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The response of zonal-mean precipitation minus evaporation (P − E) to global warming is investigated using a moist energy balance model (MEBM) with a simple Hadley cell parameterization. The MEBM accurately emulates zonal-mean P − E change simulated by a suite of global climate models (GCMs) under greenhouse gas forcing. The MEBM also accounts for most of the intermodel differences in GCM P − E change and better emulates GCM P − E change when compared to the “wet-gets-wetter, dry-gets-drier” thermodynamic mechanism. The intermodel spread in P − E change is attributed to intermodel differences in radiative feedbacks, which account for 60%–70% of the intermodel variance, with smaller contributions from radiative forcing and ocean heat uptake. Isolating the intermodel spread of feedbacks to specific regions shows that tropical feedbacks are the primary source of intermodel spread in zonal-mean P − E change. The ability of the MEBM to emulate GCM P − E change is further investigated using idealized feedback patterns. A less negative and narrowly peaked feedback pattern near the equator results in more atmospheric heating, which strengthens the Hadley cell circulation in the deep tropics through an enhanced poleward heat flux. This pattern also increases gross moist stability, which weakens the subtropical Hadley cell circulation. These two processes in unison increase P − E in the deep tropics, decrease P − E in the subtropics, and narrow the intertropical convergence zone. Additionally, a feedback pattern that produces polar-amplified warming partially reduces the poleward moisture flux by weakening the meridional temperature gradient. It is shown that changes to the Hadley cell circulation and the poleward moisture flux are crucial for understanding the pattern of GCM P − E change under warming. Significance Statement Changes to the hydrological cycle over the twenty-first century are predicted to impact ecosystems and socioeconomic activities throughout the world. While it is broadly expected that dry regions will get drier and wet regions will get wetter, the magnitude and spatial structure of these changes remains uncertain. In this study, we use an idealized climate model, which assumes how energy is transported in the atmosphere, to understand the processes setting the pattern of precipitation and evaporation under global warming. We first use the idealized climate model to explain why comprehensive climate models predict different changes to precipitation and evaporation across a range of latitudes. We show this arises primarily from climate feedbacks, which act to amplify or dampen the amount of warming. Ocean heat uptake and radiative forcing play secondary roles but can account for a significant amount of the uncertainty in regions where ocean circulation influences the rate of warming. We further show that uncertainty in tropical feedbacks (mainly from clouds) affects changes to the hydrological cycle across a range of latitudes. We then show how the pattern of climate feedbacks affects how the patterns of precipitation and evaporation respond to climate change through a set of idealized experiments. These results show how the pattern of climate feedbacks impacts tropical hydrological changes by affecting the strength of the Hadley circulation and polar hydrological changes by affecting the transport of moisture to the high latitudes.

Climate change is altering species’ range limits and transforming ecosystems. For example, warming temperatures are leading to the range expansion of tropical, cold-sensitive species at the expense of their cold-tolerant counterparts. In some temperate and subtropical coastal wetlands, warming winters are enabling mangrove forest encroachment into salt marsh, which is a major regime shift that has significant ecological and societal ramifications. Here, we synthesized existing data and expert knowledge to assess the distribution of mangroves near rapidly changing range limits in the southeastern USA. We used expert elicitation to identify data limitations and highlight knowledge gaps for advancing understanding of past, current, and future range dynamics. Mangroves near poleward range limits are often shorter, wider, and more shrublike compared to their tropical counterparts that grow as tall forests in freeze-free, resource-rich environments. The northern range limits of mangroves in the southeastern USA are particularly dynamic and climate sensitive due to abundance of suitable coastal wetland habitat and the exposure of mangroves to winter temperature extremes that are much colder than comparable range limits on other continents. Thus, there is need for methodological refinements and improved spatiotemporal data regarding changes in mangrove structure and abundance near northern range limits in the southeastern USA. Advancing understanding of rapidly changing range limits is critical for foundation plant species such as mangroves, as it provides a basis for anticipating and preparing for the cascading effects of climate-induced species redistribution on ecosystems and the human communities that depend on their ecosystem services.

