Exploration of bivalent ligands targeting putative mu opioid receptor and chemokine receptor CCR5 dimerization

Modern antiretroviral therapies have provided HIV-1 infected patients longer lifespans and better quality of life. However, several neurological complications are now being seen in these patients due to HIV-1 associated injury of neurons by infected microglia and astrocytes. In addition, these effects can be further exacerbated with opiate use and abuse. One possible mechanism for such potentiation effects of opiates is the interaction of the mu opioid receptor (MOR) with the chemokine receptor CCR5 (CCR5), a known HIV-1 co-receptor, to form MOR-CCR5 heterodimer. In an attempt to understand this putative interaction and its relevance to neuroAIDS, we designed and synthesized a series of bivalent ligands targeting the putative CCR5-MOR heterodimer. To understand how these bivalent ligands may interact with the heterodimer, biological studies including calcium mobilization inhibition, binding affinity, HIV-1 invasion, and cell fusion assays were applied. In particular, HIV-1 infection assays using human peripheral blood mononuclear cells, macrophages, and astrocytes revealed a notable synergy in activity for one particular bivalent ligand. Further, a molecular model of the putative CCR5-MOR heterodimer was constructed, docked with the bivalent ligand, and molecular dynamics simulations of the complex was performed in a membrane-water system to help understand the biological observation

A novel blood proteomic signature for prostate cancer

International audienceSimple Summary Despite intensive research, effective tools for detection and monitoring of prostate cancer remain to be found. Prostate-specific antigen (PSA), commonly used in prostate cancer assessments, can lead to overdiagnosis and overtreatment of indolent disease. This highlights the need for supporting non-invasive diagnostic, prognostic, and disease stratification biomarkers that could complement PSA in clinical decision-taking via increased sensitivity and specificity. In order to address this need, we uncover novel prostate cancer protein signatures by leveraging a cutting-edge analytical technique to measure proteins in patient samples. This strategy was used as a discovery tool to identify changes in protein levels in the serum of newly diagnosed patients as compared with healthy controls; the feature set was then further validated by reference to a second cohort of patients, achieving a high discriminatory ability. The proteomic maps generated also identified relevant changes in biological functions, notably the complement cascade. Prostate cancer is the most common malignant tumour in men. Improved testing for diagnosis, risk prediction, and response to treatment would improve care. Here, we identified a proteomic signature of prostate cancer in peripheral blood using data-independent acquisition mass spectrometry combined with machine learning. A highly predictive signature was derived, which was associated with relevant pathways, including the coagulation, complement, and clotting cascades, as well as plasma lipoprotein particle remodeling. We further validated the identified biomarkers against a second cohort, identifying a panel of five key markers (GP5, SERPINA5, ECM1, IGHG1, and THBS1) which retained most of the diagnostic power of the overall dataset, achieving an AUC of 0.91. Taken together, this study provides a proteomic signature complementary to PSA for the diagnosis of patients with localised prostate cancer, with the further potential for assessing risk of future development of prostate cancer. Data are available via ProteomeXchange with identifier PXD025484

Being user-oriented: convergences, divergences, and the potentials for systematic dialogue between disciplines and between researchers, designers, and providers

The challenge this panel addresses is drawn from intersecting literature reviews and critical commentaries focusing on: 1) user studies in multiple fields; and 2) the difficulties of bringing different disciplines and perspectives to bear on user‐oriented research, design, and practice. 1 The challenge is that while we have made some progress in collaborative work, we have some distance to go to become user‐oriented in inter‐disciplinary and inter‐perspective ways. The varieties of our approaches and solutions are, as some observers suggest, an increasing cacophony. One major difficulty is that most discussions are solution‐oriented, offering arguments of this sort ‐‐ if only we addressed users in this way… Each solution becomes yet another addition to the cacophony. This panel implements a central approach documented for its utility by communication researchers and long used by communication mediators and negotiators ‐‐ that of focusing not on communication but rather on meta‐communication: communicating about communication. The intent in the context of this panel is to help us refocus attention from too frequent polarizations between alternative solutions to the possibility of coming to understand what is behind the alternatives and where they point to experientially‐based convergences and divergences, both of which might potentially contribute to synergies. The background project for this panel comes from a series of in‐depth interviews with expert researchers, designers, and providers in three field groupings ‐‐ library and information science; human computer interaction/information technology; and communication and media studies. One set of interviews involved 5‐hour focus groups with directors of academic and public libraries serving 44 colleges and universities in central Ohio; the second involved one‐on‐one interviews averaging 50 minutes with 81 nationally‐internationally known experts in the 3 fields, 25‐27 interviews per field. Using Dervin\u27s Sense‐Making Methodological approach to interviewing, the expert interviews of both kinds asked each interviewee: what he/she considered to be the big unanswered questions about users and what explained why the questions have not been answered; and, what he/she saw as hindering versus helping in attempts to communicate about users across disciplinary and perspective gaps. 2 The panel consists of six teams, two from each field. Prior to the panel presentation at ASIST, each team will have read the set of interviews and completed impressionistic essays of what patterns and themes they saw as emerging. At this stage, team members will purposively not homogenize their differences and most will write solo‐authored essays that will be placed on a web‐site accessible to ASIST members prior to the November meeting. In addition, at least one systematic analysis will be completed and available online. 3 At the ASIST panel, each team\u27s leader will present a brief and intentionally provocative impressionist account of what his/her team came to understand about our struggles communicating across fields and perspectives about users. Again, each team will purposively not homogenize its own differences in viewpoints, but rather highlight them as fodder for discussion. A major purpose will be to invite audience members to join the panel in discussion. At least 20 minutes will be left open for this purpose

A Multisite Preregistered Paradigmatic Test of the Ego-Depletion Effect

We conducted a preregistered multilaboratory project (k = 36; N = 3,531) to assess the size and robustness of ego-depletion effects using a novel replication method, termed the paradigmatic replication approach. Each laboratory implemented one of two procedures that was intended to manipulate self-control and tested performance on a subsequent measure of self-control. Confirmatory tests found a nonsignificant result (d = 0.06). Confirmatory Bayesian meta-analyses using an informed-prior hypothesis (δ = 0.30, SD = 0.15) found that the data were 4 times more likely under the null than the alternative hypothesis. Hence, preregistered analyses did not find evidence for a depletion effect. Exploratory analyses on the full sample (i.e., ignoring exclusion criteria) found a statistically significant effect (d = 0.08); Bayesian analyses showed that the data were about equally likely under the null and informed-prior hypotheses. Exploratory moderator tests suggested that the depletion effect was larger for participants who reported more fatigue but was not moderated by trait self-control, willpower beliefs, or action orientation.</p

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals &lt;1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely