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We describe the model-independent mechanism by which dark matter and dark matter structures heavier than ~ 8 × 1011 GeV form binary pairs in the early Universe that spin down and merge both in the present and throughout the Universe’s history, producing potentially observable signals. Sufficiently dense dark objects will dominantly collide through binary mergers instead of random collisions. We detail how one would estimate the merger rate accounting for finite size effects, multibody interactions, and friction with the thermal bath. We predict how mergers of dark dense objects could be detected through gravitational and electromagnetic signals, noting that such mergers could be a unique source of high frequency gravitational waves. We rule out objects whose presence would contradict observations of the CMB and diffuse gamma-rays. [ABSTRACT FROM AUTHOR]

Background: Alcoholic hepatitis (AH) is a clinically diagnosed syndrome with high short-term mortality for which liver transplantation may be curative. A lack of validated algorithms to identify AH hospitalizations has hindered clinical epidemiology research. Methods: This was a retrospective cohort study of patients with cirrhosis using Veterans Health Administration (VHA) data from 2008 to 2015. We randomly sampled hospitalizations based upon abnormal liver tests and administrative codes for acute hepatitis or alcohol-associated liver disease (ALD). Hospitalizations were manually adjudicated for AH per society guidelines. A priori algorithms were evaluated to compute positive predicted value (PPV) and positive likelihood ratio (LR+), and were tested in an external University of Pennsylvania Health System (UPHS) cohort. Results: Of 368 hospitalizations, 142 (38.6%) were adjudicated as AH. AH patients were younger (55 vs. 58 years, p < 0.001), less likely to have prior cirrhosis decompensation (57% vs. 73.9%, p < 0.001), and had higher AST-to-ALT ratios (median 2.9 vs. 1.9 mg/dL, p < 0.001) and higher bilirubin levels (median 2.9 vs. 1.9 mg/dL, p < 0.001). Algorithms combining clinical laboratory criteria (AST > 85 U/L but < 450 U/L, AST-to-ALT ratio > 2, total bilirubin > 5 mg/dL) and administrative coding criteria yielded the highest PPV (96.4%, 95% CI 87.7–99.6) and the highest LR+ (43.0, 95% CI 10.6–173.5). Several algorithms demonstrated 100% PPV for definite AH in the UPHS external cohort. Conclusion: We have identified algorithms for AH hospitalizations with excellent PPV and LR+. These high-specificity algorithms may be used in VHA datasets to identify patients with high likelihood of AH, but should not be used to study AH incidence. [ABSTRACT FROM AUTHOR]

Background: Little is known about use of specialty care among patients admitted with cirrhosis complications. Aims: We sought to characterize the use and impact of gastroenterology/hepatology (GI/HEP) consultations in hospitalized patients with cirrhosis. We studied two national cohorts—the Veterans Affairs Costs and Outcomes in Liver Disease (VOCAL) and a nationally representative database of commercially insured patients (Optum Clinformatics™ DataMart). Methods: Cirrhosis-related admissions were classified by ICD9/10 codes for ascites, hepatic encephalopathy, alcohol-associated hepatitis, spontaneous bacterial peritonitis, or infection related. We included 20,287/222,166 index admissions from VOCAL/Optum from 2010 to 2016. Propensity-matched analyses were conducted to balance clinical characteristics. Mortality and readmission were evaluated using competing risk regression (subhazard ratios, sHR), and length of stay (LOS) was assessed using negative binomial regression. Results: GI/HEP consultations were completed among 37% and 42% patients in VOCAL and Optum, respectively. In propensity-matched analyses for VOCAL, GI/HEP consultation was associated with adjusted estimates of increased LOS (1.55 + 1.03 additional days), 90-day mortality (sHR 1.23, 95% CI 1.14–1.36), and lower 30-day readmissions (sHR 0.82, 95% CI 0.75–0.89). In Optum, inpatient consultation was associated with higher LOS (1.13 + 1.01 additional days), higher 90-day mortality (sHR 1.57, 95% CI 1.43–1.72), and higher 30-day readmission risk (sHR 1.04, 95% CI 1.02–1.05). Post-discharge primary and specialty care was higher among admissions receiving GI/HEP consultation in both cohorts. Conclusions: Use of GI/HEP consultation for cirrhosis-related admissions was low. Patients who received consultation had higher disease severity, and consultation was not associated with lower mortality but was associated with lower 30-day readmissions in the VA cohort only. [ABSTRACT FROM AUTHOR]

We present current direct and astrophysical limits on the cosmological abundance of black holes with extremal magnetic charge. Such black holes do not Hawking radiate, allowing those normally too light to survive to the present to do so. The dominant constraints come from white dwarf destruction for low and intermediate masses (2 × 10−5 g – 4 × 1012 g) and Galactic gas cloud heating for heavier masses (> 4 × 1012 g). Extremal magnetic black holes may catalyze proton decay. We derive robust limits — independent of the catalysis cross section — from the effect this has on white dwarfs. We discuss other bounds from neutron star heating, solar neutrino production, binary formation and annihilation into gamma-rays, and magnetic field destruction. Stable magnetically charged black holes can assist in the formation of neutron star mass black holes. [ABSTRACT FROM AUTHOR]

The cosmic neutrino background is both a dramatic prediction of the hot Big Bang and a compelling target for current and future observations. The impact of relativistic neutrinos in the early universe has been observed at high significance in a number of cosmological probes. In addition, the non-zero mass of neutrinos alters the growth of structure at late times, and this signature is a target for a number of upcoming surveys. These measurements are sensitive to the physics of the neutrino and could be used to probe physics beyond the standard model in the neutrino sector. We explore an intriguing possibility where light right-handed neutrinos are coupled to all, or a fraction of, the dark matter through a mediator. In a wide range of parameter space, this interaction only becomes important at late times and is uniquely probed by late-time cosmological observables. Due to this coupling, the dark matter and neutrinos behave as a single fluid with a non-trivial sound speed, leading to a suppression of power on small scales. In current and near-term cosmological surveys, this signature is equivalent to an increase in the sum of the neutrino masses. Given current limits, we show that at most 0.5% of the dark matter could be coupled to neutrinos in this way. [ABSTRACT FROM AUTHOR]

