Global electromagnetic induction constraints on transition-zone water content variations.

Small amounts of water can significantly affect the physical properties of mantle materials, including lowering of the solidus, and reducing effective viscosity and seismic velocity. The amount and distribution of water within the mantle thus has profound implications for the dynamics and geochemical evolution of the Earth. Electrical conductivity is also highly sensitive to the presence of hydrogen in mantle minerals. The mantle transition zone minerals wadsleyite and ringwoodite in particular have high water solubility, and recent high pressure experiments show that the electrical conductivity of these minerals is very sensitive to water content. Thus estimates of the electrical conductivity of the mantle transition zone derived from electromagnetic induction studies have the potential to constrain the water content of this region. Here we invert long period geomagnetic response functions to derive a global-scale three-dimensional model of electrical conductivity variations in the Earth's mantle, revealing variations in the electrical conductivity of the transition zone of approximately one order of magnitude. Conductivities are high in cold, seismically fast, areas where slabs have subducted into or through the transition zone. Significant variations in water content throughout the transition zone provide a plausible explanation for the observed patterns. Our results support the view that at least some of the water in the transition zone has been carried into that region by cold subducting slabs.

Data-Sharing Across Otolaryngology: Comparing Journal Policies and Their Adherence to the FAIR Principles.

OBJECTIVE: Data-sharing plays an essential role in advancing scientific understanding. Here, we aim to identify the commonalities and differences in data-sharing policies endorsed by otolaryngology journals and to assess their adherence to the FAIR (findable, accessible, interoperable, reusable) principles. METHODS: Data-sharing policies were searched for among 111 otolaryngology journals, as listed by Scimago Journal & Country Rank. Policy extraction of the top biomedical journals as ranked by Google Scholar metrics were used as a comparison. The FAIR principles for scientific data management and stewardship were used for the extraction framework. This occurred in a blind, masked, and independent fashion. RESULTS: Of the 111 ranked otolaryngology journals, 100 met inclusion criteria. Of those 100 journals, 79 provided data-sharing policies. There was a clear lack of standardization across policies, along with specific gaps in accessibility and reusability which need to be addressed. Seventy-two policies (of 79; 91%) designated that metadata should have globally unique and persistent identifiers. Seventy-one (of 79; 90%) policies specified that metadata should clearly include the identifier of the data they describe. Fifty-six policies (of 79; 71%) outlined that metadata should be richly described with a plurality of accurate and relevant attributes. CONCLUSION: Otolaryngology journals have varying data-sharing policies, and adherence to the FAIR principles appears to be moderate. This calls for increased data transparency, allowing for results to be reproduced, confirmed, and debated.

Osteopathic Manipulative Medicine: A Brief Review of the Hands-On Treatment Approaches and Their Therapeutic Uses.

Osteopathic manipulative medicine (OMM) is an emerging practice in the healthcare field with increasing popularity and evidence-based therapy. Osteopathic manipulative treatments (OMT) include hands-on manipulations of different body structures to increase systemic homeostasis and total patient well-being. Indeed, this new realm of the whole patient-based approach is being taught in osteopathic schools around the country, and the osteopathic principles of a mind-body-spirit-based treatment are being instilled in many new Doctor of Osteopathy (D.O.) students. However, despite their proven therapeutic value, there are still many individuals, both in and outside the medical profession, who are unaware (or misinformed) of the therapeutic uses and potential benefits of OMT. Here, we provide a brief introduction to this osteopathic therapeutic approach, focusing on the hands-on techniques that are regularly implemented in the clinical setting. It is becoming increasingly evident that different OMTs can be implemented to enhance patient recovery, both alone and in conjunction with the targeted therapies used in allopathic regimens. Therefore, it may be beneficial to inform the general medical community and educate the public and those associated with the healthcare field about the benefits of using OMT as a treatment modality. OMT is lower-cost, noninvasive, and highly effective in promoting full-body healing by targeting the nervous, lymphatic, immune, and vascular systems. There is a growing body of literature related to osteopathic research and the possible molecular pathways involved in the healing process, and this burgeoning field of medicine is expected to increase in value in the healthcare field. This brief review article explains the frequently utilized OMT modalities and their recognized therapeutic benefits, which underscore the need to understand the possible molecular mechanisms and circulating biomarkers linked to the systemic benefits of osteopathic medicine.

Citrate-based fluorometric sensor for multi-halide sensing.

