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Understanding the foraging behavior of marine animals in Antarctica is crucial for assessing their ecological significance and responses to environmental changes, such as seasonal changes in seawater or light hours. However, studying their responses to these seasonal changes remains challenging due to the difficult logistics of conducting observations, particularly during the harsh austral winter months. In this study, we investigated the influence of changes in seawater properties and light conditions on the seasonal foraging behavior of Weddell seals (Leptonychotes weddellii) in the Ross Sea, Antarctica. We affixed 64 Weddell seals with conductivity–temperature–depth tags for 3 consecutive years from 2021 to 2023 to record their locations and dive profiles, including depth, head acceleration, temperature, and salinity. We found that seals foraged more frequently in Modified Shelf Water and Ice Shelf Water than in Antarctic Surface Water. This preference could be connected to greater food availability. Seals also dove to greater depths and displayed increased activity in capturing prey during daylight hours. This behavior may correspond to the diel vertical migration of pelagic prey in response to varying light conditions. Consequently, marine fauna were confronted with distinct seasonal changes in the Antarctic environment and adjusted their foraging behaviors to respond to them. This highlights the importance of extrinsic factors in estimating their seasonal foraging behavior.

ABSTRACTBackground Orthokeratinized odontogenic cyst (OOC) is a rare developmental odontogenic cyst that is clinically and histomorphologically different than odontogenic keratocyst (OKC).Case Description OOC is a distinct entity from OKC with a unique biological behavior, pathogenesis, and prognosis. The distinction between these entities is paramount because unlike OKCs, OOCs rarely recur after simple enucleation and are not associated with nevoid basal cell carcinoma syndrome. We present a case of an 8-year-old male with an OOC of the right posterior mandible along with a differential diagnosis and discussion of OOCs and its common mimics.

Abstract Machine learning can be used to define subtypes of psychiatric conditions based on shared biological foundations of mental disorders. Here we analyzed cross-sectional brain images from 4,222 individuals with schizophrenia and 7038 healthy subjects pooled across 41 international cohorts from the ENIGMA, non-ENIGMA cohorts and public datasets. Using the Subtype and Stage Inference (SuStaIn) algorithm, we identify two distinct neurostructural subgroups by mapping the spatial and temporal ‘trajectory’ of gray matter change in schizophrenia. Subgroup 1 was characterized by an early cortical-predominant loss with enlarged striatum, whereas subgroup 2 displayed an early subcortical-predominant loss in the hippocampus, striatum and other subcortical regions. We confirmed the reproducibility of the two neurostructural subtypes across various sample sites, including Europe, North America and East Asia. This imaging-based taxonomy holds the potential to identify individuals with shared neurobiological attributes, thereby suggesting the viability of redefining existing disorder constructs based on biological factors.

Abstract Introduction Rural cancer caregivers experience obstacles in accessing services, obtaining respite, and ensuring their care recipients receive quality care. These challenges warrant opportunities to participate in evidence‐based behavioral intervention trials to fill support gaps. Adaptation to rural settings can facilitate appropriate fit, given higher caregiver service needs and unique challenges. We present findings from the adaptation process of a psychoeducational intervention designed to support cancer caregivers in rural settings. Methods We adapted Reblin's CARING intervention, designed for neuro‐oncology, to target caregivers of rural cancer patients across cancer sites. First, we conducted formative work to determine the unmet social and supportive care needs rural cancer caregivers faced. We used the Framework for Reporting Adaptations and Modifications to Evidence‐based Implementation Strategies (FRAME‐IS) to guide the modifications. To conduct the adaptation, we elicited feedback through qualitative interviews of seven caregivers and three cancer hospital staff and thematic analysis to inform intervention modifications. Our qualitative study was guided by the Consolidated Criteria for Reporting Qualitative Research (COREQ). Results Interviews revealed that service access was a pressing need, along with financial (e.g., treatment costs, employment challenges) and geographic barriers (e.g., distance to treatment, road conditions). We modified content, training, and context using the FRAME‐IS steps. Changes enhanced fit through the following adaptations: changes to social support domains, session content, interventionist training, resource offerings, screening and recruitment processes, and virtual delivery. Discussion Challenges to establishing successful psychosocial oncology interventions may be improved through participant‐centered approaches and implementation science. Additional systemic challenges, including lack of systematic documentation of caregivers, persist and may especially disadvantage under‐represented and underserved groups, such as rural dwellers. The enCompass intervention is undergoing ongoing single‐arm pilot of rural cancer patient/caregiver dyads targeting caregiver coping self‐efficacy and patient/caregiver distress (Clinical Trials #NCT05828927).

Kabuki syndrome is a genetic disorder characterised by distinctive facial features, developmental delays, and multisystem congenital anomalies. Endocrine complications such as premature thelarche and short stature are common, whereas disorders of glycaemic control are less frequent. We describe a 23-year-old white female referred to the diabetes clinic for hyperglycaemia during haemodialysis. She was subsequently diagnosed with Kabuki syndrome based on characteristic clinical features, confirmed by detecting a heterozygous pathogenic variant in KMT2D. She was known to have had multiple congenital anomalies at birth, including complex congenital heart disease and a single dysplastic ectopic kidney, and received a cadaveric transplanted kidney at the age of 13. She had hyperglycaemia consistent with post-transplant diabetes mellitus (DM) and was started on insulin. Examination at the time revealed truncal obesity. She developed acute graft rejection and graft failure 14 months post-transplant and she was started on haemodialysis. Her blood glucose levels normalised post-graft explant, but she was hyperglycaemic again during haemodialysis at the age of 23. Given her clinical phenotype, negative diabetes antibodies and normal pancreas on ultrasound, she was assumed to have type 2 DM and achieved good glycaemic control with gliclazide.

Soil water repellency (SWR) is caused by hydrophobic organic compounds and is exacerbated during warmer temperatures and dry periods. SWR can have various detrimental effects, including limited wetting capabilities, reduced soil infiltration and hydraulic conductivity, and decreased plant available water, ultimately affecting crop yield. Conventional on-farm practices and soil health management strategies are implemented to cultivate healthy, productive lands. However, these practices and strategies impact SWR differently. Considering these strategies and the current understanding of factors contributing to SWR and climate change predictions, there is a strong potential that SWR occurrence and severity will increase in the future, which will impact food security. Current climate change models used to predict crop yields do not account for climate change induced SWR or how management practices and strategies influence SWR. To address this issue, this article reviews the impact of conventional on-farm practices and soil health management strategies on SWR and crop productivity, particularly in the context of predicted increasing temperatures and extreme precipitation events due to climate change. Building a robust climate change predictive model for crop yield will require understanding sub-critical SWR and adapting modern biomarking spectral and chemometric analyses to determine the repellency potential of inputs (amendments and plants), not just the soil. Once determined, this information can be used to assist farmers in making management decisions that will increase agroecosystem and livelihood sustainability and subsequently reduce food insecurity.