In future trial design and in clinical practice, patients with CTP C cirrhosis or total bilirubin >= 3 mg/dl should not be initiated on statins and if already taking should discontinue therapy. Two CTP C patients developed myonecrosis in this study; it was only patients with CTP C cirrhosis in the Bleeding Prevention With Simvastatin (BLEPS) trial that developed rhabdomyolysis [[6]]. [Extracted from the article]

Background: The Child-Turcotte-Pugh (CTP) score is a widely used and validated predictor of long-term survival in cirrhosis. However, the cutpoints for stratifying laboratory variables in CTP have never been validated.Objective: The objective of this study was to identify evidence-based cutpoints for the CTP laboratory subscores to improve its predictive capacity for transplant-free survival.Design: Retrospective observational study.Data Source: Using a cohort of 30,897 cirrhotic US Veteran patients with at least 5 years of follow-up, we performed Cox proportional hazard survival model iterations varying the upper and lower cutpoints for INR, total bilirubin and albumin CTP subscores. Cutpoints yielding the highest Harrell's C-statistics for concordance with transplant-free survival were incorporated into a modified CTP (mCTP) score. Validation of the mCTP was performed at multiple time frames within the follow-up period of the cohort and within subsets defined by disease etiology.Results: Modification of CTP cutpoints increased the Harrell's C-statistic for age- and gender-adjusted Cox proportional hazard models from 0.701 ± 0.002 to 0.709 ± 0.002 and the risk ratio per unit change from 1.49 (1.48-1.50) to 1.53 (1.52-1.54). The modified cutpoints showed superiority in predicting 5-year transplant-free survival in various disease etiology subgroups. A mCTP substituting serum creatinine for INR performed superiorly for predicting 5-year transplant-free survival.Conclusion: We propose an evidence-based recalibration of CTP score cutpoints that optimizes this model's capacity to predict transplant-free survival in patients with cirrhosis. The CTP score remains the best predictor of 5-year overall and transplant-free survival in patients with cirrhosis. [ABSTRACT FROM AUTHOR]

Multidisciplinary tumor boards have evolved to address the increasing complexity of cancer care management. Given that hepatocellular carcinoma (HCC) often arises in the setting of underlying cirrhosis, expert input from hepatologists alongside hepatobiliary and transplant surgeons, radiation oncologists, interventional and body radiologists, and medical oncologists has become increasingly important in order to offer patients appropriate cancer treatments. The MDLTB structure has evolved since the early 2000s to bring these specialists together at regularly scheduled meetings to develop a therapeutic treatment plan for HCC management. MDLTBs have reduced the time to treatment and improved patient satisfaction. Standardized documentation with common data elements has been recommended to ensure adequate communication from MDLTB to referring healthcare providers. Retrospective studies consistently highlight the frequency of changes in treatment plans after MDLTB review to better adhere to guideline recommended care. Despite several decades of MDLTBs implementation, few studies describe clinical outcomes associated with MDLTBs such as patient survival and cost benefits. More research is needed in this area to further justify the heavy use of resources that are needed to maintain MDLTBs. Development and use of a centralized database to store such information may assist with future studies of clinical outcomes and inform quality improvement projects. [ABSTRACT FROM AUTHOR]

Climate change-driven range expansion of black mangroves ( Avicennia germinans) is predicted along the northern Gulf of Mexico, where sea level rise is also driving conversion of freshwater forest islands to salt marsh. While climate-driven A. germinans range expansion has garnered considerable scientific attention, the role of top-down controls on colonization is largely overlooked. We investigated the effects of abiotic (flooding frequency, soil depth, soil salinity) and biotic (predation, herbivory) controls on A. germinans establishment at its northern range limit along Florida's Gulf Coast by comparing fates of caged and non-caged propagules across four landscape positions (from creek edge to forest island interior) and at three sites along a tidal flooding frequency gradient. Within 12 days, grapsid crab, Sesarma reticulatum, consumed 99% of non-caged propagules. Among caged propagules, establishment increased with increasing flooding frequency; however, cages did not entirely prevent predation, which remained a primary cause of mortality, except in the rarely flooded island. Propagules that survived to seedlings experienced mild to fatal herbivory across landscape positions and sites. This study revealed that while relict forest islands and surrounding marshes can support A. germinans, predation and herbivory strongly suppress colonization, suggesting that mangrove expansion models should incorporate biotic controls. [ABSTRACT FROM AUTHOR]

Recently, it has been provocatively claimed that dynamical modeling approaches signal the emergence of a new explanatory framework distinct from that of mechanistic explanation. This paper rejects this proposal and argues that dynamical explanations are fully compatible with, even naturally construed as, instances of mechanistic explanations. Specifically, it is argued that the mathematical framework of dynamics provides a powerful descriptive scheme for revealing temporal features of activities in mechanisms and plays an explanatory role to the extent it is deployed for this purpose. It is also suggested that more attention should be paid to the distinctive methodological contributions of the dynamical framework including its usefulness as a heuristic for mechanism discovery and hypothesis generation in contemporary neuroscience and biology. [ABSTRACT FROM AUTHOR]