Halides play important roles in human health and environmental monitoring. However, different halides interfere with each other in current measurement methods. Simultaneous sensing of multiple halides in a fast and low-cost manner remains a challenge. Here, we report a fluorometric multi-halide sensing method by using a single citrate-based fluorophore, CA-Cys, on a custom-made portable device. The fluorescence emitted by CA-Cys is quenched due to the dynamic quenching of halide ions; the sensitivities vary from halide types and pH, providing the capability to obtain multiple Stern-Volmer equations at various pH values. The concentration of each halide can then be obtained by solving the resultant set of equations. A mM scale detection limit is demonstrated, which is suitable for halide wastewater monitoring. A proof-of-concept smartphone-based portable device is also fabricated and tested. The results from the fluorometer and portable device indicated that our multi-halide system is promising for real-world multi-halide sensing applications. This work represents a new direction in developing portable, low-cost, and simultaneous multi-halide sensing technologies.

Epigenetic field alterations in non-tumor prostate tissues detect prostate cancer in urine.

Prostate cancer (PC) development involves epigenetic DNA methylation changes that occur in the tumor. However, distinct DNA methylation changes have been previously found to encompass a widespread cancer field defect involving normal prostate tissue. In the current study, we analyzed a series of DNA methylation field markers to determine if they predict the presence of PC in urine. Urine samples were collected from patients undergoing prostate biopsy with biopsy-proven PC (90), and without PC (77). From the urine pellet, methylated DNA was quantified across several previously identified CpG island regions near the caveolin 1 (CAV1), even-skipped homeobox 1 (EVX1), fibroblast growth factor 1 (FGF1), natural cytotoxicity triggering receptor 2 (NCR2) and phospholipase A and acyltransferase 3 (PLA2G16) genes using bisulfite pyrosequencing. Univariate and multivariate analyses were performed. Urine cell pellets show significant increases in methylation in four of the markers from patients with PC compared to those without PC including EVX1 12.2 vs. 7.7%, CAV1 15.7 vs. 10.36%, FGF1 12.0 vs. 7.1%, and PLA2G16 12.2 vs. 8.3% [all P<0.01]. Area under the ROC Curve (AUCs) were generated for EXV1 (0.74, Odds ratios (OR) 1.09; 95% confidence intervals (CI) 0.94-1.25, CAV1 (0.72, OR 1.18; 95% CI 1.09-1.28) and PLA2G16 (0.76, OR 1.35; 95% CI 1.199-1.51). In combination, a two-marker assay performs better than prostate specific antigen (PSA), AUC 0.77 vs. PSA AUC of 0.6 (P = 0.01) with the lowest error. In addition, FGF1 distinguished between grade group 1 (GG1) and higher grade cancers (P<0.03). In conclusion, applying methylation of field defect loci to urine samples provides a novel approach to distinguish patients with and without cancer.

Synthetic Lethal Metabolic Targeting of Androgen-Deprived Prostate Cancer Cells with Metformin.

The initiation of androgen-deprivation therapy (ADT) induces susceptibilities in prostate cancer cells that make them vulnerable to synergistic treatment and enhanced cell death. Senescence results in cell-cycle arrest, but cells remain viable. In this study, we investigated the mechanisms by which prostate cancer cells undergo senescence in response to ADT, and determined whether an FDA-approved antidiabetic drug metformin has a synergistic effect with ADT in prostate cancer both in vitro and in vivo Our results show that longer term exposure to ADT induced senescence associated with p16INK4a and/or p27kip2 induction. The activation of PI3K/AKT and inactivation of AMPK in senescent cells resulted in mTORC1 activation. In addition, the antiapoptotic protein XIAP expression was increased in response to ADT. The addition of metformin following ADT induced apoptosis, attenuated mTOR activation, reduced senescent cell number in vitro, and inhibited tumor growth in prostate cancer patient-derived xenograft models. This study suggests that combining ADT and metformin may be a feasible therapeutic approach to remove persistent prostate cancer cells after ADT.

Combination therapy with androgen deprivation for hormone sensitive prostate cancer: A new frontier.

Androgen deprivation therapy (ADT) has been the standard of care for the last 75 years in metastatic hormone sensitive prostate cancer (PCa). However, this approach is rarely curative. Recent clinical trials have demonstrated that ADT combined with other agents, notably docetaxel and abiraterone, lead to improved survival. The mechanisms surrounding this improved cancer outcomes are incompletely defined. The response of cancer cells to ADT includes apoptosis and cell death, but a significant fraction remains viable. Our laboratory has demonstrated both in vitro and in vivo that cellular senescence occurs in a subset of these cells. Cellular senescence is a phenotype characterized by cell cycle arrest, senescence-associated ß-galactosidase (SA-ß-gal), and a hypermetabolic state. Positive features of cellular senescence include growth arrest and immune stimulation, although persistence may release cytokines and growth factors that are detrimental. Senescent tumor cells generate a catabolic state with increased glycolysis, protein turnover and other metabolic changes that represent targets for drugs, like metformin, to be applied in a synthetic lethal approach. This review examines the response to ADT and the putative role of cellular senescence as a biomarker and therapeutic target in this context.

