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Audio versions of bioRxiv paper abstracts

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Audio versions of bioRxiv paper abstracts

    Nicotinamide riboside augments the human skeletal muscle NAD+ metabolome and induces transcriptomic and anti-inflammatory signatures in aged subjects: a placebo-controlled, randomized trial

    Nicotinamide riboside augments the human skeletal muscle NAD+ metabolome and induces transcriptomic and anti-inflammatory signatures in aged subjects: a placebo-controlled, randomized trial

    Link to bioRxiv paper:
    http://biorxiv.org/cgi/content/short/680462v1?rss=1

    Authors: Elhassan, Y. S., Kluckova, K., Fletcher, R., Schmidt, M., Garten, A., Doig, C., Cartwright, D., Oakey, L., Burley, C., Jenkinson, N., Wilson, M., Lucas, S., Akerman, I., Seabright, A., Lai, Y.-C., Tennant, D., Nightingale, P., Wallis, G., Manolopoulos, K., Brenner, C., Philp, A., Lavery, G. G.

    Abstract:
    NAD+ is modulated by conditions of metabolic stress and has been reported to decline with aging, but human data are sparse. Nicotinamide riboside (NR) supplementation ameliorates metabolic dysfunction in rodents. We aimed to establish whether oral NR supplementation in aged participants can increase the skeletal muscle NAD+ metabolome, and questioned if tissue NAD+ levels are depressed with aging. We supplemented 12 aged men with NR 1g per day for 21-days in a placebo-controlled, randomized, double-blind, crossover trial. Targeted metabolomics showed that NR elevated the muscle NAD+ metabolome, evident by increased nicotinic acid adenine dinucleotide and nicotinamide clearance products. Muscle RNA sequencing revealed NR-mediated downregulation of energy metabolism and mitochondria pathways. NR also depressed levels of circulating inflammatory cytokines. In an additional study, 31P magnetic resonance spectroscopy-based NAD+ measurement in muscle and brain showed no difference between young and aged individuals. Our data establish that oral NR is available to aged human muscle and identify anti-inflammatory effects of NR, while suggesting that NAD+ decline is not associated with chronological aging per se in human muscle or brain.

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    Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) Induces Functional Connectivity Changes in Emotion Regulation Brain Areas for MDD Patients

    Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) Induces Functional Connectivity Changes in Emotion Regulation Brain Areas for MDD Patients

    Link to bioRxiv paper:
    http://biorxiv.org/cgi/content/short/672154v1?rss=1

    Authors: Xiao, X., Bentzley, B., Cole, E. J., Tischler, C., Stimpson, K. H., Duvio, D., Bishop, J. H., Schatzberg, A., Keller, C., Sudheimer, K., Williams, N. R.

    Abstract:
    BackgroundMajor depressive disorder (MDD) is prevalent and debilitating, and development of improved treatments is limited in part by insufficient understanding of the mechanism of disease remission. In turn, efforts to elucidate mechanisms have been challenging due to disease heterogeneity and limited effectiveness of treatments, which require weeks-to-months to induce remission. We recently developed a form of repetitive transcranial magnetic stimulation that induces remission in 90% of individuals with severe, treatment resistant MDD in 1-5 days (SAINT). This provides a new tool to begin exploring the network-level mechanisms of MDD remission.

    ObjectiveDetermine the functional connectivity (fc) changes that occur with SAINT in brain regions associated with emotion regulation.

    MethodsResting-state fMRI scans were performed just prior to (baseline), and following, open-label SAINT in 18 participants with severe, treatment-resistant MDD. Fc was determined between regions of interest (ROIs) defined a priori with well-described roles in emotion regulation.

    ResultsFollowing SAINT treatment fc was significantly decreased between the following ROI pairs: dorsolateral prefrontal cortex (DLPFC)-striatum, DLPFC-amygdala, default mode network (DMN)-subgenual cingulate cortex (sgACC), DMN-amygdala, DMN-striatum, amygdala-striatum, and between amygdala subregions. Greater clinical improvements were associated with larger decreases in fc between DLPFC-amygdala and DLPFC-insula. Greater clinical improvements were associated with smaller decreases in fc between sgACC-DMN. Significant increases and decreases in fc between insula-amygdala were observed depending on the subregions. Greater clinical improvements were associated with lower baseline fc between DMN-DLPFC, DMN-striatum, and DMN-ventrolateral prefrontal cortex.

    ConclusionSAINT-induced remission from depression is associated with fc changes that suggest improved regulation of emotion. Although preliminary, this leads us to hypothesize that interventions that augment top-down regulation of emotion may be effective depression treatments.

