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— The legume genus, Glycine, which includes the Asian annual cultivated soybean, also includes a group of Australian perennial species comprising the subgenus Glycine. Because the subgenus Glycine represents the tertiary gene pool for one of the world’s most important crops, the group has been the target of collection and study for decades, resulting in a steady growth in the number of formally recognized species, from six in the 1970s to over 20 at present, as well as a number of additional informal taxa. These studies have also produced a system of nuclear diploid “genome groups” corresponding to clades in molecular phylogenies. The aptly named G. remota is known only from a single isolated population in the Kimberley region of northwestern Australia and was named only in 2015. The species is unique within Glycine in having unifoliolate leaves; its discoverers hypothesized that G. remota, if diploid, is related to species of the I-genome that are also native to the Kimberley region. We produced low coverage short-read genome sequencing data from an herbarium specimen of G. remota. Genome size estimates from the sequencing data suggests that G. remota is a diploid, while ploidy estimation is inconclusive likely due to the history of whole genome duplication in Glycine. Phylogenomic analyses of genome-wide SNPs, as well as phylogenetic analyses of the low copy nuclear gene (histone H3D), the entire ribosomal RNA cistron, and the internal transcribed spacer all placed the species unequivocally in the diploid I-genome clade. A complete plastome sequence was also generated and its placement with a plastome phylogeny is also consistent with membership in the I-genome.

Seven different anti–PD-1 and PD-L1 mAbs are now widely used in the United States to treat a variety of cancer types, but no clinical trials have compared them directly. Furthermore, because many of these Abs do not cross-react between mouse and human proteins, no preclinical models exist in which to consider these types of questions. Thus, we produced humanized PD-1 and PD-L1 mice in which the extracellular domains of both mouse PD-1 and PD-L1 were replaced with the corresponding human sequences. Using this new model, we sought to compare the strength of the immune response generated by Food and Drug Administration–approved Abs. To do this, we performed an in vivo T cell priming assay in which anti–PD-1/L1 therapies were given at the time of T cell priming against surrogate tumor Ag (OVA), followed by subsequent B16-OVA tumor challenge. Surprisingly, both control and Ab-treated mice formed an equally robust OVA-specific T cell response at the time of priming. Despite this, anti–PD-1/L1-treated mice exhibited significantly better tumor rejection versus controls, with avelumab generating the best protection. To determine what could be mediating this, we identified the increased production of CX3CR1+PD-1+CD8+ cytotoxic T cells in the avelumab-treated mice, the same phenotype of effector T cells known to increase in clinical responders to PD-1/L1 therapy. Thus, our model permits the direct comparison of Food and Drug Administration–approved anti–PD-1/L1 mAbs and further correlates successful tumor rejection with the level of CX3CR1+PD-1+CD8 + T cells, making this model a critical tool for optimizing and better utilizing anti–PD-1/L1 therapeutics.

We aimed to establish a relationship between the amount of Montgomery tubercles (MTs) per nipple-areolar complex (NAC) given patient characteristics such as age, BMI, menopausal status, race/ethnicity, and NAC size to better inform current 3D NAC tattooing practices.Preoperative photographs of patients pursuing breast reconstruction after mastectomy in 2010 through 2018 were reviewed. The number of MTs on each native NAC was quantified. The impact of patient factors on the quantity of MTs was evaluated via Pearson correlation and bivariate analyses.Two hundred and eleven patients (399 breasts) were reviewed. On average, patients had 5.0 ± 5.2 MTs (range, 0-25 MTs). Number of MTs did not correlate with patient age, BMI, or NAC size. Premenopausal females were more likely than postmenopausal females to have a greater number of MTs per breast (p-value = 0.0183).Postmastectomy patients desiring a more "youthful" NAC may consider additional MTs when pursuing 3D NAC tattooing.

