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Abstract In the Earth, the flow of crystal-bearing magma is thought to be non-Newtonian and shear thinning, but the physical origin for this is poorly understood. We use hydro-granular theory to show that the decoupled migration of crystals toward conduit cores during magma ascent is a tenable microphysical mechanism for plug flow, emergent in an otherwise purely Newtonian crystal-bearing magma. We use a numerical conduit model to define the flow development length beyond which crystal migration dominates and strain localises near conduit margins. Applied to magma ascent scenarios, we show that this crystal-migration strain localisation only develops in high crystallinity magmas or magmas ascending in very narrow cracks/conduits. In all other scenarios, crystals do not contribute to non-Newtonian behaviour and such magmas are usually strictly Newtonian. The ascent of very crystal-rich dome magma could be associated with strain localisation and crystal depletion at the conduit margins, lubricating ascent through the crust.

Abstract The early evolution of Pan-Chelonioidea (sea turtles) is poorly understood. This is in part due to the rarity of undeformed skulls of definitive early stem chelonioids. In this work, we redescribe the holotype of Nichollsemys baieri using µCT scans and segmentations of the skull. This fossil is the best 3D preserved skull of any Campanian sea turtle, and includes partial “soft tissue” preservation. Nichollsemys is morphologically similar but clearly distinct from Toxochelys spp., and both show a mosaic of plesiomorphic and derived chelonioid features. The internal cranial anatomy documents the presence of derived characters in Nichollsemys baieri that are absent in Toxochelys spp., such as the loss of the epipterygoids and the rod-like shape of the rostrum basisphenoidale. Among the numerous plesiomorphic characters is the presence of a splenial bone, which was unnoticed before. An updated phylogenetic analysis retrieves Nichollsemys baieri as a non-protostegid early stem chelonioid in a slightly more crownward position than Toxochelys latiremis. Our phylogeny includes macrobaenids and protostegids as pan-chelonioids, and we find unorthodox results for dermochelyids. Thus, although Nichollsemys baieri provides important new insights into the early morphological evolution of sea turtles, much work remains to be done. As a completely 3D preserved specimen, we included Nichollsemys baieri into a recent landmark-based skull shape dataset of turtles. Morphospace analysis reveals an intermediate position between cryptodires and crown chelonioids. Based on these data, we also predict that Nichollsemys baieri was still capable of neck retraction, constraining the loss of this trait to more crownward pan-chelonioids.

Background: Two-stage exchange arthroplasty remains the gold standard for treating chronic hip periprosthetic joint infections. However, controversy remains regarding the optimal spacer type, particularly among patients with increased dislocation risk. This study reports on the outcomes of articulating hip spacers utilizing a single constrained-liner design. Methods: All patients who underwent treatment for hip periprosthetic joint infection at a single institution were screened. Patients were included if they received an articulating spacer utilizing a constrained liner of a single manufacturer design. Indications for constrained liner, demographic variables, and surgical variables were recorded. Patients were assessed for dislocation and component loosening prior to the second stage or at the final follow-up if the second stage was not undertaken. Comparative analysis was performed. Results: Overall, 26 constrained liners were utilized in 25 patients. Indications for constrained liner included history of dislocation (n = 14), massive proximal femoral bone loss (n = 14), greater trochanteric deficiency (n = 12), and absent abductors (n = 7). Many patients had more than one indication. In total, 9 hips (34.6%) underwent a second stage at an average of 7.4 months, while 17 hips never underwent a second stage with an average follow-up of 27.6 months. One patient experienced failure of their constrained liner prior to the second stage due to pelvic discontinuity and massive acetabular bone loss. Conclusions: Utilization of a constrained liner as an articulating spacer is a viable option for patients at high risk of instability. Meticulous cement technique, appropriate component position, and implant selection are crucial in achieving successful outcomes.

Ticks are important blood feeding ectoparasites that transmit pathogens to wildlife, domestic animals, and humans. Hard ticks can feed for several days to weeks, nevertheless they often go undetected. This phenomenon can be explained by a tick’s ability to release analgesics, immunosuppressives, anticoagulants, and vasodilators within their saliva. Several studies have identified extracellular vesicles (EVs) as carriers of some of these effector molecules. Further, EVs, and their contents, enhance pathogen transmission, modulate immune responses, and delay wound healing. EVs are double lipid-membrane vesicles that transport intracellular cargo, including microRNAs (miRNAs) to recipient cells. miRNAs are involved in regulating gene expression post-transcriptionally. Interestingly, tick-derived miRNAs have been shown to enhance pathogen transmission and affect vital biological processes such as oviposition, blood digestion, and molting. miRNAs have been found within tick salivary EVs. This review focuses on current knowledge of miRNA loading into EVs and homologies reported in ticks. We also describe findings in tick miRNA profiles, including miRNAs packed within tick salivary EVs. Although no functional studies have been done to investigate the role of EV-derived miRNAs in tick feeding, we discuss the functional characterization of miRNAs in tick biology and pathogen transmission. Lastly, we propose the possible uses of tick miRNAs to develop management tools for tick control and to prevent pathogen transmission. The identification and functional characterization of conserved and tick-specific salivary miRNAs targeting important molecular and immunological pathways within the host could lead to the discovery of new therapeutics for the treatment of tick-borne and non-tick-borne human diseases.

Abstract Viral infections remain a major risk in immunocompromised pediatric patients, and virus-specific T cell (VST) therapy has been successful for treatment of refractory viral infections in prior studies. We performed a phase II multicenter study (NCT03475212) for the treatment of pediatric patients with inborn errors of immunity and/or post allogeneic hematopoietic stem cell transplant with refractory viral infections using partially-HLA matched VSTs targeting cytomegalovirus, Epstein-Barr virus, or adenovirus. Primary endpoints were feasibility, safety, and clinical responses (>1 log reduction in viremia at 28 days). Secondary endpoints were reconstitution of antiviral immunity and persistence of the infused VSTs. Suitable VST products were identified for 75 of 77 clinical queries. Clinical responses were achieved in 29 of 47 (62%) of patients post-HSCT including 73% of patients evaluable at 1-month post-infusion, meeting the primary efficacy endpoint (>52%). Secondary graft rejection occurred in one child following VST infusion as described in a companion article. Corticosteroids, graft-versus-host disease, transplant-associated thrombotic microangiopathy, and eculizumab treatment correlated with poor response, while uptrending absolute lymphocyte and CD8 T cell counts correlated with good response. This study highlights key clinical factors that impact response to VSTs and demonstrates the feasibility and efficacy of this therapy in pediatric HSCT.

X-linked lymphoproliferative disease (XLP1) results from SH2D1A gene mutations affecting the SLAM-associated protein (SAP). A regulated lentiviral vector (LV), XLP-SMART LV, designed to express SAP at therapeutic levels in T, NK, and NKT cells, is crucial for effective gene therapy. We experimentally identified 34 genomic regulatory elements of the SH2D1A gene and designed XLP-SMART LVs to emulate the lineage and stage-specific control of SAP. We screened them for their on-target enhancer activity in T, NK, and NKT cells and their off-target enhancer activity in B cell and myeloid populations. In combination, three enhancer elements increased SAP promoter expression up to 4-fold in on-target populations in vitro. NSG-Tg(Hu-IL15) xenograft studies with XLP-SMART LVs demonstrated up to 7-fold greater expression in on-target cells over a control EFS-LV, with no off-target expression. The XLP-SMART LVs exhibited stage-specific T and NK cell expression in peripheral blood, bone marrow, spleen, and thymic tissues (mimicking expression patterns of SAP). Transduction of XLP1 patient CD8+ T cells or BM CD34+ cells with XLP-SMART LVs restored restimulation-induced cell death and NK cytotoxicity to wild-type levels, respectively. These data demonstrate that it is feasible to create a lineage and stage-specific LV to restore the XLP1 phenotype by gene therapy.