Pollution concentrations (PM2.5) in the United States have fallen in recent decades. Despite these improvements, disparities in concentrations between racial/ethnic groups persist. We combine administrative data on the universe of emergency room (ER) admissions across California with satellite information on PM2.5 concentrations and compare recent trends in racial/ethnic disparities for PM2.5 and asthma rates. We find that PM2.5 concentrations fell for the average Black, Hispanic, and White individual. Similarly, disparities in PM2.5 concentrations fell between Black and White individuals and between Hispanic and White individuals. However, racial disparities in asthma rates, as measured by asthma-related ER visits per resident, have increased overall and broadly across the income distribution.

Managing infection in patients with neutropenia is a difficult challenge, as fever is often the only clinical symptom. At JADPRO Live 2022, Kyle C. Molina, PharmD, BCIDP, AAVHIP, of the University of Colorado Hospital, discussed the epidemiology and pathophysiology associated with febrile neutropenia in patients with cancer. He reviewed appropriate treatment settings and empiric antimicrobial regimens for a patient and how to formulate a plan to safely de-escalate and target therapy for patients with febrile neutropenia.

Skiing and snowboarding are popular winter sports with significant youth participation and inherent potential for injury. We investigated the relationship between age and injury characteristics exhibited by youth skiers and snowboarders.In this cross-sectional study, we investigated injury characteristics among youth skiers and snowboarders at a ski resort, examining the association between age and injury type. We compared injury characteristics among young children (aged 3-6 y), school-aged children (aged 7-14 y), and older adolescents (aged 15-17 y) using χCompared with snowboarding, skiing was associated with greater odds of lower extremity (adjusted odds ratio [aOR]=6.8, 95% confidence interval [CI]: 4.89, 9.47, P0.001) and head/face/neck (aOR=1.63, 95% CI: 1.20, 2.21, P=0.002) injuries. Compared with skiing, snowboarding was associated with greater odds of upper extremity injury (aOR=5.9, 95% CI: 4.6, 7.6, P0.001). Age group significantly affected injury mechanism (χYouth skiers exhibited predominately lower extremity injuries, while snowboarders exhibited predominately upper extremity injuries. Age significantly affected injury mechanism and injury diagnosis in youth skiers. Specifically, younger skiers tended to suffer more fractures and collision injuries than older youth skiers.

Natural transformation, the process whereby a cell acquires DNA directly from the environment, is an important driver of evolution in microbial populations, yet the mechanism of DNA uptake is only characterized in bacteria. To expand our understanding of natural transformation in archaea, we undertook a genetic approach to identify a catalog of genes necessary for transformation in Methanococcus maripaludis. Using an optimized method to generate random transposon mutants, we screened 6144 mutant strains for defects in natural transformation and identified 25 transformation-associated candidate genes. Among these are genes encoding components of the type IV-like pilus, transcription/translation associated genes, genes encoding putative membrane bound transport proteins, and genes of unknown function. Interestingly, similar genes were identified regardless of whether replicating or integrating plasmids were provided as a substrate for transformation. Using allelic replacement mutagenesis, we confirmed that several genes identified in these screens are essential for transformation. Finally, we identified a homolog of a membrane bound substrate transporter in Methanoculleus thermophilus and verified its importance for transformation using allelic replacement mutagenesis, suggesting a conserved mechanism for DNA transfer in multiple archaea. These data represent an initial characterization of the genes important for transformation which will inform efforts to understand gene flow in natural populations. Additionally, knowledge of the genes necessary for natural transformation may assist in identifying signatures of transformation machinery in archaeal genomes and aid the establishment of new model genetic systems for studying archaea.