Abstract Cover crops (CCs) offer in‐field and environmental benefits when integrated into cropping systems. Low CC adoption in the Southern Piedmont region of South Carolina is partially due to the lack of information on CC performance and benefits within the region. To address this, eight winter CCs and a fallow/pigweed (Amaranthus spp.) treatment were investigated for their influence on soil temperature, volumetric water content (VWC), percent cover, biomass, and the occurrence of soil water repellency (SWR). A randomized complete block design experiment was conducted in the fall and winter of 2021–2022 (EXP A) and repeated in 2022–2023 (EXP B). Experiments were treated separately as methods were revised for EXP B. CCs minimally influenced soil VWC over both experiments with no consistent trend. CC did not influence soil temperatures during EXP A. In EXP B, the fallow/pigweed had the highest soil temperatures on two (out of 10) measuring events (p

Triglycerides play a crucial role in the efficient storage of energy in the body. Mild and moderate hypertriglyceridemia (HTG) is a heterogeneous disorder with significant association with atherosclerotic cardiovascular disease (ASCVD), including myocardial infarction, ischemic stroke, and peripheral artery disease and represents an important component of the residual ASCVD risk in statin treated patients despite optimal low-density lipoprotein cholesterol reduction. Individuals with severe HTG (>1,000 mg/dL) rarely develop atherosclerosis but have an incremental incidence of acute pancreatitis with significant morbidity and mortality. HTG can occur from a combination of genetic (both mono and polygenic) and environmental factors including poor diet, low physical activity, obesity, medications, and diseases like insulin resistance and other endocrine pathologies. HTG represents a potential target for ASCVD risk and pancreatitis risk reduction, however data on ASCVD reduction by treating HTG is still lacking and HTG-associated acute pancreatitis occurs too rarely to effectively demonstrate treatment benefit. In this review, we address the key aspects of HTG pathophysiology and examine the mechanisms and background of current and emerging therapies in the management of HTG.

Abstract Recently, deep generative models using machine intelligence are widely utilized to investigate scientific systems by generating scientific data. In this study, we experiment with a hybrid model of a variational autoencoder (VAE) and a generative adversarial network (GAN) to generate a variety of plausible two-dimensional magnetic topological structure data. Due to the topological properties in the system, numerous and diverse metastable magnetic structures exist, and energy and topological barriers separate them. Thus, generating a variety of plausible spin structures avoiding those barrier states is a challenging problem. The VAE-GAN hybrid model can present an effective approach to this problem because it brings the advantages of both VAE’s diversity and GAN’s fidelity. It allows one to perform various applications including searching a desired sample from a variety of valid samples. Additionally, we perform a discriminator-driven latent sampling (DDLS) using our hybrid model to improve the quality of generated samples. We confirm that DDLS generates various plausible data with large coverage, following the topological rules of the target system.

Flow cytometry facilitates the detection of multiple cell parameters simultaneously with a high level of resolution and throughput, enabling in-depth immunological evaluations. High data resolution in flow cytometry depends on multiple factors, including the concentration of reagents used in the staining protocol, and reagent validation and titration should be the first step in any assay optimization. Titration is the process of finding the concentration of the reagent that best resolves a positive signal from the background, with the saturation of all binding sites, and minimal antibody excess. The titration process involves the evaluation of serial reagent dilutions in cells expressing the antigen target for the tested antibody. The concentration of antibody that provides the highest signal to noise ratio is calculated by plotting the percentage of positive cells and the intensity of the fluorescence of the stained cells with respect to the negative events, in a concentration–response curve. The determination of the optimal antibody concentration is necessary to ensure reliable and reproducible results and is required for each sample type, reagent clone and lot, as well as the methods used for cell collection, staining, and storage conditions. If the antibody dilution is too low, the signal will be too weak to be accurately determined, leading to suboptimal data resolution, high variability across measurements, and the underestimation of the frequency of cells expressing a specific marker. The use of excess antibodies could lead to non-specific binding, reagent misuse, and detector overloading with the signal off scale and higher spillover spreading. In this publication, we summarized the titration fundamentals and best practices, and evaluated the impact of using a different instrument, sample, staining, acquisition, and analysis conditions in the selection of the optimal titer and population resolution.

Abstract Objective Women represent an increasing proportion of the otolaryngology workforce. Work‐related musculoskeletal disorders (WRMSD) are a little‐studied yet important impediment to career completion. Scant attention has been directed to study the impact of pregnancy on surgeon posture and ergonomics. We piloted the use of a pregnancy simulation suit (Empathy Belly) to assess the risk of ergonomic compromise when performing open septorhinoplasty. Study Design Surgical simulation. Setting Single session, training simulation lab at academic medical center. Methods Medical students and surgical residents performed the initial steps of a rhinoplasty procedure without and with a pregnancy simulation suit and were filmed with an artificial intelligence‐based video analysis app from Kinetica Labs that calculates joint angles and categorizes the ergonomic risk factors. Still images from videos were taken and analyzed using validated posture‐based analysis rubrics. Participants were asked to complete a qualitative questionnaire after the session. Results Twelve medical students and surgical residents participated in the study. Posture‐based analysis indicated increased ergonomics risk factors among trainees when performing a rhinoplasty while wearing the pregnancy suit. Video analysis indicated trends of worsening back angle and shoulder postures. Trainees reported experiencing pain in the neck, suprapubic area, and lower back. They acknowledged the importance of ergonomics in otolaryngology and desired further education about workplace injury risk mitigation. Conclusion Pregnancy impacts the ergonomics of performing septorhinoplasty and further investigation is required into interventions to reduce risk of WRMSDs.