ObjectiveThis study aims to determine if pretreating with enteral N-acetylcysteine (NAC) improves CNS oxidative stress and facilitates improvement in oromotor skills during transcutaneous auricular nerve stimulation (taVNS) paired with oral feedings in infants of diabetic mothers (IDMs) who are failing oral feeds.MethodsWe treated 10 IDMs who were gastrostomy tube candidates in an open-label trial of NAC and taVNS paired with oral feeding. NAC (75 or 100 mg/kg/dose) was given by nasogastric (NG) administration every 6 h for 4 days, then combined with taVNS paired with 2 daily feeds for another 14 days. NAC pharmacokinetic (PK) parameters were determined from plasma concentrations at baseline and at steady state on day 4 of treatment in conjunction with magnetic resonance spectroscopic (MRS) quantification of CNS glutathione (GSH) as a marker of oxidative stress. We compared increases in oral feeding volumes before and during taVNS treatment and with a prior cohort of 12 IDMs who largely failed to achieve full oral feeds with taVNS alone.ResultsNAC 100 mg/kg/dose every 6 h NG resulted in plasma [NAC] that increased [GSH] in the basal ganglia with a mean of 0.13 ± 0.08 mM (p = 0.01, compared to baseline). Mean daily feeding volumes increased over 14 days of NAC + taVNS compared to the 14 days before treatment and compared to the prior cohort of 12 IDMs treated with taVNS alone. Seven IDMs reached full oral feeds sufficient for discharge, while three continued to have inadequate intake.ConclusionIn IDM failing oral feeds, NAC 100 mg/kg/dose every 6 h NG for 4 days before and during taVNS paired with oral feeding increased CNS GSH, potentially mitigating oxidative stress, and was associated with improving functional feeding outcomes compared to taVNS alone in a prior cohort. This represents a novel approach to neuromodulation and supports the concept that mitigation of ongoing oxidative stress may increase response to taVNS paired with a motor task.

Hearing loss constitutes a major global health concern impacting approximately 1.5 billion people worldwide. Its incidence is undergoing a substantial surge with some projecting that by 2050, a quarter of the global population will experience varying degrees of hearing deficiency. Environmental factors such as aging, exposure to loud noise, and the intake of ototoxic medications are implicated in the onset of acquired hearing loss. Ototoxicity resulting in inner ear damage is a leading cause of acquired hearing loss worldwide. This could be minimized or avoided by early testing of hearing functions in the preclinical phase of drug development. While the assessment of ototoxicity is well defined for drug candidates in the hearing field – required for drugs that are administered by the otic route and expected to reach the middle or inner ear during clinical use – ototoxicity testing is not required for all other therapeutic areas. Unfortunately, this has resulted in more than 200 ototoxic marketed medications. The aim of this publication is to raise awareness of drug-induced ototoxicity and to formulate some recommendations based on available guidelines and own experience. Ototoxicity testing programs should be adapted to the type of therapy, its indication (targeting the ear or part of other medications classes being potentially ototoxic), and the number of assets to test. For multiple molecules and/or multiple doses, screening options are available: in vitro (otic cell assays), ex vivo (cochlear explant), and in vivo (in zebrafish). In assessing the ototoxicity of a candidate drug, it is good practice to compare its ototoxicity to that of a well-known control drug of a similar class. Screening assays provide a streamlined and rapid method to know whether a drug is generally safe for inner ear structures. Mammalian animal models provide a more detailed characterization of drug ototoxicity, with a possibility to localize and quantify the damage using functional, behavioral, and morphological read-outs. Complementary histological measures are routinely conducted notably to quantify hair cells loss with cochleogram. Ototoxicity studies can be performed in rodents (mice, rats), guinea pigs and large species. However, in undertaking, or at the very least attempting, all preclinical investigations within the same species, is crucial. This encompasses starting with pharmacokinetics and pharmacology efficacy studies and extending through to toxicity studies. In life read-outs include Auditory Brainstem Response (ABR) and Distortion Product OtoAcoustic Emissions (DPOAE) measurements that assess the activity and integrity of sensory cells and the auditory nerve, reflecting sensorineural hearing loss. Accurate, reproducible, and high throughput ABR measures are fundamental to the quality and success of these preclinical trials. As in humans, in vivo otoscopic evaluations are routinely carried out to observe the tympanic membrane and auditory canal. This is often done to detect signs of inflammation. The cochlea is a tonotopic structure. Hair cell responsiveness is position and frequency dependent, with hair cells located close to the cochlea apex transducing low frequencies and those at the base transducing high frequencies. The cochleogram aims to quantify hair cells all along the cochlea and consequently determine hair cell loss related to specific frequencies. This measure is then correlated with the ABR & DPOAE results. Ototoxicity assessments evaluate the impact of drug candidates on the auditory and vestibular systems, de-risk hearing loss and balance disorders, define a safe dose, and optimize therapeutic benefits. These types of studies can be initiated during early development of a therapeutic solution, with ABR and otoscopic evaluations. Depending on the mechanism of action of the compound, studies can include DPOAE and cochleogram. Later in the development, a GLP (Good Laboratory Practice) ototoxicity study may be required based on otic related route of administration, target, or known potential otic toxicity.

Abstract Background The involvement of the autonomic nervous system in the regulation of inflammation is an emerging concept with significant potential for clinical applications. Recent studies demonstrate that stimulating the vagus nerve activates the cholinergic anti-inflammatory pathway that inhibits pro-inflammatory cytokines and controls inflammation. The α7 nicotinic acetylcholine receptor (α7nAChR) on macrophages plays a key role in mediating cholinergic anti-inflammatory effects through a downstream intracellular mechanism involving inhibition of NF-κB signaling, which results in suppression of pro-inflammatory cytokine production. However, the role of the α7nAChR in the regulation of other aspects of the immune response, including the recruitment of monocytes/macrophages to the site of inflammation remained poorly understood. Results We observed an increased mortality in α7nAChR-deficient mice (compared with wild-type controls) in mice with endotoxemia, which was paralleled with a significant reduction in the number of monocyte-derived macrophages in the lungs. Corroborating these results, fluorescently labeled α7nAChR-deficient monocytes adoptively transferred to WT mice showed significantly diminished recruitment to the inflamed tissue. α7nAChR deficiency did not affect monocyte 2D transmigration across an endothelial monolayer, but it significantly decreased the migration of macrophages in a 3D fibrin matrix. In vitro analysis of major adhesive receptors (L-selectin, β1 and β2 integrins) and chemokine receptors (CCR2 and CCR5) revealed reduced expression of integrin αM and αX on α7nAChR-deficient macrophages. Decreased expression of αMβ2 was confirmed on fluorescently labeled, adoptively transferred α7nAChR-deficient macrophages in the lungs of endotoxemic mice, indicating a potential mechanism for α7nAChR-mediated migration. Conclusions We demonstrate a novel role for the α7nAChR in mediating macrophage recruitment to inflamed tissue, which indicates an important new aspect of the cholinergic regulation of immune responses and inflammation.

Abstract Explosive volcanic eruptions produce vast quantities of silicate ash, whose surfaces are subsequently altered during atmospheric transit. These altered surfaces mediate environmental interactions, including atmospheric ice nucleation, and toxic effects in biota. A lack of knowledge of the initial, pre-altered ash surface has required previous studies to assume that the ash surface composition created during magmatic fragmentation is equivalent to the bulk particle assemblage. Here we examine ash particles generated by controlled fragmentation of andesite and find that fragmentation generates ash particles with substantial differences in surface chemistry. We attribute this disparity to observations of nanoscale melt heterogeneities, in which Fe-rich nanophases in the magmatic melt deflect and blunt fractures, thereby focusing fracture propagation within aureoles of single-phase melt formed during diffusion-limited growth of crystals. In this manner, we argue that commonly observed pre-eruptive microtextures caused by disequilibrium crystallisation and/or melt unmixing can modify fracture propagation and generate primary discrepancies in ash surface chemistry, an essential consideration for understanding the cascading consequences of reactive ash surfaces in various environments.