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    Efficacy and safety of a novel vaginal medical device in Recurrent Bacterial Vaginosis: an international multicentre clinical trial

    Efficacy and safety of a novel vaginal medical device in Recurrent Bacterial Vaginosis: an international multicentre clinical trial

    Link to bioRxiv paper:
    http://biorxiv.org/cgi/content/short/674705v1?rss=1

    Authors: Murina, F., Crisan, C., Biris, M., Sirbu, D., Barattini, D. F., Ardolino, L. I., Casolati, E.

    Abstract:
    Several risk factors have been identified but the etiology and pathogenesis of Bacterial vaginosis (BV) are still not completely understood, and the recurrence rate of BV remains high despite adequate chemotherapy treatment.

    The primary objective of the study was to assess the effectiveness of a new vaginal medical device, which contains polycarbophil, 0.04 % lauryl glucoside, and glycerides (Polybactum(R) - Effik Italia), in reducing BV recurrence rate.

    This was a multicenter, open label, not comparative study performed in Italy and Romania. Female subjects over 18-years-old affected by recurrent BV were included. The latest episode was diagnosed by Amsel criteria 6-9 days before the start of the study and treated with vaginal metronidazole (gel 0.75% mg for 5 days or ovules 500 mg for 7 days). The recurrence was defined by at least 2 episodes in the previous 12 months. Polybactum(R) vaginal ovules, day 1-4-7, were started within the 12th and the 24th hr after the end of metronidazole therapy and repeated monthly for 3 cycles.

    The first 41 patients enrolled were evaluated for an interim analysis 6 months after the study started; 2 patients interrupted the trial, leaving 39 evaluable subjects. The recurrence rate was significantly reduced compared to previous published data (10.26% vs 40% p0.001). In 35 patients without recurrence, the assessment of Lactobacillus vaginal flora performed by phase contrast microscopy evidenced a significant improvement form baseline (p=0.022) The Investigator global assessment of tolerability was excellent in 38 out of 39 cases.

    IMPORTANCEBacterial vaginosis (BV) is the most common vaginal disorder in women of childbearing age. In BV, Lactobacillus species, which are predominant in a healthy vaginal flora, are replaced by anaerobes, mainly Gardnerella vaginalis. BV is responsible for more than 60% of vulvovaginal infections and has been linked to serious, potentially life-threatening conditions, including: pelvic inflammatory disease, postoperative infections, acquisition and transmission of the human immunodeficiency virus, preterm birth, and several adverse pregnancy outcomes. Our research showed that 3 monthly cycles of Polybactum(R) ovules administered after one course of metronidazole vaginal therapy can reduce the rate of Bacterial vaginosis recurrence and improve the vaginal milieu, favouring the growth of vaginal lactobacillus species. Taken together our results confirm that Polibactum(R) is a safe and effective treatment to reduce BV recurrence rate after a first line therapy with metronidazole.

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    Targeting the Autonomic Nervous System Balance in Patients with Chronic Low Back Pain using Transcranial Alternating Current Stimulation: A Randomized, Crossover, Double-Blind, Placebo-Controlled Pilot Study

    Targeting the Autonomic Nervous System Balance in Patients with Chronic Low Back Pain using Transcranial Alternating Current Stimulation: A Randomized, Crossover, Double-Blind, Placebo-Controlled Pilot Study

    Link to bioRxiv paper:
    http://biorxiv.org/cgi/content/short/668541v1?rss=1

    Authors: Prim, J. H., Ahn, S., Davila, M. I., Alexander, M. L., McCulloch, K. L., Frohlich, F.

    Abstract:
    BackgroundChronic low back pain (CLBP) is characterized by an alteration in pain processing by the central nervous system that may affect autonomic nervous system (ANS) balance. Heart rate variability (HRV) reflects the balance of parasympathetic and sympathetic ANS activation. In particular, respiratory sinus arrhythmia (RSA) solely reflects parasympathetic input and is reduced in CLBP patients. Yet, it remains unknown if non-invasive brain stimulation can alter ANS balance in CLBP patients.

    ObjectiveTo evaluate if non-invasive brain stimulation modulates the ANS, we analyzed HRV metrics collected in a previously published study of transcranial alternating current stimulation (tACS) for the modulation of CLBP through enhancing alpha oscillations. We hypothesized that tACS would increase RSA.

    MethodsA randomized, crossover, double-blind, sham-controlled pilot study was conducted to investigate the effects of 10Hz-tACS on metrics of ANS balance calculated from electrocardiogram (ECG). ECG data were collected for 2 minutes before and after 40 minutes of 10Hz-tACS or sham stimulation.