Abstract Despite strides in immunotherapy, glioblastoma multiforme (GBM) remains challenging due to low inherent immunogenicity and suppressive tumor microenvironment. Converting “cold” GBMs to “hot” is crucial for immune activation and improved outcomes. This study comprehensively characterized a therapeutic vaccination strategy for preclinical GBM models. The vaccine consists of Mannan‐BAM‐anchored irradiated whole tumor cells, Toll‐like receptor ligands [lipoteichoic acid (LTA), polyinosinic‐polycytidylic acid (Poly (I:C)), and resiquimod (R‐848)], and anti‐CD40 agonistic antibody (rWTC‐MBTA). Intracranial GBM models (GL261, SB28 cells) are used to evaluate the vaccine efficacy. A substantial number of vaccinated mice exhibited complete regression of GBM tumors in a T‐cell‐dependent manner, with no significant toxicity. Long‐term tumor‐specific immune memory is confirmed upon tumor rechallenge. In the vaccine‐draining lymph nodes of the SB28 model, rWTC‐MBTA vaccination triggered a major rise in conventional dendritic cell type 1 (cDC1) 12 h post‐treatment, followed by an increase in conventional dendritic cell type 2 (cDC2), monocyte‐derived dendritic cell (moDC), and plasmacytoid dendritic cell (pDC) on Day 5 and Day 13. Enhanced cytotoxicity of CD4+ and CD8+ T cells in vaccinated mice is verified in co‐culture with tumor cells. Analyses of immunosuppressive signals (T‐cell exhaustion, myeloid‐derived suppressor cells (MDSC), M2 macrophages) in the GBM microenvironment suggest potential combinations with other immunotherapies for enhanced efficacy. In conclusion, the authors findings demonstrate that rWTC‐MBTA induces potent and long‐term adaptive immune responses against GBM.

Converging evidence links schizophrenia risk to synaptic dysfunction due to genetic variants. Synaptic dysplasticity in at-risk individuals lead to excessive synapse elimination, impacting brain connectivity. MRI studies highlight initial hyperconnectivity followed by later hypoconnectivity, impacting information transmission. Imbalance between Hebbian and homeostatic plasticity likely causes this shift. Highly connected hub regions of the brain experience synapse reduction, causing what we call as ‘global retuning’. Such post-psychotic changes aid resolution of active symptoms but lead to cognitive and motivational deficits. Antipsychotics may restore connectivity but worsen cognitive symptoms. In this framework, we present schizophrenia as an illness with disrupted ‘topological homeostasis’ due to synaptic dysplasticity. Our framework leaves room for an intrinsic, albeit inefficient, antipsychotic defense process that aids in adaptation. Studying successful adaptation in animal models and recovered individuals is crucial to design avant-garde interventions for schizophrenia.

Abstract We construct a deep neural network to enhance the resolution of spin structure images formed by spontaneous symmetry breaking in the magnetic systems. Through the deep neural network, an image is expanded to a super-resolution image and reduced to the original image size to be fitted with the input feed image. The network does not require ground truth images in the training process. Therefore, it can be applied when low-resolution images are provided as training datasets, while high-resolution images are not obtainable due to the intrinsic limitation of microscope techniques. To show the usefulness of the network, we train the network with two types of simulated magnetic structure images; one is from self-organized maze patterns made of chiral magnetic structures, and the other is from magnetic domains separated by walls that are topological defects of the system. The network successfully generates high-resolution images highly correlated with the exact solutions in both cases. To investigate the effectiveness and the differences between datasets, we study the network’s noise tolerance and compare the networks’ reliabilities. The network is applied with experimental data obtained by magneto-optical Kerr effect microscopy and spin-polarized low-energy electron microscopy.

Abstract The challenge underlying superconducting quantum computing is to remove materials bottleneck for highly coherent quantum devices. The nonuniformity and complex structural components in the underlying quantum circuits often lead to local electric field concentration, charge scattering, dissipation and ultimately decoherence. Here we visualize interface dipole heterogeneous distribution of individual Al/AlO x /Al junctions employed in transmon qubits by broadband terahertz scanning near-field microscopy that enables the non-destructive and contactless identification of defective boundaries in nano-junctions at an extremely precise nanoscale level. Our THz nano-imaging tool reveals an asymmetry across the junction in electromagnetic wave-junction coupling response that manifests as hot (high intensity) vs cold (low intensity) spots in the spatial electrical field structures and correlates with defected boundaries from the multi-angle deposition processes in Josephson junction fabrication inside qubit devices. The demonstrated local electromagnetic scattering method offers high sensitivity, allowing for reliable device defect detection in the pursuit of improved quantum circuit fabrication for ultimately optimizing coherence times.

Effective oral care is important for maintaining a high quality of life. Therefore, plaque control can prevent the development and recurrence of periodontitis. Brushing with a toothbrush and toothpaste is a common way to remove plaque; however, excessive brushing or brushing with abrasive toothpaste can cause wear and tear on the dental crown. Hence, we aimed to quantitatively compare the plaque-removal efficiency and tooth wear of toothbrushes using the bioelectric effect (BE) with those of electric–mechanical toothbrushes. To generate the BE signal, an electronic circuit was developed and embedded in a toothbrush. Further, typodonts were coated with cultured artificial plaques and placed in a brushing simulator. A toothpaste slurry was applied, and the typodonts were eluted with tap water after brushing. The plaques of the typodonts were captured, and the images were quantified. For the tooth wear experiment, polymethyl methacrylate disk resin blocks were brushed twice a day, and the thickness of the samples was measured. Subsequently, statistical differences between the experimental toothbrushes and typical toothbrushes were analyzed. The BE toothbrush had a higher plaque-removal efficiency and could minimize tooth wear. This study suggests that the application of BE may be a new solution for oral care.