Persons with drug-resistant epilepsy may benefit from epilepsy surgery and should undergo presurgical testing to determine potential candidacy and appropriate intervention. Institutional expertise can influence use and availability of evaluations and epilepsy surgery candidacy. This census survey study aims to examine the influence of geographic region and other center characteristics on presurgical testing for medically intractable epilepsy.We analyzed annual report and supplemental survey data reported in 2020 from 206 adult epilepsy center directors and 136 pediatric epilepsy center directors in the United States. Test utilization data were compiled with annual center volumes, available resources, and US Census regional data. We used Wilcoxon rank-sum, Kruskal-Wallis, and chi-squared tests for univariate analysis of procedure utilization. Multivariable modeling was also performed to assign odds ratios (ORs) of significant variables.The response rate was 100% with individual element missingness 11% across 342 observations undergoing univariate analysis. A total of 278 complete observations were included in the multivariable models, and significant regional differences were present. For instance, compared to centers in the South, those in the Midwest used neuropsychological testing (OR = 2.87, 95% confidence interval [CI] = 1.2-6.86; p = .018) and fluorodeoxyglucose-positron emission tomography (OR = 2.74, 95% CI = = 1.14-6.61; p = .025) more commonly. For centers in the Northeast (OR = .46, 95% CI = .23-.93; p = .031) and West (OR = .41, 95% CI = .19-.87; p = .022), odds of performing single-photon emission computerized tomography were lower by nearly 50% compared to those in the South. Center accreditation level, demographics, volume, and resources were also associated with varying individual testing rates.Presurgical testing for drug-resistant epilepsy is influenced by US geographic region and other center characteristics. These findings have potential implications for comparing outcomes between US epilepsy centers and may inject disparities in access to surgical treatment.

Background and ObjectiveNearly one-third of persons with epilepsy will continue having seizures despite trialing multiple antiseizure medications. Epilepsy surgery may be beneficial in these cases, and evaluation at a comprehensive epilepsy center is recommended. Numerous palliative and potentially curative approaches exist, and types of surgery performed may be influenced by center characteristics. This article describes epilepsy center characteristics associated with epilepsy surgery access and volumes in the United States.MethodsWe analyzed National Association of Epilepsy Centers 2019 annual report and supplemental survey data obtained with responses from 206 adult epilepsy center directors and 136 pediatric epilepsy center directors in the United States. Surgical treatment volumes were compiled with center characteristics, including US Census region. We used multivariable modeling with zero-inflated Poisson regression models to present ORs and incidence rate ratios of receiving a given surgery type based on center characteristics.ResultsThe response rate was 100% with individual element missingness less than 4% across 352 observations undergoing univariate analysis. Multivariable models included 319 complete observations. Significant regional differences were present. The rates of laser interstitial thermal therapy (LITT) were lower at centers in the Midwest (incidence rate ratio [IRR] 0.74, 95% CI 0.59–0.92;p= 0.006) and Northeast (IRR 0.77, 95% CI 0.61–0.96;p= 0.022) compared with those in the South. Conversely, responsive neurostimulation implantation rates were higher in the Midwest (IRR 1.45, 95% CI 1.1–1.91;p= 0.008) and West (IRR 1.91, 95% CI 1.49–2.44;p< 0.001) compared with the South. Center accreditation level, institution type, demographics, and resources were also associated with variations in access and rates of potentially curative and palliative surgical interventions.DiscussionEpilepsy surgery procedure volumes are influenced by US epilepsy center region and other characteristics. These variations may affect access to specific surgical treatments for persons with drug resistant epilepsy across the United States.

Despite substantial global mean warming, surface cooling has occurred in both the tropical eastern Pacific Ocean and the Southern Ocean over the past 40 years, influencing both regional climates and estimates of Earth’s climate sensitivity to rising greenhouse gases. While a tropical influence on the extratropics has been extensively studied in the literature, here we demonstrate that the teleconnection works in the other direction as well, with the southeast Pacific sector of the Southern Ocean exerting a strong influence on the tropical eastern Pacific. Using a slab ocean model, we find that the tropical Pacific sea surface temperature (SST) response to an imposed Southern Ocean surface heat flux forcing is sensitive to the longitudinal location of that forcing, suggesting an atmospheric pathway associated with regional dynamics rather than reflecting a zonal-mean energetic constraint. The transient response shows that an imposed Southern Ocean cooling in the southeast Pacific sector first propagates into the tropics by mean-wind advection. Once tropical Pacific SSTs are perturbed, they then drive remote changes to atmospheric circulation in the extratropics that further enhance both Southern Ocean and tropical cooling. These results suggest a mutually interactive two-way teleconnection between the Southern Ocean and tropical Pacific through atmospheric circulations, and highlight potential impacts on the tropics from the extratropical climate changes over the instrumental record and in the future.

Coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) is a mitochondrial protein that plays important roles in cristae structure, oxidative phosphorylation and apoptosis. Multiple mutations in CHCHD2 have been associated with Lewy body disorders (LBDs), such as Parkinson’s disease (PD) and dementia with Lewy bodies, with the CHCHD2-T61I mutation being the most widely studied. However, at present, only CHCHD2 knockout or CHCHD2/CHCHD10 double knockout mouse models have been investigated. They do not recapitulate the pathology seen in patients with CHCHD2 mutations. We generated the first transgenic mouse model expressing the human PD-linked CHCHD2-T61I mutation driven by the mPrP promoter. We show that CHCHD2-T61I Tg mice exhibit perinuclear mitochondrial aggregates, neuroinflammation, and have impaired long-term synaptic plasticity associated with synaptic dysfunction. Dopaminergic neurodegeneration, a hallmark of PD, is also observed along with α-synuclein pathology. Significant motor dysfunction is seen with no changes in learning and memory at 1 year of age. A minor proportion of the CHCHD2-T61I Tg mice (~10%) show a severe motor phenotype consistent with human Pisa Syndrome, an atypical PD phenotype. Unbiased proteomics analysis reveals surprising increases in many insoluble proteins predominantly originating from mitochondria and perturbing multiple canonical biological pathways as assessed by ingenuity pathway analysis, including neurodegenerative disease-associated proteins such as tau, cofilin, SOD1 and DJ-1. Overall, CHCHD2-T61I Tg mice exhibit pathological and motor changes associated with LBDs, indicating that this model successfully captures phenotypes seen in human LBD patients with CHCHD2 mutations and demonstrates changes in neurodegenerative disease-associated proteins, which delineates relevant pathological pathways for further investigation.

Total poleward atmospheric heat transport (AHT) is similar in both magnitude and latitudinal structure between the Northern and Southern Hemispheres. These similarities occur despite more major mountain ranges in the Northern Hemisphere, which help create substantial stationary eddy AHT that is largely absent in the Southern Hemisphere. However, this hemispheric difference in stationary eddy AHT is compensated by hemispheric differences in other dynamic components of AHT so that total AHT is similar between hemispheres. To understand how AHT compensation occurs, we add midlatitude mountain ranges in two different general circulation models that are otherwise configured as aquaplanets. Even when midlatitude mountains are introduced, total AHT is nearly invariant. We explore the near invariance of total AHT in response to orography through dynamic, energetic, and diffusive perspectives. Dynamically, orographically induced changes to stationary eddy AHT are compensated by changes in both transient eddy and mean meridional circulation AHT. This creates an AHT system with three interconnected components that resist large changes to total AHT. Energetically, the total AHT can only change if the top-of-the-atmosphere net radiation changes at the equator-to-pole scale. Midlatitude orography does not create large-enough changes in the equator-to-pole temperature gradient to alter outgoing longwave radiation enough to substantially change total AHT. In the zonal mean, changes to absorbed shortwave radiation also often compensate for changes in outgoing longwave radiation. Diffusively, the atmosphere smooths anomalies in temperature and humidity created by the addition of midlatitude orography, such that total AHT is relatively invariant. Significance Statement The purpose of this study is to better understand how orography influences heat transport in the atmosphere. Enhancing our understanding of how atmospheric heat transport works is important, as heat transport helps moderate Earth’s surface temperatures and influences precipitation patterns. We find that the total amount of atmospheric heat transport does not change in the presence of mountains in the midlatitudes. Different pieces of the heat transport change, but they change in compensatory ways, such that the total heat transport remains roughly constant.

NASICON (sodium superionic conductor) materials are promising host compounds for the reversible capture of Na

Biofilm-associated infections lead to substantial morbidity. Omadacycline (OMC) is a novel aminomethylcycline with potent in vitro activity against Staphylococcus aureus and Staphylococcus epidermidis , but data surrounding its use in biofilm-associated infections are lacking.