Advocates of extended cognition argue that the boundaries of cognition span brain, body, and environment. Critics maintain that cognitive processes are confined to a boundary centered on the individual. All participants to this debate require a criterion for distinguishing what is internal to cognition from what is external. Yet none of the available proposals are completely successful. I offer a new account, the mutual manipulability account, according to which cognitive boundaries are determined by relationships of mutual manipulability between the properties and activities of putative components and the overall behavior of the cognitive mechanism in which they figure. Among its main advantages, this criterion is capable of (a) distinguishing components of cognition from causal background conditions and lower-level correlates, and (b) showing how the core hypothesis of extended cognition can serve as a legitimate empirical hypothesis amenable to experimental test and confirmation. Conceiving the debate in these terms transforms the current clash over extended cognition into a substantive empirical debate resolvable on the basis of evidence from cognitive science and neuroscience. [ABSTRACT FROM AUTHOR]

This paper praises and criticizes Peter-Paul Verbeek’s What Things Do (). The four things that Verbeek does well are: (1) remind us of the importance of technological things; (2) bring Karl Jaspers into the conversation on technology; (3) explain how technology “co-shapes” experience by reading Bruno Latour’s actor-network theory in light of Don Ihde’s post-phenomenology; (4) develop a material aesthetics of design. The three things that Verbeek does not do well are: (1) analyze the material conditions in which things are produced; (2) criticize the social-political design and use context of things; and (3) appreciate how liberal moral-political theory contributes to our evaluation of technology. [ABSTRACT FROM AUTHOR]

Advanced thermal analysis methods, such as temperature modulated DSC (differential scanning calorimetry) and quasi-isothermal TMDSC were used to analyze the protein–metallic ion interactions in silk fibroin proteins. The precise heat capacities were measured and theoretically predicted in this study. To remove bound water and simplify the system, a thermal cycling treatment through both standard DSC and TMDSC was used to detect the underlying heat capacity and reveal the phase transitions of the silk–metallic salts system. Results show that K+ metallic salts play the role of plasticizer in silk fibroin proteins, which reduces the glass transition (Tg) of the pure silk protein and negatively affects its structural thermal stability. On the other hand, Ca2+ metallic salts act as an anti-plasticizer, and increase the glass transition and the thermal stability of the silk protein structure. This indicates that the thermal analysis methods offer a new pathway to study protein–metallic ion systems, yielding very fruitful information for the study of protein structures in the future. [ABSTRACT FROM AUTHOR]

RX J1856.5–3754 is one of the brightest nearby isolated neutron stars, and considerable observational resources have been devoted to it. However, current models are unable to satisfactorily explain the data. We show that our latest models of a thin, magnetic, partially ionized hydrogen atmosphere on top of a condensed surface can fit the entire spectrum, from X-rays to optical, of RX J1856.5–3754, within the uncertainties. In our simplest model, the best-fit parameters are an interstellar column density N H≈1×1020 cm−2 and an emitting area with R ∞≈17 km (assuming a distance to RX J1856.5–3754 of 140 pc), temperature T ∞≈4.3×105 K, gravitational redshift z g ∼0.22, atmospheric hydrogen column y H≈1 g cm−2, and magnetic field B≈(3–4)×1012 G; the values for the temperature and magnetic field indicate an effective average over the surface. [ABSTRACT FROM AUTHOR]

Silk spinning by insects and spiders leads to the formation of fibres that exhibit high strength and toughness. The lack of understanding of the protein processing in silk glands has prevented the recapitulation of these properties in vitro from reconstituted or genetically engineered silks. Here we report the identification of emulsion formation and micellar structures from aqueous solutions of reconstituted silkworm silk fibroin as a first step in the process to control water and protein-protein interactions. The sizes (100-200?nm diameter) of these structures could be predicted from hydrophobicity plots of silk protein primary sequence. These micelles subsequently aggregated into larger ‘globules’ and gel-like states as the concentration of silk fibroin increased, while maintaining solubility owing to the hydrophilic regions of the protein interspersed among the larger hydrophobic regions. Upon physical shearing or stretching structural transitions, increased birefringence and morphological alignment were demonstrated, indicating that this process mimics the behaviour of similar native silk proteins in vivo. Final morphological features of these silk materials are similar to those observed in native silkworm fibres. [ABSTRACT FROM AUTHOR]

Background: The Freiburg index of post-TIPS survival (FIPS) score was recently demonstrated to improve prediction of post-TIPS mortality relative to existing standards. As this score was derived from a German cohort over an extended time period, it is unclear if performance will translate well to other settings. This study aimed to externally validate the FIPS score in a large Veterans Affairs (VA) cohort over two separate eras of TIPS-related care. Methods: This was a retrospective cohort study of patients with cirrhosis who underwent TIPS placement in the VA from 2008 to 2020. Cox regression models for post-TIPS survival were constructed using FIPS, MELD, MELD-Na, or CTP scores as predictors. Discrimination (Harrell's C) and calibration (joint tests of calibration curve slope and intercept) were evaluated for each score. A stratified analysis was performed for time periods between 2008–2013 and 2014–2020. Results: The cohort of 1,274 patients was 97.3% male with mean age 60.9 years and mean MELD-Na 14. The FIPS score demonstrated the highest overall discrimination versus MELD, MELD-Na, and CTP (0.634 vs. 0.585, 0.626, 0.612, respectively). However, in the modern treatment era (2014–2020), the FIPS score performed similarly to MELD-Na. Additionally, the FIPS score demonstrated poor calibration at one-month and six-month post-TIPS timepoints (joint p = 0.04 and 0.004, respectively). MELD, MELD-Na, and CTP were well-calibrated at each timepoint (each joint p > 0.05). Conclusion: The FIPS score performed similarly to MELD-Na in the modern TIPS treatment era and demonstrated regions of poor calibration. Future models derived with contemporary data may improve prediction of post-TIPS mortality. [ABSTRACT FROM AUTHOR]

Background: The Food and Drug Administration requested withdrawal of ranitidine formulations, due to a potentially carcinogenic contaminant, N-nitrosodimethylamine. Aims: We evaluate whether ranitidine use is associated with gastric cancer. Methods: This is a retrospective multicenter, nationwide cohort study within the Veterans Health Administration, among patients with Helicobacter pylori (HP) prescribed long-term acid suppression with either: (1) ranitidine, (2) other histamine type 2 receptor blocker (H2RB), or (3) proton pump inhibitor (PPI)) between May 1, 1998, and December 31, 2018. Covariates included race, ethnicity, smoking, age, HP treatment, HP eradication. Primary outcome was non-proximal gastric adenocarcinomas, using multivariable Cox proportional hazards analysis. Results: We identified 279,505 patients with HP prescribed long-term acid suppression (median 53.4 years; 92.9% male). Compared to ranitidine, non-ranitidine H2RB users were more likely to develop cancer (HR 1.83, 95%CI 1.36–2.48); PPI users had no significant difference in future cancer risk (HR 0.92, 95% CI 0.82–1.04), p < 0.001. Demographics associated with future cancer included increasing age (HR 1.18, 95% CI 1.15–1.20, p < 0.001), Hispanic/Latino ethnicity (HR 1.46, 95% CI 1.21–1.75, p < 0.001), Black race (HR 1.89, 95% CI 1.68–2.14) or Asian race (HR 2.03, 95% CI 1.17–3.52), p < 0.001, and gender (female gender HR 0.64, 95% CI 0.48–0.85, p = 0.02). Smoking was associated with future cancer (HR 1.38, 95% CI 1.23–1.54, p < 0.001). Secondary analysis demonstrated decreased cancer risk in those with confirmed HP eradication (HR 0.24, 95% CI 0.14–0.40). No association between ranitidine and increased gastric cancer was found. Conclusion: There is no demonstrable association between ranitidine use and future gastric cancer among individuals with HP on long-term acid suppression. [ABSTRACT FROM AUTHOR]

The article focuses on the use of silk in connecting the worlds of optics and biology. The use of silk will open opportunities for a new class of biophotonics devices like bioactive optical filters, photonic crystals, and biodetectors. It discusses that the availability of a free-standing biological matrix that has the material toughness to endure room-temperature use under ordinary environmental conditions while concurrently showing high optical quality as well as biological activity is unique.

This article reports that tissue engineering aims to grow tissue replacements by combining cells and matrices under defined laboratory conditions. The shortage of donor tissues and organs and the increasing demand for tissue repair from an aging population have catalyzed research in the field. Current therapeutic approaches with replacement tissues are rather empirical owing to the enormous complexity of the cells, scaffolds and stimuli that must be screened and the fact that the clinical problem is not always well articulated at the outset.

In a pilot study, 14 patients with chronic hepatitis B, median age of 40 yr, who had previously failed to respond to prior standard interferon therapy with persistent hepatitis B viremia (hepatitis B virus DNA >100 pg/ml by DNA assay) were treated with lamivudine 100 mg/day alone for 20 wk, then with both interferon α-2b 5 MU three times per week and lamivudine for 4 wk, and lastly with interferon alone for 24 wk. Hepatitis B e antigen was positive in 11 of 14 patients. At the end of lamivudine therapy, all patients had undetectable serum hepatitis B virus DNA, clearance which was sustained 6 months after the end of sequential treatment in eight of 14 patients. Hepatitis B e antigen to anti-hepatitis B e seroconversion was achieved in five of 11 patients, and hepatitis B e antigen and hepatitis B surface antigen seroconversions in three of 14 patients. All sustained responders had normalized their ALT values and exhibited histological improvements. [Copyright &y& Elsevier]

Studies the role of neurotrophins in synaptic development and plasticity. Signaling pathways that regulate neurotrophin-induced synaptic transmitter release; Promotion and stimulation of neuronal survival and growth; Mechanism for neutrophin-mediated synaptic plasticity.

Editorial. Discusses the role of neurotrophins in mediating cellular apoptosis through the p75 neurothropin receptor. Cellular mechanisms that regulate neuronal survival during naturally-occuring cell death or in the traumatized mature nervous system; Discussion of the biological rationale for having a proapoptotic neurotrophin receptor; Role of the Trk family of tyrosine kinase receptor.

Climate change is altering the frequency and intensity of extreme weather events. Quantifying ecosystem responses to extreme events at the landscape scale is critical for understanding and responding to climate-driven change but is constrained by limited data availability. Here, we integrated remote sensing with ground-based observations to quantify landscape-scale vegetation damage from an extreme climatic event. We used ground- and satellite-based black mangrove (Avicennia germinans) leaf damage data from the northern Gulf of Mexico (USA and Mexico) to examine the effects of an extreme freeze in a region where black mangroves are expanding their range. The February 2021 event produced coastal temperatures as low as − 10 °C in some areas, exceeding thresholds for A. germinans damage and mortality. We used Sentinel-2 surface reflectance data to assess vegetation greenness before and after the freeze, along with ground-based observations of A. germinans leaf damage. Our results show a negative, nonlinear threshold relationship between A. germinans leaf damage and minimum temperature, with a temperature threshold for leaf damage near − 6 °C. Satellite-based analyses indicate that, at the landscape scale, damage was particularly severe along the central Texas coast, where the freeze event affected > 2000 ha of A. germinans-dominated coastal wetlands. Our analyses highlight the value of pairing remotely sensed data with regional, ground-based observations for quantifying and extrapolating the effects of extreme freeze events on mangroves and other tropical, cold-sensitive plants. The results also demonstrate how extreme freeze events govern the expansion and contraction of mangroves near northern range limits in North America. [ABSTRACT FROM AUTHOR]

