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Recently acquired memories are reactivated in the hippocampus during sleep, an initial step for their consolidation1, 2–3. This process is concomitant with the hippocampal reactivation of previous memories4, 5–6, posing the problem of how to prevent interference between older and recent, initially labile, memory traces. Theoretical work has suggested that consolidating multiple memories while minimizing interference can be achieved by randomly interleaving their reactivation7, 8, 9–10. An alternative is that a temporal microstructure of sleep can promote the reactivation of different types of memories during specific substates. Here, to test these two hypotheses, we developed a method to simultaneously record large hippocampal ensembles and monitor sleep dynamics through pupillometry in naturally sleeping mice. Oscillatory pupil fluctuations revealed a previously unknown microstructure of non-REM sleep-associated memory processes. We found that memory replay of recent experiences dominated in sharp-wave ripples during contracted pupil substates of non-REM sleep, whereas replay of previous memories preferentially occurred during dilated pupil substates. Selective closed-loop disruption of sharp-wave ripples during contracted pupil non-REM sleep impaired the recall of recent memories, whereas the same manipulation during dilated pupil substates had no behavioural effect. Stronger extrinsic excitatory inputs characterized the contracted pupil substate, whereas higher recruitment of local inhibition was prominent during dilated pupil substates. Thus, the microstructure of non-REM sleep organizes memory replay, with previous versus new memories being temporally segregated in different substates and supported by local and input-driven mechanisms, respectively. Our results suggest that the brain can multiplex distinct cognitive processes during sleep to facilitate continuous learning without interference.

Introduction:Hypertension is a prevalent condition in the United States and leads to an increased risk of developing various comorbidities. However, the impact of new-onset hypertension after severe burns on patient outcomes is not known. We posit that hypertension onset after severe burn is associated with increased risk of developing comorbidities and mortality. Methods:Using the TriNetX database, burned patients diagnosed with essential hypertension after injury were compared with those who did not develop hypertension; neither had prior hypertension. Each cohort was grouped by sex, percent total body surface area (TBSA) burned, and age, then propensity matched for sex, race, ethnicity, and laboratory values. Outcomes assessed were acute kidney injury (AKI), hyperglycemia, heart failure, myocardial infarction (MI), and death. Results:Those diagnosed with hypertension after severe burn were 4.9 times more likely to develop AKI, 3.6 times for hyperglycemia, 5.3 times for heart failure, 4.7 times for acute MI, and 1.5 times for mortality. Sex analysis shows that men were at greater risk for AKI (1.5 times), heart failure (1.1 times), and death (1.4 times). Women were 1.3 times more likely to develop hyperglycemia. Percent TBSA burned grouping showed increased risk for all outcomes with increasing severity. Age grouping indicated an elevated risk of developing AKI, heart failure, acute MI, and death. Conclusion:New-onset hypertension diagnosis in severely burned patients is associated with acute kidney injury, heart failure, acute MI, and death. Overall, males, older patients, and those with a higher % TBSA burned are at a higher risk of developing these comorbidities.

Deep brain stimulation (DBS) is a well-established surgical therapy for movement disorders that comprises implantation of stimulation electrodes and a pacemaker. These procedures can be performed separately, leaving the possibility of externalizing the electrodes for local field potential recording or testing multiple targets for therapeutic efficacy. It is still debated whether the temporary externalization of DBS electrodes leads to an increased risk of infection. We therefore aimed to assess the risk of infection during and after lead externalization in DBS surgery.

Relapse represents a consistent clinical problem for individuals with substance use disorder. In the incubation of craving model of persistent craving and relapse, cue-induced drug seeking progressively intensifies or “incubates” during the first weeks of abstinence from drug self-administration and then remains high for months. Previously, we and others have demonstrated that expression of incubated cocaine craving requires strengthening of excitatory synaptic transmission in the nucleus accumbens core (NAcc). However, despite the importance of dopaminergic signaling in the NAcc for motivated behavior, little is known about the role that dopamine (DA) plays in the incubation of cocaine craving. Here we used fiber photometry to measure DA transients in the NAcc of male and female rats during cue-induced seeking tests conducted in early abstinence from cocaine self-administration, prior to incubation, and late abstinence, after incubation of craving has plateaued. We observed DA transients time-locked to cue-induced responding but their magnitude did not differ significantly when measured during early versus late abstinence seeking tests. Next, we tested for a functional role of these DA transients by injecting DA receptor antagonists into the NAcc just before the cue-induced seeking test. Blockade of either D1 or D2 DA receptors reduced cue-induced cocaine seeking after but not before incubation. We found no main effect of sex or significant interaction of sex with other factors in our experiments. These results suggest that DA contributes to incubated cocaine seeking but the emergence of this role reflects changes in postsynaptic responsiveness to DA rather than presynaptic alterations.

