As transcription and replication use DNA as substrate, conflicts between transcription and replication can occur, leading to genome instability with direct consequences for human health. To determine how the two processes are coordinated throughout S phase, we characterize both processes together at high resolution. We find that transcription occurs during DNA replication, with transcription start sites (TSSs) not fully replicated along with surrounding regions and remaining under-replicated until late in the cell cycle. TSSs undergo completion of DNA replication specifically when cells enter mitosis, when RNA polymerase II is removed. Intriguingly, G2/M DNA synthesis occurs at high frequency in unperturbed cell culture, but it is not associated with increased DNA damage and is fundamentally separated from mitotic DNA synthesis. TSSs duplicated in G2/M are characterized by a series of specific features, including high levels of antisense transcription, making them difficult to duplicate during S phase.Obesity is frequently caused by calorie-rich dietary choices across the animal kingdom. As prandial preference toward a high-fat diet develops in mice, an anti-preference or devaluation of a nutritionally balanced but less palatable standard chow diet occurs concomitantly. Although mechanistic insights underlying devaluation have been observed physiologically in the brain, it is unclear how peripheral sensory processing affects food choice. Because olfactory cues and odor perception help coordinate food preference and intake, we determine the role of smell in the targeted consumption of a high-fat diet and simultaneous devaluation of a standard chow diet. Using inaccessible food and loss-of-function manipulations, we find that olfactory information is neither sufficient nor necessary for both the acute and chronic selection of high-fat diet and coincident diminished value of standard diet. This work suggests alternative means are behind the immediate and sustained consumption of high-fat diet and concurrent standard diet devaluation.The objective of study was to investigate the inhibitory effect of sinomenine on neuropathic pain on dorsal root ganglia (DRG). The DRG cell line and spinal nerve ligation (SNL) model were used in this study. The effect of sinomenine on the cell viability was examined by MTT assay. The expression of p38 MAPK, NF-κB, c-fos, SP and TNF-α was detected by using immunofluorescence and immunohistochemistry assay. We also assessed the level of p-CaMKII, COX-2, p-CREB, IL-17A, TLR4 and IL-1β via western blotting and RT-qPCR. Compared to the controls, sinomenine showed a protective effect on TNF-α-induced apoptosis on DRG cells in a dose-dependent manner, with an increase of cell viability and a decrease of reactive oxygen species level as well as LDH release. Parallelly, sinomenine treatment significantly reduced the expression of various factors related to stress and inflammation, including p38 MAPK, NF-κB, c-fos, p-CAMKII, COX-2, p-CREB, TLR4 and IL-17A in DRG cells in vitro. Furthermore, we found that administration of sinomenine significantly reduced mechanical withdrawal threshold and thermal withdrawal latency and inhibited the inflammation and activation of p38 signaling in SNL rats. It is noting that combined therapy of sinomenine and pulsed radiofrequency exhibited higher efficacy of dorsal root ganglia inflammation than single treatment as well as the combination of oxycodone and pulsed radiofrequency. Sinomenine inhibited the apoptosis of DRG cell by regulating p38 MAPK/CREB signalling pathway, which provides evidence to alleviate neuropathic pain in clinic.

To examine the proportion of high-sensitivity urine pregnancy test (HSPT) results that were positive by time after successful medication abortion.

We used data from an ongoing study that provides mifepristone and misoprostol for medication abortion by direct-to-patient telemedicine and mail. Providers evaluated abortion outcomes by patient interview and clinical tests per clinical judgment and participant preference. We identified all participants enrolled July 2016 to September, 2020 who had an HSPT result and no indication of viable pregnancy after treatment. We used logistic regression to examine the association between the timing of the initial post-treatment HSPT, gestational age, and the proportion of HSPTs that gave a positive result.