Purpose: Tumor-associated macrophages are present within neuroblastoma, and interferon-gamma (IFN-γ) can polarize macrophages into cancer-inhibiting M1 type. We hypothesize that treating neuroblastoma with interferon-gamma (IFN-γ) can suppress tumor growth, and the concurrent treatment with IFN-γ and vincristine can lead to enhanced tumor killing as compared to vincristine alone. Methods: We loaded IFN-γ or vincristine into silk biomaterials and recorded the amount released over time. Orthotopic, syngeneic neuroblastoma xenografts were generated by injecting 9464D cells into adrenal gland of C57BL/6 mice, and IFN-γ-loaded and/or vincristine-loaded silk biomaterials were implanted into the tumor once the tumors reached 100 mm3. Drug release at different timepoints was measured and tumor growth after different treatments were compared. Results: 1–2% of IFN-γ and 70% of vincristine were released from the biomaterials by the fifth day. Combining IFN-γ and vincristine significantly slowed tumor growth as compared to the controls (12.2 ± 2.7 days to reach 800 mm3 versus 5.7 ± 1.2 days, p = 0.01), and IFN-γ alone also delayed tumor growth as compared to the controls (10.9 ± 1.5 days versus 5.7 ± 1.2 days, p = 0.001). Hematoxylin and eosin staining demonstrated tumor necrosis adjacent to the drug-loaded silk biomaterials. Conclusion: Local delivery of sustained release IFN-γ can inhibit neuroblastoma tumor growth by itself and in combination with vincristine. [ABSTRACT FROM AUTHOR]

Enzyme catalysis in the synthesis of polyaniline is reviewed. Oxidoreductase enzymes and biomimetic catalysts have been used for the polymerization in aqueous, aqueous organic, and interfacial or templating environments to optimize polymer features. The results showed significant structural control in the presence of templates to produce water soluble and processable polymeric materials. Dip-pen nanolithography technology has also been used to process these materials into conducting nano-wires and thus provides new opportunities for the formation of electrical contacts among biological components for various applications such as synthetic biological interfaces. [ABSTRACT FROM AUTHOR]

The article offers insights on the relationship between the structures and functions in orb webs regarding hierarchical structure of silk proteins. Illustrated are the mechanical properties of spider-silk fibres and webs through combinations of modelling and experiments. Noted are the primary sequence of silk proteins as the answer in response to nonlinear responses from the proteic structure of silk.

Discusses the results of a study by Nykjaer and colleagues which provide a molecular explanation for why p75 neutrophin receptor (p75NTR) signals the death of some cells but not others. Interaction of the protein sortilin with unprocessed nerve growth factor (proNGF); Sortilin's role as a receptor for neurotensin; Cell death in the nervous system.

Discusses factors contributing to axon growth inhibition after injury to the central nervous system. Impact of growth inhibitors found in myelin on axon growth; Mediator between the interaction of the Nogo receptor with p75 neurotrophin receptors during the inhibition process.

Evaluates the periodical 'Macromolecular Bioscience.' Journal format; Sections; Presentation of papers; Periodical layout.

Reports that Lazaris et al. have heterologously expressed and isolated a spider-silk protein from mammalian epithelial cells, successfully spinning the protein into fibers whose properties closely resemble those of native silk fibers. Mechanical properties of silk fibers; Genetic organization related to different silks in different spiders; Technical barriers to the duplication of the silk's native mechanical properties in an environmentally compatible process.

Background: Acute-on-chronic liver failure (ACLF) is a syndrome in patients with cirrhosis with high short-term mortality. Infection is a frequent precipitant of ACLF; however, it is unclear if prognosis varies by difference infectious sources. To address this knowledge gap, we utilized a large national database of patients with cirrhosis. Methods: This was a retrospective cohort study of patients with cirrhosis in the Veterans Health Administration between 2008 and 2016. First ACLF hospitalizations were identified and infections were classified using validated algorithms, categorized as bacteremia, fungal, spontaneous bacterial peritonitis (SBP), pyelonephritis/urinary tract infection, or skin and soft tissue/musculoskeletal infection (SST/MSK). Inverse probability treatment weighing for infection-associated ACLF followed by multivariable logistic regression was used to evaluate the association between infection type and 90-day mortality. Results: A total 22,589 ACLF hospitalizations were included, 3998 (17.7%) of which had ACLF grade 3. Infection was associated with 12,405 (54.9%) of ACLF hospitalizations. In regression models, SBP was associated with a 1.79-fold increased odds of 90-day mortality vs. no infection (95% confidence interval [CI] 1.58–2.02, p < 0.001), whereas SST/MSK infections had a lower relative odds of mortality (odds ratio 0.48, 95% CI 0.42–0.53, p < 0.001). There was a significant interaction between infection category and ACLF grade on the outcome of 90-day mortality (p < 0.001). Conclusions: The impact of infection on short-term mortality in ACLF varies depending on the source of infection. This has relevance for ACLF prognostication and challenges previous notions that bacterial infection invariably worsens prognosis among all patients with ACLF. [ABSTRACT FROM AUTHOR]

Cell-cultivated fish offers the potential for a more ethical, sustainable, and safe seafood system. However, fish cell culture is relatively understudied in comparison to mammalian cells. Here, we established and characterized a continuous Atlantic mackerel (Scomber scombrus) skeletal muscle cell line ("Mack" cells). The cells were isolated from muscle biopsies of fresh-caught fish, with separate isolations performed from two distinct fish. Mack1 cells (cells from the first isolation) were cultured for over a year and subcultured over 130 times. The cells proliferated at initial doubling times of 63.9 h (± 19.1 SD). After a spontaneous immortalization crisis from passages 37–43, the cells proliferated at doubling times of 24.3 h (± 4.91 SD). A muscle phenotype was confirmed through characterization of muscle stemness and differentiation via paired-box protein 7 and myosin heavy chain immunostaining, respectively. An adipocyte-like phenotype was also demonstrated for the cells through lipid accumulation, confirmed via Oil Red O staining and quantification of neutral lipids. New qPCR primers (HPRT, PAX3B, MYOD1, MYOG, TNNT3A, and PPARG) were tailored to the mackerel genome and used to characterize mackerel cell genotypes. This work provides the first spontaneously immortalized fish muscle cell line for research, ideally serving as a reference for subsequent investigation. [ABSTRACT FROM AUTHOR]