Dopamine (DA) plays multiple roles in a wide range of physiological and pathological processes via a large network of dopaminergic projections. To dissect the spatiotemporal dynamics of DA release in both dense and sparsely innervated brain regions, we developed a series of green and red fluorescent G-protein-coupled receptor activation-based DA (GRABDA) sensors using a variety of DA receptor subtypes. These sensors have high sensitivity, selectivity and signal-to-noise ratio with subsecond response kinetics and the ability to detect a wide range of DA concentrations. We then used these sensors in mice to measure both optogenetically evoked and behaviorally relevant DA release while measuring neurochemical signaling in the nucleus accumbens, amygdala and cortex. Using these sensors, we also detected spatially resolved heterogeneous cortical DA release in mice performing various behaviors. These next-generation GRABDAsensors provide a robust set of tools for imaging dopaminergic activity under a variety of physiological and pathological conditions.

Enabled by surface-mediated equilibration, physical vapour deposition can create high-density stable glasses comparable with liquid-quenched glasses aged for millions of years. Deposition is often performed at various rates and temperatures on rigid substrates to control the glass properties. Here we demonstrate that on soft, rubbery substrates, surface-mediated equilibration is enhanced up to 170 nm away from the interface, forming stable glasses with densities up to 2.5% higher than liquid-quenched glasses within 2.5 h of deposition. Gaining similar properties on rigid substrates would require 10 million times slower deposition, taking ~3,000 years. Controlling the modulus of the rubbery substrate provides control over the glass structure and density at constant deposition conditions. These results underscore the significance of substrate elasticity in manipulating the properties of the mobile surface layer and thus the glass structure and properties, allowing access to deeper states of the energy landscape without prohibitively slow deposition rates.

Rats heard an 8-s tone before a pump dispensed water or 5% sucrose-water into a dish. Nosepokes into the drinking area during tone canceled liquid delivery on that trial. Nevertheless, rats nosepoked at higher rates during sessions when tone preceded sucrose solution than during sessions when tone preceded water. These results demonstrate the viability of nosepoking in an omission contingency with sucrose-water reward. The relative ease of manipulating sucrose concentrations in water suggests omission-contingency may be useful for investigating interactions between operants and sucrose-induced respondents, and as a measure in nonhuman animal studies of response suppression.

Geospatial proximity to American Burn Association (ABA)-verified burn centers or self-designated burn care facilities varies across the country. This study evaluates the effect of distance to treatment center on long-term, patient-reported outcomes. Data from the Burn Model System (BMS) National Longitudinal Database were analyzed. Demographic and clinical data were compared between three cohorts stratified by distance to BMS center (<20, 20–49.9, ≥50 miles). Distance to BMS center was calculated as driving distance between discharge and BMS center ZIP code centroids. The following patient-reported outcomes, collected at 12-months follow-up, were examined: Veterans RAND 12-Item Health Survey (VR-12), Satisfaction with Life (SWL) scale, employment status, and days to return to work. Mixed model regression analyses were used to examine the associations between distance to BMS center and each outcome, controlling for demographic and clinical variables. Of 726 patients included in this study, 26.3% and 28.1% were <20 and between 20 and 49.9 miles to a BMS center, respectively; 46.6% were ≥50 miles to a BMS center. Greater distance was associated with white/non-Hispanic race/ethnicity, preinjury employment, flame injury, and larger burn size (P< .001). Regression analyses did not identify significant associations between distance to BMS center and any patient-reported outcomes. This study suggests that patients treated at BMS centers have similar long-term, patient-reported outcomes of physical and psychosocial function, as well as employment, despite centralization of burn care and rehabilitation services. Given a steady decline in the incidence of burn injury, continued concentration of key resources is logical and safe.

Biallelic variants in UCHL1have been associated with a progressive early-onset neurodegenerative disorder, autosomal recessive spastic paraplegia type 79. In this study, we investigated heterozygous UCHL1variants on the basis of results from cohort-based burden analyses.

