Mullenraun4810

Prognostication in patients with chronic lymphocytic leukemia (CLL) is challenging due to heterogeneity in clinical course. We hypothesize that constitutional genetic variation affects disease progression and could aid prognostication. Pooling data from seven studies incorporating 842 cases identifies two genomic locations associated with time from diagnosis to treatment, including 10q26.13 (rs736456, hazard ratio (HR) = 1.78, 95% confidence interval (CI) = 1.47-2.15; P = 2.71 × 10-9) and 6p (rs3778076, HR = 1.99, 95% CI = 1.55-2.55; P = 5.08 × 10-8), which are particularly powerful prognostic markers in patients with early stage CLL otherwise characterized by low-risk features. Expression quantitative trait loci analysis identifies putative functional genes implicated in modulating B-cell receptor or innate immune responses, key pathways in CLL pathogenesis. In this work we identify rs736456 and rs3778076 as prognostic in CLL, demonstrating that disease progression is determined by constitutional genetic variation as well as known somatic drivers.Artificial moiré superlattices in 2d van der Waals heterostructures are a new venue for realizing and controlling correlated electronic phenomena. Recently, twisted bilayer WSe2 emerged as a new robust moiré system hosting a correlated insulator at moiré half-filling over a range of twist angle. In this work, we present a theory of this insulating state as an excitonic density wave due to intervalley electron-hole pairing. We show that exciton condensation is strongly enhanced by a van Hove singularity near the Fermi level. Our theory explains the remarkable sensitivity of the insulating gap to the vertical electric field. In contrast, the gap is weakly reduced by a perpendicular magnetic field, with quadratic dependence at low field. The different responses to electric and magnetic field can be understood in terms of pair-breaking versus non-pair-breaking effects in a BCS analog of the system. We further predict superfluid spin transport in this electrical insulator, which can be detected by optical spin injection and spatial-temporal imaging.Preeclampsia is a severe gestational hypertensive condition linked to child neuropsychiatric disorders, although underlying mechanisms are unclear. We used a recently developed, clinically relevant animal model of preeclampsia to assess offspring. C57BL/6J mouse dams were chronically infused with arginine vasopressin (AVP) or saline (24 ng/h) throughout pregnancy. Adult offspring were behaviorally tested (Y-maze, open field, rotarod, social approach, and elevated plus maze). Offspring brain was assessed histologically and by RNA sequencing. Preeclampsia-exposed adult males exhibited increased anxiety-like behavior and social approach while adult females exhibited impaired procedural learning. Adult AVP-exposed males had reduced total neocortical volume. Adult AVP-exposed females had increased caudate-putamen volume, increased caudate-putamen cell number, and decreased excitatory synapse density in hippocampal dentate gyrus (DG), CA1, and CA3. At postnatal day 7 (P7), AVP-exposed male and female offspring both had smaller neocortex. At P7, AVP-exposed males also had smaller caudate-putamen volume, while females had increased caudate-putamen volume relative to neocortical size. Similar to P7, E18 AVP-exposed offspring had smaller dorsal forebrain, mainly in reduced intermediate, subventricular, and ventricular zone volume, particularly in males. Decreased volume was not accounted for by cell size or cerebrovascular vessel diameter changes. E18 cortical RNAseq revealed 49 differentially-expressed genes in male AVP-exposed offspring, over-representing cytoplasmic translation processes. In females, 31 genes were differentially-expressed, over-representing collagen-related and epithelial regulation pathways. Gene expression changes in E18 AVP-exposed placenta indicated potential underlying mechanisms. Deficits in behavior and forebrain development in this AVP-based preeclampsia model were distinctly different in males and females, implicating different neurobiological bases.

To describe what characterises the lived experience of performing a periodontal treatment in the context of general dentistry.

Three dental hygienists from general dentistry in Sweden, were purposively selected as participants and interviewed. The participants described a situation in which they had performed a periodontal treatment. The descriptions were analysed using the descriptive phenomenological psychological method.

The general meaning structure of the lived experience of performing a periodontal treatment comprised five constituents, (a) an established treatment routine, (b) importance of oral hygiene, (c) self-awareness and motivation of the patient, (d) support and doubt, and (e) mechanical infection control. The periodontal treatment is perceived as being set prior to its commencement and as following established routines, in which the patients' oral hygiene is experienced as a crucial part. The patients' self-awareness and a supportive clinician are seen as important factors in motivating the patient towards positive behavioural change, although there is a presence of doubt in patients' ability to maintain this positive change. Mechanical infection control is perceived as successful but sometimes difficult to perform.

Important, patient-related, factors are constituting the phenomenon of performing a periodontal treatment but an experience that the pre-existing standardised workflow influences patient management was also present.