ObjectiveAdults with pediatric-onset spinal cord injury (SCI) require long-term care and demonstrate elevated risk of secondary health conditions and psychosocial challenges. Medical providers are typically found in more populous and wealthy areas, resulting in a relative lack of providers in rural areas, a discrepancy even more pronounced among specialty providers. As a result, those who reside in rural regions potentially have unmet medical needs, representing a significant public health concern. The purpose of this study was to assess differences between rural and urban-residing participants with pediatric-onset SCI in factors affecting healthcare usage (e.g., employment, income, access to private insurance, community integration) and long-term healthcare outcomes (i.e., secondary health conditions and psychosocial functioning).MethodsData were gathered from an ongoing study examining long-term outcomes of adults with pediatric-onset SCI. Participants (N = 490) completed measures of sociodemographics, injury characteristics, and medical outcomes. Participant zip codes were classified as rural or urban using the ProximityOne database based on the ZIP Code Tabulation Areas from the 2020 census.ResultsIndividuals residing in rural regions report lower levels of education, income, employment rates, private health insurance, and community integration (mobility, occupation, and social engagement), as well increased incidence of pressure injuries, urinary tract infections, hospitalizations, bowel incontinence, sleep difficulties, and perceived physical health. No differences in incidence of psychosocial functioning were identified.ConclusionMitigating identified disparities and obstacles to treatment of SCI due to residing in rural environments would result in important improvements in treatment outcomes and future prevention efforts of secondary health complications, improving the overall health of adults with pediatric-onset SCI.

The extracellular polymeric matrix of biofilms presents an impediment to antibiotic diffusion, facilitating the emergence of multidrug-resistant populations. While most phage cocktails are designed for the planktonic state of bacteria, it is important to take the biofilm mode of growth (the predominant mode of bacterial growth in nature) into consideration, as it is unclear how interactions between any specific phage and its bacterial hosts will depend on the physical properties of the growth environment.

Dead-space associated rebreathing of expired air and heat-trapping with use of surgical masks and N95 respirators may underlie anecdotal reports of adverse symptoms associated with medical face barriers. Limited data exists directly comparing the physiological effects of masks and respirators at rest. We assessed the short-term physiological effects of both barrier types over 60-min at rest, including face microclimate temperature, end-tidal gases, and venous blood acid-base variables. We recruited 34 participants into two trials: surgical masks (n=17) and N95 respirators (n=17). In a seated position, participants underwent a 10-min baseline without a barrier, and then wore a standardized surgical mask or dome-shaped N95 respirator for 60-min, followed by a 10-min washout. We instrumented participants with a peripheral pulse oximeter (SpO2) and a nasal cannula connected to a dual gas analyzer for measurement of the pressure of end-tidal (PET)CO2 and PETO2, with an associated temperature probe for face microclimate temperature. Venous (v) blood samples were obtained at baseline and following 60-min mask/respirator wearing to assess PvCO2, [HCO3-]v and pHv. Compared to baseline during/following 60-min, temperature, PETCO2, PvCO2, and [HCO3-]v were mildly but significantly higher, and PETO2 and PvO2 were significantly lower, but SpO2 was unaffected. The magnitude of effects was similar between barrier types. Temperature and PETCO2 returned to baseline levels within 1-2 min following removal of the barrier. These mild physiological effects may underly reports of qualitative symptoms while wearing masks or respirators. However, the magnitudes were mild, not physiologically-relevant and reversed immediately with the removal of the barrier.

Psychedelic drugs are currently being investigated for their potential to facilitate a variety of long-lasting psychological changes. One area of psychological functioning that has yet to be systematically investigated in psychedelic research regards aesthetic experiences. This is surprising given the notable acute changes in perception induced by the drugs as well as the wealth of anecdotal reports of individuals reporting increased engagement in aesthetic experiences after psychedelic use. The current study was designed to address this gap in the literature by administering a validated measure of aesthetic experience one-week before, one-week after, and one-month after participants (N = 54) attended an ayahuasca retreat center. Participants also completed surveys indexing the extent to which they endorsed mystical-type experiences, awe, and ego dissolution during their ayahuasca sessions to identify potential predictors of long-term change. We found that compared to baseline, participants exhibited increased levels of aesthetic experience at both follow-ups. Measures of acute drug effects did not predict changes in aesthetic experience. Although the study was limited by an open-label design, the results support anecdotal reports regarding changes in aesthetic experience after psychedelic use and provide important groundwork for future study.