    ResultsThere were no significant changes in RSA or other frequency-domain HRV components from 10Hz-tACS. However, exploratory time-domain HRV analysis revealed a significant increase in the standard deviation of normal RR intervals (SDNN) for 10Hz-tACS relative to sham.

    Conclusion(s)Although tACS did not significantly increase RSA, we found in an exploratory analysis that tACS modulated an integrated HRV measure of both ANS branches. These findings support the further study of how the ANS and alpha oscillations interact and are modulated by tACS.

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    PARP1 as a biomarker for early detection and intraoperative tumor delineation in epithelial cancers - first-in-human results

    PARP1 as a biomarker for early detection and intraoperative tumor delineation in epithelial cancers - first-in-human results

    Link to bioRxiv paper:
    http://biorxiv.org/cgi/content/short/663385v1?rss=1

    Authors: Kossatz, S., Pirovano, G., Demetrio De Souza Franca, P., Strome, A. L., Sunny, S. P., Karassawa Zanoni, D., Mauguen, A., Carney, B., Brand, C., Shah, V., Ramanajinappa, R. D., Hedne, N., Birur, P., Sihag, S., Ghossein, R. A., Gonen, M., Strome, M., Suresh, A., Molena, D., Kuriakose, M. A., Patel, S. G., Reiner, T.

    Abstract:
    Major determining factors for survival of patients with oral, oropharyngeal, and esophageal cancer are early detection, the quality of surgical margins, and the contemporaneous detection of residual tumor. Intuitively, the exposed location at the epithelial surface qualifies these tumor types for utilization of visual aids to assist in discriminating tumor from healthy surrounding tissue. Here, we explored the DNA repair enzyme PARP1 as imaging biomarker and conducted optical imaging in animal models, human tissues and as part of a first-in-human clinical trial. Our data suggests that PARP1 is a quantitative biomarker for oral, oropharyngeal, and esophageal cancer and can be visualized with PARPi-FL, a fluorescently labeled small molecule contrast agent for topical or intravenous delivery. We show feasibility of PARPi-FL-assisted tumor detection in esophageal cancer, oropharyngeal and oral cancer. We developed a contemporaneous PARPi-FL topical staining protocol for human biospecimens. Using fresh oral cancer tissues within 25 min of biopsy, tumor and margin samples were correctly identified with >95% sensitivity and specificity without terminal processing. PARPi-FL imaging can be integrated into clinical workflows, potentially providing instantaneous assessment of the presence or absence of microscopic disease at the surgical margin. Additionally, we showed first-in-human PARPi-FL imaging in oral cancer. In aggregate, our preclinical and clinical studies have the unifying goal of verifying the clinical value of PARPi-FL-based optical imaging for early detection and intraoperative margin assignment.

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    Quadruplex qPCR for qualitative and quantitative analysis of the HIV-1 latent reservoir

    Quadruplex qPCR for qualitative and quantitative analysis of the HIV-1 latent reservoir

    Link to bioRxiv paper:
    http://biorxiv.org/cgi/content/short/641951v1?rss=1

    Authors: Gaebler, C., Cetrulo Lorenzi, J. C., Oliveira, T. Y., Nogueira, L., Ramos, V., Lu, C.-L., Pai, J. A., Mendoza, P., Jankovic, M., Caskey, M., Nussenzweig, M. C.

    Abstract:
    HIV-1 infection requires life-long therapy with anti-retroviral drugs due to the existence of a latent reservoir of transcriptionally inactive integrated proviruses. The goal of HIV-1 cure research is to eliminate or functionally silence this reservoir. To this end there are numerous ongoing studies to evaluate immunologic approaches including monoclonal antibody therapies. Evaluating the results of these studies requires sensitive and specific measures of the reservoir. Here we describe a relatively high throughput combined quantitative polymerase chain reaction (qPCR) and next generation sequencing method. Four different qPCR probes covering the packaging signal (PS), group-specific antigen (gag), polymerase (pol), and envelope (env) are combined in a single multiplex reaction to detect the HIV-1 genome in limiting dilution samples followed by sequence verification of individual reactions that are positive for combinations of any 2 of the 4 probes (Q4PCR). This sensitive and specific approach allows for an unbiased characterization of the HIV-1 latent reservoir.

    SummaryHIV-1 cure research seeks to decrease or eliminate the latent reservoir. The evaluation of such curative strategies requires accurate measures of the reservoir. Gaebler et al. describe a combined multicolor qPCR and next generation sequencing method that enables the sensitive and specific characterization of the HIV-1 latent reservoir.

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