Of the 472 participants in our analysis, 88 (19%) had positive initial HSPTs. The proportions that were positive at ≤20 days, 21 to 27 days, 28 to 34 days, and ≥35 days after mifepristone ingestion was 14 of 29 (48%), 15 of 58 (26%), 49 of 258 (19%), and 10 of 127 (Ts provide an inexpensive, convenient option for confirming success of medication abortion at home. However, a substantial minority of patients without ongoing pregnancy have positive HSPT results. Development of a symptom-based strategy for medication abortion outcome assessment without any confirmatory tests should be a priority.The WiSE system is a novel, leadless endocardial system that can provide cardiac resynchronization therapy in patients who cannot be treated with a conventional epicardial left ventricular lead. Safety and efficacy were being evaluated in the pivotal, randomized, double-blind SOLVE-CRT Trial (Stimulation of the Left Ventricular Endocardium for Cardiac Resynchronization Therapy.) The trial was initiated in 2018; however, patient enrollment was significantly impacted by the COVID-19 pandemic necessitating a change in design. This article describes the revised trial and the scientific rationale for the specific changes in the protocol.Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.Obesity is a major risk factor for adverse outcomes in breast cancer; however, the underlying molecular mechanisms have not been elucidated. To investigate the role of crosstalk between mammary adipocytes and neoplastic cells in the tumor microenvironment (TME), we performed transcriptomic analysis of cancer cells and adjacent adipose tissue in a murine model of obesity-accelerated breast cancer and identified glycine amidinotransferase (Gatm) in adipocytes and Acsbg1 in cancer cells as required for obesity-driven tumor progression. Gatm is the rate-limiting enzyme in creatine biosynthesis, and deletion in adipocytes attenuated obesity-driven tumor growth. Similarly, genetic inhibition of creatine import into cancer cells reduced tumor growth in obesity. In parallel, breast cancer cells in obese animals upregulated the fatty acyl-CoA synthetase Acsbg1 to promote creatine-dependent tumor progression. These findings reveal key nodes in the crosstalk between adipocytes and cancer cells in the TME necessary for obesity-driven breast cancer progression.A father’s lifestyle impacts offspring health; yet, the underlying molecular mechanisms remain elusive. We hypothesized that a diet that changes methyl donor availability will alter the sperm and embryo epigenomes to impact embryonic gene expression and development. Here, we demonstrate that a folate-deficient (FD) diet alters histone H3 lysine 4 trimethylation (H3K4me3) in sperm at developmental genes and putative enhancers. A subset of H3K4me3 alterations in sperm are retained in the pre-implantation embryo and associated with deregulated embryonic gene expression. Using a genetic mouse model in which sires have pre-existing altered H3K4me2/3 in sperm, we show that a FD diet exacerbates alterations in sperm H3K4me3 and embryonic gene expression, leading to an increase in developmental defect severity. These findings imply that paternal H3K4me3 is transmitted to the embryo and influences gene expression and development. It further suggests that epigenetic errors can accumulate in sperm to worsen offspring developmental outcomes.Characterization of the humoral response to SARS-CoV-2, the etiological agent of COVID-19, is essential to help control the infection. The neutralization activity of plasma from patients with COVID-19 decreases rapidly during the first weeks after recovery. However, the specific role of each immunoglobulin isotype in the overall neutralizing capacity is still not well understood. In this study, we select plasma from a cohort of convalescent patients with COVID-19 and selectively deplete immunoglobulin A, M, or G before testing the remaining neutralizing capacity of the depleted plasma. We find that depletion of immunoglobulin M is associated with the most substantial loss of virus neutralization, followed by immunoglobulin G. This observation may help design efficient antibody-based COVID-19 therapies and may also explain the increased susceptibility to SARS-CoV-2 of autoimmune patients receiving therapies that impair the production of immunoglobulin M (IgM).Human and non-human animal behavior is highly malleable and adapts successfully to internal and external demands. Such behavioral success stands in striking contrast to the apparent instability in neural activity (i.e., variability) from which it arises. Here, we summon the considerable evidence across scales, species, and imaging modalities that neural variability represents a key, undervalued dimension for understanding brain-behavior relationships at inter- and intra-individual levels. We believe that only by incorporating a specific focus on variability will the neural foundation of behavior be comprehensively understood.Foot and Mouth Disease Virus (FMDV) causes economy losses and is controlled by vaccination in many countries. Vaccine formulations based on empty capsids or Virus-Like Particles (VLPs) have the advantage of avoiding the biological hazard of using infectious FMDV, albeit are poorly immunogenic. Recently, we have described that ISPA a new Immune Stimulating Complex adjuvant, is useful to improve the response against FMD of vaccines that use inactivated virus. Now, the adjuvant effects of ISPA and ISA 206 (water/oil/water) on a VLPs-based FMD vaccine were evaluated. VLPs (strain A/Argentina/2001) were obtained in mammalian cell cultures and their elicitation of an immune response against FMDV with and without ISPA or ISA 206 was evaluated in mice as a first approach. Notably, VLPs-ISPA and VLPs-ISA 206 vaccines induced protection against viral challenge in 100 % of mice, while protection induced by VLPs alone was of 40 %. Total and neutralizing FMDV antibodies were higher in the VLPs-ISPA and VLPs-ISA 206 groups compared to the VLPs group. VLPs-ISPA induced significantly higher (p less then 0.001) IgG1, IgG2a, IgG2b and IgG3 titers than the VLPs vaccine. Moreover, in comparison with non-adjuvanted VLPs, VLPs-ISPA and VLPs-ISA 206 elicited an increased virus-specific T response, including higher IFNγ+/CD8 + lymphocyte production in mice. When these vaccines were tested in calves, antibody titers reached an Expected Percentage of Protection (EPP) above 90 % in the case of the VLPs-ISPA and VLPs-ISA 206 vaccines, while, in the VLPs group, EPP reached 25 %. IFNγ levels secreted by mononuclear cells of VLP-ISPA-vaccinated cattle were significantly higher than in the VLPs group. Overall, the results demonstrate that VLPs-ISPA or VLPs-ISA 206 are promising formulations for the development of a novel FMD vaccine.Different types of susceptibility tests are available to identify antimicrobial activity, including the disc agar diffusion and broth micro-dilution methods. In recent years, high throughput screening (HTS) methods have been considered and evaluated as an efficient method to rapidly monitor the antimicrobial potential of a wide range