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Abstract Plant respiration and photosynthesis are the two main processes influencing carbon (C) flux balance at leaf‐to‐ecosystem scales. The ratio of respiration to photosynthesis (R:A) or carbon use efficiency (CUE) is considered an important trait for determining global carbon storage in the near future. One school of thought assumes that R:A is constant in terrestrial productivity models, irrespective of biomass, climate, and species. Others believe it is variable, although within a limited range. Semiarid systems dominated by woody vegetation, such as sagebrush steppe, have been recognized as potentially important C sinks on regional to global scales in the context of future climate scenarios. Therefore, there is a critical need to study R:A over different organizational scales (i.e., at the leaf, whole plant, and ecosystem scales) to use this approach for future C flux predictions under climate change scenarios. The objective of this study was to compare leaf‐, shrub‐, and ecosystem‐scale R:A among three sagebrush (Artemisia spp.) communities, and to determine how R:A varies throughout the growing season (i.e., early, mid‐, and late summer) among these communities. We measured photosynthesis and respiration monthly in three sagebrush communities spanning a 685‐m elevation gradient at the Reynolds Creek Experimental Watershed and Critical Zone Observatory in southwestern Idaho. Consistent with our expectations, we found large seasonal variations in R and A at all scales, but with differences in A among the three sagebrush communities significant only at the leaf scale. The R:A ratio was not significantly different among the three species at all organizational scales. However, the R:A ratio did vary among months at the leaf level and there was a statistical interaction between species and month at both leaf and shrub levels. Our study indicates that the R:A ratio is generally conservative, although not tightly constrained (range: 0.12–0.77) among three sagebrush species. Therefore, approaches that assume conservative R:A ratios in terrestrial productivity models need to be considered carefully to evaluate the impact of projected climatic changes on future C cycling in shrub‐dominated rangeland ecosystems.

Abstract INTRODUCTION Soluble amyloid beta (Aβ) oligomers have been suggested as initiating Aβ related neuropathologic change in Alzheimer's disease (AD) but their quantitative distribution and chronological sequence within the AD continuum remain unclear. METHODS A total of 526 participants in early clinical stages of AD and controls from a longitudinal cohort were neurobiologically classified for amyloid and tau pathology applying the AT(N) system. Aβ and tau oligomers in the quantified cerebrospinal fluid (CSF) were measured using surface‐based fluorescence intensity distribution analysis (sFIDA) technology. RESULTS Across groups, highest Aβ oligomer levels were found in A+ with subjective cognitive decline and mild cognitive impairment. Aβ oligomers were significantly higher in A+T− compared to A−T− and A+T+. APOE ε4 allele carriers showed significantly higher Aβ oligomer levels. No differences in tau oligomers were detected. DISCUSSION The accumulation of Aβ oligomers in the CSF peaks early within the AD continuum, preceding tau pathology. Disease‐modifying treatments targeting Aβ oligomers might have the highest therapeutic effect in these disease stages. Highlights Using surface‐based fluorescence intensity distribution analysis (sFIDA) technology, we quantified Aβ oligomers in cerebrospinal fluid (CSF) samples of the DZNE‐Longitudinal Cognitive Impairment and Dementia (DELCODE) cohort Aβ oligomers were significantly elevated in mild cognitive impairment (MCI) Amyloid‐positive subjects in the subjective cognitive decline (SCD) group increased compared to the amyloid‐negative control group Interestingly, levels of Aβ oligomers decrease at advanced stages of the disease (A+T+), which might be explained by altered clearing mechanisms

Abstract The interior oceans of several icy moons are considered as affected by rotation. Observations suggest a larger heat transport around the poles than at the equator. Rotating Rayleigh‐Bénard convection (RRBC) in planar configuration can show an enhanced heat transport compared to the non‐rotating case within this “rotation‐affected” regime. We investigate the potential for such a (polar) heat transport enhancement in these subglacial oceans by direct numerical simulations of RRBC in spherical geometry for Ra = 106 and 0.7 ≤ Pr ≤ 4.38. We find an enhancement up to 28% in the “polar tangent cylinder,” which is globally compensated by a reduced heat transport at low latitudes. As a result, the polar heat transport can exceed the equatorial by up to 50%. The enhancement is mostly insensitive to different radial gravity profiles, but decreases for thinner shells. In general, polar heat transport and its enhancement in spherical RRBC follow the same principles as in planar RRBC.