Abstract Explosivity in erupting volcanoes is controlled by the degassing dynamics and the viscosity of the ascending magma in the conduit. Magma crystallisation enhances both heterogeneous bubble nucleation and increases in magma bulk viscosity. Nanolite crystallisation has been suggested to enhance such processes too, but in a noticeably higher extent. Yet the precise causes of the resultant strong viscosity increase remain unclear. Here we report experimental results for rapid nanolite crystallisation in natural silicic magma and the extent of the subsequent viscosity increase. Nanolite-free and nanolite-bearing rhyolite magmas were subjected to heat treatments, where magmas crystallised or re-crystallised oxide nanolites depending on their initial state, showing an increase of one order of magnitude as oxide nanolites formed. We thus demonstrate that oxide nanolites crystallisation increases magma bulk viscosity mainly by increasing the viscosity of its melt phase due to the chemical extraction of iron, whereas the physical effect of particle suspension is minor, almost negligible. Importantly, we further observe that this increase is sufficient for driving magma fragmentation depending on magma degassing and ascent dynamics.

In 2017, we reported the discovery of Berkeleylactone A (BPLA), a novel, potent antibiotic produced exclusively in co-culture by two extremophilic fungi, Penicillium fuscum and P. camembertii/clavigerum, which were isolated from the Berkeley Pit, an acid mine waste lake, in Butte, Montana. Neither fungus synthesized BPLA when grown in axenic culture. Recent studies suggest that secondary metabolites (SMs) are often synthesized by enzymes encoded by co-localized genes that form “biosynthetic gene clusters” (BGCs), which might remain silent (inactive) under various fermentation conditions. Fungi may also harbor cryptic BGCs that are not associated with previously characterized molecules. We turned to the tools of Fungal Artificial Chromosomes (FAC)-Next-Gen-Sequencing (NGS) to understand how co-culture activated cryptic biosynthesis of BPLA and several related berkeleylactones and to further investigate the true biosynthetic potential of these two fungi. FAC-NGS enables the capture of BGCs as individual FACs for heterologous expression in a modified strain of Aspergillus nidulans (heterologous host, FAC-AnHH). With this methodology, we created ten BGC-FACs that yielded fourteen different SMs, including strobilurin, which was previously isolated exclusively from basidiomycetes. Eleven of these compounds were not detected in the extracts of the FAC-AnHH. Of this discrete set, only the novel compound citreohybriddional had been isolated from either Penicillium sp. before and only at very low yield. We propose that through heterologous expression, FACs activated these silent BGCs, resulting in the synthesis of new natural products (NPs) with yields as high as 50%–60% of the crude organic extracts.

Abstract Nanoscale liquid immiscibility is observed in the 2018–2021 Fani Maoré submarine lavas (Comoros archipelago). Heat transfer calculations, Raman spectroscopy, scanning and transmission electron microscopy reveal that in contrast to thin (500 µm) outer rims of homogeneous glassy lava (rapidly quenched upon eruption, >1000 °C s−1), widespread liquid immiscibility is observed in thick (1 cm) inner lava rims (moderately quenched, 1–1000 °C s−1), which exhibit a nanoscale coexistence of Si- and Al-rich vs. Ca-, Fe-, and Ti-rich melt phases. In this zone, rapid nanolite crystallization contrasts with the classical crystallization process inferred for the slower cooled (

Explosive volcanic eruptions generate electrical discharges, a phenomenon termed volcanic lightning (VL). VL is increasingly well-investigated and monitored for modern eruptions, however volcanism has been active since Earth’s origin. Thus, investigating VL under different atmospheric conditions is relevant for studies of early atmospheric chemistry and potential prebiotic reactions. We developed an experimental setup to investigate VL in varying atmospheres. We present the first experiments of laboratory discharges in particle-laden jets in varying atmospheric conditions. The new experimental setup is a mobile fragmentation bomb erupting into a gas-tight particle collector tank. This setup enables the testing of different atmospheric conditions, changes in the carrier gas of the jet, changes in the pressure within the tank, monitoring of the jet behaviour, and sampling of the atmosphere together with the decompressed solid materials. We find that the number and magnitude of near-vent electrical discharge events are similar in CO2-CO and air atmospheres.

The vulnerability of biodiversity to climate change and habitat alterations is a growing global concern. In the case of reptiles, it has been widely documented that relatively small changes in temperature can have drastic effects on biological processes with significant ecological consequences. This study used biophysical models to investigate how climate change and levels of shade influence the activity period of a vulnerable tropical tortoise (Gopherus evgoodei). The results revealed that reduced shading, serving as an indicator of decreased vegetation cover, has a significant and negative impact on the activity time of this species. Furthermore, it is projected that a 1.8°C increase in ambient temperature due to climate change would lead to an even further reduction in its activity time. This finding highlights the critical importance of shade, vegetation, and thermal limitations in the physiology of this tortoise, emphasizing the challenges that tropical reptiles face due to climate change and habitat alteration. The study also emphasizes the utility of mechanistic niche models in understanding how climate change and habitat modification can affect organisms. In conclusion, this study provides valuable eco-physiological information for the conservation of vulnerable species in tropical environments, highlighting the importance of preserving vegetation cover in tortoise habitats and carefully considering the implications of climate change in an ever-changing world amidst the biodiversity crisis.

ABSTRACT The cellular junctional architecture remodeling by Listeria adhesion protein-heat shock protein 60 (LAP-Hsp60) interaction for Listeria monocytogenes (Lm) passage through the epithelial barrier is incompletely understood. Here, using the gerbil model, permissive to internalin (Inl) A/B-mediated pathways like in humans, we demonstrate that Lm crosses the intestinal villi at 48 h post-infection. In contrast, the single isogenic (lap− or ΔinlA) or double (lap−ΔinlA) mutant strains show significant defects. LAP promotes Lm translocation via endocytosis of cell-cell junctional complex in enterocytes that do not display luminal E-cadherin. In comparison, InlA facilitates Lm translocation at cells displaying apical E-cadherin during cell extrusion and mucus expulsion from goblet cells. LAP hijacks caveolar endocytosis to traffic integral junctional proteins to the early and recycling endosomes. Pharmacological inhibition in a cell line and genetic knockout of caveolin-1 in mice prevents LAP-induced intestinal permeability, junctional endocytosis, and Lm translocation. Furthermore, LAP-Hsp60-dependent tight junction remodeling is also necessary for InlA access to E-cadherin for Lm intestinal barrier crossing in InlA-permissive hosts.IMPORTANCEListeria monocytogenes (Lm) is a foodborne pathogen with high mortality (20%–30%) and hospitalization rates (94%), particularly affecting vulnerable groups such as pregnant women, fetuses, newborns, seniors, and immunocompromised individuals. Invasive listeriosis involves Lm’s internalin (InlA) protein binding to E-cadherin to breach the intestinal barrier. However, non-functional InlA variants have been identified in Lm isolates, suggesting InlA-independent pathways for translocation. Our study reveals that Listeria adhesion protein (LAP) and InlA cooperatively assist Lm entry into the gut lamina propria in a gerbil model, mimicking human listeriosis in early infection stages. LAP triggers caveolin-1-mediated endocytosis of critical junctional proteins, transporting them to early and recycling endosomes, facilitating Lm passage through enterocytes. Furthermore, LAP-Hsp60-mediated junctional protein endocytosis precedes InlA’s interaction with basolateral E-cadherin, emphasizing LAP and InlA’s cooperation in enhancing Lm intestinal translocation. This understanding is vital in combating the severe consequences of Lm infection, including sepsis, meningitis, encephalitis, and brain abscess.