of plant products. The objective of this study was to test the ability of a 96-well plate reader as HTS method to evaluate the antimicrobial potential of extracts of Terminalia ferdinandiana (Kakadu plum). The main changes observed in the UV-VIS spectra of the bacteria samples were related to the biochemical and chemical compounds that might originate from the effect of the T. ferdinandiana extracts and the bacteria. Partial least squares discriminant analysis (PLS-DA) allowed the correct classification of samples according to the concentration of extract added to the culture (e.g. high, medium and low). The results of this study indicated that might be possible to record changes in the UV-VIS spectra associated with the interactions between bacteria and T. ferdinandiana extracts using a 96-well plate reader. The method was able to detect or differentiate between live and dead bacteria based on the UV-VIS spectra as a function of the addition of the T. ferdinandiana extracts.Extreme lateral interbody fusion (XLIF) has become the standard of minimally invasive lumbar segmental scoliosis treatment. Our objective is to determine the safety and efficacy of XLIF in spinal canal stenosis (SCS) and spondylodiscitis (SD). Patients treated with XLIF in our department between 2012 and 2018 were retrospectively analyzed. Patient records with clinical and radiographical parameters were evaluated. The patient cohort consists of 40 male and 32 female patients with a median age of 66.6 years. Forty-five patients had an SCS and 27 patients SD. The mean follow-up was 23 months. One level XLIF was performed in 49 patients, 2 levels in 15, 3 levels in 7 patients and 4 levels in 1 patient. All but one patient received an additional dorsal stabilization. The pain was present in all patients with a mean Visual Analogue Scale (VAS) score of 8.8 vs. postoperative VAS of 2.8 (p less then 0.05). Preoperative neurological deficits were found in 44 patients. Only 6 patients had a neurological deterioration, 45 patients improved, and 21 patients remained unchanged. One patient experienced a perioperative complication. Non-fusion occurred in 8 cases. There were no outcome differences regarding pain and radiological outcome between patients with SCS and SD as well as between patients with one level vs. multilevel surgery. Baseline characteristics and the radiological outcome did not differ between the two groups. Patients with SD had a higher rate of worsening of neurological deficits following surgery, a higher rate of non-fusion, and a longer hospital stay. Patients with spinal canal stenosis SCS had a longer surgery time and more frequent adjacent segment disease.Kaposi sarcoma is a rare disease and there is a gap in the literature about which chemotherapeutics should be applied, especially for the classical type. We aimed to present our institutional data on the demographic characteristics, treatment, and treatment efficacy in 16 Kaposi sarcoma (KS) patients treated with chemotherapy. We retrospectively analyzed the demographic and clinical characteristics, and the chemotherapeutic agents administered to the 16 KS patients diagnosed in our center and treated with chemotherapy, based on the medical records obtained. The median age, gender, type of KS, site of involvement, cytotoxic agents administered, progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety profiles of the patients were evaluated. The median age at disease onset was 61.07 years (range, 39.4-85.8 years). Among the patients, 1 had immunosuppression-related KS, 4 had AIDS-related KS, and 11 had classical KS. In the first-line cytotoxic therapy, 7 patients received pegylated-liposomal doxorubicin (PLD), 6 patients received paclitaxel, 2 patients received oral etoposide, and 1 patient received the adriamycin, bleomycin, and vincristine regimen. In the Kaplan-Meier analysis, the PFS was 39.9 months (95% CI, 7.7-72.0). In the first-line setting, a significant difference in terms of PFS was observed between the PLD- and paclitaxel-treated groups (not reached vs. 12.8 months, p = 0.033). The OS was 66.1 months (95% CI, 30.2-102.0). The ORR of the 16 patients was 43.8%, and their DCR was 81.3%. No grade 3 or 4 toxicity was observed. This retrospective study showed that PLD seems better than paclitaxel in terms of PFS and response rates and it has shown to have a good safety profile in KS patients.COVID-19 is the current pandemic caused by the novel coronavirus, SARS-CoV-2, that emerged from China at the end of December 2019. The scientific community is making extraordinary efforts to understand the virus structure and the pathophysiology and immunological processes activated in the host, in order to identify biomarkers, diagnostic tools, treatments, and vaccines to decrease COVID-19 incidence and mortality. Various abnormalities have been noted during SARS-CoV-2 infection both in lymphoid and myeloid cells. Such abnormalities may disturb the immune system function and cause a massive inflammatory response that impairs tissue function. This review discusses the close relationship between the immune system abnormalities and the broad spectrum of clinical manifestations, including fibrosis, in the context of COVID-19 disease. Moreover, we described the current strategies for COVID-19 diagnosis, and we provide a summary of the most useful clinical laboratory parameters to identify severe COVID-19 patients.Lung signet-ring cell carcinoma (LSRCC) is a very rare type of lung cancer, the clinical characteristics, and prognosis of which remain to be clarified. In order to explore the clinicopathological and survival-related factors associated with LSRCC, we performed a large population-based cohort analysis of data included in the Surveillance, Epidemiology, and End Results (SEER) registry from 2001 to 2015. A total of 752 LSRCC and 7518 lung mucinous adenocarcinoma (LMAC) patients were incorporated into our analysis, with respective mean ages of 63.8 and 67.5 years at the time of diagnosis. LSRCC patients were significantly more likely than LMAC patients to have distant-stage disease (72.1% vs. 45.8%, p less then 0.0001), tumors of a high pathological grade (40.6% vs. 10.8%, p less then 0.0001), have undergone chemotherapy (62.1% vs. 39.9%, p less then 0.0001), be male (52.7% vs. 48.5%, p = 0.03), and be less then 40 years old (3.3% vs. 1.3%, p = 0.022), whereas they were less likely to have undergone surgical treatment (52.4% vs. 77.0%, p less then 0.0001). LSRCC and LMAC patients exhibited median overall survival (OS) duration of 8 and 18 months (p less then 0.0001), respectively, although these differences were not significant after adjusting for confounding variables. Independent factors associated with a favorable patient prognosis included a primary site in the middle or lower lung lobe, underwent surgery, and underwent chemotherapy. However, age ≥80 years, higher grade, distant summary stage disease, and T4 stage disease were linked to poor prognosis. Patient age, tumor grade, primary tumor site, summary stage, T stage, surgery, and chemotherapy were all significantly associated with LSRCC patient prognosis.