Abstract Background Cognitive difficulties have been described after chemotherapy for breast cancer, but there is no standard of care to improve cognitive outcomes in these patients. This trial examined the feasibility, tolerability, acceptability, and preliminary effects of memantine to prevent cognitive decline during chemotherapy for breast cancer. Methods Patients with stage I–III breast cancer, scheduled for neo/adjuvant chemotherapy, completed a cognitive battery prior to and 4 weeks after completing chemotherapy. Memantine (10 mg BID) was administered concurrent with chemotherapy. Our primary cognitive outcome was visual working memory assessed by the Delayed Matching to Sample test. We used the Brief Medication Questionnaire to assess acceptability. Results Of 126 patients approached, 56 (44%) enrolled. Forty‐five (80%) received ≥1 dose of memantine and completed pre‐post assessments. Seventy‐six percent reported taking ≥90% of scheduled doses. Participants were mean age of 56, 77% White, and 57% had stage I disease. Sixty‐four percent had stable or improved Delayed Matching to Sample test scores. Stable or improved cognition was observed in 87%–91% across objective cognitive domain composite measures. Sixty‐six percent self‐reported stable or improved cognitive symptoms. There were seven greater than or equal to grade 3 adverse events; two were possibly related to memantine. Only 5% reported that taking memantine was a disruption to their lives. Conclusions Memantine was well‐tolerated and consistently taken by a large majority of patients receiving breast cancer chemotherapy. The majority demonstrated stable or improved cognition from pre‐ to post‐assessment. Randomized trials are needed to determine memantine's efficacy to ameliorate cognitive loss. Trial Registration ClinicalTrials.gov NCT04033419.

Abstract Objective We attempted to investigate the long‐term outcomes, prognostic factors, treatment failures, second primary malignancies, and salvage therapies in early (pT1‐2N0) oral tongue squamous cell carcinoma (OTSCC). Methods We retrospectively analyzed the medical records of 295 early stage OTSCC patients. Results Two hundred ninety‐five patients were enrolled. The average follow‐up period was 64.5 months (range, 1–190 months). Five‐year recurrence‐free survival rate was 84.8% and disease‐specific survival rate was 91.2%. On multivariate analysis, only the depth of invasion (DOI) exhibited significant correlations with the disease recurrence. Patient's age and DOI demonstrated a significant association with survival. A total of 53 recurrence and 35 death events occurred, with the main cause of treatment failure being regional or local recurrence. In recurrent cases, the success rate of salvage treatment was 42% at 5 years. During the follow‐up period, second primary malignancy occurred in 13 patients, and 8 (61.5%) of those patients were successfully treated. Conclusions In pT1‐2N0 OTSCC, regional or local recurrence is the main recurrence pattern, whereas age and DOI >5 mm are significant prognostic factors related to recurrence and survival. Since several patients experienced second primary malignancies in the head and neck, careful and thorough surveillance may be required to detect second primary lesions. Level of Evidence 4.

Air masses within the Asian monsoon anticyclone (AMA) show anomalous signatures in various trace gases. In this study, we investigate how air masses are transported from the planetary boundary layer (PBL) to the AMA based on multiannual trajectory analyses. In particular, we focus on the climatological perspective and on the intraseasonal and interannual variability. Further, we also discuss the relation of the interannual east–west displacements of the AMA with the transport from the PBL to the AMA. To this end we employ backward trajectories, which were computed for 14 northern summer (June–August) seasons using reanalysis data. Further, we backtrack forward trajectories from a free-running chemistry–climate model (CCM) simulation, which includes parametrized Lagrangian convection. The analysis of 30 monsoon seasons of this additional model data set helps us to carve out robust or sensitive features of transport from the PBL to the AMA with respect to the employed model. Results from both the trajectory model and the Lagrangian CCM emphasize the robustness of the three-dimensional transport pathways from the top of the PBL to the AMA. Air masses are transported upwards on the south-eastern side of the AMA and subsequently recirculate within the full AMA domain, where they are lifted upwards on the eastern side and transported downwards on the western side of the AMA. The contributions of different PBL source regions to AMA air are robust across the two models for the Tibetan Plateau (TP; 17 % vs. 15 %) and the West Pacific (around 12 %). However, the contributions from the Indian subcontinent and Southeast Asia are considerably larger in the Lagrangian CCM data, which might indicate an important role of convective transport in PBL-to-AMA transport for these regions. The analysis of both model data sets highlights the interannual and intraseasonal variability of the PBL source regions of the AMA. Although there are differences in the transport pathways, the interannual east–west displacement of the AMA – which we find to be related to the monsoon Hadley index – is not connected to considerable differences in the overall transport characteristics. Our results from the trajectory model data reveal a strong intraseasonal signal in the transport from the PBL over the TP to the AMA: there is a weak contribution of TP air masses in early June (less than 4 % of the AMA air masses), whereas in August the contribution is considerable (roughly 24 %). The evolution of the contribution from the TP is consistent across the two modelling approaches and is related to the northward shift of the subtropical jet and the AMA during this period. This finding may help to reconcile previous results and further highlights the need of taking the subseasonal (and interannual) variability of the AMA and associated transport into account.

ABSTRACT Pathogens must adapt to disparate environments in permissive host species, a feat that is especially pronounced for vector-borne microbes, which transition between vertebrate hosts and arthropod vectors to complete their lifecycles. Most knowledge about arthropod-vectored bacterial pathogens centers on their life in the mammalian host, where disease occurs. However, disease outbreaks are driven by the arthropod vectors. Adapting to the arthropod is critical for obligate intracellular rickettsial pathogens, as they depend on eukaryotic cells for survival. To manipulate the intracellular environment, these bacteria use type IV secretion systems (T4SS) to deliver effectors into the host cell. To date, few rickettsial T4SS translocated effectors have been identified and have only been examined in the context of mammalian infection. We identified an effector from the tick-borne rickettsial pathogen Anaplasma phagocytophilum, HGE1_02492, as critical for survival in tick cells and acquisition by ticks in vivo. Conversely, HGE1_02492 was dispensable during mammalian cell culture and murine infection. We show that HGE1_02492 is translocatable in a T4SS-dependent manner to the host cell cytosol. In eukaryotic cells, the HGE1_02492 localized with cortical actin filaments, which is dependent on multiple sub-domains of the protein. HGE1_02492 is the first arthropod-vector specific T4SS translocated effector identified from a rickettsial pathogen. Moreover, the subcellular target of HGE1_02492 suggests that A. phagocytophilum is manipulating actin to enable arthropod colonization. Based on these findings, we propose the name AteA for Anaplasma (phagocytophilum) tick effector A. Altogether, we show that A. phagocytophilum uses distinct strategies to cycle between mammals and arthropods. IMPORTANCE Ticks are the number one vector of pathogens for livestock worldwide and for humans in the United States. The biology of tick transmission is an understudied area. Understanding this critical interaction could provide opportunities to affect the course of disease spread. In this study, we examined the zoonotic tick-borne agent Anaplasma phagocytophilum and identified a secreted protein, AteA, which is expressed in a tick-specific manner. These secreted proteins, termed effectors, are the first proteins to interact with the host environment. AteA is essential for survival in ticks and appears to interact with cortical actin. Most effector proteins are studied in the context of the mammalian host; however, understanding how this unique set of proteins affects tick transmission is critical to developing interventions.

