to minimize the cost and maximize the performance of the system. In the fog computing domain, recent research works have proposed various resource-allocation algorithms without considering the compensation to resource providers and the cost estimation of the fog resources. Moreover, the existing cost models in similar paradigms such as in the cloud are not suitable for fog environments as the scaling of different autonomous resources with heterogeneity and variety of offerings is much more complicated. To fill this gap, this study first proposes a micro-level compensation cost model and then proposes a new resource-allocation method based on the cost model, which benefits both providers and users. Experimental results show that the proposed algorithm ensures better resource-allocation performance and lowers application processing costs when compared to the existing best-fit algorithm.

Graph theoretical analysis is a powerful tool for quantitatively evaluating brain connectivity networks. Conventionally, brain connectivity is assumed to be temporally stationary, whereas increasing evidence suggests that functional connectivity exhibits temporal variations during dynamic brain activity. Although a number of methods have been developed to estimate time-dependent brain connectivity, there is a paucity of studies examining the utility of brain dynamics for assessing brain disease states. Therefore, this paper aims to assess brain connectivity dynamics in Parkinson's disease (PD) and determine the utility of such dynamic graph measures as potential components to an imaging biomarker. Resting-state functional magnetic resonance imaging data were collected from 29 healthy controls and 69 PD subjects. Time-varying functional connectivity was first estimated using a sliding windowed sparse inverse covariance matrix. Then, a collection of graph measures, including the Fiedler value, were computed and the dynamics of the graph measures were investigated. The results demonstrated that PD subjects had a lower variability in the Fiedler value, modularity, and global efficiency, indicating both abnormal dynamic global integration and local segregation of brain networks in PD. Autoregressive models fitted to the dynamic graph measures suggested that Fiedler value, characteristic path length, global efficiency, and modularity were all less deterministic in PD. With canonical correlation analysis, the altered dynamics of functional connectivity networks, and particularly dynamic Fiedler value, were shown to be related with disease severity and other clinical variables including age. Similarly, Fiedler value was the most important feature for classification. Collectively, our findings demonstrate altered dynamic graph properties, and in particular the Fiedler value, provide an additional dimension upon which to non-invasively and quantitatively assess PD.

Typical methods for image segmentation, or labeling, formulate and solve an optimization problem to produce a single optimal solution. For applications in clinical decision support relying on automated medical image segmentation, it is also desirable for methods to inform about (i) the uncertainty in label assignments or object boundaries or (ii) alternate close-to-optimal solutions. However, typical methods fail to do so. To estimate uncertainty, while some Bayesian methods rely on simplified prior models and approximate variational inference schemes, others rely on sampling segmentations from the associated posterior model using (i) traditional Markov chain Monte Carlo (MCMC) methods based on Gibbs sampling or (ii) approximate perturbation models. However, in such typical approaches, in practice, the resulting inference or generated sample set are approximations that deviate significantly from those indicated by the true posterior. To estimate uncertainty, we propose the modern paradigm of perfect MCMC sampling to sample multi-label segmentations from generic Bayesian Markov random field (MRF) models, in finite time for exact inference. Furthermore, for exact sampling in generic Bayesian MRFs, we extend the theory underlying Fill's algorithm to generic MRF models by proposing a novel bounding-chain algorithm. On several classic problems in medical image analysis, and several modeling and inference schemes, results on simulated data and clinical brain magnetic resonance images show that our uncertainty estimates gain accuracy over several state-of-the-art inference methods., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Host immune responses play an important role in the outcome of infection with hepatitis C virus (HCV). They can lead to viral clearance and a positive outcome, or progression and severity of chronic disease. Extensive research in the past >25 years into understanding the immune responses against HCV have still resulted in many unanswered questions implicating a role for unknown factors and events. In our earlier studies, we made a surprising discovery that peptides derived from structural and non-structural proteins of HCV have substantial amino acid sequence homologies with various proteins of adenoviruses and that immunizing mice with a non-replicating, non-recombinant adenovirus vector leads to induction of a robust cross-reactive cellular and humoral response against various HCV antigens. In this work, we further demonstrate antibody cross-reactivity between Ad and HCV in vivo. We also extend this observation to show that recombinant adenoviruses containing antigens from unrelated pathogens also possess the ability to induce cross-reactive immune responses against HCV antigens along with the induction of transgene antigen-specific immunity. This cross-reactive immunity can (a) accommodate the making of dual-pathogen vaccines, (b) play an important role in the natural course of HCV infection and (c) provide a plausible answer to many unexplained questions regarding immunity to HCV.