Hypermobile Ehlers-Danlos syndrome (hEDS) is the most frequent heritable disorder of the connective tissue. This is characterized by a generalized fragility of tissues leading to chronic pain, disability and high levels of psychological distress. Suicidal behaviors in those affected are not uncommon but they have not been well studied. We aimed to explore aspects of suicidality and related factors in a group of patients with hEDS.

Thirty-five women with hEDS were included in this cross-sectional study. They were assessed with the Mini-International Neuropsychiatric Interview for Axis 1 DSM-IV mental disorders and suicidality. They also responded to self-questionnaires assessing health (pain, BMI, and diagnosis delay) and psychosocial variables (social support, physical functioning, coping strategies, personality disturbances, and resilience).

Eleven patients (31.4%) had attempted suicide in the past. Fifteen patients (42.9%) had some degree of suicide risk at the time of evaluation, mainly mild risk (60.

Consistent with previous reports, these data highlight the high frequency of suicidal behaviors in hEDS patients as well as the importance to explore psychopathology in those affected in order to identify vulnerable individuals and provide specific support.HIGHLIGHTSAttempted suicide in patients with hEDS is not uncommon.Age and the presence of psychopathology are associated with suicide attempt in hEDS patients.Personality disturbances and lifetime anxiety disorders predicted suicide attempted in this sample.Purpose To determine the association of monocyte-to-high-density lipoprotein ratio (MHR) and neutrophil-to-lymphocyte ratio (NLR) with diabetic macular edema (DME) and early anti-VEGF treatment response.Material methods This was a retrospective and cross-sectional study conducted with 143 patients with diabetes mellitus (53 diabetic retinopathy with DME, 38 diabetic retinopathy without DME, and 52 without diabetic retinopathy).Results 13.9 was the best cutoff value to predict DME for MHR, and 2 was for NLR (59% and 75% sensitivity and 81% and 59% specificity, respectively). Logistic regression analysis showed that NLR≥2 and MHR≥13.9 were significantly associated with DME prediction. However, neither NLR≥2 nor MHR≥13.9 was associated with central retinal thickness(CRT) or best corrected visual acuity(BCVA) outcomes after anti-VEGF treatment. On the other hand, increased NLR was associated with inferior CRT outcomes.Conclusion MHR and NLR were simple and cost-effective biomarkers to predict DME. Moreover, higher NLR may contribute to poor CRT outcomes.

The objective of the current study was to investigate whether mindfulness and self-compassion are negatively associated with engagement in non-suicidal self-injury (NSSI) and whether emotion dysregulation would mediate this relation.

343 participants (82.2% female;

= 23.98;

 = 7.47) were recruited from university and community settings, and completed online questionnaires. Two groups of participants were created those with lifetime engagement in NSSI (

 = 153) and a comparison group with no prior engagement in NSSI (

 = 190).