The poultry industry is an important and still growing sector in many parts of the world. For ethical reasons and due to increased consumer awareness for animal welfare in production animals, it is of importance to establish a reliable and objective test system for monitoring and improving health and welfare. During the rearing process, broiler chickens are exposed to numerous potential stressors and management interventions (e.g. weighing of individual animals, preslaughter fasting and capture processes), but assessing the level of stress perceived by the animals entirely through behavioral observations can be challenging. Monitoring stress-related physiological markers, such as glucocorticoids, can be an accurate and presumably more objective addition. To avoid additional stressors induced by blood collection, a noninvasive approach using urofecal samples is advisable. However, a thorough validation is needed to establish a suitable test system for measuring stress hormone levels, including potential effects of the time of day of collection or the time that has elapsed since defecation.

Severe alpha‐1‐antitrypsin deficiency (AATD), phenotype PiZZ, was associated with venous thromboembolism (VTE) in a case‐control study.

Severe alpha‐1‐antitrypsin deficiency (AATD), phenotype PiZZ, was associated with venous thromboembolism (VTE) in a case‐control study. This study aimed to determine the genetic variation in the SERPINA1gene and a possible thrombotic risk of these variants in a population‐based cohort study. The coding sequence of SERPINA1was analyzed for the Z (rs28929474), S (rs17580), and other qualifying variants in 28,794 subjects without previous VTE (born 1923–1950, 60% women), who participated in the Malmö Diet and Cancer study (1991–1996). Individuals were followed from baseline until the first event of VTE, death, or 2018. Resequencing the coding sequence of SERPINA1identified 84 variants in the total study population, 21 synonymous, 62 missense, and 1 loss‐of‐function variant. Kaplan‐Meier analysis showed that homozygosity for the Z allele increased the risk of VTE whereas heterozygosity showed no effect. The S (rs17580) variant was not associated with VTE. Thirty‐one rare variants were qualifying and included in collapsing analysis using the following selection criteria, loss of function, in frame deletion or non‐benign (PolyPhen‐2) missense variants with minor allele frequency (MAF) <0.1%. Combining the rare qualifying variants with the Z variant showed that carrying two alleles (ZZ or compound heterozygotes) showed increased risk. Cox regression analysis revealed an adjusted hazard ratio of 4.5 (95% confidence interval 2.0–10.0) for combinations of the Z variant and rare qualifying variants. One other variant (rs141620200; MAF = 0.002) showed an increased risk of VTE. The SERPINA1ZZ genotype and compound heterozygotes for severe AATD are rare but associated with VTE in a population‐based Swedish study.

Over the past half century, computational chemistry has evolved from a niche field to a ubiquitous pillar of modern chemical research. Driven by the increased demand for computational chemistry in research settings, the undergraduate curriculum has evolved alongside to ensure that students are well-equipped for modern research. Toward this end, many excellent computational chemistry exercises have been developed that aim to teach students what kinds of questions computational chemistry can answer and how to properly interpret the results. However, there has been far less attention given to the complexities of determining how reliable computational results are and how constraining computational scaling can be. We present an undergraduate lab exercise that uses ab initio methods to predict the combustion energy of methane. The exercise walks students through the process of benchmarking errors on a small system (methane), estimating the computational cost to perform the same analysis on a larger system (propane), and justifying an affordable yet accurate method for a hypothetical study of the larger system. Furthermore, students are introduced to other cost-saving measures like basis set extrapolation and additive corrections. The entire exercise is intentionally designed to require little technical knowledge of computational chemistry and to be flexibly grafted into a standard undergraduate curriculum. In order to ensure accessibility, the exercise utilizes the free open source software Psi4(available on any operating system) and provides a detailed installation and use guide for completing this lab. This lab will provide students the understanding of how to properly judge, select, and justify different computational models where cost and accuracy compete, a highly desirable set of skills that generalize to any computational science.

The costs required to provide acute care for patients with serious burn injuries are significant. In the United States, these costs are often shared by patients. However, the impacts of preinjury finances on health-related quality of life (HRQL) have been poorly characterized. We hypothesized that lower income and public payers would be associated with poorer HRQL. Burn survivors with complete data for preinjury personal income and payer status were extracted from the longitudinal Burn Model System National Database. HRQL outcomes were measured with VR-12 scores at 6, 12, and 24 months postinjury. VR-12 scores were evaluated using generalized linear models, adjusting for potential confounders (eg, age, sex, self-identified race, burn injury severity). About 453 participants had complete data for income and payer status. More than one third of BMS participants earned less than $25,000/year (36%), 24% earned $25,000 to 49,000/year, 23% earned $50,000 to 99,000/year, 11% earned $100,000 to 149,000/year, 3% earned $150,000 to 199,000/year, and 4% earned more than $200,000/year. VR-12 mental component summary (MCS) and physical component summary (PCS) scores were highest for those who earned $150,000 to 199,000/year (55.8 and 55.8) and lowest for those who earned less than $25,000/year (49.0 and 46.4). After adjusting for demographics, payer, and burn severity, 12-month MCS and PCS and 24-month PCS scores were negatively associated with Medicare payer (P< .05). Low income was not significantly associated with lower VR-12 scores. There was a peaking relationship between HRQL and middle-class income, but this trend was not significant after adjusting for covariates. Public payers, particularly Medicare, were independently associated with poorer HRQL. The findings might be used to identify those at risk of financial toxicity for targeting assistance during rehabilitation.