Apathy is a common non-motor symptom of Parkinson's disease (PD) that is difficult to quantify and poorly understood. Some studies have used incentivized motor tasks to assess apathy, as the condition is often associated with a reduction in motivated behavior. Normally event-related desynchronization, a reduction of power in specific frequency bands, is observed in the motor cortex during the peri-movement period. Also, alpha (8-12 Hz) and theta (4-7 Hz) oscillations are sensitive to rewards that are closely related to motivational states however these oscillations have not been widely investigated in relation to apathy in PD. Using EEG recordings, we investigated the neural oscillatory characteristics of apathy in PD during an incentivized motor task with interleaved rest periods. Apathetic and non-apathetic PD subjects on dopaminergic medication and healthy control subjects were instructed to squeeze a hand grip device for a monetary reward proportional to the subject's grip force and the monetary value attributed to that trial. Apathetic PD subjects exhibited higher alpha and theta powers in the pre-trial baseline rest period compared to non-apathetic PD subjects and healthy subjects. Further, we found that both resting power and relative power in alpha and theta bands during incentivized movement predicted PD subjects' apathy scores. Our results suggest that apathetic PD patients may need to overcome greater baseline alpha and theta oscillatory activity in order to facilitate incentivized movement. Clinically, resting alpha and theta power as well as alpha and theta event-related desynchronization during movement may serve as potential neural markers for apathy severity in PD., (Copyright © 2019. Published by Elsevier Inc.)

Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis ( Mtb ), kills 5,000 people per day globally. Rapid development and spread of various multi drug-resistant strains of Mtb emphasize that an effective vaccine is still the most cost-effectives and efficient way of controlling and eradicating TB. Bacillus Calmette-Guerin (BCG), the only licensed TB vaccine, still remains the most widely administered human vaccine, but is inefficient in protecting from pulmonary TB in adults. The protective immunity afforded by BCG is thought to wane with time and considered to last only through adolescent years. Heterologous boosting of BCG-primed immune responses using a subunit vaccine represents a promising vaccination approach to promote strong cellular responses against Mtb . In our earlier studies, we discovered lipopeptides of ESAT-6 antigen with strong potential as a subunit vaccine candidate. Here, we have investigated that potential as a booster to BCG vaccine in both a pre-exposure preventive vaccine and a post-exposure therapeutic vaccine setting. Surprisingly, our results demonstrated that boosting BCG with subunit vaccine shortly before Mtb challenge did not improve the BCG-primed immunity, whereas the subunit vaccine boost after Mtb challenge markedly improved the quantity and quality of effector T cell responses and significantly reduced Mtb load in lungs, liver and spleen in mice. These studies suggest that ESAT-6 lipopeptide-based subunit vaccine was ineffective in overcoming the apparent immunomodulation induced by BCG vaccine in Mtb uninfected mice, but upon infection, the subunit vaccine is effective in re-educating the protective immunity against Mtb infection. These important results have significant implications in the design and investigation of effective vaccine strategies and immunotherapeutic approaches for individuals who have been pre-immunized with BCG vaccine but still get infected with Mtb .