First, two one-way MANOVAs revealed significant mean differences (NSSI/comparison) across the self-compassion dimensions and specific mindfulness facets. Second, logistic regressions revealed that the self-coldness dimension of self-compassion significantly predicted engagement in NSSI, and specific mindfulness facets (nonjudging and acting with awareness) were found to negatively predict NSSI engagement. Lastly, mediation analyses revealed that emotion dysregulation fullyey aspects of mindfulness and self-compassion as healthier and kinder alternatives to coping with dysregulated emotions.HighlightsMindfulness and self-compassion significantly differ between NSSI/comparison groupsKey mindfulness facets and self-compassion dimensions negatively predict engagement in NSSIEmotion dysregulation fully mediates self-coldness and mindfulness with NSSI group status.Research on the pretesting effect has shown that attempting to retrieve or generate information, even when unsuccessful, can potentiate the subsequent learning and remembering of that information. In the current research, we tested the hypothesis that when information can be accessed online, people may be less likely to retrieve or generate information on their own, thus making them less likely to benefit from the pretesting effect. The results of two experiments failed to provide support for this hypothesis. Participants remembered pretested information better than non-pretested information regardless of whether they were required to attempt to retrieve answers from memory or search for the answers using Google. The results suggest that the benefits of pretesting can be observed even when people rely on the internet to answer the questions they encounter.Vaccination has had tremendous impact on human health. The tendency to hesitate or delay vaccination has been increasing, which has contributed to outbreaks of vaccine-preventable diseases. This cross-sectional study aimed to investigate the prevalence of childhood vaccine hesitancy and social media misconceptions in vaccine refusal among randomly selected parents from October 2019 through March 2020 in the outpatient clinics of King Khalid University Hospital, Riyadh, Saudi Arabia. The data were collected using a three-part questionnaire the socio-demographic and economic questions, the Parents’ Attitudes about Childhood Vaccines (PACV) survey, and questions concerning social media use. Based on the PACV survey tool, 37 parents (11%) scored a value > 50 and were suggested as hesitant (8% hesitant and 3% very hesitant). Overall, 288 parents (89%) scored less then 50, hence deemed to not be hesitant about childhood vaccination. There was no significant association between high educational level or social media exposure with vaccine hesitancy. The most commonly used social media platform was Twitter (40%). In conclusion, we report a low prevalence of vaccine hesitancy about childhood vaccination among parents, with no significant impact of education level or social media on vaccine hesitancy. Further studies are required to replicate these findings in other regions and cities to generalize these observations for Saudi Arabia.Purpose/Objectives to evaluate new onset uveitis or reactivated uveitis by biologic agents and characterize their features.Materials and Methods This is a multicenter, retrospective case series. Patients under biologic therapy were included if they developed uveitis for the first time or experienced intraocular inflammation which was different in location or laterality to previous inflammation.Results Sixteen patients were identified. The underlying disorders included ankylosing spondylitis, juvenile idiopathic arthritis, rheumatoid arthritis, and Behçet’s Disease. The biologic agents associated with a first episode of uveitis (n = 11) or with a new recurrence of uveitis (n = 5) were etanercept, adalimumab, abatacept, infliximab, and golimumab. Sarcoidosis based on bihilar lymphadenopathy, other computer tomography-findings, or biopsy was diagnosed in five patients under therapy with etanercep, adalimumab, and abatacept. Additionally, seven patients developed clinical changes in their uveitis pattern, suggesting sarcoid uveitis.Conclusions Biologic treatment-induced uveitis often presents as granulomatous disease.We report the incorporation of substitutional Mn atoms in high-quality, epitaxial graphene on Cu(111), using ultralow-energy ion implantation. We characterize in detail the atomic structure of substitutional Mn in a single carbon vacancy and quantify its concentration. In particular, we are able to determine the position of substitutional Mn atoms with respect to the Moiré superstructure (i.e., local graphene-Cu stacking symmetry) and to the carbon sublattice; in the out-of-plane direction, substitutional Mn atoms are found to be slightly displaced toward the Cu surface, that is, effectively underneath the graphene layer. Regarding electronic properties, we show that graphene doped with substitutional Mn to a concentration of the order of 0.04%, with negligible structural disorder (other than the Mn substitution), retains the Dirac-like band structure of pristine graphene on Cu(111), making it an ideal system in which to study the interplay between local magnetic moments and Dirac electrons. Our work also establishes that ultralow-energy ion implantation is suited for substitutional magnetic doping of graphene. Given the flexibility, reproducibility, and scalability inherent to ion implantation, our work creates numerous opportunities for research on magnetic functionalization of graphene and other two-dimensional materials.Strychnine is the prototypic antagonist of glycine receptors, a family of pentameric ligand-gated ion channels. Recent high-resolution structures of homomeric glycine receptors have confirmed the presence of five orthosteric binding sites located in the extracellular subunit interfaces of the receptor complex that are targeted by strychnine. Here, we report the synthesis and extensive pharmacological evaluation of bivalent ligands composed of two strychnine pharmacophores connected by appropriate spacers optimized toward simultaneous binding to two adjacent orthosteric sites of homomeric α1 glycine receptors. In all bivalent ligands, the two strychnine units were linked through C-2 by amide spacers of various lengths ranging from 6 to 69 atoms. Characterization of the compounds in two functional assays and in a radioligand binding assay indicated that compound 11a, with a spacer consisting of 57 atoms, may be capable of bridging the homomeric α1 GlyRs by simultaneous occupation of two adjacent strychnine-binding sites. The findings are supported by docking experiments to the crystal structure of the homomeric glycine receptor. Based on its unique binding mode, its relatively high binding affinity and antagonist potency, and its slow binding kinetics, the bivalent strychnine analogue 11a could be a valuable tool to study the functional properties of glycine receptors.We study nuclear quantum effects in H/D sticking to graphene, comparing scattering experiments at near-zero coverage with classical, quantized, and transition-state calculations. The experiment shows H/D sticking probabilities that are indistinguishable from one another and markedly smaller than those expected from a consideration of zero-point energy shifts of the chemisorption transition state. Inclusion of dynamical effects and vibrational anharmonicity via ring-polymer molecular dynamics (RPMD) yields results that are in good agreement with the experimental results. RPMD also reveals that nuclear quantum effects, while modest, arise primarily from carbon and not from H/D motion, confirming the importance of a C atom rehybridization mechanism associated with H/D sticking on graphene.It was recently found that extremely large plasticity is exhibited in bulk compression of single-crystal ZnS in complete darkness. Such effects are believed to be caused by the interactions between dislocations and photoexcited electrons and/or holes. However, methods for evaluating dislocation behavior in such semiconductors with small dimensions under a particular light condition had not been well established. Here, we propose the „photoindentation” technique to solve this issue by combining nanoscale indentation tests with a fully controlled lighting system. The quantitative data analyses based on this