Abstract Fulgurites have been documented in geological deposits from throughout Earth's history. They have also been assigned a potential role in prebiotic chemistry as a source of reactants. Fulgurites are generated in nature by cloud-to-ground lightning strikes. The unpredictability in space and time of the occurrence of lightning events has limited the investigation of both the mechanisms by, and the conditions under, which fulgurites form. A laboratory-based approach can mitigate these limitations. Here, we describe experimentally generated fulgurites generated from Laacher See volcanic ash. We employ a DC source with a trigger-pulse setup in a high voltage laboratory, whose capabilities enable experimental conditions that correspond closely to the electrical characteristics of natural lightning strikes. The experimentally generated fulgurites closely resemble naturally-occurring fulgurites in both state and texture. These experimental investigations yield a high reproducibility of the characteristic of fulgurites generated under well-constrained conditions, enabling some inferences to be made regarding the processes involved in the generation of fulgurites in nature. This work provides a basis for a systematic characterization of experimental fulgurites and the characteristic of lightning discharges.

Abstract Background: We describe a retrospective assessment of practitioner and patient recruitment strategies, patient retention strategies, and rates for five clinical studies conducted in the National Dental Practice-Based Research Network between 2012 and 2019, and practitioner and patient characteristics associated with retention. Methods: Similar recruitment strategies were adopted in the studies. The characteristics of the practitioners and patients are described. The proportion of patients who either attended a follow-up (FU) assessment or completed an online assessment was calculated. For studies with multiple FU visits or questionnaire assessments, rates for completing each FU were calculated, as were the rates for completing any and for completing all FU assessments. The associations of practitioner and patient characteristics with all clinic FU visits, and with the completion of all assessments for a study were ascertained. Results: Overall, 591 practitioners and 12,159 patients were included. FU rates by patients for any assessment varied from 91% to 96.5%, and rates for participating in all assessments ranged from 68% to 87%. The mean total number of patients each practitioner recruited was 21 (sd = 15); the mean number per study was 13 (sd = 7). For practitioners, practice type and patient enrollment were associated with greater clinic retention, while only race was associated with their patients completing post-visit online assessments. For patients, age was associated with clinic retention, while female gender, age, race, and education were all associated with greater completion of post-visit online assessments. Conclusion: The Network efficiently recruited practitioners and patients and achieved high patient retention rates for the five studies.

Abstract Mounting evidence has shown that personality and behavioral syndromes have a substantial influence on interspecific interactions and individual fitness. However, the stability of covariation among multiple behavioral traits involved in antipredator responses has seldom been tested. Here, we investigate whether sex, gravidity, and parasite infestations influence the covariation between risk aversion (hiding time within a refuge) and escape response (immobility, escape distance) using a viviparous lizard, Zootoca vivipara, as a model system. Our results demonstrated a correlation between risk‐averse and escape behavior at the among‐individual level, but only in gravid females. We found no significant correlations in either males or neonates. A striking result was the loss of association in postparturition females. This suggests that the “risk‐averse – escape” syndrome is ephemeral and only emerges in response to constraints on locomotion driven by reproductive burden. Moreover, parasites have the potential to dissociate the correlations between risk aversion and escape response in gravid females, yet the causal chain requires further examination. Overall, our findings provide evidence of differences in the association between behaviors within the lifetime of an individual and indicate that individual states, sex, and life stages can together influence the stability of behavioral syndromes.

Summary: Vascular calcification is a hallmark of atherosclerotic disease and serves as a strong predictor and risk factor for cardiovascular events. Growing evidence suggests that autophagy may play a protective role in early atherosclerosis. The precise effects of autophagy on VSMC-mediated calcification remain unknown. In this study, we utilized multi-omic profiling to investigate impaired autophagy at the transcriptional level as a key driver of VSMC calcification. Our findings revealed that impaired autophagy is an essential determinant of VSMC calcification. We observed that an osteogenic environment affects the open chromatin status of VSMCs, compromising the transcriptional activation of autophagy initiation genes. In vivo experiments involve pharmacological and genetic activation of autophagy using mouse models of spontaneous large (Mgp−/−) and small (Abcc6−/−) artery calcification. Taken together, these data advance our mechanistic understanding of vascular calcification and provide important insights for a broad range of cardiovascular diseases involving VSMC phenotype switch.

Abstract Clinical and preclinical studies established that supplementing diets with ω3 polyunsaturated fatty acids (PUFA) can reduce hepatic dysfunction in nonalcoholic steatohepatitis (NASH) but molecular underpinnings of this action were elusive. Herein, we used multi‐omic network analysis that unveiled critical molecular pathways involved in ω3 PUFA effects in a preclinical mouse model of western diet induced NASH. Since NASH is a precursor of liver cancer, we also performed meta‐analysis of human liver cancer transcriptomes that uncovered betacellulin as a key EGFR‐binding protein upregulated in liver cancer and downregulated by ω3 PUFAs in animals and humans with NASH. We then confirmed that betacellulin acts by promoting proliferation of quiescent hepatic stellate cells, inducing transforming growth factor–β2 and increasing collagen production. When used in combination with TLR2/4 agonists, betacellulin upregulated integrins in macrophages thereby potentiating inflammation and fibrosis. Taken together, our results suggest that suppression of betacellulin is one of the key mechanisms associated with anti‐inflammatory and anti‐fibrotic effects of ω3 PUFA on NASH.

Ventricular arrhythmias (VAs) in heart failure are enhanced by sympathoexcitation. However, radiotracer studies of catecholamine uptake in failing human hearts demonstrate a proclivity for VAs in patients with reduced cardiac sympathetic innervation. We hypothesized that this counterintuitive finding is explained by heterogeneous loss of sympathetic nerves in the failing heart. In a murine model of dilated cardiomyopathy (DCM), delayed PET imaging of sympathetic nerve density using the catecholamine analog [11C]meta-Hydroxyephedrine demonstrated global hypoinnervation in ventricular myocardium. Although reduced, sympathetic innervation in 2 distinct DCM models invariably exhibited transmural (epicardial to endocardial) gradients, with the endocardium being devoid of sympathetic nerve fibers versus controls. Further, the severity of transmural innervation gradients was correlated with VAs. Transmural innervation gradients were also identified in human left ventricular free wall samples from DCM versus controls. We investigated mechanisms underlying this relationship by in silico studies in 1D, 2D, and 3D models of failing and normal human hearts, finding that arrhythmogenesis increased as heterogeneity in sympathetic innervation worsened. Specifically, both DCM-induced myocyte electrical remodeling and spatially inhomogeneous innervation gradients synergistically worsened arrhythmogenesis. Thus, heterogeneous innervation gradients in DCM promoted arrhythmogenesis. Restoration of homogeneous sympathetic innervation in the failing heart may reduce VAs.

Observations and measurements on active volcanoes are commonly conducted at a distance considered safe from the inherent dangers linked to volcanic explosions. This reduction in proximity adds a degree of uncertainty to the interpretation of monitoring data due to enhanced signal path effects. Here, we describe custom-built, drone-deployable sensor platforms designed to acquire data at high proximity to volcanic vents. They are equipped with an environmental sensor capable of measuring temperature, relative humidity and barometric pressure, a microphone (6 Hz–20 kHz) to reconstruct the acoustic pressure, and an electrical resonant circuit to detect electrical signals in the 500 kHz frequency band. Communication and data transfer is achieved through a radio link between the sensor platform and the base station. Our sensor platforms may be employed in the collection of data of near-vent characteristics of volcanic explosions, observations that are essential for quantifying and understanding the driving forces underlying volcanic explosions.