Background: As the era of interferon-alpha (IFN)-based therapy for hepatitis C ends, long-term treatment outcomes are now being evaluated.Aim: To more fully understand the natural history of hepatitis C infection by following a multisite cohort of patients.Methods: Patients with chronic HCV were prospectively enrolled in 1999-2000 from 11 VA medical centers and followed through retrospective medical record review.Results: A total of 2211 patients were followed for an average of 8.5 years after enrollment. Thirty-one percent of patients received HCV antiviral therapy, 15 % with standard IFN/ribavirin only, 16 % with pegylated IFN/ribavirin, and 26.7 % of treated patients achieved sustained virologic response (SVR). Cirrhosis developed in 25.8 % of patients. Treatment nonresponders had a greater than twofold increase in the hazard of cirrhosis and hepatocellular carcinoma, compared to untreated patients, whereas SVR patients were only marginally protected from cirrhosis. Nearly 6 % developed hepatocellular carcinoma, and 27.1 % died during the follow-up period. Treated patients, regardless of response, had a significant survival benefit compared to untreated patients (HR 0.58, CI 0.46-0.72). Improved survival was also associated with college education, younger age, lower levels of alcohol consumption, and longer duration of medical service follow-up-factors typically associated with treatment eligibility.Conclusions: As more hepatitis C patients are now being assessed for all-oral combination therapy, these results highlight that patient compliance and limiting harmful behaviors contribute a significant proportion of the survival benefit in treated patients and that the long-term clinical benefits of SVR may be less profound than previously reported. [ABSTRACT FROM AUTHOR]

Cell-cultured meat offers the potential for a more sustainable, ethical, resilient, and healthy food system. However, research and development has been hindered by the lack of serum-free media that enable the robust expansion of relevant cells (e.g., muscle satellite cells) over multiple passages. Recently, a low-cost serum-free media (B8) was described for pluripotent stem cells. Here, B8 is adapted for bovine satellite cells through the addition of a single component, recombinant albumin, which renders it suitable for long-term satellite cell expansion without sacrificing myogenicity. This new media (Beefy-9) maintains cell growth over the entire period tested (seven passages), with an average doubling time of 39 h. Along with demonstrated efficacy for bovine cells, Beefy-9 offers a promising starting-point for developing serum-free media for other meat-relevant species. Ultimately, this work offers a foundation for escaping cultured meat research's reliance on serum, thereby accelerating the field. A substitution of FBS in culturing of bovine satellite cells for the purpose of culturing meat is presented, addressing both basal media and growth factors in relation to proliferating and differentiating cells. [ABSTRACT FROM AUTHOR]

Cell-cultured meat offers the potential for a more sustainable, ethical, resilient, and healthy food system. However, research and development has been hindered by the lack of serum-free media that enable the robust expansion of relevant cells (e.g., muscle satellite cells) over multiple passages. Recently, a low-cost serum-free media (B8) was described for pluripotent stem cells. Here, B8 is adapted for bovine satellite cells through the addition of a single component, recombinant albumin, which renders it suitable for long-term satellite cell expansion without sacrificing myogenicity. This new media (Beefy-9) maintains cell growth over the entire period tested (seven passages), with an average doubling time of 39 h. Along with demonstrated efficacy for bovine cells, Beefy-9 offers a promising starting-point for developing serum-free media for other meat-relevant species. Ultimately, this work offers a foundation for escaping cultured meat research's reliance on serum, thereby accelerating the field. A substitution of FBS in culturing of bovine satellite cells for the purpose of culturing meat is presented, addressing both basal media and growth factors in relation to proliferating and differentiating cells. [ABSTRACT FROM AUTHOR]

Background: Accuracy of glomerular filtration rate estimating (eGFR) equations has significant implications in cirrhosis, potentially guiding simultaneous liver kidney allocation and drug dosing. Most equations adjust for Black race, partially accounted for by reported differences in muscle mass by race. Patients with cirrhosis, however, are prone to sarcopenia which may mitigate such differences. We evaluated the association between baseline eGFR and incident acute kidney injury (AKI) in patients with cirrhosis with and without race adjustment. Methods: We conducted a retrospective national cohort study of veterans with cirrhosis. Baseline eGFR was calculated using multiple eGFR equations including Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), both with and without race adjustment. Poisson regression was used to investigate the association between baseline eGFR and incident AKI events per International Club of Ascites criteria. Results: We identified 72,267 patients with cirrhosis, who were 97.3% male, 57.8% white, and 19.7% Black. Over median follow-up 2.78 years (interquartile range 1.22–5.16), lower baseline eGFR by CKD-EPI was significantly associated with higher rates of AKI in adjusted models. For all equations this association was minimally impacted when race adjustment was removed. For example, removal of race adjustment from CKD-EPI resulted in a 0.1% increase in the association between lower eGFR and higher rate of AKI events per 15 mL/min/1.73 m2 change (p < 0.001). Conclusions: Race adjustment in eGFR equations did not enhance AKI risk estimation in patients with cirrhosis. Further study is warranted to assess the impacts of removing race from eGFR equations on clinical outcomes and policy. [ABSTRACT FROM AUTHOR]