Important, patient-related, factors are constituting the phenomenon of performing a periodontal treatment but an experience that the pre-existing standardised workflow influences patient management was also present.

This research synthesis protocol addresses the question what is the evidence concerning measurement properties of dental patient reported outcome measures (dPROMs), and regarding the real-world value of dPROMs, and where are the gaps in this evidence? Evidence mapping will systematically examine reviews of quantitative dPROMs used to assess the impact of oral health on the quality of life of dental patients and research participants. Evidence gaps where future research or systematic reviews are required will be identified.

This protocol accords with the PRISMA-P guideline. Open Science Framework Registration https//doi.org/10.17605/OSF.IO/RZD3N . Biomedical and grey literature databases will be searched, adapting the same search strategy. Published or unpublished reviews evaluating any dPROM will be considered for inclusion. There will be no restriction by date, setting, or language. AMSTAR2 and ROBIS will evaluate risk of bias. Psychometric criteria will be adapted from COSMIN. Data will be summarised separately for specific populations and conditions.

The findings will enable clinicians and researchers to identify methodologically robust dPROMs, appropriate for use with relevant populations and conditions. Implications for real-world practice and research will be discussed.

The findings will enable clinicians and researchers to identify methodologically robust dPROMs, appropriate for use with relevant populations and conditions. Implications for real-world practice and research will be discussed.Except remdesivir, no specific antivirals for SARS-CoV-2 infection are currently available. Here, we characterize two small-molecule-compounds, named GRL-1720 and 5h, containing an indoline and indole moiety, respectively, which target the SARS-CoV-2 main protease (Mpro). We use VeroE6 cell-based assays with RNA-qPCR, cytopathic assays, and immunocytochemistry and show both compounds to block the infectivity of SARS-CoV-2 with EC50 values of 15 ± 4 and 4.2 ± 0.7 μM for GRL-1720 and 5h, respectively. Remdesivir permitted viral breakthrough at high concentrations; however, compound 5h completely blocks SARS-CoV-2 infection in vitro without viral breakthrough or detectable cytotoxicity. Combination of 5h and remdesivir exhibits synergism against SARS-CoV-2. Additional X-ray structural analysis show that 5h forms a covalent bond with Mpro and makes polar interactions with multiple active site amino acid residues. The present data suggest that 5h might serve as a lead Mpro inhibitor for the development of therapeutics for SARS-CoV-2 infection.Oral squamous cell carcinoma (OSCC) become a heavy burden of public health, with approximately 300 000 newly diagnosed cases and 145 000 deaths worldwide per year. Nucleotide metabolism fuel DNA replication and RNA synthesis, which is indispensable for cell proliferation. But how tumor cells orchestrate nucleotide metabolic enzymes to support their rapid growth is largely unknown. Here we show that expression of pyrimidine metabolic enzyme dihydroorotate dehydrogenase (DHODH) is upregulated in OSCC tissues, compared to non-cancerous adjacent tissues. Enhanced expression of DHODH is correlated with a shortened patient survival time. Inhibition of DHODH by either shRNA or selective inhibitors impairs proliferation of OSCC cells and growth of tumor xenograft. Further, loss of functional DHODH imped de novo pyrimidine synthesis, and disrupt mitochondrial respiration probably through destabilizing the MICOS complex. Mechanistic study shows that transcriptional factor SOX2 plays an important role in the upregulation of DHODH in OSCC. DRB18 inhibitor Our findings add to the knowledge of how cancer cells co-opt nucleotide metabolism to support their rapid growth, and thereby highlight DHODH as a potential prognostic and therapeutic target for OSCC treatment.The precise engineering of materials and surfaces has been at the heart of some of the recent advances in optics and photonics. These advances related to the engineering of materials with new functionalities have also opened up exciting avenues for designing trainable surfaces that can perform computation and machine-learning tasks through light-matter interactions and diffraction. Here, we analyze the information-processing capacity of coherent optical networks formed by diffractive surfaces that are trained to perform an all-optical computational task between a given input and output field-of-view. We show that the dimensionality of the all-optical solution space covering the complex-valued transformations between the input and output fields-of-view is linearly proportional to the number of diffractive surfaces within the optical network, up to a limit that is dictated by the extent of the input and output fields-of-view. Deeper diffractive networks that are composed of larger numbers of trainable surfaces can cover a higher-dimensional subspace of the complex-valued linear transformations between a larger input field-of-view and a larger output field-of-view and exhibit depth advantages in terms of their statistical inference, learning, and generalization capabilities for different image classification tasks when compared with a single trainable diffractive surface. These analyses and conclusions are broadly applicable to various forms of diffractive surfaces, including, e.g., plasmonic and/or dielectric-based metasurfaces and flat optics, which can be used to form all-optical processors.