Abstract The sympathetic nervous system is crucial for controlling multiple cardiac functions. However, a comprehensive, detailed neuroanatomical map of the sympathetic innervation of the heart is unavailable. Here, we used a combination of state-of-the-art techniques, including flat-mount tissue processing, immunohistochemistry for tyrosine hydroxylase (TH, a sympathetic marker), confocal microscopy and Neurolucida 360 software to trace, digitize, and quantitatively map the topographical distribution of the sympathetic postganglionic innervation in whole atria of C57Bl/6 J mice. We found that (1) 4–5 major extrinsic TH-IR nerve bundles entered the atria at the superior vena cava, right atrium (RA), left precaval vein and the root of the pulmonary veins (PVs) in the left atrium (LA). Although these bundles projected to different areas of the atria, their projection fields partially overlapped. (2) TH-IR axon and terminal density varied considerably between different sites of the atria with the greatest density of innervation near the sinoatrial node region (P

Abstract Background Pain management is a critical component of comprehensive postsurgical care, as it influences patient safety and outcomes, and inadequate control has been associated with the development of chronic pain syndromes. Despite recent improvements, the management of postoperative pain following total knee arthroplasty (TKA) remains a challenge. The use of opioid-sparing, multimodal analgesic regimens has broad support, but there is a paucity of high-quality evidence regarding optimal postoperative protocols and novel approaches are needed. Dextromethorphan stands out among both well-studied and emerging pharmacological adjuncts for postoperative pain due its robust safety profile and unique pharmacology. The purpose of this study is to evaluate the efficacy of multi-dose dextromethorphan for postoperative pain control following TKA. Methods This is a single-center, multi-dose, randomized, double-blinded, placebo-controlled trial. A total of 160 participants will be randomized 1:1 to receive either 60 mg oral dextromethorphan hydrobromide preoperatively, as well as 30 mg 8 h and 16 h postoperatively, or matching placebo. Outcome data will be obtained at baseline, during the first 48 h, and the first two follow-up visits. The primary outcome measure will be total opioid consumption at 24 h postoperatively. Secondary outcomes related to pain, function, and quality of life will be evaluated using standard pain scales, the Knee Injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS, JR) questionnaire, the Patient-Reported Outcomes Measurement Information System (PROMIS-29) questionnaire, and clinical anchors. Discussion This study has a number of strengths including adequate power, a randomized controlled design, and an evidence-based dosing schedule. As such, it will provide the most robust evidence to date on dextromethorphan utilization for postoperative pain control following TKA. Limitations include not obtaining serum samples for pharmacokinetic analysis and the single-center study design. Trial registration This trial has been registered on the National Institute of Health’s ClinicalTrials.gov (NCT number: NCT05278494). Registered on March 14, 2022.

Integrating vectors are associated with alterations in cellular function related to disruption of normal gene function. This has been associated with clonal expansion of cells and, in some instances, cancer. These events have been associated with replication-defective vectors and suggest that the inadvertent exposure to a replication-competent virus arising during vector manufacture would significantly increase the risk of treatment-related adverse events. These risks have led regulatory agencies to require specific monitoring for replication-competent viruses, both prior to and after treatment of patients with gene therapy products. Monitoring the risk of cell expansion and malignancy is also required. In this review, we discuss the rational potential approaches and challenges to meeting the US FDA expectations listed in current guidance documents.

BackgroundNonalcoholic fatty liver disease (NAFLD) is a global health problem. Identifying early gene indicators contributing to the onset and progression of NAFLD has the potential to develop novel targets for early therapeutic intervention. We report on the early and late transcriptomic signatures of western diet (WD)-induced nonalcoholic steatohepatitis (NASH) in female and male Ldlr−/− mice, with time-points at 1 week and 40 weeks on the WD. Control Ldlr−/− mice were maintained on a low-fat diet (LFD) for 1 and 40 weeks.MethodsThe approach included quantitation of anthropometric and hepatic histology markers of disease as well as the hepatic transcriptome.ResultsOnly mice fed the WD for 40 weeks revealed evidence of NASH, i.e., hepatic steatosis and fibrosis. RNASeq transcriptome analysis, however, revealed multiple cell-specific changes in gene expression after 1 week that persisted to 40 weeks on the WD. These early markers of disease include induction of acute phase response (Saa1-2, Orm2), fibrosis (Col1A1, Col1A2, TGFβ) and NASH associated macrophage (NAM, i.e., Trem2 high, Mmp12 low). We also noted the induction of transcripts associated with metabolic syndrome, including Mmp12, Trem2, Gpnmb, Lgals3 and Lpl. Finally, 1 week of WD feeding was sufficient to significantly induce TNFα, a cytokine involved in both hepatic and systemic inflammation.ConclusionThis study revealed early onset changes in the hepatic transcriptome that develop well before any anthropometric or histological evidence of NALFD or NASH and pointed to cell-specific targeting for the prevention of disease progression.

Abstract Background The vagus nerve affects innate immune responses by activating spleen-projecting sympathetic neurons, which modulate leukocyte function. Recent basic and clinical research investigating vagus nerve stimulation to engage the cholinergic anti-inflammatory pathway (CAP) has shown promising therapeutic results for a variety of inflammatory diseases. Abundant sympathetic innervation occurs in rodent spleens, and use of these species has dominated mechanistic research investigating the CAP. However, previous neuroanatomical studies of human spleen found a more restricted pattern of innervation compared to rodents. Therefore, our primary goal was to establish the full extent of sympathetic innervation of human spleens using donor tissue with the shortest procurement to fixation time. Parallel studies of porcine spleen, a large animal model, were performed as a positive control and for comparison. Methods Human and porcine spleen tissue were fixed immediately after harvest and prepared for immunohistochemistry. Human heart and porcine spleen were stained in conjunction as positive controls. Several immunohistochemical protocols were compared for best results. Tissue was stained for tyrosine hydroxylase (TH), a noradrenergic marker, using VIP purple chromogen. Consecutive tissue slices were stained for neuropeptide Y (NPY), which often co-localizes with TH, or double-labelled for TH and CD3, a T cell marker. High-magnification images and full scans of the tissue were obtained and analyzed for qualitative differences between species. Results TH had dominant perivascular localization in human spleen, with negligible innervation of parenchyma, but such nerves were abundant throughout ventricular myocardium. In marked contrast, noradrenergic innervation was abundant in all regions of porcine spleen, with red pulp having more nerves than white pulp. NPY stain results were consistent with this pattern. In human spleen, noradrenergic nerves only ran close to T cells at the boundary of the periarterial lymphatic sheath and arteries. In porcine spleen, noradrenergic nerves were closely associated with T cells in both white and red pulp as well as other leukocytes in red pulp. Conclusion Sympathetic innervation of the spleen varies between species in both distribution and abundance, with humans and pigs being at opposite extremes. This has important implications for sympathetic regulation of neuroimmune interactions in the spleen of different species and focused targeting of the CAP in humans.

Can volcanoes erupt ore deposits? This study combines observations, experiments, and simulations to show that iron ore deposits on El Laco volcano formed by eruption of melt sourced from separation of Fe-rich melt from a silicate magma body beneath.

The concern for firefighters’ occupational exposure to harmful contaminants is growing due to the increase in health issues in the firefighting community. At such times, effective decontamination of personnel and equipment is an essential component of a hazard mitigation strategy. The current decontamination practices used for firefighter protective clothing have been shown to not be very effective. Hence, the scientific community is looking for several alternatives to conventional washing procedures. Liquid carbon dioxide (CO2) has been used in laundering and has distinct advantages over conventional dry-cleaning solvents such as perchloroethylene. The following study is aimed to assess how different washing procedures affect the durability of the turnout material. The study includes using three washing procedures on different samples: 1) conventional washing procedure, 2) liquid CO2 washing procedure, and 3) a high-temperature washing procedure. Samples for durability testing were constructed from a common aramid fabric used in firefighter turnout ensembles. These swatches were subjected to different washing techniques. The durability assessment was performed for physical testing of the samples, visual inspection, water repellency, and quantifying color changes using spectrophotometric analysis. The conventional wash and high-temperature washing affected the durability of the outer shell material in a significant manner. The liquid CO2 process did not affect the samples’ water repellency or physical strength. In contrast, conventional and high-temperature washing significantly affected the durability of the outer shell material. However, all samples met the criteria for tearing strength outlined in the NFPA 1971 standard subsection 7.1.11.