In this work, we examine the problem of efficiently preprocessing and denoising high volume environmental acoustic data, which is a necessary step in many bird monitoring tasks. Preprocessing is typically made up of multiple steps which are considered separately from each other. These are often resource intensive, particularly because the volume of data involved is high. We focus on addressing two challenges within this problem: how to combine existing preprocessing tasks while maximising the effectiveness of each step, and how to process this pipeline quickly and efficiently, so that it can be used to process high volumes of acoustic data. We describe a distributed system designed specifically for this problem, utilising a master-slave model with data parallelisation. By investigating the impact of individual preprocessing tasks on each other, and their execution times, we determine an efficient and accurate order for preprocessing tasks within the distributed system. We find that, using a single core, our pipeline executes 1.40 times faster compared to manually executing all preprocessing tasks. We then apply our pipeline in the distributed system and evaluate its performance. We find that our system is capable of preprocessing bird acoustic recordings at a rate of 174.8 seconds of audio per second of real time with 32 cores over 8 virtual machines, which is 21.76 times faster than a serial process., Competing Interests: The authors have declared that no competing interests exist.

The clinicopathological correlations between aspects of cognition, disease severity and imaging in Parkinson's Disease (PD) have been unclear. We studied cognitive profiles, demographics, and functional connectivity patterns derived from resting-state fMRI data (rsFC) in 31 PD subjects from the Parkinson's Progression Markers Initiative (PPMI) database. We also examined rsFC from 19 healthy subjects (HS) from the Pacific Parkinson's Research Centre. Graph theoretical measures were used to summarize the rsFC patterns. Canonical correlation analysis (CCA) was used to relate separate cognitive profiles in PD that were associated with disease severity and demographic measures as well as rsFC network measures. The CCA model relating cognition to demographics suggested female gender and education supported cognitive function in PD, age and depression scores were anti-correlated with overall cognition, and UPDRS had little influence on cognition. Alone, rsFC global network measures did not significantly differ between PD and controls, yet some nodal network measures, such as network segregation, were distinguishable between PD and HS in cortical "hub" regions. The CCA model relating cognition to rsFC global network values, which was not related to the other CCA model relating cognition to demographic information, suggested modularity, rich club coefficient, and transitivity was also broadly related to cognition in PD. Our results suggest that education, aging, comorbidity, and gender impact cognition more than overall disease severity in PD. Cortical "hub" regions are vulnerable in PD, and impairments of processing speed, attention, scanning abilities, and executive skills are related to enhanced functional segregation seen in PD.

Falls and balance difficulties remain a major source of morbidity in Parkinson's Disease (PD) and are stubbornly resistant to therapeutic interventions. The mechanisms of gait impairment in PD are incompletely understood but may involve changes in the Pedunculopontine Nucleus (PPN) and its associated connections. We utilized fMRI to explore the modulation of PPN connectivity by Galvanic Vestibular Stimulation (GVS) in healthy controls ( n = 12) and PD subjects even without overt evidence of Freezing of Gait (FOG) while on medication ( n = 23). We also investigated if the type of GVS stimuli (i.e., sinusoidal or stochastic) differentially affected connectivity. Approximate PPN regions were manually drawn on T1 weighted images and 58 other cortical and subcortical Regions of Interest (ROI) were obtained by automatic segmentation. All analyses were done in the native subject's space without spatial transformation to a common template. We first used Partial Least Squares (PLS) on a subject-by-subject basis to determine ROIs across subjects that covaried significantly with the voxels within the PPN ROI. We then performed functional connectivity analysis on the PPN-ROI connections. In control subjects, GVS did not have a significant effect on PPN connectivity. In PD subjects, baseline overall magnitude of PPN connectivity was negatively correlated with UPDRS scores ( p < 0.05). Both noisy and sinusoidal GVS increased the overall magnitude of PPN connectivity ( p = 6 × 10 -5 , 3 × 10 -4 , respectively) in PD, and increased connectivity with the left inferior parietal region, but had opposite effects on amygdala connectivity. Noisy stimuli selectively decreased connectivity with basal ganglia and cerebellar regions. Our results suggest that GVS can enhance deficient PPN connectivity seen in PD in a stimulus-dependent manner. This may provide a mechanism through which GVS assists balance in PD, and may provide a biomarker to develop individualized stimulus parameters.