Screening of urine identifies PLA2G16 as a field defect methylation biomarker for prostate cancer detection.

BACKGROUND: Prostate cancer (PC) is a multifocal disease. DNA methylation alterations are not restricted to the immediate peritumor environment, but spatially widespread in the adjacent and distant histologically normal prostate tissues. In the current study, we utilized high-throughput methylation arrays to identify epigenetic changes in the urine from men with and without cancer. DESIGN, SETTING, AND PARTICIPANTS: DNA urine samples were enriched for methylated fragments using MBD methyl-binding antibodies and applied to high density CytoScanHD arrays. Significant loci were validated using quantitative pyrosequencing and binary logistic regression modeling applied to urine sample analyses in a training (n = 83) and validation approach (n = 84). Methylation alterations in prostate tissues using pyrosequencing at the PLA2G16 locus were examined in 38 histologically normal specimens from men with (TA, n = 26) and without (NTA, n = 12) cancer and correlated to gene expression. RESULTS: Methylation microarrays identified 3,986 loci showing significantly altered methylation in the urine samples from patients with PC compared to those without (TA vs NTA; p<0.01). These loci were then compared against subjects with their prostates removed to exclude non-prostate cell markers yielding 196 significant regions. Multiple CpGs adjacent to PLA2G16 CpG island showed increased methylation in TA compared to NTA (p<0.01) in a large validation study of urine samples. The predictive accuracy of PLA2G16 methylation at CG2 showed the highest predictive value at 0.8 (odds ratio, 1.37; 95% confidence interval, 1.16-1.62; p<0.001). Using a probability cutoff of 0.065, the sensitivity and specificity of the multivariate model was 92% and 35%. When histologically normal prostate tissues/biopsies from patients with PC (TA) were compared to subjects without cancer, significant hypermethylation of PLA2G16 was noted (odds ratio, 1.35; 95% confidence interval, 1.07-1.71; p = 0.01). CONCLUSION: PLA2G16 methylation defines an extensive field defect in histologically normal prostate tissue associated with PC. PLA2G16 methylation in urine and prostate tissues can detect the presence of PC.

Validation of an epigenetic field of susceptibility to detect significant prostate cancer from non-tumor biopsies.

BACKGROUND: An epigenetic field of cancer susceptibility exists for prostate cancer (PC) that gives rise to multifocal disease in the peripheral prostate. In previous work, genome-wide DNA methylation profiling identified altered regions in the normal prostate tissue of men with PC. In the current multicenter study, we examined the predictive strength of a panel of loci to detect cancer presence and grade in patients with negative biopsy tissue. RESULTS: Four centers contributed benign prostate biopsy tissues blocks from 129 subjects that were either tumor associated (TA, Grade Group [GG] ≥ 2, n = 77) or non-tumor associated (NTA, n = 52). Biopsies were analyzed using pyrosequencing for DNA methylation encompassing CpG loci near CAV1, EVX1, FGF1, NCR2, PLA2G16, and SPAG4 and methylation differences were detected within all gene regions (p < 0.05). A multiplex regression model for biomarker performance incorporating a gene combination discriminated TA from NTA tissues (area under the curve [AUC] 0.747, p = 0.004). A multiplex model incorporating all the above genes and clinical information (PSA, age) identified patients with GG ≥ 2 PC (AUC 0.815, p < 0.0001). In patients with cancer, increased variation in gene methylation levels occurs between biopsies across the prostate. CONCLUSIONS: A widespread epigenetic field defect is utilized to detect GG ≥ 2 PC in patients with histologically negative biopsies. These alterations in non-tumor cells display increased heterogeneity of methylation extent and are spatially distant from tumor foci. These findings have the potential to decrease the need for repeated prostate biopsy.

Decreased OLA1 (Obg-Like ATPase-1) Expression Drives Ubiquitin-Proteasome Pathways to Downregulate Mitochondrial SOD2 (Superoxide Dismutase) in Persistent Pulmonary Hypertension of the Newborn.