The role of physiology on habitat specialization in terrestrial ectotherms constitutes a rarely addressed topic, despite the fact that habitat specialization often involves the coadaptation of multiple physiological traits, which in turn may confer a higher vulnerability to climate change. Here we documented aspects of the thermal and hydric physiology of Sceloporus macdougalli, a lizard restricted to granite boulders in a tiny area of a tropical dry forest of Mexico, and estimated its vulnerability to climate change. We aimed to determine the physiological and behavioral adjustments used by this species to cope with a striking seasonal environment, to elucidate whether ecophysiology could help explain its habitat specialization, microendemicity, and how increasing environmental temperatures will restrict activity of this species. The effectiveness of thermoregulation and indications of water conservation strategies changed markedly over seasons. As expected, granite boulders and associated vegetation were more suitable for thermo- and hydroregulation than surrounding (and unoccupied) habitat. However, our model indicated that by 2041-2060 climate change will restrict activity of this species, enhancing its threat of extinction. These results highlight the importance of granite microhabitats for the thermal and water relations of S. macdougalli, in the context of climate change, and suggest that the current habitat and range restriction of the species might be an outcome of its physiology, thus demanding urgent actions to preserve the species from extinction.

In Argentina, some people add peanuts to their beer. Once immersed, the peanuts initially sink part way down into the beer before bubbles nucleate and grow on the peanut surfaces and remain attached. The peanuts move up and down within the beer glass in many repeating cycles. In this work, we propose a physical description of this dancing peanuts spectacle. We break down the problem into component physical phenomena, providing empirical constraint of each: (i) heterogeneous bubble nucleation occurs on peanut surfaces and this is energetically preferential to nucleation on the beer glass surfaces; (ii) peanuts enshrouded in attached bubbles are positively buoyant in beer above a critical attached gas volume; (iii) at the beer top surface, bubbles detach and pop, facilitated by peanut rotations and rearrangements; (iv) peanuts containing fewer bubbles are then negatively buoyant in beer and sink; and (v) the process repeats so long as the beer remains sufficiently supersaturated in the gas phase for continued nucleation. We used laboratory experiments and calculations to support this description, including constraint of the densities and wetting properties of the beer–gas–peanut system. We draw analogies between this peanut dance cyclicity and industrial and natural processes of wide interest, ultimately concluding that this bar-side phenomenon can be a vehicle for understanding more complex, applied systems of general interest and utility.

The α7-nicotinic acetylcholine receptor (α7nAChR) is a key protein in the cholinergic anti-inflammatory pathway (CAP) that links the nervous and immune systems. Initially, the pathway was discovered based on the observation that vagal nerve stimulation (VNS) reduced the systemic inflammatory response in septic animals. Subsequent studies form a foundation for the leading hypothesis about the central role of the spleen in CAP activation. VNS evokes noradrenergic stimulation of ACh release from T cells in the spleen, which in turn activates α7nAChRs on the surface of macrophages. α7nAChR-mediated signaling in macrophages reduces inflammatory cytokine secretion and modifies apoptosis, proliferation, and macrophage polarization, eventually reducing the systemic inflammatory response. A protective role of the CAP has been demonstrated in preclinical studies for multiple diseases including sepsis, metabolic disease, cardiovascular diseases, arthritis, Crohn’s disease, ulcerative colitis, endometriosis, and potentially COVID-19, sparking interest in using bioelectronic and pharmacological approaches to target α7nAChRs for treating inflammatory conditions in patients. Despite a keen interest, many aspects of the cholinergic pathway are still unknown. α7nAChRs are expressed on many other subsets of immune cells that can affect the development of inflammation differently. There are also other sources of ACh that modify immune cell functions. How the interplay of ACh and α7nAChR on different cells and in various tissues contributes to the anti-inflammatory responses requires additional study. This review provides an update on basic and translational studies of the CAP in inflammatory diseases, the relevant pharmacology of α7nAChR-activated drugs and raises some questions that require further investigation.

Abstract We study the rheology of silicate melts containing platinum-group element (PGE) particles. They exhibit a shear-thinning behaviour, an intense aggregation tendency, and an anomalously high apparent viscosity in the low shear rate limit, even at very low particle volume fraction. Using a compilation of published experimental data, we analyse these effects in three steps. Firstly, we observe that the viscosities of these suspensions are much higher than those of natural silicate crystal-bearing melts for low shear rate regimes. Secondly, we demonstrate that the viscosities at low shear rate limit cannot be estimated by classical rheological models but rather may be understood as the result of particle aggregation, trapping dead fluid, and thereby increasing the effective particle volume fraction. Finally, we scale the critical shear rates for shear-thinning using a Peclet number analysis—invoking a competition between random thermal particle motion and hydrodynamic shearing motion—and, using an empirical extension, we additionally account for the particle–particle interaction energetics. We propose a framework in which the rheology of this family of particle-bearing melts can be predicted, and demonstrate that at low Peclet numbers, PGE-bearing particle aggregation is driven by interparticle forces and Brownian motion.

Jones et al. identify a new type of volcanic deposit, inflated pyroclasts, that form by continued gas expansion post-deposition. They show how these deposits can be indicative of abrupt transitions in eruptive behaviour at mafic volcanoes.

Abstract Anthropogenic global warming and deforestation are significant drivers of the global biodiversity crisis. Ectothermic and viviparous animals are especially vulnerable since high environmental temperatures can impair embryonic development, but we lack knowledge about these effects upon Neotropical organisms. Here, we estimate how much of the current area with suitable habitats overlaps with protected areas and model the combined effects of climate change and deforestation on the geographic distribution of the viviparous Neotropical lizard Notomabuya frenata (Scincidae). This species ranges in Brazil, Argentina, Paraguay, and Bolivia. We use environmental and physiological variables (locomotor performance and hours of activity) to predict suitable present and future areas, considering different scenarios of greenhouse gas emissions and deforestation. The most critical predictors of habitat suitability were isothermality (i.e., the ratio between mean diurnal temperature range and annual temperature range), precipitation during winter, and hours of activity under lower thermal extremes. Still, our models predict a contraction of suitable habitats in all future scenarios and the displacement of these areas towards eastern South America. In addition, protected areas are not enough to ensure suitable habitats for this species. Our findings highlight the vulnerability of tropical and viviparous ectotherms and suggest that even widely distributed species, such as N. frenata, may have their conservation compromised shortly due to the low representativeness of their suitable habitats in protected areas combined with the synergistic effects of climate change and deforestation. We stress the need for decision‐makers to consider the impact of range shifts in creating protected areas and managing endangered species.

Abstract Volcanic ash is a major threat to aviation safety. The softening/melting temperatures of volcanic ash lie far below typical aero‐engine operating temperatures. Thus, molten ash can accelerate the failure of thermal barrier coatings (TBCs). Here, inspired by natural superhydrophobic surfaces (e.g., the lotus leaf), a molten‐volcanic‐ash‐phobic TBC, which provides a large possibility to eliminate molten ash issues of TBCs, is developed. A hierarchically structured surface is first prepared on a (Gd0.9Yb0.1)2Zr2O7 (GYbZ) pellet by ultrafast laser direct writing technology, aiming to confirm the feasibility of the biomimetic microstructure to repel molten volcanic ash wetting. Then biomimetic‐structured GYbZ TBCs are successfully fabricated using plasma spray physical vapor deposition, which reveals “silicate” phobicity at high temperatures. The exciting molten‐volcanic‐ash‐phobic attribute of the designed surfaces is attributed to the lotus‐leaf‐like dual‐scale microstructure, emulating in particular the existence of nanoparticles. These findings may be an important step toward the development of next‐generation aviation engines with greatly reduced vulnerability to environmental siliceous debris.