The resurgence of mycobacterial infections and the emergence of drug-resistant strains urgently require a new class of agents that are distinct than current therapies. A group of 5-ethynyl (6-10), 5-(2-propynyloxy) (16, 18, 20, 22, 24), 5-(2-propynyloxy)-3-N-(2-propynyl) (17, 19, 21, 23, 25) and 5-hydroxymethyl-3-N-(2-propynyl) (30-33) derivatives of pyrimidine nucleosides were synthesized and evaluated against mycobacteria [Mycobacterium tuberculosis (Mtb), Mycobacterium bovis (BCG) and Mycobacterium avium], gram-positive bacteria (Staphylococcus aureus and Enterococcus faecalis) and gram-negative bacteria (Escherichia coli, Salmonella typhimurium and Pseudomonas aeruginosa) alone and in combination with existing drugs in in vitro assays. Although several compounds exhibited marked inhibitory activity at a higher concentration against Mtb, M. bovis, S. aureus and E. faecalis, they displayed unexpected synergistic and additive interactions at their lower concentrations with antitubercular drugs isoniazid and rifampicin, and antibacterial drug gentamicin. The active analogues were also found to inhibit intracellular Mtb in a human monocytic cell line infected with H37Ra. Oral administration of 5-hydroxymethyl-3-N-(2-propynyl)-3'-azido-2',3'-dideoxyuridine (32) and 5-hydroxymethyl-3-N-(2-propynyl)-2',3'-dideoxyuridine (33) at a dose of 100mg/kg for two weeks showed promising in vivo effects in mice infected with Mtb (H37Ra). No in vitro cytotoxicity of the test compounds was observed up to the highest concentration tested (CC50>300μg/mL)., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

We present ChromATin, a quantitative high-resolution imaging approach for investigating chromatin organization in complex tissues. This method combines analysis of epigenetic modifications by immunostaining, localization of specific DNA sequences by FISH, and high-resolution segregation of nuclear compartments using array tomography (AT) imaging. We then apply this approach to examine how the genome is organized in the mammalian brain using female Rett syndrome mice, which are a mosaic of normal and Mecp2-null cells. Side-by-side comparisons within the same field reveal distinct heterochromatin territories in wild-type neurons that are altered in Mecp2-null nuclei. Mutant neurons exhibit increased chromatin compaction and a striking redistribution of the H4K20me3 histone modification into pericentromeric heterochromatin, a territory occupied normally by MeCP2. These events are not observed in every neuronal cell type, highlighting ChromATin as a powerful in situ method for examining cell-type-specific differences in chromatin architecture in complex tissues., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Mice that are deficient in the transcription factor methyl-CpG-binding protein 2 (MeCP2) have a depressed hypercapnic ventilatory response (HCVR). The expression of MeCP2 can be selectively removed from astrocytes or neurons, thus offering a tool to dissect the role of this transcription factor in astrocytes from that in neurons. Studies were carried out in the progeny of mice that were a cross between those harboring a tamoxifen (TAM)-inducible Cre recombinase transgene driven by the human astrocytic glial fibrillary acidic protein (hGFAP) promoter, or Cre recombinase under control of the synapsin promoter, with mice containing a Cre-excisable exon III in the Mecp2 gene. The TAM-conditional excision of the Mecp2 exon allowed the respiratory CO2 response to be studied in the same animals before and after selective depletion of MeCP2 in astrocytes. Immunohistochemistry showed that following TAM treatment only ∼20% of GFAP-labeled cells in the retrotrapazoid nucleus and in the raphé magnus were positive for MeCP2. The slope of the relative increase in minute ventilation as a function of 1, 3, and 5% inspired CO2 was depressed in mice with depleted astrocyte MeCP2 compared with wild-type littermates. In contrast, selective depletion of MeCP2 in neurons did not significantly affect slope. While neurons which constitute the respiratory network ultimately determine the ventilatory response to CO2, this study demonstrates that loss of MeCP2 in astrocytes alone is sufficient to result in a dramatic attenuation of the HCVR. We propose that the glial contribution to HCVR is under the control of the MeCP2 gene., (Copyright © 2015 the American Physiological Society.)