Persistent pulmonary hypertension of the newborn (PPHN) is a failure of pulmonary vascular resistance to decline at birth rapidly. One principal mechanism implicated in PPHN development is mitochondrial oxidative stress. Expression and activity of mitochondrial SOD2 (superoxide dismutase) are decreased in PPHN; however, the mechanism remains unknown. Recently, OLA1 (Obg-like ATPase-1) was shown to act as a critical regulator of proteins controlling cell response to stress including Hsp70, an obligate chaperone for SOD2. Here, we investigated whether OLA1 is causally linked to PPHN. Compared with controls, SOD2 expression is reduced in distal-pulmonary arteries (PAs) from patients with PPHN and fetal-lamb models. Disruptions of the SOD2 gene reproduced PPHN phenotypes, manifested by elevated right ventricular systolic pressure, PA-endothelial cells apoptosis, and PA-smooth muscle cells proliferation. Analyses of SOD2 protein dynamics revealed higher ubiquitinated-SOD2 protein levels in PPHN-lambs, suggesting dysregulated protein ubiquitination. OLA1 controls multiple proteostatic mechanisms and is overexpressed in response to stress. We demonstrated that OLA1 acts as a molecular chaperone, and its activity is induced by stress. Strikingly, OLA1 expression is decreased in distal-PAs from PPHN-patients and fetal-lambs. OLA1 deficiency enhanced CHIP affinity for Hsp70-SOD2 complexes, facilitating SOD2 degradation. Consequently, mitochondrial H2O2 formation is impaired, leading to XIAP (X-linked inhibitor of apoptosis) overexpression that suppresses caspase activity in PA-smooth muscle cells, allowing them to survive and proliferate, contributing to PA remodeling. In-vivo, ola1-/- downregulated SOD2 expression, induced distal-PA remodeling, and right ventricular hypertrophy. We conclude that decreased OLA1 expression accounts for SOD2 downregulation and, therefore, a therapeutic target in PPHN treatments.

VGLUT1 synapses and P-boutons on regenerating motoneurons after nerve crush.

Stretch-sensitive Ia afferent monosynaptic connections with motoneurons form the stretch reflex circuit. After nerve transection, Ia afferent synapses and stretch reflexes are permanently lost, even after regeneration and reinnervation of muscle by motor and sensory afferents is completed in the periphery. This loss greatly affects full recovery of motor function. However, after nerve crush, reflex muscle forces during stretch do recover after muscle reinnervation and reportedly exceed 140% baseline values. This difference might be explained by structural preservation after crush of Ia afferent synapses on regenerating motoneurons and decreased presynaptic inhibitory control. We tested these possibilities in rats after crushing the tibial nerve (TN), and using Vesicular GLUtamate Transporter 1 (VGLUT1) and the 65 kDa isoform of glutamic acid-decarboxylase (GAD65) as markers of, respectively, Ia afferent synapses and presynaptic inhibition (P-boutons) on retrogradely labeled motoneurons. We analyzed motoneurons during regeneration (21 days post crush) and after they reinnervate muscle (3 months). The results demonstrate a significant loss of VGLUT1 terminals on dendrites and cell bodies at both 21 days and 3 months post-crush. However, in both cellular compartments, the reductions were small compared to those observed after TN full transection. In addition, we found a significant decrease in the number of GAD65 P-boutons per VGLUT1 terminal and their coverage of VGLUT1 boutons. The results support the hypothesis that better preservation of Ia afferent synapses and a change in presynaptic inhibition could contribute to maintain or even increase the stretch reflex after nerve crush and by difference to nerve transection.

Evaluation of the flexion relaxation phenomenon of the trunk muscles in sitting.

STUDY DESIGN: A normative, single-group study was conducted. OBJECTIVE: To investigate the flexion relaxation phenomenon in the thoraco-lumbopelvic muscles among a pain-free population when moving from an upright to a slump sitting posture. SUMMARY OF BACKGROUND DATA: The presence of the flexion relaxation phenomenon (FRP) of the back muscles is well documented at end-range spinal flexion when standing. This phenomenon is commonly found disrupted in low back subjects. However, whether FRP occurs in sitting remains controversial. METHODS: The sample consisted of 24 healthy pain-free adults. Surface electromyography was used to measure activity in the superficial lumbar multifidus (SLM), the thoracic erector spinae (TES), and the transverse fibers of the internal oblique (IO) muscles while subjects moved from an erect to a slump sitting posture. An electromagnetic motion-tracking device simultaneously measured thoracolumbar kinematics during this task. RESULTS: There was a significant decrease in both the SLM and the IO activity when moving from an erect to a slump sitting posture (P = 0.001 and P = 0.004, respectively), indicating the presence of FRP. TES activity was highly variable. While 13 subjects exhibited an increase in activity (P = 0.001), 11 demonstrated a decrease in activity (P = 0.001), indicating the presence of FRP. FRP occurred in the mid-range of spinal flexion for the SLM, IO and TES when present. CONCLUSION: The findings show that the SLM and the IO are facilitated in neutral lordotic sitting postures and exhibit FRP at mid range flexion while moving from upright sitting to slump sitting. These findings show that FRP in sitting differs from that in standing. Variable motor patterns (activation or FRP) of the TES were observed. These findings suggest that sustaining mid to end-range flexed sitting spinal postures result in relaxation of the spinal stabilizing muscles.