Phenolic compounds are a major type of phytochemicals and among them, phenolic acids are the most potent biologically active compounds. Cashew nutshell liquid (CNSL) is a by-product that serves as a rich source of phenolic acids. Gallic acid is a major category of phenolic acids and is notable for its antimicrobial, antiviral, and antifungal properties as well as for industrial applications. The global annual requirement of gallic acid is around 8000 tonnes. Currently, the industrial production of gallic acid is facilitated by acid hydrolysis of naturally derived gGallotannins. Since the present industrial process demands higher production costs along with low product yield and release of huge volumes of toxic effluents as by-products, an enzyme dependant eco-friendly production process for gallic acid is mandatory. Microorganisms can serve as substitutes for gallic acid production since they are endowed with the capability to degrade tannic acid by producing tannase. The bacteria Streptomyces olivochromogeneswas found to be capable of producing gallic acid in the present research. The gallic acid thus produced was found to possess effective antioxidant properties, thereby preventing protein denaturation in cells. The viability of the cancer cells was found to be significantly reduced. Reduction in oxidative stress along with upregulation of the apoptotic gene BAX coupled with the downregulation of the anti-apoptotic gene BCL2 is supposed to be the underlying mechanisms behind the anticancer activity of gallic acid. Our research manifests the therapeutic efficiency, especially the anticancer property, of gallic acid produced by Streptomyces olivochromogenes.

It is well established that an elevated potassium level (hyperkalemia) is associated with a risk of adverse events including morbidity, mortality and healthcare system cost. Hyperkalemia is commonly encountered in many chronic conditions including kidney disease, diabetes and heart failure. Furthermore, hyperkalemia may result from the use of renin-angiotensin-aldosterone system inhibitors (RAASi), which are disease-modifying treatments for these conditions. Therefore, balancing the benefits of optimizing treatment with RAASi while mitigating hyperkalemia is crucial to ensure patients are optimally treated. In this review, we will briefly discuss the definition, causes, epidemiology and consequences of hyperkalemia. The majority of the review will be focused on management of hyperkalemia in the acute and chronic setting, emphasizing contemporary approaches and evolving data on the relevance of dietary restriction and the use of novel potassium binders.

Phosphate rock, pre-concentrated phosphate ore, is the primary raw material for the production of mineral phosphate fertilizer. Phosphate rock is among the fifth most mined materials on earth, and it is also mined and processed to fertilizers in East Africa. Phosphate ore can contain relevant heavy metal impurities such as toxic cadmium and radiotoxic uranium. Prolonged use of phosphate rock powder as a fertilizer and application of mineral fertilizers derived from phosphate rock on agricultural soils can lead to an accumulation of heavy metals that can then pose an environmental risk. This work assesses the uranium concentrations in four major phosphate rocks originating from East Africa and four mineral phosphate fertilizers commonly used in the region. The concentration measurements were performed using energy-dispersive X-ray fluorescence spectrometry. The results showed that the uranium concentration in phosphate rock ranged from as low as 10.7 mg kg−1 (Mrima Hill deposit, Kenya) to as high as 631.6 mg kg−1 (Matongo deposit, Burundi), while the concentrations in phosphate fertilizers ranged from 107.9 for an imported fertilizer to 281.0 mg kg−1 for a local fertilizer produced from Minjingu phosphate rock in Tanzania. In this context, it is noteworthy that the naturally occurring concentration of uranium in the earth crust is between 1.4 and 2.7 mg kg−1 and uranium mines in Namibia commercially process ores with uranium concentrations as low as 100–400 mg kg−1. This study thus confirms that East African phosphate rock, and as a result the phosphate fertilizer produced from it can contain relatively high uranium concentrations. Options to recover this uranium are discussed, and it is recommended that public–private partnerships are established that could develop economically competitive technologies to recover uranium during phosphate rock processing at the deposits with the highest uranium concentrations.

PurposeThis case study considered the relationship between collective efficacy, trust and principal leadership within Stonefields School, a unique primary school in New Zealand. Methods: A total of 24 surveys and 32 interviews were conducted among teachers, administrators, and staff based on Tschannen-Moran’s efficacy (both self- and collective) and trust scales. Findings: Survey results revealed a significant positive relationship between self-efficacy and collective efficacy. In addition, faculty and staff at this school demonstrated high trust in their principal and clients (students and parents) compared to other schools but average trust among teachers, as well as higher overall collective efficacy. Qualitative analysis of faculty and staff interviews revealed 14 facets that were grouped into four themes: cultural, intrinsic, relational, and transactional. Findings also included a connection between trust and collective efficacy and a significant correlation with the principal’s leadership role in fostering both, as well as a connection between the 14 facets and efficacy, trust, and enabling school structures. Implications: Principal’s effect on student achievement is indirect, therefore, principals must focus their efforts on improving the school culture and developing a shared vision centered on student achievement. Collective efficacy and trust are positively associated with student achievement and are two variables that can be influenced by principals’ leadership and facilitated by district administrators, superintendents and school board members.