photoindentation approach successfully demonstrate that the first pop-in stress indicating dislocation nucleation near the surface of ZnS clearly increases by light irradiation. Additionally, the room-temperature indentation creep tests show a drastic reduction of the dislocation mobility under light. Our approach demonstrates great potential in understanding the light effects on dislocation nucleation and mobility at the nanoscale, as most advanced technology-related semiconductors are limited in dimensions.Extracellular vesicles (EVs) are nano-sized lipid bilayer encapsulated particles with a molecular cargo that appears to play important roles within the human body, such as in cell-to-cell communication. Unraveling the composition of EV cargos remains one of the most fundamental steps toward understanding the role of EVs in intercellular communication and the discovery of new biomarkers. One of the unmet needs in this field is the lack of a robust, sensitive, and multiplexed method for EV mRNA profiling. We established a new protocol using the NanoString low RNA input nCounter assay by which the targeted mRNA transcripts in EVs can be efficiently and specifically amplified and then assayed for 770 mRNAs in one reaction. Prostate cancer cells with epithelial (PC3-Epi) or mesenchymal (PC3-EMT) phenotypes and their progeny EVs were analyzed by the same panel. Among these mRNAs, 157 were detected in PC3-Epi EVs and 564 were detected in PC3-EMT EVs. NOTCH1 was the most significantly abundant mRNA transcripts in PC3-EMT EVs compared to PC3-Epi EVs. Our results demonstrated that when cells undergo epithelial-to-mesenchymal transition (EMT), a more active loading of cancer progression-related mRNA transcripts may occur. The mRNA cargos of EVs derived from mesenchymal prostate cancer cells may contribute to the pro-EMT function. We found that mRNA transcripts are different in progeny EVs compared to parental cells. EV cargos are not completely reflective of their cell origin, and the underlying mechanism of cargo sorting is complicated and needs to be further elucidated.Flaviviruses, including Zika, dengue, and West Nile viruses, are important human pathogens. The highly conserved NS2B-NS3 protease of Flavivirus is essential for viral replication and therefore a promising drug target. Through compound screening, followed by medicinal chemistry studies, a novel series of 2,5,6-trisubstituted pyrazine compounds are found to be potent, allosteric inhibitors of Zika virus protease (ZVpro) with IC50 values as low as 130 nM. Their structure-activity relationships are discussed. The ZVpro inhibitors also inhibit homologous proteases of dengue and West Nile viruses, and their inhibitory activities are correlated. The most potent compounds 47 and 103 potently inhibited Zika virus replication in cells with EC68 values of 300-600 nM and in a mouse model of Zika infection. These compounds represent novel pharmacological leads for drug development against Flavivirus infections.The typical layered transition metal dichalcogenide (TMDC) material, MoS2, is considered a promising candidate for the next-generation electronic device due to its exceptional physical and chemical properties. In chemical vapor deposition synthesis, the sulfurization of MoO3 powders is an essential reaction step in which the MoO3 reactants are converted into MoS2 products. Recent studies have suggested using an H2S/H2 mixture to reduce MoO3 powders in an effective way. However, reaction mechanisms associated with the sulfurization of MoO3 by the H2S/H2 mixture are yet to be fully understood. Here, we perform quantum molecular dynamics (QMD) simulations to investigate the sulfurization of MoO3 flakes using two different gaseous environments pure H2S precursors and a H2S/H2 mixture. Our QMD results reveal that the H2S/H2 mixture could effectively reduce and sulfurize the MoO3 reactants through additional reactions of H2 and MoO3, thereby providing valuable input for experimental synthesis of higher-quality TMDC materials.Here, we present a study of how liposomes are loaded and release their contents during their electrochemical detection. We loaded 200 nm liposomes with a redox mediator, ferrocyanide, and used amperometry to detect their collision on a carbon-fiber microelectrode (CFE). We found that we could control the favorability of their electroporation process and the amount of ferrocyanide released by modifying the osmolarity of the buffer in which the liposomes were suspended. Interestingly, we observed that the quantity of the released ferrocyanide varied significantly with buffer osmolarity in a nonmonotonic fashion. Using stimulated Raman scattering (SRS), we confirmed that this behavior was partly explained by fluctuations in the intravesicular redox concentration in response to osmotic pressure. To our surprise, the redox concentration obtained from SRS was much greater than that obtained from amperometry, implying that liposomes may release only a fraction of their contents during electroporation. Consistent with this hypothesis, we observed barrages of electrochemical signals that far exceeded the frequency predicted by Poisson statistics, suggesting that single liposomes can collide with the CFE and electroporate multiple times. With this study, we have resolved some outstanding questions surrounding electrochemical detection of liposomes while extending observations from giant unilamellar vesicles to 200 nm liposomes with high temporal resolution and sensitivity.Three novel dinuclear Cu(II) complexes based on a N,N,O-chelating salphen-like ligand scaffold and bearing varying aromatic substituents (-H, -Cl, and -Br) have been synthesized and characterized. The experimental and computational data obtained suggest that all three complexes exist in the dimeric form in the solid state and adopt the same conformation. The mass spectrometry and electron paramagnetic resonance results indicate that the dimeric structure coexists with the monomeric form in solution upon solvent (dimethyl sulfoxide and water) coordination. The three synthesized Cu(II) complexes exhibit high potentiality as ROS generators, with the Cu(II)/Cu(I) redox potential inside the biological redox window, and thus being able to biologically undergo Cu(II)/Cu(I) redox cycling. The formation of ROS is one of the most promising reported cell death mechanisms for metal complexes to offer an inherent selectivity to cancer cells. In vitro cytotoxic studies in two different cancer cell lines (HeLa and MCF7) and in a normal fibroblast cell line show promising selective cytotoxicity for cancer cells (IC50 about 25 μM in HeLa cells, which is in the range of cisplatin and improved with respect to carboplatin), hence placing this N,N,O-chelating salphen-like metallic core as a promising scaffold to be explored in the design of future tailor-made Cu(II) cytotoxic compounds.In this paper, we demonstrate the ability to fabricate temperature sensors by using our newly developed carbon nanotube-graphene oxide (CNT-GO) ink to print temperature-sensitive traces on highly flexible, thin, and adhesive PET (polyethylene terephthalate) tapes, which in turn are integrated on surfaces of different curvatures and wettabilities. Therefore, the strategy provides a facile, low-cost, and environmentally friendly method to deploy printed temperature sensors on surfaces of widely varying curvatures and wettabilities. The temperature sensing occurs through a thermally induced change in the resistance of the printed traces and we quantify the corresponding negative temperature coefficient of resistance (α) for different conditions of curvatures and wettabilities. In addition, we identify that at low temperatures (below 15 °C), the printed traces show an α value that can be as large (in magnitude) as 60 × 10-3/°C, which is several times higher than the typical α values reported for temperature sensors fabricated with CNT or other materials. Furthermore, we achieve the printing of traces that are only 1-3 μm thick on a 50 μm-thick PET film therefore, our design represents an ultrathin additively fabricated temperature sensor that can be easily integrated for wearable electronic applications. Finally, we show that despite being subjected to repeated temperature cycling, there is little degradation of the CNT-GO microarchitectures, making these printed traces capable of repeated uses as potential temperature sensors.