Genome-wide association studies have identified hundreds of single nucleotide variations (formerly single nucleotide polymorphisms) associated with several cancers, but the predictive ability of polygenic risk scores (PRSs) is unclear, especially among non-Whites.

Abstract: Stem cells hold great potential in tissue engineering due to their prolonged self-renewal and ability to differentiate into a variety of cell lines. Leveraging stem cells in regenerative healing requires the ability to support stem cell vitality, localize and retain the stem cells at the site where they are needed, and control their differentiation into specified cell types. To address these needs, graphene oxide (GO), a two-dimensional nanocarbon material, has been widely investigated due to its unique structural characteristics that interface with biomolecules and impart cytocompatibility. To expand on the utility of GO in tissue engineering applications, researchers have incorporated GO with peptides and proteins to provide an additional level of control over stem cell fate. This review focuses on how peptide- and protein-GO conjugates are utilized for stem cell instruction, growth, delivery, and retention in the following ways: GO as a delivery vehicle for stem cell-inducing proteins; peptide- and protein-GO conjugates as two- or three-dimensional cell scaffolds; and GO as an additive in peptide- and protein-based hydrogels. These technologies highlight the value that peptide- and protein-GO conjugates possess in addressing the challenges associated with stem cell therapies. Future directions for the continued research of peptide- and protein-GO conjugates are projected as we look to further advance the field of regenerative tissue engineering using these powerful hybrid materials. Lay Summary: Stem cell therapies can be used to replace or rebuild damaged tissue through natural healing pathways. However, using stem cells in tissue engineering requires novel technologies that control stem cell fate. Hybrid materials comprised of graphene oxide (GO) and proteins represent a promising new technology with the ability to interface with stem cells. In these systems, the GO acts as a scaffold for cell growth and supports the protein which, in turn, supplies the appropriate chemical cues to direct stem cell fate toward regenerative healing.

Burn survivors experience barriers to returning to work. For those who do return to work, little is known regarding whether they achieve preinjury productivity (i.e., equivalent or gain in income compared to preinjury income). Identifying patients at risk of not achieving preinjury productivity is important for targeting services that support this population. They extracted occupational and income data through 24 months postinjury from the multicenter, longitudinal Burn Model System National Database. Annual income was reported in six groups: <$25k, $25k–50k, $50k–99k, $100k–149k, $150k–199k, and $>199k. Participants were classified by change in income at each follow-up (i.e., gain, loss, and equivalent). Explanatory variables included demographics, injury characteristics, insurance payer, employment status, and job type. Multilevel, multivariable logistic regression was used to model return to productivity. Four hundred fifty-three participants provided complete income data at discharge and follow-up. Of the 302 participants employed preinjury, 180 (60%) returned to work within 24 months postinjury. Less than half (138) returned to productivity (46% of participants employed preinjury; 77% of those who returned to work). Characteristics associated with return to productivity included older age (median 46.9 vs 45.9 years, OR 1.03, P= .006), Hispanic ethnicity (24% vs 11%, OR 1.80, P= 0.041), burn size >20% TBSA (33.7% vs 33.0%, OR 2.09, P= 0.045), and postinjury employment (54% vs 26%, OR 3.41, P< 0.001). More than half of employed people living with burn injury experienced loss in productivity within 24 months postinjury. Even if they return to work, people living with burn injuries face challenges returning to productivity and may benefit from vocational rehabilitation and/or financial assistance.