ABSTRACT A crucial phase in the life cycle of tick-borne pathogens is the time spent colonizing and persisting within the arthropod. Tick immunity is emerging as a key force shaping how transmissible pathogens interact with the vector. How pathogens remain in the tick despite immunological pressure remains unknown. In persistently infected Ixodes scapularis, we found that Borrelia burgdorferi (causative agent of Lyme disease) and Anaplasma phagocytophilum (causative agent of granulocytic anaplasmosis) activate a cellular stress pathway mediated by the endoplasmic reticulum receptor PKR-like ER kinase (PERK) and the central regulatory molecule eIF2α. Disabling the PERK pathway through pharmacological inhibition and RNA interference (RNAi) significantly decreased microbial numbers. In vivo RNAi of the PERK pathway not only reduced the number of A. phagocytophilum and B. burgdorferi colonizing larvae after a bloodmeal but also significantly reduced the number of bacteria that survive the molt. An investigation into PERK pathway-regulated targets revealed that A. phagocytophilum and B. burgdorferi induce activity of the antioxidant response regulator, nuclear factor erythroid 2-related factor 2 (Nrf2). Tick cells deficient for nrf2 expression or PERK signaling showed accumulation of reactive oxygen and nitrogen species in addition to reduced microbial survival. Supplementation with antioxidants rescued the microbicidal phenotype caused by blocking the PERK pathway. Altogether, our study demonstrates that the Ixodes PERK pathway is activated by transmissible microbes and facilitates persistence in the arthropod by potentiating an Nrf2-regulated antioxidant environment. IMPORTANCE Recent advances demonstrate that the tick immune system recognizes and limits the pathogens they transmit. Innate immune mediators such as antimicrobial peptides and reactive oxygen/nitrogen species are produced and restrict microbial survival. It is currently unclear how pathogens remain in the tick, despite this immune assault. We found that an antioxidant response controlled by the PERK branch of the unfolded protein response is activated in ticks that are persistently infected with Borrelia burgdorferi (Lyme disease) or Anaplasma phagocytophilum (granulocytic anaplasmosis). The PERK pathway induces the antioxidant response transcription factor, Nrf2, which coordinates a gene network that ultimately neutralizes reactive oxygen and nitrogen species. Interfering with this signaling cascade in ticks causes a significant decline in pathogen numbers. Given that innate immune products can cause collateral damage to host tissues, we speculate that this is an arthropod-driven response aimed at minimizing damage to “self” that also inadvertently benefits the pathogen. Collectively, our findings shed light on the mechanistic push and pull between tick immunity and pathogen persistence within the arthropod vector.

Otolith traits such as size and mass were investigated in 60 fish specimens of C. kais and C. macrostomum collected from the Tigris River, Şırnak region, Türkiye collected from September 2015 to December 2015. The purpose of this work was to determine the asymmetry level in the otolith length (OL), otolith width (OW), and otolith mass (OM). OL's rate of asymmetry was greater than OW’s and OM's. The asymmetry in the three otolith traits rose with the fish length. The plausible reason for asymmetry in the otolith features explored has been considered relative to the inconsistency of growth triggered by ecological influence associated with the inconsistency in water temperature, salinity, depth, and contaminants occurring in the Tigris River System.

Kar4p, the yeast homolog of the mammalian methyltransferase subunit METTL14, is required for efficient mRNA m6A methylation, which regulates meiotic entry. Kar4p is also required for a second seemingly non-catalytic function during meiosis. Overexpression of the early meiotic transcription factor, IME1, can bypass the requirement for Kar4p in meiotic entry but the additional overexpression of the translational regulator, RIM4, is required to permit sporulation in kar4Δ/Δ. Using microarray analysis and RNA sequencing, we sought to determine the impact of removing Kar4p and consequently mRNA methylation on the early meiotic transcriptome in a strain background (S288c) that is sensitive to the loss of early meiotic regulators. We found that kar4Δ/Δ mutants have a largely wild type transcriptional profile with the exception of two groups of genes that show delayed and reduced expression: (1) a set of Ime1p-dependent early genes as well as IME1, and (2) a set of late genes dependent on the mid-meiotic transcription factor, Ndt80p. The early gene expression defect is likely the result of the loss of mRNA methylation and is rescued by overexpressing IME1, but the late defect is only suppressed by overexpression of both IME1 and RIM4. The requirement for RIM4 led us to predict that the non-catalytic function of Kar4p, like methyltransferase complex orthologs in other systems, may function at the level of translation. Mass spectrometry analysis identified several genes involved in meiotic recombination with strongly reduced protein levels, but with little to no reduction in transcript levels in kar4Δ/Δ after IME1 overexpression. The low levels of these proteins were rescued by overexpression of RIM4 and IME1, but not by the overexpression of IME1 alone. These data expand our understanding of the role of Kar4p in regulating meiosis and provide key insights into a potential mechanism of Kar4p's later meiotic function that is independent of mRNA methylation.

KAR4, the yeast homolog of the mammalian mRNA N6A-methyltransferase complex component METTL14, is required for two disparate developmental programs in Saccharomyces cerevisiae: mating and meiosis. To understand KAR4's role in yeast mating and meiosis, we used a genetic screen to isolate 25 function-specific mutant alleles, which map to non-overlapping surfaces on a predicted structure of the Kar4 protein (Kar4p). Most of the mating-specific alleles (Mat-) abolish Kar4p's interaction with the transcription factor Ste12p, indicating that Kar4p's mating function is through Ste12p. In yeast, the mRNA methyltransferase complex was previously defined as comprising Ime4p (Kar4p's paralog and the homolog of mammalian METTL3), Mum2p (homolog of mammalian WTAP), and Slz1p (MIS), but not Kar4p. During meiosis, Kar4p interacts with Ime4p, Mum2p, and Slz1p. Moreover, cells lacking Kar4p have highly reduced levels of mRNA methylation during meiosis indicating that Kar4p is a key member of the methyltransferase complex, as it is in humans. Analysis of kar4Δ/Δ and 7 meiosis-specific alleles (Mei-) revealed that Kar4p is required early in meiosis, before initiation of S-phase and meiotic recombination. High copy expression of the meiotic transcriptional activator IME1 rescued the defect of these Mei- alleles. Surprisingly, Kar4p was also found to be required at a second step for the completion of meiosis and sporulation. Over-expression of IME1 in kar4Δ/Δ permits pre-meiotic S-phase, but most cells remained arrested with a monopolar spindle. Analysis of the function-specific mutants revealed that roughly half became blocked after premeiotic DNA synthesis and did not sporulate (Spo-). Loss of Kar4p's Spo function was suppressed by overexpression of RIM4, a meiotic translational regulator. Overexpression of IME1 and RIM4 together allowed sporulation of kar4Δ/Δ cells. Taken together, these data suggest that Kar4p regulates meiosis at multiple steps, presumably reflecting requirements for methylation in different stages of meiotic gene expression.