Abstract The aim of this cross‐sectional study was to examine whether a history of selective estrogen receptor modifiers (SERMs), tamoxifen and raloxifene, use was associated with cognitive performance, odds of mild cognitive impairment (MCI), or magnetic resonance imaging (MRI) markers of neurodegeneration associated with Alzheimer's disease. We included women with prior history of breast cancer or no prior history of any cancer at enrollment in the Mayo Clinic Study of Aging (MCSA). This information was abstracted using the Rochester Epidemiology Project medical‐linkage system. Logistic regression was used to examine associations of SERMs with odds of MCI. Linear regression models were used to examine associations of SERMs with cognitive z‐scores (Memory, Executive Function, Language, Visuospatial Skills, Global Cognition), and MRI markers. Among 2840 women aged 50 and older in the MCSA, 151 had a history of breast cancer, and 42 (28%) of these had a history of tamoxifen treatment. A total of 2235 women had no prior history of any cancer, and 76 (3%) of these had a history of raloxifene use. No significant associations between tamoxifen use and cognition, or odds of MCI were observed among women with a history of breast cancer after adjusting for confounders. Similarly, raloxifene use was not significantly associated with cognition, or odds of MCI in women without a history of cancer after adjusting for confounders. We did not find significant associations between the use of either SERM and MRI markers. Use of tamoxifen or raloxifene was not significantly associated with cognition in postmenopausal women.

Abstract The Reynolds Creek Experimental Watershed (RCEW) and Critical Zone Observatory (CZO), located south of the western Snake River Plain in the Intermountain West of the United States, is the site of over 60 years of research aimed at understanding integrated earth processes in a semi‐arid climate to aid sustainable use of environmental resources. Meteoric water lines (MWLs) are used to interpret hydrologic processes, though equilibrium and nonequilibrium processes affect the linear function and can reveal seasonal and climatological effects, necessitating the development of local meteoric water lines (LMWLs). At RCEW‐CZO, an RCEW LMWL was developed using non‐volume‐weighted, orthogonal regression with assumed error in both predictor and response variables from several years of precipitation (2015, 2017, 2019, 2020, and 2021) primarily at three different elevations (1203, 1585, and 2043 m). As most precipitation is evaporated or intercepted by vegetation in the driest months, an RCEW LMWL for groundwater recharge (RCEW LMWL‐GWR) was also developed using precipitation from the wettest months (November through April). The RCEW LMWL (δ2H = 7.41 × δ18O – 3.09) is different from the RCEW LMWL‐GWR (δ2H = 8.21 × δ18O + 9.95) and compares favorably to other LMWLs developed for the region and climate. Comparative surface, spring, and subsurface water datasets within the RCEW‐CZO are more similar to precipitation during the wettest months than dry months, illustrating that some semi‐arid hydrologic systems may most appropriately be compared to MWLs developed from precipitation only from the wettest season.

Abstract Objective To characterize normative adult ranges for cochlear promontory thickness relevant to the development of subendosteal and transpromontory electrodes to rehabilitate various neurotologic disorders. Patients Adults (≥18 years). Intervention In vivo radiologic assessment using a 192‐slice CT scanner (Force‐192; Siemens Healthcare) with ultrahigh‐resolution scan mode combined and iterative reconstruction. Main Outcome Measure Cochlear promontory thickness. Results Among 48 included patients (96 ears), the mean (SD) age was 56 (18) years (range 25–94) and included 25 (52%) women. Of that 12 patients (25%) had osteopenia (n = 6) or osteoporosis (n = 6). The mean (SD) body mass index was 28 (5) kg/m2. The mean (SD) promontory thickness for the 96 temporal bones under study was 1.22 (0.24) mm (range 0.55–1.85). There was not a statistically significant association between age and promontory thickness (correlation coefficient .08; p = .44). Promontory thickness was significantly greater for men than women (mean 1.28 vs. 1.17 mm; p = .03) and increased with increasing body mass index (correlation coefficient .30; p = .004). Last, promontory thickness was significantly less for patients with osteopenia or osteoporosis compared with those without these conditions (mean 1.09 vs. 1.27 mm; p = .002). Conclusions Cochlear promontory thickness can vary by almost 1.5 mm across patients and is significantly associated with patient sex, body mass index, and comorbid osteopenia/osteoporosis. Subendosteal and transpromontory electrode placement techniques must account for this degree of variability. Level of Evidence IV