The aim of the present study was to develop a prognostic model using demographic characteristics, comorbidities, and clinical variables measured on day 4 of mechanical ventilation (MV) for patients with prolonged acute mechanical ventilation (PAMV; MV for >96 hours).

Data from 437 patients (70.9% male; median age, 68 years) were obtained over a period of 9 years. All patients were diagnosed with pneumonia. Binary logistic regression identified factors predicting mortality at 90 days after the start of MV. A PAMV prognosis score was calculating ß-coefficient values and assigning points to variables.

The overall 90-day mortality rate was 47.1%. Five factors (age ≥65 years, body mass index <18.5 kg/m2, hemato-oncologic diseases as comorbidities, requirement for vasopressors on day 4 of MV and requirement for neuromuscular blocking agents on day 4 of MV) were identified as prognostic indicators. Each factor was valued as +1 point, and used to develop a PAMV prognosis score. This score showed acceptable discrimination (area under the receiver operating characteristic curve of 0.695 for mortality, 95% confidence interval 0.650-0.738, p<0.001), and calibration (Hosmer-Lemeshow chi-square=6.331, with df 7 and p=0.502). The cutoff value for predicting mortality based on the maximum Youden index was ≤2 (sensitivity, 87.5%; specificity, 41.3%). For patients with PAMV scores ≤1, 2, 3 and ≥4, the 90-day mortality rates were 29.2%, 45.7%, 67.9%, and 90.9%, respectively (P<0.001).

Our study developed a PAMV prognosis score for predicting 90-day mortality. Further research is needed to validate the utility of this score.

Our study developed a PAMV prognosis score for predicting 90-day mortality. Further research is needed to validate the utility of this score.

Uterine fibroids are a common cause of heavy menstrual bleeding and pain. Treatment with the combination of relugolix (an oral gonadotropin-releasing hormone-receptor antagonist), estradiol, and norethindrone acetate, administered once daily, may have efficacy in women with uterine fibroids and heavy bleeding while avoiding hypoestrogenic effects.

We conducted two replicate international, double-blind, 24-week, phase 3 trials involving women with fibroid-associated heavy menstrual bleeding. Participants were randomly assigned in a 111 ratio to receive once-daily placebo, relugolix combination therapy (40 mg of relugolix, 1 mg of estradiol, and 0.5 mg of norethindrone acetate), or delayed relugolix combination therapy (40 mg of relugolix monotherapy, followed by relugolix combination therapy, each for 12 weeks). The primary efficacy end point in each trial was the percentage of participants with a response (volume of menstrual blood loss <80 ml and a ≥50% reduction in volume from baseline) in the relugoerapy and placebo. Bone mineral density was similar with relugolix combination therapy and placebo but decreased with relugolix monotherapy.

Once-daily relugolix combination therapy resulted in a significant reduction in menstrual bleeding, as compared with placebo, and preserved bone mineral density in women with uterine fibroids. (Funded by Myovant Sciences; LIBERTY 1 [L1] and LIBERTY 2 [L2] ClinicalTrials.gov numbers, NCT03049735 and NCT03103087, respectively.).

Once-daily relugolix combination therapy resulted in a significant reduction in menstrual bleeding, as compared with placebo, and preserved bone mineral density in women with uterine fibroids. (Funded by Myovant Sciences; LIBERTY 1 [L1] and LIBERTY 2 [L2] ClinicalTrials.gov numbers, NCT03049735 and NCT03103087, respectively.).

The C5a receptor inhibitor avacopan is being studied for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.

In this randomized, controlled trial, we assigned patients with ANCA-associated vasculitis in a 11 ratio to receive oral avacopan at a dose of 30 mg twice daily or oral prednisone on a tapering schedule. All the patients received either cyclophosphamide (followed by azathioprine) or rituximab. The first primary end point was remission, defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 (on a scale from 0 to 63, with higher scores indicating greater disease activity) at week 26 and no glucocorticoid use in the previous 4 weeks. The second primary end point was sustained remission, defined as remission at both weeks 26 and 52. Both end points were tested for noninferiority (by a margin of 20 percentage points) and for superiority.

A total of 331 patients underwent randomization; 166 were assigned to receive avacopan, and 165 were assigned to receive predniserior to prednisone taper with respect to sustained remission at week 52. All the patients received cyclophosphamide or rituximab. The safety and clinical effects of avacopan beyond 52 weeks were not addressed in the trial. (Funded by ChemoCentryx; ADVOCATE ClinicalTrials.gov number, NCT02994927.).