Even with the advent of next-generation sequencing (NGS) technologies which have revolutionised the field of bacterial genomics in recent years, a major barrier still exists to the implementation of NGS for routine microbiological use (in public health and clinical microbiology laboratories). Such routine use would make a big difference to investigations of pathogen transmission and prevention/control of (sometimes lethal) infections. The inherent complexity and high frequency of data analyses on very large sets of bacterial DNA sequence data, the ability to ensure data provenance and automatically track and log all analyses for audit purposes, the need for quick and accurate results, together with an essential user-friendly interface for regular non-technical laboratory staff, are all critical requirements for routine use in a public health setting. There are currently no systems to answer positively to all these requirements, in an integrated manner. In this paper, we describe a system for sequence analysis and interpretation that is highly automated and tackles the issues raised earlier, and that is designed for use in diagnostic laboratories by healthcare workers with no specialist bioinformatics knowledge.

The bivalent hypothesis posits that genes encoding developmental regulators required for early lineage decisions are poised in stem/progenitor cells by the balance between a repressor histone modification (H3K27me3), mediated by the Polycomb Repressor Complex 2 (PRC2), and an activator modification (H3K4me3). In this study, we test whether this mechanism applies equally to genes that are not required until terminal differentiation. We focus on the RE1 Silencing Transcription Factor (REST) because it is expressed highly in stem cells and is an established global repressor of terminal neuronal genes. Elucidation of the REST complex, and comparison of chromatin marks and gene expression levels in control and REST-deficient stem cells, shows that REST target genes are poised by a mechanism independent of Polycomb, even at promoters which bear the H3K27me3 mark. Specifically, genes under REST control are actively repressed in stem cells by a balance of the H3K4me3 mark and a repressor complex that relies on histone deacetylase activity. Thus, chromatin distinctions between pro-neural and terminal neuronal genes are established at the embryonic stem cell stage by two parallel, but distinct, repressor pathways.

Background: The position, shape, size, and depth of the umbilicus influence the overall aesthetics of the abdomen. Hence, umbilicoplasty is a common adjunct to aesthetic and reconstructive surgery of the abdominal wall. Delineation of the position and shape of the "beautiful" umbilicus can aid in the planning of abdominoplasty and lipoabdominoplasty., Objectives: The authors aimed to identify key parameters of the beautiful umbilicus., Methods: Previously, the authors developed software (the Aesthetic Analyzer) for marking and analyzing parameters from images of the nose, breast, and umbilicus. In the present study, the Aesthetic Analyzer was utilized to determine parameters of the beautiful umbilicus from images of 37 Playboy playmates. The vertical position, horizontal position, length, and shape of the umbilicus were assessed., Results: Based on these images, the beautiful umbilicus possesses the following properties: a vertical ratio of 46:54 (with respect to the xiphoid process and lower limit of the vulvar cleft), a midline horizontal position, a length that is 5% of the length from the xiphoid process to the lower limit of the vulvar cleft, and an oval shape with no hooding (29.8%) or superior hooding (21.6%)., Conclusions: Awareness of the ideal position, shape, and size of the umbilicus can be useful for achieving successful reconstruction of the umbilicus during abdominoplasty and lipoabdominoplasty., (© 2014 The American Society for Aesthetic Plastic Surgery, Inc.)