Abstract Burkitt lymphoma (BL) represents the most aggressive B‐cell‐lymphoma. Beside the hallmark of IG‐MYC‐translocation, surface B‐cell receptor (BCR) is expressed, and mutations in the BCR pathway are frequent. Coincidental infections in endemic BL, and specific extra‐nodal sites suggest antigenic triggers. To explore this hypothesis, BCRs of BL cell lines and cases were screened for reactivities against a panel of bacterial lysates, lysates of Plasmodium falciparum, a custom‐made virome array and against self‐antigens, including post‐translationally modified antigens. An atypically modified, SUMOylated isoform of Bystin, that is, SUMO1‐BYSL was identified as the antigen of the BCR of cell line CA46. SUMO1‐BYSL was exclusively expressed in CA46 cells with K139 as site of the SUMOylation. Secondly, an atypically acetylated isoform of HSP40 was identified as the antigen of the BCR of cell line BL41. K104 and K179 were the sites of immunogenic acetylation, and the acetylated HSP40 isoform was solely present in BL41 cells. Functionally, addition of SUMO1‐BYSL and acetylated HSP40 induced BCR pathway activation in CA46 and BL41 cells, respectively. Accordingly, SUMO1‐BYSL‐ETA’ immunotoxin, produced by a two‐step intein‐based conjugation, led to the specific killing of CA46 cells. Autoantibodies directed against SUMO1‐BYSL were found in 3 of 14 (21.4%), and autoantibodies against acetylated HSP40 in 1/14(7.1%) patients with sporadic Burkitt‐lymphoma. No reactivities against antigens of the infectious agent spectrum could be observed. These results indicate a pathogenic role of autoreactivity evoked by immunogenic post‐translational modifications in a subgroup of sporadic BL including two EBV‐negative BL cell lines.

Abstract Objectives To examine the degree of agreement between MRI and histologically generated volumetric measurements of residual injection laryngoplasty material. Methods Following left recurrent laryngeal nerve transection, rabbit vocal cords were injected with jellyfish collagen, Cymetra®, or Restylane®. Laryngeal tissue was harvested 4 or 12 weeks post injection followed by MRI imaging and histologic cross‐sectioning. Two raters estimated the volume of remaining injection material in specimens within MRI and histologic axial cross sections. Wilcoxon signed rank tests were employed to detect gross differences between inter‐rater measurements and between imaging modalities across time. Agreement between rater measurements and imaging (histology and MRI) was assessed using intra‐class correlation coefficients. Results Data was available from 16 rabbits sacrificed at 4 weeks (n = 8) and 12 weeks (n = 8). Inter‐rater testing of MRI imaging revealed no significant differences (p > .05) between rater measurements across time points, and excellent agreement (0.93; 95% confidence interval 0.80–0.98) while histologically estimated volumes demonstrated a significant difference at 4 weeks (p .05). Overall, there is only moderate agreement between MRI and histology estimates (0.72; 95% confidence interval 0.22–0.90). Conclusions MRI imaging demonstrates good reliability and similar estimates of volume to histologically estimated measurements of residual injection laryngoplasty material at time points clinically relevant for future injection laryngoplasty experiments. Level of Evidence NA.

Abstract Objective Otolaryngology residency is highly competitive, and applicant academic metrics are scrutinized. The predictive value of preresidency academic metrics on applicants’ future research productivity and career aspirations remains largely undefined. Study Design Retrospective cohort study Setting Academic otolaryngology department, 2014 to 2015. Methods Applicant demographics, publication history, and United States Medical Licensing Examination (USMLE) scores were downloaded from Electronic Residency Application Service archives. Publications during residency were tallied from all PubMed articles indexed between July 1, 2015 and June 30, 2020. Postresidency career paths were examined by 2 investigators (D.J.C. and L.X.Y.) using Google searches with an emphasis on program websites, Doximity, and LinkedIn profiles. Associations with publication potential and postresidency positions were evaluated with Spearman rank correlation coefficients and Kruskal‐Wallis, Wilcoxon rank sum, and χ2 tests. Results Of 321 applicants, 226 (70%) matched, and 205 (64%) completed residency by June 2020. Matched residents published a median of 4 (range: 0‐41) manuscripts during residency. USMLE scores, Alpha Omega Alpha status, and the number of preresidency publications did not significantly correlate with publication potential during residency. The number of research experiences had a significant positive correlation with publications during residency (p