BACKGROUND Silent corticotroph adenomas (SCAs) are the only pituitary adenomas thought to originate from the pars intermedia. This case report presents the rare finding of a multimicrocystic corticotroph macroadenoma displacing the anterior and posterior lobes of the pituitary gland on magnetic resonance imaging (MRI). This finding supports the hypothesis that silent corticotroph adenomas may originate from the pars intermedia and should be considered in the differential for tumors arising from this location. OBSERVATIONS A 55-year-old man presented with an episode of confusion and blurred vision. MRI demonstrated separation of the anterior and posterior glands by a solid-cystic lesion located within the pars intermedia that superiorly displaced the optic chiasm. Endocrinologic evaluation was unremarkable. The differential diagnosis included pituitary adenoma, Rathke cleft cyst, and craniopharyngioma. The tumor was confirmed to be an SCA on pathology and was completely removed through the endoscopic endonasal transsphenoidal approach. LESSONS The case highlights the importance of preoperative screening for subclinical hypercortisolism for tumors arising from this location. Knowledge of a patient’s preoperative functional status is critical and dictates their postoperative biochemical assessment to determine remission. The case also illustrates surgical strategies for resecting pars intermedia lesions without injuring the gland.

Methanogens are essential for the complete remineralization of organic matter in anoxic environments. Most cultured methanogens are hydrogenotrophic, using H2as an electron donor to reduce CO2to CH4, but in the absence of H2many can also use formate. Formate dehydrogenase (Fdh) is essential for formate oxidation, where it transfers electrons for reduction of coenzyme F420or to a flavin-based electron bifurcating reaction catalyzed by heterodisulfide reductase (Hdr), the terminal reaction of methanogenesis. How these competing reactions are coordinated is unknown. Furthermore, methanogens that use formate encode at least two isoforms of Fdh in their genomes, but how these different isoforms participate in methanogenesis is also unknown. UsingMethanococcus maripaludis, we undertook a biochemical characterization of both Fdh isoforms involved in methanogenesis. Both Fdh1 and Fdh2 interacted with Hdr to catalyze the flavin-based electron bifurcating reaction, and both reduced F420at similar rates. F420reduction preceded flavin-based electron bifurcation activity for both enzymes. In a Δfdh1mutant background, a suppressor mutation was required for Fdh2 activity. Genome sequencing revealed that this mutation resulted in loss of a specific molybdopterin transferase (moeA), allowing for Fdh2-dependent growth. This suggests that both isoforms of Fdh are functionally redundant, but their activitiesin vivomay be limited by gene regulation under different growth conditions. Together these results expand our understanding of formate oxidation and the role of Fdh in methanogenesis.

The chemical modification of ribosomal RNA and proteins is critical for ribosome assembly, for protein synthesis and may drive ribosome specialisation in development and disease. However, the inability to accurately visualise these modifications has limited mechanistic understanding of the role of these modifications in ribosome function. Here we report the 2.15 Å resolution cryo-EM reconstruction of the human 40S ribosomal subunit. We directly visualise post-transcriptional modifications within the 18S rRNA and four post-translational modifications of ribosomal proteins. Additionally, we interpret the solvation shells in the core regions of the 40S ribosomal subunit and reveal how potassium and magnesium ions establish both universally conserved and eukaryote-specific coordination to promote the stabilisation and folding of key ribosomal elements. This work provides unprecedented structural details for the human 40S ribosomal subunit that will serve as an important reference for unravelling the functional role of ribosomal RNA modifications.

Spatial synchrony, the tendency for populations across space to show correlated fluctuations, is a fundamental feature of population dynamics, linked to central topics of ecology such as population cycling, extinction risk, and ecosystem stability. A common mechanism of spatial synchrony is the Moran effect, whereby spatially synchronized environmental signals drive population dynamics and hence induce population synchrony. After reviewing recent progress in understanding Moran effects, we here elaborate a general theory of how Moran effects of different environmental drivers acting on the same populations can interact, either synergistically or destructively, to produce either substantially more or markedly less population synchrony than would otherwise occur. We provide intuition for how this newly recognized mechanism works through theoretical case studies and application of our theory to California populations of giant kelp. We argue that Moran interactions should be common. Our theory and analysis explain an important new aspect of a fundamental feature of spatiotemporal population dynamics.