In this trial involving patients with ANCA-associated vasculitis, avacopan was noninferior but not superior to prednisone taper with respect to remission at week 26 and was superior to prednisone taper with respect to sustained remission at week 52. All the patients received cyclophosphamide or rituximab. The safety and clinical effects of avacopan beyond 52 weeks were not addressed in the trial. (Funded by ChemoCentryx; ADVOCATE ClinicalTrials.gov number, NCT02994927.).

16S rRNA amplicon sequencing is an accurate method of detecting microbial infection without culture. It is unclear if sequencing has additional benefits over routine diagnostic methods for Helicobacter pylori testing.

We enrolled Mongolian volunteers with dyspepsia. Using routine diagnostic methods, positive H.pylori was defined as positive results on histology/immunohistochemistry, culture, rapid urease test, or serology; negative H.pylori was defined by negative results from all these tests. We performed 16S rRNA sequencing on gastric biopsy specimens and calculated cutoffs for operational taxonomic units (OTUs) and relative abundance (RA) to define positive results using ROC curves.

We examined 161 individuals with a mean age of 43.6years, and 64.6% were women. Using routine diagnostic methods, 122 (75.8%) participants were H.pylori positive, the sensitivity and specificity for 16S rRNA sequencing were 94.3% and 82.1% or 93.4% and 82.1% when cutoff values were set to 1113 (OTU number) or 4.4% RA, resr microbiota.

Nonalcoholic steatohepatitis (NASH) is a risk factor for nonvirus-related hepatocellular carcinoma, which is increasing in prevalence. The aim of this study was to clarify the clinical application of fucosylated alpha-fetoprotein (AFP-L3) in the process of nonalcoholic fatty liver (NAFL) disease development.

Serum samples from 115 diabetes mellitus (DM), 36 NAFL, and 119 NASH patients were analyzed for AFP-L3 expression using raw data of a micro total analysis system. These data were then compared with the clinical characteristics of the patients. A validation study was also undertaken with 55 samples (17 NAFL and 38 NASH).

Trace amounts of AFP-L3 were detected in 3.5%, 16.7%, and 58.0% of patients with DM, NAFL, and NASH, respectively. The odds ratio of AFP-L3 positivity for the diagnosis of NASH in multivariate analysis was 9.81 (95% confidence interval,3.77-25.5). The rates in patients without fibrosis or with stage 1, stage 2, stage 3, and stage 4 fibrosis were 14.7%, 31.3%, 63.0%, 86.2%, and 100%, respectively. The rates were significantly increased according to the advancement of liver fibrosis (p<0.001); however, no difference in the positive rate of AFP-L3 was observed between patients with and without fatty livers and between patients with normal and abnormal transaminase. The same relationship was also observed in the validation cohort.

Abnormal fucosylation of AFP occurred in patients with NASH, so it could be useful for the screening of NASH in patients with DM, as well as for the differential diagnosis of NASH and the evaluation of fibrosis.

Abnormal fucosylation of AFP occurred in patients with NASH, so it could be useful for the screening of NASH in patients with DM, as well as for the differential diagnosis of NASH and the evaluation of fibrosis.

The role of neoadjuvant therapy (NT) for ampullary carcinoma (AC) has not been clearly established.

Patients who underwent pancreatoduodenectomy for AC between 2004 and 2016 were identified in the National Cancer Database. Overall survival (OS) was compared between those who received NT before resection and those who underwent surgery first (SF). Propensity score matching (PSM) was performed using age, pathologic T and N stage, and tumor differentiation.

Among 8688 patients with AC, 175 (2.0%) received NT before surgery. While patients who received NT were younger (p = .022) and more likely to have nodal metastasis (43.3% vs. 35.1%, p < .001), there was no difference in OS on univariate (43 vs. 33 months; hazard ratio [HR] 1.10, 95% confidence interval [CI] 0.88-1.37, p = .401) or multivariate (HR 1.09, 95% CI 0.88-1.36, p = .416) analysis between groups. After PSM, there remained no difference in OS between NT or SF groups on univariate (37 vs. 32 months; HR 1.20, 95% CI 0.87-1.64, p = .350) or multivariate (HR 0.99, 95% CI 0.71-1.38, p = .943) analysis.

NT followed by surgery was not associated with improved survival outcomes compared with SF among patients with localized AC. While NT is an acceptable alternative for patients with advanced disease, SF should remain the standard of care.

NT followed by surgery was not associated with improved survival outcomes compared with SF among patients with localized AC. While NT is an acceptable alternative for patients with advanced disease, SF should remain the standard of care.

Eradication rate of standard triple therapy for H.pylori has declined to unacceptable level, and alternative regimens such as concomitant and sequential therapy have been introduced. We aimed to assess the consistency of eradication rates of concomitant and sequential therapies as for the first-line H.pylori eradication in Korea.

A nationwide multicenter retrospective study was conducted including 18 medical centers from January 2008 to December 2017. We included 3,800 adults who had test to confirm H.pylori eradication within 1year after concomitant or sequential therapy.

Concomitant and sequential therapy were prescribed for 2508 and 1292 patients, respectively. The overall eradication rate of concomitant therapy was significantly higher than that of sequential therapy (91.8% vs. 86.1%, p<.001). In time trend analysis, the eradication rates of concomitant therapy were 90.2%, 88.2%, 92.1%, 94.3%, 91.1%, and 93.4% for each year from 2012 to 2017 with an increasing trend (p=.0146), while those of ST showed no significant trend (p=.