A contemporary, age-specific model for the distribution of burn mortality in children has not been developed for over a decade. Using data from TriNetX, a global federated health research network, and the American Burn Association’s Nation Burn Repository (NBR), we investigated nonsurvival distributions for pediatric burns in the United States. Pediatric burn patients aged 0 to 20 between 2010 and 2020 were identified in TriNetX from 41 Healthcare Organizations using ICD-10 codes (T.20-T.30) and identified as lived/died. These were compared to the nonsurvival data from 90 certified burn centers in the NBR database between 2016 and 2018. The patient population was stratified by age into subgroups of 0 to 4, 5 to 9, 10 to 14, and 15 to 20 years. Overall, mortality rates for pediatric burn patients were found to be 0.62% in NBR and 0.52% in TrinetX. Boys had a higher incidence of mortality than girls in both databases (0.34% vs 0.28% NBR, P= .13; 0.31% vs 0.21% TriNetX, P< .001). Comparison of ethnic cohorts between 2010 to 2015 and 2016 to 2020 subgroups showed that nonsurvival rates of African American children increased relative to white children (TriNetX, P< .001); however, evidence was insufficient to conclude that African American children die more frequently than other ethnicities (NBR, P= .054). When analyzing subgroups in TriNetX, burned children aged 5 to 9 had significantly increased frequency of nonsurvival (P< .001). However, NBR data suggested that children aged 0 to 4 experience the highest frequency of mortality (P< .001). The nonsurvival distributions between these two large databases accurately reflect nonsurvival rates in burned children.

Teaching chemistry without access to a traditional laboratory space is an ongoing challenge that has become especially relevant because of the SARS-CoV-2 pandemic. While several remote learning options exist for covering general chemistry concepts (including kitchen-based experiments, online modules, and virtual reality), few options provide opportunities for hands-on learning about the chemistry of synthetic polymer materials. Here, we offer remote learning modules that use household adhesives as a platform for teaching polymer chemistry outside of the laboratory. These modules are designed for students who have taken at least one semester of organic chemistry and have varied hands-on time commitments, ranging from 2 to 10 total hours each. Concepts covered include polymer synthesis, intermolecular interactions, thermomechanical properties, structure–function relationships, and molecular design. The experiments described in these modules also give students a chance to practice research-relevant skills such as searching for primary literature sources, fabricating test samples, explaining unexpected experimental results, and revising experimental procedures to improve methodologies. Ultimately, these modules provide educators with an additional tool for teaching experimental chemistry outside of the laboratory.

This contribution highlights selected current activities of the SOC development at Forschungszentrum Jülich. Continued efforts are being made to gain a better understanding of degradation process in our cells and stacks. New materials are being developed to mitigate known degradation phenomena. Systems development was directed at the improvement of reversible operation, especially in electrolysis mode. On cell and stack level investigation of electrolysis operation was also intensified, focusing on CO2-valorization.

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m2/year or more (“Rapid3”; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m2at follow-up among those with eGFRcrea 60 mL/min/1.73m2or more at baseline (“CKDi25”; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT(2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATMor LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.

Severe cases of COVID‐19 infection, often leading to death, have been associated with variants of acute respiratory distress syndrome (ARDS). Cell therapy with mesenchymal stromal cells (MSCs) is a potential treatment for COVID‐19 ARDS based on preclinical and clinical studies supporting the concept that MSCs modulate the inflammatory and remodeling processes and restore alveolo‐capillary barriers. The authors performed a systematic literature review and random‐effects meta‐analysis to determine the potential value of MSC therapy for treating COVID‐19‐infected patients with ARDS. Publications in all languages from 1990 to March 31, 2020 were reviewed, yielding 2691 studies, of which nine were included. MSCs were intravenously or intratracheally administered in 117 participants, who were followed for 14 days to 5 years. All MSCs were allogeneic from bone marrow, umbilical cord, menstrual blood, adipose tissue, or unreported sources. Combined mortality showed a favorable trend but did not reach statistical significance. No related serious adverse events were reported and mild adverse events resolved spontaneously. A trend was found of improved radiographic findings, pulmonary function (lung compliance, tidal volumes, PaO2/FiO2ratio, alveolo‐capillary injury), and inflammatory biomarker levels. No comparisons were made between MSCs of different sources. In ARDS, pro‐inflammatory cytokines contribute to the disruption of the alveolar – capillary membrane, edema, and pneumocyte damage. MSCs modulate the inflammatory milieu by T‐cell and macrophage redirection, and anti‐inflammatory cytokine production. Clinical trials assessing MSC therapy in ARDS have shown that MSCs have been associated with a favorable trend in morality reduction, pulmonary function improvement, and cytokine correction.

Using micropatterned epithelial tissues, we found that mechanical stress gradients that arise from the intercellular transmission of cytoskeletal tension lead to the opening of connexin hemichannels, causing local membrane depolarization, nuclear translocation of Yap/Taz, and cell proliferation.