Climate change is driving widespread changes in ecological communities. Warming temperatures often shift community composition toward more heat-tolerant taxa. The factors influencing the rate of this “thermophilization” process remain unclear. Using 10-y census data from an extensive forest plot network, we show that mature tree communities of the western United States have undergone thermophilization. The mean magnitude of climate warming over the 10-y study interval was 0.32 °C, whereas the mean magnitude of thermophilization was 0.039 °C. Differential tree mortality was the strongest demographic driver of thermophilization, rather than growth or recruitment. Thermophilization rates are associated with recent changes in temperature and hydrologic variables, as well as topography and disturbance, with insect damage showing the strongest standardized effect on thermophilization rates. On average, thermophilization occurred more rapidly on cool, north-facing hillslopes. Our results demonstrate that warming temperatures are outpacing the composition of western US forest tree communities, and that climate change may erode biodiversity patterns structured by topographic variation.

Many multi-domain proteins including the serpin family of serine protease inhibitors contain non-sequential domains composed of regions that are far apart in sequence. Because proteins are translated vectorially from N-to C-terminus, such domains pose a particular challenge: how to balance the conformational lability necessary to form productive interactions between early and late translated regions while avoiding aggregation. This balance is mediated by the protein sequence properties and the interactions of the folding protein with the cellular quality control machinery. For serpins, particularly α1-antitrypsin (AAT), mutations often lead to polymer accumulation in cells and consequent disease suggesting that the lability/aggregation balance is especially precarious. Therefore, we investigated the properties of progressively longer AAT N-terminal fragments in solution and in cells. The N-terminal subdomain, residues 1-190 (AAT190), is monomeric in solution and efficiently degraded in cells. More ý-rich fragments, 1-290 and 1-323, form small oligomers in solution, but are still efficiently degraded, and even the polymerization promoting Siiyama (S53F) mutation did not significantly affect fragment degradation.In vitro,the AAT190 region is among the last regions incorporated into the final structure. Hydrogen-deuterium exchange mass spectrometry and enhanced sampling molecular dynamics simulations show that AAT190 has a broad, dynamic conformational ensemble that helps protect one particularly aggregation prone ý-strand from solvent. These AAT190 dynamics result in transient exposure of sequences that are buried in folded, full-length AAT, which may provide important recognition sites for the cellular quality control machinery and facilitate degradation and, under favorable conditions, reduce the likelihood of polymerization.

Background Planting tree seedlings may help promote forest recovery after extensive high-severity wildfire. We evaluated the influence of growing environment characteristics on the performance of seedlings planted in the 2016 Cold Springs Fire, Colorado, USA. In 2021, four growing seasons after planting, we measured survival, height, and 2021 height growth for 300 ponderosa pine, limber pine, and Douglas-fir seedlings permanently marked along “stake rows.” For each seedling, we also recorded one site-level growing environment characteristic, aspect, and two microsite-level characteristics, the presence of coarse wood or other shade object and the presence of water-capturing microtopographic depressions. To examine a potential mechanism through which these growing environment characteristics could influence seedling responses, we also measured summer soil moisture at each ponderosa pine seedling. We used generalized linear mixed models to examine the influence of aspect, shade object presence, and depression presence on seedling survival, height, and height growth, and on soil moisture. Results The growing environment had a clear influence on tree seedlings. We found greater seedling survival on more northerly aspects, in shade, and in depressions. Across all species, seedlings on north aspects had 37% greater survival than those on south aspects (76% vs. 39%, respectively). Seedlings planted in shaded microsites had 20% greater survival, and seedlings planted in depression microsites had 14% greater survival relative to microsites without shading or depressions, respectively. Seedling height was greater on more northerly aspects and in shade. Likewise, seedling height growth was generally greater on north aspects and in shade, although the influence of aspect and shade depended on species. Soil moisture was greater in depressions. Conclusions The findings of this opportunistic study demonstrate how positioning seedlings to take advantage of cooler, wetter growing environments can increase their performance in what are often climatically stressful post-fire landscapes. Overall, planting seedlings on north-facing aspects, in shaded microsites, and in depression microsites, practices commonly employed by land managers, were effective at promoting survival and growth, thereby facilitating planting success. These practices will likely become ever more relevant as the pace and scale of post-fire planting increases and as planting conditions become more stressful due to ongoing climate change.