Beyond the four basic language skills – speaking, listening, reading and writing – other communication skills, including body language and eye contact, are important for communication and should be included as rating criteria in the assessment of interaction. Also, using technology in novel ways for purposes such as remote assessment is possible in the 21st century. Professor Natsumi Onaka, Associate Professor Daniel Newbury and Associate Professor Jacob B Petersen are striving to create a cost-effective peer-to-peer interaction English assessment system that supports foreign language education and testing through widely-used technology and an assessment system that places interaction as central to effective communication. In the context of globalisation, Onaka, International Education Center, Iwate University, Japan, believes that the focus of English education should be meaningful interaction rather than rote memorization of grammar and vocabulary for testing purposes. She is heading up this research and is a proponent of 'spontaneous interaction'. She and the team are developing a simple and standardised method for evaluating English-speaking skills by creating tasks and related rubrics focused on interactional situations. Videos of a subject's English speech and communication are recorded and stored in a Learning Management System (LMS) and then evaluated by a third-party, off-site evaluator. The focus is on CEFR (Common European Framework of Reference for Languages) A2 to B1 level speaking skills. By focusing on novice-level interaction, the researchers are able to observe nascent interactional competence among university-aged students and they are attempting to apply some rating criteria to identify differences in ability. By using video as the text format, non-verbal communication such as gestures can be taken into consideration, along with important traditional factors such as grammatical accuracy.

Alcohol intoxication is a prevalent feature of university life and campus sexual assault cases. While previous research has examined how students perceive obvious cases of assault, less is known about how students evaluate more ambiguous sexual scenarios—such as those including two intoxicated individuals. In three survey experiments with college students (N = 990), we examined how manipulating the intoxication (sober vs. drunk) of a man accused of assault (the respondent) influenced perceptions of a hook-up scenario involving an intoxicated woman. Although university policies indicate that respondent intoxication should not influence evaluations of these scenarios, we hypothesized that students would be influenced by cues of respondent intoxication when making judgments of the hook-up and the individuals involved. Students reported that the hook-up was a sexual assault more often when the respondent was sober compared to when he was drunk, and they found sober respondents more responsible for the encounter than drunk respondents. Although effect sizes fluctuated across studies, an internal meta-analysis found evidence of significant (but modest) aggregate effects. Furthermore, perceptions of the respondent’s agency mediated the effects of intoxication on perceptions of respondent responsibility (Studies 2 & 3). We also manipulated whether the respondent should have reasonably known the complainant was drunk (Studies 1 & 2) and whether the complainant or the complainant’s friend reported the incident (Study 3), but these manipulations had little effect on students’ perceptions of the vignettes. We discuss how our findings can guide future research and consider implications of our results for university stakeholders.

General control nonderepressible 2 (GCN2) protein kinase is a cellular stress sensor within the tumor microenvironment (TME), whose signaling cascade has been proposed to contribute to immune escape in tumors. Herein, we report the discovery of cell-potent GCN2 inhibitors with excellent selectivity against its closely related Integrated Stress Response (ISR) family members heme-regulated inhibitor kinase (HRI), protein kinase R (PKR), and (PKR)-like endoplasmic reticulum kinase (PERK), as well as good kinome-wide selectivity and favorable PK. In mice, compound

The effect of postoperative sensation on quality-of-life (QoL) following nipple-sparing mastectomy (NSM) with implant-based reconstruction is not well described. We evaluated the impact of breast and nipple sensation on patient QoL by using BREAST-Q.Patients undergoing NSM with implant reconstruction from 2008 to 2020 were mailed a survey to characterize their postoperative breast and nipple sensation. BREAST-Q metrics were compared between totally numb patients and those with sensation.A total of 349 patients were included. Overall, 131 (38%) responded; response rates regarding breast and nipple sensation were 36% (N = 124/349) and 34% (N = 117/349). Median time from surgery to survey completion was 6 years. The majority had bilateral procedures (101, 77%), including direct-to-implant (99, 76%) and tissue expander (32, 24%) reconstruction. Regarding breast sensation, the majority of patients reported their reconstructed breasts as totally numb (47, 38%) or much less sensation than before surgery (59, 48%). Regarding nipple sensation, the majority of patients reported their nipples were totally numb (67, 57%) or had much less sensation than before surgery (37, 32%). Total numbness of reconstructed breasts resulted in a significantly lower chest physical well-being (mean score: 73.5 vs. 81.2, respectively, P = 0.048). Total numbness of postoperative nipple(s) resulted in significantly lower chest physical (mean score: 74.8 vs. 85.2, respectively, P = 0.007), psychosocial (mean score 77.4 vs. 84.4, respectively, P = 0.041), and sexual well-being (mean score: 55.7 vs. 68.3, respectively, P = 0.002).Long-term breast and nipple sensation are significantly diminished after NSM with implant reconstruction. Patients with preserved sensation experience better physical, psychosocial, and sexual well-being.