Abstract Policy interest in socio‐ecological systems has driven attempts to define and map socio‐ecological zones (SEZs), that is, spatial regions, distinguishable by their conjoined social and bio‐geo‐physical characteristics. The state of Idaho, USA, has a strong need for SEZ designations because of potential conflicts between rapidly increasing and impactful human populations, and proximal natural ecosystems. Our Idaho SEZs address analytical shortcomings in previously published SEZs by: (1) considering potential biases of clustering methods, (2) cross‐validating SEZ classifications, (3) measuring the relative importance of bio‐geo‐physical and social system predictors, and (4) considering spatial autocorrelation. We obtained authoritative bio‐geo‐physical and social system datasets for Idaho, aggregated into 5‐km grids = 25 km2, and decomposed these using principal components analyses (PCAs). PCA scores were classified using two clustering techniques commonly used in SEZ mapping: hierarchical clustering with Ward's linkage, and k‐means analysis. Classification evaluators indicated that eight‐ and five‐cluster solutions were optimal for the bio‐geo‐physical and social datasets for Ward's linkage, resulting in 31 SEZ composite types, and six‐ and five‐cluster solutions were optimal for k‐means analysis, resulting in 24 SEZ composite types. Ward's and k‐means solutions were similar for bio‐geo‐physical and social classifications with similar numbers of clusters. Further, both classifiers identified the same dominant SEZ composites. For rarer SEZs, however, classification methods strongly affected SEZ classifications, potentially altering land management perspectives. Our SEZs identify several critical regions of social–ecological overlap. These include suburban interface types and a high desert transition zone. Based on multinomial generalized linear models, bio‐geo‐physical information explained more variation in SEZs than social system data, after controlling for spatial autocorrelation, under both Ward's and k‐means approaches. Agreement (cross‐validation) levels were high for multinomial models with bio‐geo‐physical and social predictors for both Ward's and k‐means SEZs. A consideration of historical drivers, including indigenous social systems, and current trajectories of land and resource management in Idaho, indicates a strong need for rigorous SEZ designations to guide development and conservation in the region. Our analytical framework can be broadly applied in SES research and applied in other regions, when categorical responses—including cluster designations—have a spatial component.

Abstract Aims Chronic heart failure (CHF) can be caused by autoantibodies stimulating the heart via binding to first and/or second extracellular loops of cardiac β1‐adrenoceptors. Allosteric receptor activation depends on conformational features of the autoantibody binding site. Elucidating these features will pave the way for the development of specific diagnostics and therapeutics. Our aim was (i) to fine‐map the conformational epitope within the second extracellular loop of the human β1‐adrenoceptor (β1ECII) that is targeted by stimulating β1‐receptor (auto)antibodies and (ii) to generate competitive cyclopeptide inhibitors of allosteric receptor activation, which faithfully conserve the conformational auto‐epitope. Methods and results Non‐conserved amino acids within the β1ECII loop (compared with the amino acids constituting the ECII loop of the β2‐adrenoceptor) were one by one replaced with alanine; potential intra‐loop disulfide bridges were probed by cysteine–serine exchanges. Effects on antibody binding and allosteric receptor activation were assessed (i) by (auto)antibody neutralization using cyclopeptides mimicking β1ECII ± the above replacements, and (ii) by (auto)antibody stimulation of human β1‐adrenoceptors bearing corresponding point mutations. With the use of stimulating β1‐receptor (auto)antibodies raised in mice, rats, or rabbits and isolated from exemplary dilated cardiomyopathy patients, our series of experiments unmasked two features of the β1ECII loop essential for (auto)antibody binding and allosteric receptor activation: (i) the NDPK211–214 motif and (ii) the intra‐loop disulfide bond C209↔C215. Of note, aberrant intra‐loop disulfide bond C209↔C216 almost fully disrupted the functional auto‐epitope in cyclopeptides. Conclusions The conformational auto‐epitope targeted by cardio‐pathogenic β1‐receptor autoantibodies is faithfully conserved in cyclopeptide homologues of the β1ECII loop bearing the NDPK211–214 motif and the C209↔C215 bridge while lacking cysteine C216. Such molecules provide promising tools for novel diagnostic and therapeutic approaches in β1‐autoantibody‐positive CHF.