Recent advances in DNA sequencing technologies have the potential to transform the field of clinical and public health microbiology, and in the last few years numerous case studies have demonstrated successful applications in this context. Among other considerations, a lack of user-friendly data analysis and interpretation tools has been frequently cited as a major barrier to routine use of these techniques. Here we consider the requirements of microbiology laboratories for the analysis, clinical interpretation and management of bacterial whole-genome sequence (WGS) data. Then we discuss relevant, existing WGS analysis tools. We highlight many essential and useful features that are represented among existing tools, but find that no single tool fulfils all of the necessary requirements. We conclude that to fully realise the potential of WGS analyses for clinical and public health microbiology laboratories of all scales, we will need to develop tools specifically with the needs of these laboratories in mind.

Disturbances in respiration are common and debilitating features of Rett syndrome (RTT). A previous study showed that the 5-HT1a receptor agonist (R)-(+)-8-hydroxy-dipropyl-2-aminotetralin hydrobromide (8-OH-DPAT) significantly reduced the incidence of apnea and the irregular breathing pattern in a mouse model of the disorder. 8-OH-DPAT, however, is not available for clinical practice. Sarizotan, a full 5-HT1a agonist and a dopamine D2-like agonist/partial agonist, has been used in clinical trials for the treatment of l-dopa-induced dyskinesia. The purpose of this study was to evaluate the effects of sarizotan on respiration and locomotion in mouse models of RTT. Studies were performed in Bird and Jaenisch strains of methyl-CpG-binding protein 2--deficient heterozygous female and Jaenisch strain Mecp2 null male mice and in knock-in heterozygous female mice of a common nonsense mutation (R168X). Respiratory pattern was determined with body plethysmography, and locomotion was determined with open-field recording. Sarizotan or vehicle was administered 20 minutes before a 30-minute recording of respiratory pattern or motor behavior. In separate studies, a crossover design was used to administer the drug for 7 and for 14 days. Sarizotan reduced the incidence of apnea in all three RTT mouse models to approximately 15% of their pretreatment levels. The irregular breathing pattern was corrected to that of wild-type littermates. When administered for 7 or 14 days, apnea decreased to 25 to 33% of the incidence seen with vehicle. This study indicates that the clinically approved drug sarizotan is an effective treatment for respiratory disorders in mouse models of RTT.

De novo mutations in the X-linked gene encoding the transcription factor methyl-CpG binding protein 2 (MECP2) are the most frequent cause of the neurological disorder Rett syndrome (RTT). Hemizygous males usually die of neonatal encephalopathy. Heterozygous females survive into adulthood but exhibit severe symptoms including microcephaly, loss of purposeful hand motions and speech, and motor abnormalities, which appear after a period of apparently normal development. Most studies have focused on male mouse models because of the shorter latency to and severity in symptoms, yet how well these mice mimic the disease in affected females is not clear. Very few therapeutic treatments have been proposed for females, the more gender-appropriate model. Here, we show that self-complementary AAV9, bearing MeCP2 cDNA under control of a fragment of its own promoter (scAAV9/MeCP2), is capable of significantly stabilizing or reversing symptoms when administered systemically into female RTT mice. To our knowledge, this is the first potential gene therapy for females afflicted with RTT.