Alzheimer’s disease (AD) is believed to occur when abnormal amounts of the proteins amyloid beta and tau aggregate in the brain, resulting in a progressive loss of neuronal function. Hippocampal neurons in transgenic mice with amyloidopathy or tauopathy exhibit altered intrinsic excitability properties. We introduce a novel parameter inference technique, deep hybrid modeling (DeepHM), that combines deep learning with biophysical modeling to map experimental data recorded from hippocampal CA1 neurons in transgenic AD mice and age-matched wildtype littermate controls to the parameter space of a conductance-based CA1 model. Although mechanistic modeling and machine learning methods are by themselves powerful tools for approximating biological systems and making accurate predictions from data, when used in isolation these approaches suffer from distinct shortcomings: model and parameter uncertainty limit mechanistic modeling, whereas machine learning methods disregard the underlying biophysical mechanisms. DeepHM addresses these shortcomings by using conditional generative adversarial networks (cGANs) to provide an inverse mapping of data to mechanistic models that identifies the distributions of mechanistic modeling parameters coherent to the data. Here, we demonstrate that DeepHM accurately infers parameter distributions of the conductance-based model and outperforms a Markov chain Monte Carlo method on several test cases using synthetic data. We then use DeepHM to estimate parameter distributions corresponding to the experimental data and infer which ion channels are altered in the Alzheimer’s mouse models compared to their wildtype controls at 12 and 24 months. We find that the conductances most disrupted by tauopathy, amyloidopathy, and aging are delayed rectifier potassium, transient sodium, and hyperpolarization-activated potassium, respectively.

This file contains a detailed description of the synthesis as well as the characterization of lead compounds PG-S3-001, PG-S3-002, and PG-S3-003. Results pertaining to the interaction of PG-S3-001 with relevant kinases is also included; Table 1. Results of Kinome Screen for Kinases involved in Regulation of STAT3.

Mouse Strains from Jackson Laboratories used in experimentation.

Ingenuity Canonical Pathways.

This file contains supplementary methods, supplementary references, supplementary figures S1-S6, supplementary tables S1, S3-S6, S8-S15, and S17, and legends for all supplementary figures and tables. Supplementary Figure S1. Summary of Ewing sarcoma tumor and cell line cohorts. Supplementary Figure S2. RNASeq validation of mutations identified by WES and WGS. Supplementary Figure S3. Power calculations for the detection of significantly mutated genes. Supplementary Figure S4. Copy number variants in Ewing sarcoma tumors. Supplementary Figure S5. ETS1 deletions associated with EWS/FLI rearrangements. Supplementary Figure S6. Copy number variants in diagnostic vs. treated Ewing sarcoma tumors. Supplementary Figure S7. SCNAs in paired Ewing sarcoma tumor samples. Supplementary Table S1. Tissue samples. Supplementary Table S3. Multiply mutated genes. Supplementary Table S4. Rearrangements and fusions detected by WGS and RNASeq. Supplementary Table S5. Mutational significance for tumor/normal pairs. Supplementary Table S6. Rate of coding mutations in Ewing sarcoma tumors. Supplementary Table S8. Mutational significance for all tumors. Supplementary Table S9. Gene set enrichment analyses of mutated genes. Supplementary Table S10. Significance of arm-level SCNAs. Supplementary Table S11. Multiply mutated genes of interest in all sample cohorts. Supplementary Table S12. Immunohistochemical staining of STAG2 in Ewing sarcoma tumors. Supplementary Table S13. Gene set enrichment analyses of STAG2 expressing vs. STAG2 loss. Supplementary Table S14. Gene and gene-fragment RPKM Values for EWS and ETS genes. Supplementary Table S15. ETS1 copy-number changes. Supplementary Table S17. Gene set enrichment analyses of tumors vs. cell lines.

P815 tumor cell line authentication.

Variants identified from WES of 92 tumors after filtering.

IFNγ resistance in E.G7-OVA and P815 tumors.