Three-dimensional (3D) in vitro culture systems using human induced pluripotent stem cells (hiPSCs) are useful tools to model neurodegenerative disease biology in physiologically relevant microenvironments. Though many successful biomaterials-based 3D model systems have been established for other neurogenerative diseases, such as Alzheimer’s disease, relatively few exist for Parkinson’s disease (PD) research. We employed tissue engineering approaches to construct a 3D silk scaffold-based platform for the culture of hiPSC-dopaminergic (DA) neurons derived from healthy individuals and PD patients harboring LRRK2 G2019S or GBA N370S mutations. We then compared results from protein, gene expression, and metabolic analyses obtained from two-dimensional (2D) and 3D culture systems. The 3D platform enabled the formation of dense dopamine neuronal network architectures and developed biological profiles both similar and distinct from 2D culture systems in healthy and PD disease lines. PD cultures developed in 3D platforms showed elevated levels of α-synuclein and alterations in purine metabolite profiles. Furthermore, computational network analysis of transcriptomic networks nominated several novel molecular interactions occurring in neurons from patients with mutations in LRRK2 and GBA. We conclude that the brain-like 3D system presented here is a realistic platform to interrogate molecular mechanisms underlying PD biology. [ABSTRACT FROM AUTHOR]

Introduction: Topical therapies are considered first-line treatment in the management of plaque psoriasis (PSO). However, data on patient-reported outcomes for topicals are scarce. We designed a survey to record the treatment experience of patients with mild-to-moderate PSO using prescription topicals. Methods: An online cross-sectional survey was conducted among adult patients on prescription topicals for mild-to-moderate PSO (body surface area [BSA] ≤ 10%) in the US. Data on treatment goals, changes in PSO after current treatment, satisfaction with current treatment (assessed with the Treatment Satisfaction Questionnaire for Medication [TSQM]), and treatment adherence (how often current treatment was taken as instructed) were collected. Descriptive analysis was used to evaluate outcomes. Results: Of the 175 patients with mild-to-moderate PSO who completed the survey, 67.4% were female, with a median age of 55.0 years and 10.8 years since PSO diagnosis. Patients reported (medians) the use of three topicals since diagnosis, with 5 years on the current prescription topical. The top three treatment goals for current topical treatment were improvements in visible skin, 97.1%; non-skin related symptoms, 62.9%; and social/emotional well-being, 60.0%. Overall, 43.4% of patients reported 0% BSA change and 5.7% reported ≥ 75% BSA reduction. Approximately 75.0% each reported improvement in itch and pain symptoms. Embarrassment/self-consciousness because of skin symptoms persisted in 72.6% of patients. Median TSQM scores for global satisfaction, convenience, and effectiveness ranged between 58 and 72, indicating partial treatment satisfaction, except for side effects, which was high (median: 100). Approximately half of patients (49.7%) reported not being highly adherent to treatment. Conclusion: Contrary to their treatment goals, patients with mild-to-moderate PSO using prescription topicals reported partial effectiveness, incomplete symptom resolution, impacted emotional and social well-being, and suboptimal global satisfaction, effectiveness, adherence, and convenience. Our findings highlight several unmet needs among topical-experienced, systemic-naïve patients with mild-to-moderate PSO using prescription topicals. Plain Language Summary: Psoriasis is a chronic skin disease caused by inflammation in the body. Raised areas, called plaques, are one of the main symptoms. These plaques may be red, flaky, itchy, and/or painful. Living with psoriasis can negatively impact a person's well-being, especially when it affects visible areas such as the head, face, hands and nails, and/or sensitive areas like the genitals. Topical treatments, such as creams and lotions, are often the first therapy a doctor prescribes for psoriasis. Since these treatments are applied directly on the plaques, they can be messy and inconvenient. We conducted an online survey of adults with mild-to-moderate psoriasis, meaning that less than 10% of their body had plaques. We wanted to learn how they felt about their disease and their prescription topical treatments. Most people had psoriasis for about 10 years and had been using their current prescription topical for about 5 years. Approximately three of four people reported embarrassment/self-consciousness because of skin symptoms. Although three of four people reported some improvement in itch and pain, almost all people desired better resolution of plaques in visible areas. People also reported that: their current prescription topical did not completely resolve their symptoms, their emotional and social well-being was still suboptimal, they did not always apply their therapy as often as instructed, and they were not completely satisfied with their treatment overall. These results highlight the need for additional treatment options for people with mild-to-moderate psoriasis, particularly options that offer improved symptom control and are more convenient to use. [ABSTRACT FROM AUTHOR]

We used advanced thermal analysis methods to characterize a new family of A-B di-block copolymers based on the amino acid sequences of Nephila clavipes major ampulate dragline spider silk. Using temperature modulated differential scanning calorimetry with a thermal cycling method and thermogravimetry, we captured the effect of bound water acting as a plasticizer for spider silk-like biopolymer films which had been cast from water solution and then dried. A low glass transition because of bound water removal was observed in the first heating cycle, after which, a shift of glass transition was observed in A-block film due to crystallization and annealing, and in BA film due to annealing. No shift of glass transition after bound water removal was observed in B-block film. The reversing heat capacities, C, for temperatures below and above the glass transition were measured and compared to the calculated values. The solid state heat capacity was modeled below T, based on the vibrational motions of the constituent poly(amino acid)s, heat capacities of which are known from the ATHAS Data Bank. Excellent agreement was found between the measured and calculated values of the heat capacity, showing that this model can serve as a standard method to predict the solid state C for other biologically inspired block-copolymers. We also calculated the liquid state heat capacities of the 100% amorphous biopolymer at T, and this predicted value can be use to determined the crystallinity of protein-based materials. [ABSTRACT FROM AUTHOR]