Silicate material from environmental dust melts and adheres to the surfaces of thermal barrier coatings (TBCs) on hot-components of turbine engines accelerating their eventual failure. To mitigate against the wettability and spreadability of such molten deposits on TBCs, dual-scale structured (Gd0.9Yb0.1)2Zr2O7 TBCs with “lotus leaf” like surface morphology were fabricated using novel PS-PVD technology, which revealed an enhanced resistance to the wetting of molten silicate but experienced some degradation at high temperatures. By the ultrafast laser direct writing technology, the surface of the PS-PVD TBC was re-constructed, obtaining a triple-scale structure, consisting of conical micro-pillars, cauliflower-like domed micro-protuberances and nanoparticles. The contact angle of molten deposits at 1200 °C on this TBC was measured to be ∼ 127.2°, and after exposure to 1300 °C for 10 h, the TBC is still silicophobic (i.e., contact angle of ∼ 124.7°). This superior silicate phobicity is largely attributed to the increased surface roughness of the triple-scale structure. Further, the reaction layer appears to resist effectively further melt penetration. We thus propose that PS-PVD technology together with ultrafast laser direct writing may have great potential for the fabrication of molten silicophobic TBCs for turbine engines.

Background: Delayed paraplegia is a devastating complication of thoracoabdominal aortic surgery. Hydrogen sulfide (H2S) was reported to be protective in a mouse model of spinal cord ischemia and the beneficial effect of H2S has been attributed to polysulfides. The objective of this study was to investigate the effects of polysulfides on delayed paraplegia after spinal cord ischemia. Methods and results: Spinal cord ischemia was induced in male and female C57BL/6J mice by clamping the aortic arch and the left subclavian artery. Glutathione trisulfide (GSSSG), glutathione (GSH), glutathione disulfide (GSSG), or vehicle alone was administered intranasally at 0, 8, 23, and 32 h after surgery. All mice treated with vehicle alone developed paraplegia within 48 h after surgery. GSSSG, but not GSH or GSSG, prevented paraplegia in 8 of 11 male mice (73%) and 6 of 8 female mice (75%). Intranasal administration of 34S-labeled GSSSG rapidly increased 34S-labeled sulfane sulfur species in the lumbar spinal cord. In mice treated with intranasal GSSSG, there were increased sulfane sulfur levels, and decreased neurodegeneration, microglia activation, and caspase-3 activation in the lumbar spinal cord. In vitro studies using murine primary cortical neurons showed that GSSSG increased intracellular levels of sulfane sulfur. GSSSG, but not GSH or GSSG, dose-dependently improved cell viability after oxygen and glucose deprivation/reoxygenation (OGD/R). Pantethine trisulfide (PTN-SSS) also increased intracellular sulfane sulfur and improved cell viability after OGD/R. Intranasal administration of PTN-SSS, but not pantethine, prevented paraplegia in 6 of 9 male mice (66%). Conclusions: Intranasal administration of polysulfides rescued mice from delayed paraplegia after transient spinal cord ischemia. The neuroprotective effects of GSSSG were associated with increased levels of polysulfides and sulfane sulfur in the lumbar spinal cord. Targeted delivery of sulfane sulfur by polysulfides may prove to be a novel approach to the treatment of neurodegenerative diseases.

تتخذ هذه الدراسةُ المعقودةُ لتحليل شخصية ابن تيمية (ت 728هـ/1328م) من الحُكْم الذي قرره ابنُ بطوطة (779هـ/1377م تقريبًا) بشأنه، وهو أنه كان يفتقر إلى الاتزان العقلي= مُنْطَلقًا لها. ولئن كانت تهدف في الأساس إلى تقييمَ هذا الحُكْم، فإن لها هدفًا آخر يتمثَّل في بيان ما إذا كانت شخصيةُ ابن تيمية قد أثَّرت على سيرته، وكيف أثَّرت، وعلى وجه الخصوص تحديد ما إذا كان التحيُّزُ العاطفيُّ الذي أثاره سواءٌ أكان لصالحه أم ضده يمكن أن يُعْزَى بدرجةٍ كبيرةٍ إلى سلوكه. على أننا سنضرب صفحًا هنا عن مناقشة مسألةٍ أخرى لا تقل في أهميتها عن سابقتها إن لم تكن أهمَّ منها، ألا وهي مقدارُ الأثر الذي تركته شخصيةُ ابن تيمية على كتاباتِهِ؛ لأن الترتيب الزمني لمؤلفاته التي تَنِدُّ عن الحصر، والتي لا يزال أكثرُها مخطوطًا، لم يُدْرَس بعدُ درسًا وافيًا. وثمة سؤالٌ آخر يرد ضمنًا في تضاعيف هذه الدراسة، وهو: هل المعلومات التي تتيحها لنا المصادرُ الإسلاميةُ الوسيطةُ تكفي للوفاء بمقاصد التحليل النفسي الجاد [لشخصية ابن تيمية]؟

A universal taxonomy of viruses is essential for a comprehensive view of the virus world and for communicating the complicated evolutionary relationships among viruses. However, there are major differences in the conceptualisation and approaches to virus classification and nomenclature among virologists, clinicians, agronomists, and other interested parties. Here, we provide recommendations to guide the construction of a coherent and comprehensive virus taxonomy, based on expert scientific consensus. Firstly, assignments of viruses should be congruent with the best attainable reconstruction of their evolutionary histories, i.e., taxa should be monophyletic. This fundamental principle for classification of viruses is currently included in the International Committee on Taxonomy of Viruses (ICTV) code only for the rank of species. Secondly, phenotypic and ecological properties of viruses may inform, but not override, evolutionary relatedness in the placement of ranks. Thirdly, alternative classifications that consider phenotypic attributes, such as being vector-borne (e.g., "arboviruses"), infecting a certain type of host (e.g., "mycoviruses," "bacteriophages") or displaying specific pathogenicity (e.g., "human immunodeficiency viruses"), may serve important clinical and regulatory purposes but often create polyphyletic categories that do not reflect evolutionary relationships. Nevertheless, such classifications ought to be maintained if they serve the needs of specific communities or play a practical clinical or regulatory role. However, they should not be considered or called taxonomies. Finally, while an evolution-based framework enables viruses discovered by metagenomics to be incorporated into the ICTV taxonomy, there are essential requirements for quality control of the sequence data used for these assignments. Combined, these four principles will enable future development and expansion of virus taxonomy as the true evolutionary diversity of viruses becomes apparent.

Abstract Background and objectives Projections that 60 transformative cell and gene therapies could be approved by the U.S. Food and Drug Administration (FDA) within 10 years underscore an urgent need to modernize the newborn screening (NBS) system. This study convened expert stakeholders to assess challenges to the NBS system and propose solutions for its modernization. Methods NBS stakeholders (researchers, clinicians, state NBS leaders, advocates, industry professionals, and current/former advisory committee members) participated in one of five mixed-stakeholder panel discussions. Prior to panels, participants completed a survey in which they reviewed and ranked NBS challenges generated from relevant literature. During panels, participants deliberated on challenges and explored potential solutions. Pre-panel survey data were analyzed descriptively. Data from panel discussions were analyzed using a rapid qualitative analysis. Results Median scores of the ranked challenges (1 = most important) reveal the top three most important barriers to address: critical missing data for NBS decision-making (Median = 2), burden on state NBS laboratories (Median = 3), and the amount of time required for state-level implementation of screening for new conditions (Median = 4). Panel discussions were rooted in recurring themes: the infant’s well-being should be the focal point; the transformative therapy pipeline, although undeniably positive for individuals with rare diseases, is a threat to NBS capacity; decisions about modernizing NBS should be evidence-based; additional financial support is required but not sufficient for modernization; and modernization will require participation of multiple NBS stakeholders. This final overarching theme is reported in depth, including expertise, coordination, and collaboration challenges facing NBS and novel approaches to oversight, partnership, and coordination that were suggested by participants. Conclusions This study engaged representatives from multiple stakeholder groups to generate potential solutions to challenges facing NBS in the United States. These solutions provide a rich starting point for policy makers and other stakeholders who desire to maximize the impact of new transformative therapies for babies, families, and society.