Abstract Cholinergic dysfunction has been implicated in the pathophysiology of psychosis and psychiatric disorders such as schizophrenia, depression, and bipolar disorder. The basal forebrain (BF) cholinergic nuclei, defined as cholinergic cell groups Ch1-3 and Ch4 (Nucleus Basalis of Meynert; NBM), provide extensive cholinergic projections to the rest of the brain. Here, we examined microstructural neuroimaging measures of the cholinergic nuclei in patients with untreated psychosis (~31 weeks of psychosis, 0.05). Case-control differences in qT1 and AxD were observed in the Ch1-3, with increased qT1 (reflecting reduced myelin content) and AxD (reflecting reduced axonal integrity). We found clinical correlates between left NBM qT1 with manic symptom severity, and AxD with negative symptom burden in FEP. Intracortical and subcortical myelin maps were derived and correlated with BF myelin. BF-cortical and BF-subcortical myelin correlations demonstrate known projection patterns from the BF. Using data from the Allen Human Brain Atlas, cholinergic nuclei showed significant enrichment for schizophrenia and depression-related genes. Cell-type specific enrichment indicated enrichment for cholinergic neuron markers as expected. Further relating the neuroimaging correlations to transcriptomics demonstrated links with cholinergic receptor genes and cell type markers of oligodendrocytes and cholinergic neurons, providing biological validity to the measures. These results provide genetic, neuroimaging, and clinical evidence for cholinergic dysfunction in schizophrenia.

Abstract Searching for the ground state of a given system is one of the most fundamental and classical questions in scientific research fields. However, when the system is complex and large, it often becomes an intractable problem; there is essentially no possibility of finding a global energy minimum state with reasonable computational resources. Recently, a novel method based on deep learning techniques was devised as an innovative optimization method to estimate the ground state. We apply this method to one of the most complicated spin-ice systems, aperiodic Penrose P3 patterns. From the results, we discover new configurations of topologically induced emergent frustrated spins, different from those previously known. Additionally, a candidate of the ground state for a still unexplored type of Penrose P3 spin-ice system is first proposed through this study. We anticipate that the capabilities of the deep learning techniques will not only improve our understanding on the physical properties of artificial spin-ice systems, but also bring about significant advances in a wide range of scientific research fields requiring computational approaches for optimization.

This study investigates how the enhanced loading of microphysically and radiatively active aerosol particles impacts tropical sea breeze convective systems and whether these impacts are modulated by the many environments that support these cloud systems. Comparisons of two 130-member pristine and polluted ensembles demonstrate that aerosol direct effects reduce the surface incoming shortwave radiation and the surface outgoing longwave radiation. Changes in the ensemble median values of the surface latent heat flux, the mixed layer depth, the mixed layer convective available potential energy, the maximum inland sea breeze extent, and the sea breeze frontal lift suggest that enhanced aerosol loading generally creates a less favorable environment for sea breeze convective systems. However, the sign and magnitude of these aerosol-induced changes are occasionally modulated by the surface, wind, and low-level thermodynamic conditions. As reduced surface fluxes and instability inhibit the convective boundary layer development, updraft velocities of the daytime cumulus convection developing ahead of the sea breeze front are robustly reduced in polluted environments across the environments tested. Statistical emulators and variance-based sensitivity analyses reveal that the soil saturation fraction is the most important environmental factor contributing to the updraft velocity variance of this daytime cumulus convection, but that it becomes a less important contributor with enhanced aerosol loading. It is also demonstrated that increased aerosol loading generally results in a weakening of the sea-breeze-initiated convection. This suppression is particularly robust when the sea-breeze-initiated convection is shallower and, hence, restricted to warm rain processes. While the less favorable convective environment arising from aerosol direct effects also restricts the development of sea-breeze-initiated deep convection in some cases, the response does appear to be environmentally modulated, with some cases producing stronger convective updrafts in more polluted environments. Sea breeze precipitation is ubiquitously suppressed with enhanced aerosol loading across all of the environments tested; however, the magnitude of this suppression remains a function of the initial environment. Altogether, our results highlight the importance of evaluating both direct and indirect aerosol effects on convective systems under the wide range of convective environments.

Purpose: Pigmented paravenous chorioretinal atrophy (PPCRA) is a rare retinal disease with inflammatory or infectious associations affecting the retinal pigment epithelium (RPE) and choriocapillaris. While the clinical manifestations and imaging findings are well-documented in the literature, no reports exist describing potential biomarkers of intraocular inflammation or ischemia in this condition, such as the presence of posterior vitreous cortex hyalocytes. Observations: We report a case of a 26-year-old female who presented with progressive peripheral vision loss in both eyes over one year. Dilated fundus examination revealed bilateral, asymmetric bone-spicule pigmentary changes along the retinal veins, which appeared more advanced in the left eye. Optical coherence tomography (OCT) revealed the presence of numerous hyalocytes in both eyes 3 μm anterior to the inner limiting membrane (ILM). The morphology of the hyalocytes differed between the two eyes, suggesting different levels of activation related to the stage of the disease. Specifically, the left eye, with more advanced disease, exhibited hyalocytes with multiple elongated processes consistent with a quiescent state, whereas the right eye, with the less advanced disease state, exhibited amoeboid-appearing hyalocytes suggestive of more active inflammation. Conclusions: This case illustrates how hyalocyte morphology may reflect the underlying activity of an indolent retinal degeneration and provide a useful biomarker of disease progression.