Platelets are subcellular anucleate components of blood primarily responsible for initiating and maintaining hemostasis. After injury to a blood vessel, platelets can be activated via several pathways, resulting in changed shape, adherence to the injury site, aggregation to form a plug, degranulation to initiate activation in other nearby platelets, and acceleration of thrombin formation to convert fibrinogen to fibrin before contracting to strengthen the clot. Platelet function assays use agonists to induce and measure one or more of these processes to identify alterations in platelet function that increase the likelihood of bleeding or thrombotic events. In severe trauma, these assays have revealed that platelet dysfunction is strongly associated with poor clinical outcomes. However, to date, the mechanism(s) causing clinically significant platelet dysfunction remain poorly understood. We review the pros, cons, and evidence for use of many of the popular assays in trauma, discuss limitations of their use in this patient population, and present approaches that can be taken to develop improved functional assays capable of elucidating mechanisms of trauma-induced platelet dysfunction. Platelet dysfunction in trauma has been associated with need for transfusions and mortality; however, most of the current platelet function assays were not designed for evaluating trauma patients, and there are limited data regarding their use in this population. New or improved functional assays will help define the mechanisms by which platelet dysfunction occurs, as well as help optimize future treatment.

The chloramination of bromide containing waters results in the formation of bromine containing haloamines: monobromamine (NH

The White Mountain magma series is the largest Mesozoic felsic igneous province on the eastern North American margin. Previous geochronology suggests that magmatism occurred over 50 m.y., with ages for the oldest units apparently coeval with the ca. 201 Ma Central Atlantic Magmatic Province, the flood basalt province associated with the end-Triassic mass extinction and the opening of the Atlantic Ocean. We use zircon U-Pb geochronology to show that emplacement of White Mountain magma series plutons was already underway at 207.5 Ma. The largest volcanic-plutonic complex, the White Mountain batholith, was emplaced episodically from ca. 198.5 Ma to ca. 180 Ma and is ~25 m.y. older than published ages suggest, and all samples we dated from the Moat Volcanics are between ca. 185 Ma and 180 Ma. The Moat Volcanics and the White Mountain batholith are broadly comagmatic, which constrains the age of a key Jurassic paleomagnetic pole. Our data indicate that a regional mantle thermal anomaly in eastern North America developed at least 5 m.y. prior to the main stage of Central Atlantic Magmatic Province flood basalt volcanism and suggest a geodynamic link between the White Mountain magma series and the Central Atlantic Magmatic Province.

Recent studies suggest climate change consensus messages may cause psychological reactance for conservatives. However, it remains unknown how much this reactance impacts the effectiveness of consensus messaging. Using data from a recent meta-analysis on climate change interventions, the current paper seeks to add context to the debate over reactance. We integrated data from 20 experiments (N = 19,200 participants) that test how consensus messages (compared to a control condition) impact climate change attitudes. The effect of consensus messages on attitudes was small yet statistically significant and positive (g = 0.09), and not significantly moderated by political affiliation. Moreover, the moderating role of political affiliation was similar for consensus messages compared to other interventions for climate change attitudes. While conservatives may experience resistance to consensus messages, there is little meta-analytic evidence that consensus messages backfire.