The present study used light and scanning electron microscopy to describe the integrative morphological description of the tongue and laryngeal mound of Heremites vittatus, an endemic lizard of Saharan Africa. Additionally, ultrastructure, histology, histochemistry, and immunohistochemical approaches were used to characterize the lingual apparatus adaptations. In the present study, Heremites vittatus consisted of a complex lingual papillary system in which the ventral apical surface of the foretongue comprised conical papillae. The dorsal surface consisted of different filiform papillary (papillae filiformes) types: the anterior section had two types (bifid and pointed), and the posterior section had four types (triangular, trifid, quadrifid, and pentafid) papillae. The dorsal midtongue surface exhibits scale-like, serrated filiform papillae with anterior gland openings. The hindtongue consisted of two overlapping filiform papillae: scale-like, board-serrated papillae on the median portion and finger-like papillae on the wings. The dorsal surface of the laryngeal mound had 18 longitudinal folds with glandular openings. Histologically, the foretongue was covered by a slightly keratinized layer that was absent in the mid- and hindtongue. The lingual glands were absent from the foretongue but present in the interpapillary space in the mid- and hindtongues. We observed a few rounded taste buds in the conical papilla epithelium. Histochemical analysis revealed strong glandular Alcian Blue (AB)-positive and Periodic Acid–Schiff (PAS)-positive reactions. Immunohistochemistry showed strong cytokeratin immunopositivity in all parts of the tongue. In conclusion, the obtained data about the lingual characterizations have been consistent with the active foraging behavior of the species and its environmental conditions.

BackgroundNonalcoholic fatty liver disease (NAFLD) is a global health problem. Identification of factors contributing to the onset and progression of NAFLD have the potential to direct novel strategies to combat NAFLD.MethodsWe examined the time course of western diet (WD)-induced NAFLD and its progression to nonalcoholic steatohepatitis (NASH) in age-matched female and male Ldlr-/- mice, with time-points at 1, 4, 8, 20 and 40 weeks on the WD. Controls included Ldlr-/- mice maintained on a purified low-fat diet (LFD) for 1 and 40 weeks. The approach included quantitation of anthropometric, plasma and liver markers of disease, plus hepatic histology, lipids, oxylipins, gene expression and selected metabolites.ResultsOne week of feeding the WD caused a significant reduction in hepatic essential fatty acids (EFAs: 18:2, ω6, 18:3, ω3) which preceded the decline in many C20-22 ω3 and ω6 polyunsaturated fatty acids (PUFA) and PUFA-derived oxylipins after 4 weeks on the WD. In addition, expression of hepatic inflammation markers (CD40, CD44, Mcp1, Nlrp3, TLR2, TLR4, Trem2) increased significantly in both female & male mice after one week on the WD. These markers continued to increase over the 40-week WD feeding study. WD effects on hepatic EFA and inflammation preceded all significant WD-induced changes in body weight, insulin resistance (HOMA-IR), oxidative stress status (GSH/GSSG ratio) and histological and gene expression markers of macrosteatosis, extracellular matrix remodeling and fibrosis.ConclusionsOur findings establish that feeding Ldlr-/- mice the WD rapidly lowered hepatic EFAs and induced key inflammatory markers linked to NASH. Since EFAs have an established role in inflammation and hepatic inflammation plays a major role in NASH, we suggest that early clinical assessment of EFA status and correcting EFA deficiencies may be useful in reducing NASH severity.

BackgroundThe supraclavicular fossa is the dominant location for human brown adipose tissue (BAT). Activation of BAT promotes non-shivering thermogenesis by utilization of glucose and free fatty acids and has been the focus of pharmacological and non-pharmacological approaches for modulation in order to improve body weight and glucose homeostasis. Sympathetic neural control of supraclavicular BAT has received much attention, but its innervation has not been extensively investigated in humans.MethodsDissection of the cervical region in human cadavers was performed to find the distribution of sympathetic nerve branches to supraclavicular fat pad. Furthermore, proximal segments of the 4th cervical nerve were evaluated histologically to assess its sympathetic components.ResultsNerve branches terminating in supraclavicular fat pad were identified in all dissections, including those from the 3rd and 4th cervical nerves and from the cervical sympathetic plexus. Histology of the proximal segments of the 4th cervical nerves confirmed tyrosine hydroxylase positive thin nerve fibers in all fascicles with either a scattered or clustered distribution pattern. The scattered pattern was more predominant than the clustered pattern (80% vs. 20%) across cadavers. These sympathetic nerve fibers occupied only 2.48% of the nerve cross sectional area on average.ConclusionsHuman sympathetic nerves use multiple pathways to innervate the supraclavicular fat pad. The present finding serves as a framework for future clinical approaches to activate human BAT in the supraclavicular region.

Messenger RNA processing bodies (P-bodies) are cytoplasmic membrane-free organelles that contain proteins involved in mRNA silencing, storage and decay. The mechanism by which P-body components interact and the factors that regulate the stability of these structures are incompletely understood. In this study, we used a fluorescence-based, two-hybrid assay to investigate interactions between P-body components that occur inside the cell. LSm14a, PATL1, XRN1, and NBDY were found to interact with the N-terminal, WD40-domain-containing portion of EDC4. The N-terminus of full-length PATL1 was required to mediate the interaction between EDC4 and DDX6. The C-terminal, alpha helix-domain- containing portion of EDC4 was sufficient to mediate interaction with DCP1a and CCHCR1. In the absence of endogenous P-bodies, caused by depletion of LSm14a or DDX6, expression of the portion of EDC4 that lacked the N-terminus retained the ability to form cytoplasmic dots that were indistinguishable from P-bodies at the level of UV light microscopy. Despite the absence of endogenous P-bodies, this portion of EDC4 was able to recruit DCP1a, CCHCR1 and EDC3 to cytoplasmic dots. The results of this study permit the development of a new model of P-body formation and suggest that the N-terminus of EDC4 regulates the stability of these structures.

Lentiviral vectors (LVs) are robust delivery vehicles for gene therapy as they can efficiently integrate transgenes into host cell genomes. However, LVs with lengthy or complex expression cassettes typically are produced at low titers and have reduced gene transfer capacity, creating barriers for clinical and commercial applications. Modifications of the packaging cell line and methods may be able to produce complex vectors at higher titer and infectivity and may improve production of many different LVs. In this study, we identified two host restriction factors in HEK293T packaging cells that impeded LV production, 2′-5′-oligoadenylate synthetase 1 (OAS1) and low-density lipoprotein receptor (LDLR). Knocking out these two genes separately led to ∼2-fold increases in viral titer. We created a monoclonal cell line, CRISPRed HEK293T to Disrupt Antiviral Response (CHEDAR), by successively knocking out OAS1, LDLR, and PKR, a previously identified factor impeding LV titers. Packaging in CHEDAR yielded ∼7-fold increases in physical particles, full-length vector RNA, and vector titers. In addition, overexpressing transcription elongation factors, SPT4 and SPT5, during packaging improved the production of full-length vector RNA, thereby increasing titers by ∼2-fold. Packaging in CHEDAR with over-expression of SPT4 and SPT5 led to ∼11-fold increases of titers. These approaches improved the production of a variety of LVs, especially vectors with low titers or with internal promoters in the reverse orientation, and may be beneficial for multiple gene therapy applications.