The Comprehensive Automobile Research System (CARS) is an open-source Python-based automobile emissions inventory model designed to efficiently estimate high-quality emissions from motor vehicle emission sources. It can estimate air pollutant, greenhouse gas, and air toxin criteria at any spatial resolution based on the spatiotemporal resolutions of input datasets. The CARS is designed to utilize local vehicle activity data, such as vehicle travel distance, road-link-level network geographic information system (GIS) information, and vehicle-specific average speed by road type, to generate an automobile emissions inventory for policymakers, stakeholders, and the air quality modeling community. The CARS model adopted the European Environment Agency's on-road automobile emissions calculation methodologies to estimate the hot exhaust, cold start, and evaporative emissions from on-road automobile sources. It can optionally utilize average speed distribution (ASD) of all road types to reflect more realistic vehicle speed variations. In addition, through utilizing high-resolution road GIS data, the CARS can estimate the road-link-level emissions to improve the inventory's spatial resolution. When we compared the official 2015 national mobile emissions from Korea's Clean Air Policy Support System (CAPSS) against the ones estimated by the CARS, there is a significant increase in volatile organic compounds (VOCs) (33 %) and carbon monoxide (CO) (52 %) measured, with a slight increase in fine particulate matter (PM2.5) (15 %) emissions. Nitrogen oxide (NOx) and sulfur oxide (SOx) measurements are reduced by 24 % and 17 %, respectively, in the CARS estimates. The main differences are driven by different vehicle activities and the incorporation of road-specific ASD, which plays a critical role in hot exhaust emission estimates but was not implemented in Korea's CAPSS mobile emissions inventory. While 52 % of vehicles use gasoline fuel and 35 % use diesel, gasoline vehicles only contribute 7.7 % of total NOx emissions, whereas diesel vehicles contribute 85.3 %. However, for VOC emissions, gasoline vehicles contribute 52.1 %, whereas diesel vehicles are limited to 23 %. Diesel buses comprise only 0.3 % of vehicles and have the largest contribution to NOx emissions (8.51 % of NOx total) per vehicle due to having longest daily vehicle kilometer travel (VKT). For VOC emissions, compressed natural gas (CNG) buses are the largest contributor at 19.5 % of total VOC emissions. For primary PM2.5, more than 98.5 % is from diesel vehicles. The CARS model's in-depth analysis feature can assist government policymakers and stakeholders in developing the best emission abatement strategies.

Abstract We propose a strategy for optimizing physical quantities based on exploring in the latent space of a variational autoencoder (VAE). We train a VAE model using various spin configurations formed on a two-dimensional chiral magnetic system. Three optimization algorithms are used to explore the latent space of the trained VAE. The first algorithm, the single-code modification algorithm, is designed for improving the local energetic stability of spin configurations to generate physically plausible spin states. The other two algorithms, the genetic algorithm and the stochastic algorithm, aim to optimize the global physical quantities, such as topological index, magnetization, energy, and directional correlation. The advantage of our method is that various optimization algorithms can be applied in the latent space containing the abstracted representation constructed by the trained VAE model. Our method based on latent space exploration is utilized for efficient physical quantity optimization.

Antimicrobial resistance (AMR) is a global threat fueled by incorrect (and overuse) of antibiotic drugs, giving rise to the evolution of multi- and extreme drug-resistant bacterial strains. The longer time to antibiotic administration (TTA) associated with the gold standard bacterial culture method has been responsible for the empirical usage of antibiotics and is a key factor in the rise of AMR. While polymerase chain reaction (PCR) and other nucleic acid amplification methods are rapidly replacing traditional culture methods, their scope has been restricted mainly to detect genotypic determinants of resistance and provide little to no information on phenotypic susceptibility to antibiotics. The work presented here aims to provide phenotypic antimicrobial susceptibility testing (AST) information by pairing short growth periods (~3–4 h) with downstream PCR assays to ultimately predict minimum inhibitory concentration (MIC) values of antibiotic treatment. To further simplify the dual workflows of the AST and PCR assays, these reactions are carried out in a single-vessel format (PCR tube) using novel lyophilized reagent beads (LRBs), which store dried PCR reagents along with primers and enzymes, and antibiotic drugs separately. The two reactions are separated in space and time using a melting paraffin wax seal, thus eliminating the need to transfer reagents across different consumables and minimizing user interactions. Finally, these two-step single-vessel reactions are multiplexed by using a microfluidic manifold that allows simultaneous testing of an unknown bacterial sample against different antibiotics at varying concentrations. The LRBs used in the microfluidic system showed no interference with the bacterial growth and PCR assays and provided an innovative platform for rapid point-of-care diagnostics (POC-Dx).

Abstract Background Postoperative seroma is the most common donor site complication following anterolateral thigh (ALT) free flap harvest for head and neck reconstruction. The utility of novel microporous polysaccharide hemospheres (MPH) has not been studied as a hemostatic agent in this setting. Methods Prospective, single‐blind, randomized controlled trial of patients undergoing fasciocutaneous ALT harvest for head and neck reconstruction at a tertiary academic medical center between April 2018 and February 2020. The intervention (MPH) group received 3 g of topical MPH to the ALT donor site prior to closure whereas the control group did not receive application of MPH. Outcomes included total drain output (ml), drain output during postoperative days (POD) 1–3 alone, drain duration (days), and incidence of donor site hematoma, seroma, or infection. Results Twenty‐nine patients were randomized to the MPH group and 26 to the control group. For MPH and control groups, mean total drain output was 284.7 ± 153.0 ml versus 317.9 ± 177.6 ml (p = .527), mean POD 1–3 drain output alone was 169.3 ± 88.8 ml versus 157.9 ± 78.7 ml (p = .749), and drain duration was 5.9 ± 1.5 days versus 6.5 ± 1.6 days (p = .144), respectively. There was no significant difference in seroma (p = .733), hematoma (p = .492), or infection (p = 1.000). Drain output was not significantly influenced by gender, age, body weight, or smoking habits. Conclusion MPH administration to ALT free flap donor sites did not significantly improve drain output, hematoma formation, or seroma formation. Level of Evidence 2

Abstract The properties of complicated magnetic domain structures induced by various spin–spin interactions in magnetic systems have been extensively investigated in recent years. To understand the statistical and dynamic properties of complex magnetic structures, it is crucial to obtain information on the effective field distribution over the structure, which is not directly provided by magnetization. In this study, we use a deep learning technique to estimate the effective fields of spin configurations. We construct a deep neural network and train it with spin configuration datasets generated by Monte Carlo simulation. We show that the trained network can successfully estimate the magnetic effective field even though we do not offer explicit Hamiltonian parameter values. The estimated effective field information is highly applicable; it is utilized to reduce noise, correct defects in the magnetization data, generate spin configurations, estimate external field responses, and interpret experimental images.