Spontaneous tumor shrinkage during wait-and-scan management of sporadic vestibular schwannoma is generally considered an uncommon phenomenon. However, most data informing this understanding stem from single-slice linear tumor measurements taken in the axial imaging plane. The objective of the current work was to characterize the regression capacity of sporadic vestibular schwannomas using volumetric tumor measurements.Retrospective cohort study using slice-by-slice, three-dimensional volumetric tumor measurements.Three tertiary referral centers.Patients with sporadic vestibular schwannoma.Wait-and-scan.Regression-free survival rates with regression defined as a decrease of at least 20% of the tumor volume.Among 952 patients undergoing a total of 3,505 magnetic resonance imaging studies during observation, 123 experienced volumetric tumor regression after diagnosis at a median of 1.2 years (interquartile range, 0.6-2.9 yr). Volumetric regression-free survival rates (95% confidence interval; number still at risk) at 1, 3, and 5 years after diagnosis were 94% (92-95%; 662), 86% (83-89%; 275), and 78% (73-82%; 132), respectively. Among 405 patients who demonstrated an initial period of tumor growth but continued wait-and-scan management, 48 experienced volumetric regression at a median of 1.2 years (interquartile range, 0.8-2.6 yr) after initial growth. Volumetric regression-free survival rates at 1, 3, and 5 years after initial growth were 94% (92-97%; 260), 84% (79-89%; 99), and 75% (67-83%; 43), respectively. Ultimately, only 82 of the 952 patients studied showed exclusively volumetric tumor regression (i.e., without any periods of tumor growth) by the time of last follow-up.Spontaneous volumetric tumor shrinkage during wait-and-scan management occurs more frequently than suggested by previous studies using linear tumor measurements and can even occur after previous episodes of documented tumor growth. These data further highlight the dynamic nature of vestibular schwannoma growth. To this end, the application of natural history data to patient management requires a nuanced approach that parallels the complex tumor behavior of vestibular schwannoma.

This study aimed to assess the durability of audiological outcomes after radiation and surgery in the management of vestibular schwannoma.Retrospective review.Tertiary academic center.Adults with sporadic vestibular schwannoma and serviceable hearing at the time of intervention.Gamma Knife, middle cranial fossa, or retrosigmoid approaches.Pure-tone audiometry and speech discrimination scores.Postintervention serviceable hearing (class A/B) was preserved in 70.4% (n = 130; mean follow-up, 3.31 yr; range, 0-15.25 yr). Of the 49 patients treated with radiation, 19 (39.6%) had serviceable hearing at last follow-up, compared with 38 (46.9% of 81) who underwent retrosigmoid (n = 36 [44.4%]) and middle cranial fossa (n = 45 [55.6%]) approaches (odds ratio [OR], 1.40; 95% confidence interval [CI], 0.67-2.82; p = 0.47). A matched analysis by age, tumor volume, and preintervention hearing (n = 38) also found no difference in hearing preservation (HP) likelihood between surgery and radiation (OR, 2.33; 95% CI, 0.24-35.91; p = 0.59). After initial HP, 4 (9.5%) surgical versus 10 (37.0%) radiated patients subsequently lost residual serviceable (A/B) hearing (OR, 0.18; 95% CI, 0.06-0.69; p = 0.01) at a mean 3.74 ± 3.58 and 4.73 ± 3.83 years after surgery and radiation, respectively. Overall, 5- and 10-year HP rates (A/B) after initially successful HP surgery were 84.4 and 63.0%, respectively. However, survival estimates declined to 48.9% at 5 years and 32.7% at 10 years when patients with immediate postoperative serviceable hearing loss were also included, which were comparable to radiation-HP rates at 5 and 10 years of 28.0 and 14.2%, respectively ( p = 0.75).After vestibular schwannoma intervention, overall HP was similar between radiated and surgical cohorts. However, when successful, surgical approaches offered more durable hearing outcomes at long-term follow-up.

The Lewisian Complex in northwest Scotland presents a record of the transition from the Neo-Archean to the Paleoproterozoic. However, this record is complicated by a long and varied history after peak metamorphism that has erased and/or partially reset much of the early history of the rocks. Such overprinting is a common feature of Archean granulites and poses a substantial problem when trying to understand the tectonic processes that were active prior to the onset of modern plate tectonics. By combining careful petrography with phase diagram modeling and a range of exchange thermometers we obtain the peak and retrograde temperature history of the Lewisian Complex from a single, well-preserved, representative sample of garnet-bearing mafic granulite. We present the application of high-resolution electron probe microanalysis (HR-EPMA) to characterize sub-micrometer orthopyroxene exsolution lamellae in clinopyroxene. We discuss ways to mitigate issues associated with HR-EPMA including surface contamination, beam drift, standards, and the need to correct for secondary fluorescence effects. The resulting compositions from our HR-EPMA analyses provide an independent measure of the retrograde temperature conditions and can also be used to back-calculate the compositions of clinopyroxene in the peak assemblage. We obtain peak metamorphic conditions for the Lewisian of >11 kbar and >1025 °C, and constrain subsequent metamorphic overprints to 850 °C (Grt-Cpx), 590 °C (Opx-Cpx), and 460 °C (Mag-Ilm). These peak and retrograde temperatures span the range of those found in the literature. Whereas recent phase equilibrium studies assume equilibrium among all preserved high-T minerals, this study considers microstructural and mineral-chemical evidence for corona formation that reflects post-peak decompression with partial equilibration at ~850 °C, as recognized in some earlier studies.