Background Persistent sensorimotor impairments after stroke can negatively impact quality of life. The hippocampus is vulnerable to poststroke secondary degeneration and is involved in sensorimotor behavior but has not been widely studied within the context of poststroke upper‐limb sensorimotor impairment. We investigated associations between non‐lesioned hippocampal volume and upper limb sensorimotor impairment in people with chronic stroke, hypothesizing that smaller ipsilesional hippocampal volumes would be associated with greater sensorimotor impairment. Methods and Results Cross‐sectional T1‐weighted magnetic resonance images of the brain were pooled from 357 participants with chronic stroke from 18 research cohorts of the ENIGMA (Enhancing NeuoImaging Genetics through Meta‐Analysis) Stroke Recovery Working Group. Sensorimotor impairment was estimated from the FMA‐UE (Fugl‐Meyer Assessment of Upper Extremity). Robust mixed‐effects linear models were used to test associations between poststroke sensorimotor impairment and hippocampal volumes (ipsilesional and contralesional separately; Bonferroni‐corrected, P

Abstract The aims of this study were to examine presence of GAD65 autoantibodies (GAD65aab) in offspring born to women with type 1 diabetes (T1D) and controls and if more were GAD65aab‐positive if diagnosed with diabetes or pre‐diabetes. This EPICOM study is a prospective follow‐up study focussing on pregnancies complicated by maternal T1D. The EPICOM study includes offspring (n = 278) born to mothers with pre‐gestational T1D between 1993 and 1999 and matched un‐exposed controls (n = 303). Age at the time of follow‐up was 16.7 years (13.0–20.4 years). GAD65aab was measured using the Glutamic Acid Decarboxylase Autoantibody RIA kit from RSR©. An Oral Glucose Tolerance Test (OGTT) was performed, and abnormal glucose tolerance was defined as having either diabetes, impaired fasting glucose (IFG) or impaired glucose tolerance (IGT). GAD65aab could be measured in 561 participants. Of these, 17 (3%) were positive for GAD65aab (≥25 U/ml) with 11 (4%) offspring being born to women with T1D and 6 (2%) controls. The difference in GAD65aab status was not statistically significant (p = .2). One was diagnosed with GAD65aab‐negative diabetes during the study, 18 were diagnosed with IFG, and 44 with IGT. Overall, more were GAD65aab‐positive if diagnosed with abnormal glucose tolerance (p = .03). We found no association between GAD65aab status and HOMA‐IR, HOMA‐IS, birthweight, mode of delivery or maternal BMI prior to pregnancy. Our study found no overall difference in GAD65 status between offspring born to women with T1D and their matched controls. However, among the participants diagnosed with pre‐diabetes more were GAD65‐positive.

Abstract Ultrasound‐based brain stimulation techniques may become a powerful new technique to modulate the human brain in a focal and targeted manner. However, for clinical brain stimulation no certified systems exist and the current techniques have to be further developed. Here, a clinical sonication technique is introduced, based on single ultrashort ultrasound pulses (transcranial pulse stimulation, TPS) which markedly differs from existing focused ultrasound techniques. In addition, a first clinical study using ultrasound brain stimulation and first observations of long term effects are presented. Comprehensive feasibility, safety, and efficacy data are provided. They consist of simulation data, laboratory measurements with rat and human skulls and brains, in vivo modulations of somatosensory evoked potentials (SEP) in healthy subjects (sham controlled) and clinical pilot data in 35 patients with Alzheimer's disease acquired in a multicenter setting (including neuropsychological scores and functional magnetic resonance imaging (fMRI)). Preclinical results show large safety margins and dose dependent neuromodulation. Patient investigations reveal high treatment tolerability and no major side effects. Neuropsychological scores improve significantly after TPS treatment and improvement lasts up to three months and correlates with an upregulation of the memory network (fMRI data). The results encourage broad neuroscientific application and translation of the method to clinical therapy and randomized sham‐controlled clinical studies.

The Reynolds Creek Experimental Watershed (RCEW) was established in 1960 as an “outdoor hydrological laboratory” to investigate hydrological processes of interest in the interior northwestern part of the United States. Initial emphasis was on installing and testing instrumentation and data collection and dissemination. The initial instrumentation network sampled the climatic gradient within the 239-km watershed and focused on specific subwatersheds for intensive instrumentation. This network has expanded and supported ad hoc research and provides a stable platform for the development of long-term programs supporting research and model development in snow hydrology, climate change, water and energy balance, land management, carbon cycling, and critical zone hydrology. Recently, the challenge taken up at the RCEW is to integrate different processes over space for applications to larger areas outside the watershed. The presence of steep local environmental gradients associated with topography in addition to more gradual, elevational gradients requires high-resolution modeling. The snow hydrology program has demonstrated the potential for high-resolution, process-based modeling across large landscapes. The direct linkage of biogeochemical processes with hydrological processes ultimately requires a multidisciplinary approach that has been adopted at the RCEW since inclusion in the Critical Zone Observatory program. We think that coupling of these processes will lead to a better understanding and management of natural resources on the landscape.