The coordination of attention between individuals is a fundamental part of everyday human social interaction. Previous work has focused on the role of gaze information for guiding responses during joint attention episodes. However, in many contexts, hand gestures such as pointing provide another valuable source of information about the locus of attention. The current study developed a novel virtual reality paradigm to investigate the extent to which initiator gaze information is used by responders to guide joint attention responses in the presence of more visually salient and spatially precise pointing gestures. Dyads were instructed to use pointing gestures to complete a cooperative joint attention task in a virtual environment. Eye and hand tracking enabled real-time interaction and provided objective measures of gaze and pointing behaviours. Initiators displayed gaze behaviours that were spatially congruent with the subsequent pointing gestures. Responders overtly attended to the initiator's gaze during the joint attention episode. However, both these initiator and responder behaviours were highly variable across individuals. Critically, when responders did overtly attend to their partner's face, their saccadic reaction times were faster when the initiator's gaze was also congruent with the pointing gesture, and thus predictive of the joint attention location. These results indicate that humans attend to and process gaze information to facilitate joint attention responsivity, even in contexts where gaze information is implicit to the task and joint attention is explicitly cued by more spatially precise and visually salient pointing gestures. [ABSTRACT FROM AUTHOR]

There is an unresolved question about whether realigned visual feedback is beneficial or costly to laparoscopic task performance. We provide evidence that camera realignment imposes a reliable cost on performance across both naive controls and experienced surgeons. This finding clarifies an important ongoing discussion in the literature about the effects of camera realignment, which could inform the strategies that laparoscopic surgeons use in the operating room. [ABSTRACT FROM AUTHOR]

Artificial reefs (ARs) are one of the most popular means of supporting marine ecosystem conservation and coastal fisheries, particularly in developing countries. However, ARs generate complex socio-bio-economic interactions that require careful evaluation. This is particularly the case for ARs outside no-take zones, where fish might be subject to enhanced exploitation due to easier catchability. Here, we conducted an interdisciplinary study on how ARs impact fish and fishing yields, combining mathematical and sociological approaches. Both approaches converge to confirm that fishery yields decline when ARs are exploited as if they were open access areas. This situation typically occurs in areas with weak governance and/or high levels of illegal fishing activity, both of which are common in many developing countries. To avoid these adverse effects and their associated ecological consequences, we recommend prioritizing the onset of a long-term surveillance system against illegal fishing activities, and adapting design and location of the ARs based on both and local and academic knowledge, before the deployment of ARs. [ABSTRACT FROM AUTHOR]

The mammary gland is a dynamic organ that continually changes its architecture and function. Reciprocal interactions between epithelium and adipocyte-containing stroma exert profound effects on all stages of its development, even though the details of these events are not fully understood. To address this issue, enormous potential exists in the utilization of synthetic adipose tissue model systems to uncover the properties and functions of adipocytes in the mammary gland. The first part of this review focuses on mammary adipose tissue (or adipocyte)-related model systems developed in recent years and their utility in investigating adipose-epithelial interactions, mammary gland morphogenesis, development and tumorigenesis. The second part shifts to the field of adipose-based breast tissue engineering, focusing on how these synthetic adipose tissue models are being constructed in vitro or in vivo for regeneration of the mammary gland, and their potentials in adipose tissue engineering also are discussed. [ABSTRACT FROM AUTHOR]

FoxP3 + CD4 + regulatory T cells (Tregs) are important mediators of peripheral immune tolerance, acting via multiple mechanisms to suppress cellular immunity including antitumor responses. Although therapeutic strategies have been proposed to deplete Tregs in patients with breast cancer and other malignancies, dynamic changes in the Treg compartment as a function of stage and treatment of breast cancer remain poorly understood. Here, we evaluated peripheral blood CD4+ T cells and FoxP3+ CD4+ T cells from 45 patients with early or late stage breast cancer and compared percentages, absolute counts, and Treg function to those from healthy volunteers (HV) of comparable age. Patients having completed adjuvant chemotherapy and patients with metastatic cancer exhibited significantly lower absolute CD4 counts and significantly higher percentages of FoxP3+ CD4+ T cells. In contrast, the absolute counts of circulating FoxP3+ CD4+ T cells did not differ significantly among early stage patients, late stage patients, or HV. Functionally, FoxP3+ CD4+ T cells from all donor groups similarly expressed CTLA-4 and failed to secrete IFN-γ in response to stimulation. Thus, although Tregs comprise an increased percentage of circulating CD4+ T cells in patients with metastatic breast cancer and patients in remission after completing the adjuvant chemotherapy, the systemic Treg pool, as measured by absolute counts, appears relatively constant regardless of disease stage or treatment status. Total CD4+ T cell counts are not constant, however, suggesting that homeostatic mechanisms, or susceptibility to cytotoxic or malignant insults, fundamentally differ for regulatory and non-regulatory CD4+ T cells. [ABSTRACT FROM AUTHOR]

Biophysical signaling, an integral regulator of long-term cell behavior in both excitable and non-excitable cell types, offers enormous potential for modulation of important cell functions. Of particular interest to current regenerative medicine efforts, we review several examples that support the functional role of transmembrane potential (Vmem) in the regulation of proliferation and differentiation. Interestingly, distinct Vmem controls are found in many cancer cell and precursor cell systems, which are known for their proliferative and differentiation capacities, respectively. Collectively, the data demonstrate that bioelectric properties can serve as markers for cell characterization and can control cell mitotic activity, cell cycle progression, and differentiation. The ability to control cell functions by modulating bioelectric properties such as Vmem would be an invaluable tool for directing stem cell behavior toward therapeutic goals. Biophysical properties of stem cells have only recently begun to be studied and are thus in need of further characterization. Understanding the molecular and mechanistic basis of biophysical regulation will point the way toward novel ways to rationally direct cell functions, allowing us to capitalize upon the potential of biophysical signaling for regenerative medicine and tissue engineering. [ABSTRACT FROM AUTHOR]