ObjectivesPrediction of pediatric emergency department (PED) workload can allow for optimized allocation of resources to improve patient care and reduce physician burnout. A measure of PED workload is thus required, but to date no variable has been consistently used or could be validated against for this purpose. Billing codes, a variable assigned by physicians to reflect the complexity of medical decision making, have the potential to be a proxy measure of PED workload but must be assessed for reliability. In this study, we investigated how reliably billing codes are assigned by PED physicians, and factors that affect the inter-rater reliability of billing code assignment.MethodsA retrospective cross-sectional study was completed to determine the reliability of billing code assigned by physicians (n = 150) at a quaternary-level PED between January 2018 and December 2018. Clinical visit information was extracted from health records and presented to a billing auditor, who independently assigned a billing code-considered as the criterion standard. Inter-rater reliability was calculated to assess agreement between the physician-assigned versus billing auditor-assigned billing codes. Unadjusted and adjusted logistic regression models were used to assess the association between covariables of interest and inter-rater reliability.ResultsOverall, we found substantial inter-rater reliability (AC2 0.72 [95% CI 0.64-0.8]) between the billing codes assigned by physicians compared to those assigned by the billing auditor. Adjusted logistic regression models controlling for Pediatric Canadian Triage and Acuity scores, disposition, and time of day suggest that clinical trainee involvement is significantly associated with increased inter-rater reliability.ConclusionsOur work identified that there is substantial agreement between PED physician and a billing auditor assigned billing codes, and thus are reliably assigned by PED physicians. This is a crucial step in validating billing codes as a potential proxy measure of pediatric emergency physician workload.

Abstract Chronic thromboembolic pulmonary hypertension (CTEPH) is believed to involve both vascular obstruction and vasoconstriction; hence, pulmonary vasodilators such as riociguat may be beneficial. Acute vasoreactivity testing (AVT) is seldom performed routinely in CTEPH patients, so there is limited understanding of the frequency and significance of an acute vasodilator response. Systematic vasodilator testing with oxygen (O2) and oxygen plus inhaled nitric oxide (O2 + iNO) was performed as part of the Pulmonary Vascular Disease Omics (PVDOMICS) NHLBI project, providing an opportunity to examine AVT responses in CTEPH. Patients with CTEPH enrolled in PVDOMICS (n = 49, 40 with prevalent CTEPH [82%]) underwent right heart catheterization including AVT with O2 and O2 + iNO. Hemodynamics were obtained at baseline and with each challenge. Fourteen of 49 patients (29%) had >20% drop in pulmonary vascular resistance (PVR) with O2. With O2 + iNO, 30/49 (61%) had >20% drop in PVR, 20% had >20% drop in mean pulmonary artery pressure (mPAP) and PVR, and 8% had >10 mmHg decline in mPAP to mPAP

Efficient sampling strategies expedite behavioral data collection. While multiple studies have evaluated sampling strategies for core behaviors in cattle, few have focused on social interactions. To identify sampling strategies that accurately captured cattle social behaviors and brush use feedlot steers (n = 3 pens; 9 steers/pen) were observed from 8:00 to 17:00. Average bout duration (sec), total duration per day (sec), and bout frequency were recorded for allogrooming, bar licking, tongue rolling, and brush utilization. Frequency was recorded for headbutting and mounting. Data was extracted from continuous observation datasets using eight different sampling strategies and the results subsequently compared. Differences among sampling strategies were evaluated using a non-parametric One-Way ANOVA Kruskal-Wallis Test. Pearson correlation evaluated the strength of association between a specific sampling strategy and continuous observations. Bout duration for allogrooming (P > 0.65), bar licking (P > 0.60), tongue rolling (P > 0.99), brush use (P > 0.99), and mounting frequency (P > 0.70) did not differ from continuous observations. Tongue rolling (r2 > 0.95, P 0.70, P < 0.0003) were best captured when cattle were observed from 08:00 to 14:00. When cattle were continuously observed from 08:00 to 14:00 or for 15 minutes every 30 minutes, allogrooming (P > 0.2) (frequency, duration), bar licking (P > 0.95) (frequency, duration), brush use (P > 0.1) (frequency, duration), heat butt (P > 0.30) (frequency), or tongue rolling (P > 0.30) (frequency, duration) did not differ from continuous observations. Observing cattle for 15 minutes every 30 minutes yielded the highest accuracy for all behavioral metrics and was considered the most effective strategy for comprehensively evaluating cattle social behavior (r2 > 75; P < 0.05). These results provide insight into accurate and efficient sampling strategies that expedite social behavior data collection in cattle and will facilitate efficient generation of new knowledge regarding cattle social behaviors.

Renal cell carcinoma metastases to the testes are a rare occurrence, with less than 50 described in the literature. We describe a man who presented with a metastasis in his contralateral testicle five years after nephrectomy for clear cell renal cell carcinoma, as well as a review of the available literature. This case highlights the diagnostic challenges associated with this presentation.

Social robots are marketed as human tools promising us a better life. This marketing strategy commodifies not only the labor of care but the caregiver as well, conjuring a fantasy of technoliberal futurism that echoes a colonial past. Against techno-utopian fantasies of a good life as one involving engineered domestic help, I draw here on the techno-dystopian television show Humans (stylized HUMⱯNS) to suggest that we should find our desires for such help unsettling. At the core of my argument is a return of the “uncanny valley” problem, from its reformulation as an engineering/design problem to its origins as a psychosocial symptom of an unresolved, traumatic past. I conclude that our sense of the uncanny may be best understood as a moral capacity that should be honed rather than evaded.

Alterations in metabolism and bioenergetics are hypothesized in the mechanisms leading to pulmonary vascular remodeling and heart failure in pulmonary hypertension (PH). To test this, we performed metabolomic analyses on 30 PH individuals and 12 controls. Furthermore, using 2‐[18F]fluoro‐2‐deoxy‐D‐glucose positron emission tomography, we dichotomized PH patients into metabolic phenotypes of high and low right ventricle (RV) glucose uptake and followed them longitudinally. In support of metabolic alterations in PH and its progression, the high RV glucose group had higher RV systolic pressure (p