Proteolytic control can govern the levels of specific regulatory factors, such as Spx, a transcriptional regulator of the oxidative stress response in Gram-positive bacteria. Under oxidative stress, Spx concentration is elevated and upregulates transcription of genes that function in the stress response. When stress is alleviated, proteolysis of Spx catalysed by ClpXP reduces Spx concentration. Proteolysis is enhanced by the substrate recognition factor YjbH, which possesses a His-Cys-rich region at its N terminus. However, mutations that generate H12A, C13A, H14A, H16A and C31/34A residue substitutions in the N terminus of Bacillus subtilis YjbH (BsYjbH) do not affect functionality in Spx proteolytic control in vivo and in vitro. Because of difficulties in obtaining soluble BsYjbH, the Geobacillus thermodenitrificans yjbH gene was cloned, which yielded soluble GtYjbH protein. Despite its lack of a His-Cys-rich region, GtYjbH complements a B. subtilis yjbH null mutant, and shows high activity in vitro when combined with ClpXP and Spx in an approximately 30 : 1 (ClpXP/Spx : GtYjbH) molar ratio. In vitro interaction experiments showed that Spx and the protease-resistant Spx(DD) (in which the last two residues of Spx are replaced with two Asp residues) bind to GtYjbH, but deletion of 12 residues from the Spx C terminus (SpxΔC) significantly diminished interaction and proteolytic degradation, indicating that the C terminus of Spx is important for YjbH recognition. These experiments also showed that Spx, but not GtYjbH, interacts with ClpX. Kinetic measurements for Spx proteolysis by ClpXP in the presence and absence of GtYjbH suggest that YjbH overcomes non-productive Spx-ClpX interaction, resulting in rapid degradation.

In the present study, asymmetric membrane capsules (AMCs) with two compartments were successfully developed for simultaneous delivery of two poorly water-soluble drugs, Atenolol and Amlodipine Besylate, by using solubility modulation approach. Scanning electron microscopy (SEM) before dissolution showed presence of outer dense region and inner porous region for the prepared asymmetric membrane and the pore size increased after dissolution for both outer and inner layer. Diffuse reflectance spectroscopy (DRS) showed no incompatibility between the drug(s) and the excipients used in the study. The developed system was able to control the release of ATN and AMB by increasing the solubility through buffering agents of different strengths (0.25N to 1.0N). As the level of buffering agent was increased, the solubility of drugs also increased inside the asymmetric membrane capsule. The developed system was independent of the agitation intensity of the dissolution fluid but was dependent on the polymer diffusibility and osmotic pressure of the media, which clearly stated that osmotic pumping was the primary mechanism of drug(s) release from AMCs. The results of in-vitro demonstration of effect of membrane thickness on dissolution fluid entering AMCs showed that as the membrane thickness increased the volume of dissolution fluid entering into AMC decreased. The release kinetic studies of different formulations of AMCs showed that formulation code six, which consists of the highest amount of osmotic agents and optimum amount of buffering agents, was the best formulation, and it followed zero order release kinetics (r(2)=0.9990 for ATN and r(2)=0.9988 for AMB).

The alternate sigma factor sigH of Mycobacterium tuberculosis is expressed under stress and acts as a major regulator of several genes, including some other sigma factors and redox systems. While it is auto-regulated by its own promoter at the transcriptional level, its regulation at the post-translational level is through its cognate protein, an anti-sigma factor, RshA. Hither before RshA was believed to be a zinc-associated anti-sigma factor (ZAS) and the binding of RshA to SigH is redox dependent. Here, we show that RshA coordinates a [2Fe-2S] cluster using cysteines as ligands and native RshA has more affinity to [2Fe-2S] cluster than to zinc. Furthermore, we used amide hydrogen deuterium exchange mass spectrometry (HDX-MS), followed by site-directed mutagenesis in SigH and RshA, to elucidate the interaction mechanism of RshA and SigH and the potential role of metal ion clustering in SigH regulation. Three regions in SigH, comprising of residues 1-25, 58-69, 90-111, 115-132 and 157-196 and residues 35-57 of RshA show decreased deuterium exchange and reflect decreased solvent accessibility upon complexation with SigH. Of the three RshA mutants, created based on the HDX results, the RsHA E37A mutant shows stronger interaction with SigH, relative to WT RshA, while the H49A mutant abolishes interactions and the C(53)XXC(56)AXXA mutant has no effect on complexation with SigH. The D22A, D160A and E162 SigH mutants show significantly decreased binding to RshA and the E168A mutant completely abolished interactions with RshA, indicating that the SigH-RshA interaction is mediated by salt bridges. In addition, SigH-RshA interaction does not require clustering of metal ions. Based on our results, we propose a molecular model of the SigH-RshA interaction.