To assess endoscopic and microscopic ossiculoplasty audiometric outcomes.Retrospective review.Tertiary academic center.Adult patients who underwent ossiculoplasty with either partial ossicular replacement prosthesis (PORP) or total ossicular replacement prosthesis (TORP) from 2010 to 2019 with at least 1 year of audiometric follow-up were included.Endoscopic or microscopic ossiculoplasty.Postoperative air-bone gap (ABG) after at least 1 year.A total of 198 patients, 53.5% female, and a median age of 47.5 years, met inclusion criteria. 64.1% of patients were reconstructed with a PORP, and 31.8% were reconstructed using an endoscopic approach. The median audiometric follow-up was 27 months. The median postoperative ABG was 16.9 dB overall, 15.6 dB for PORP reconstruction, and 19.4 dB for TORP reconstruction (PORP versus TORP, p = 0.002). For TORP reconstructions, the median ABG for both endoscopic and microscopic TORP was 19.4 dB ( p = 0.92). For PORP reconstructions, the median ABG for endoscopic PORP was 12.3 dB compared with 16.3 dB for microscopic PORP ( p = 0.02). Using multivariate linear regression to predict postoperative PORP ABG, and controlling for age, prior ossiculoplasty, middle ear mucosal disease (granulation, fibrosis, polyposis), middle ear atelectasis, myringitis, contralateral middle ear disease, and use of byte prostheses, endoscopic PORP reconstruction was associated with improvement in ABG over the microscopic approach by 4.4 dB ( p = 0.04).For PORP ossiculoplasty procedures, endoscopic ossiculoplasty is associated with improved postoperative ABG compared with microscopic ossiculoplasty.

Behavioral problems, such as noncompliance and aggression, are a common referral reason to mental health services for young children. Behavioral parent training (BPT) is the leading intervention for addressing behavioral problems and leads to benefits in a variety of parental factors (e.g., parenting efficacy and parenting stress). While the COVID-19 pandemic dramatically shifted service delivery toward telehealth services, limited work has evaluated the effectiveness of BPT when delivered in a brief, group format through telehealth. The current retrospective chart review study evaluated the engagement to and preliminary effectiveness of a brief version of BPT delivered through telehealth to 64 families of 3- to 7-year-olds referred for behavioral problems. Families attended an average of 4.55 of 6 sessions and most families had two caregivers who engaged in the intervention. Significant reductions in caregivers’ report of children’s behavioral problems and improvements in parenting self-efficacy resulted. Future research and clinical implications are discussed.

Chronic musculoskeletal pain (CMP) is a significant burden for Persian Gulf War Veterans (GWVs), yet the causes are poorly understood. Brain structure abnormalities are observed in GWVs, however relationships with modifiable lifestyle factors such as physical activity (PA) are unknown. We evaluated gray matter volumes and associations with symptoms, PA, and sedentary time in GWVs with and without CMP. Ninety-eight GWVs (10 females) with CMP and 56 GWVs (7 females) controls completed T1-weighted magnetic resonance imaging, pain and fatigue symptom questionnaires, and PA measurement via actigraphy. Regional gray matter volumes were analyzed using voxel-based morphometry and were compared across groups using analysis of covariance (ANCOVA). Separate multiple linear regression models were used to test associations between PA intensities, sedentary time, symptoms, and gray matter volumes. Familywise cluster error rates were used to control for multiple comparisons (α = 0.05). GWVs with CMP reported greater pain and fatigue symptoms, worse mood, and engaged in less moderate-to-vigorous PA and more sedentary time than healthy GWVs (all p values < 0.05). GWVs with CMP had smaller gray matter volumes in the bilateral insula and larger volumes in the frontal pole (p < 0.05(adjusted)). Gray matter volumes in the left insula were associated with pain symptoms (r(partial) = 0.26, −0.29; p < 0.05(adjusted)). No significant associations were observed for either PA or sedentary time (p > 0.05(adjusted)). GWVs with CMP had smaller gray matter volumes within a critical brain region of the descending pain processing network and larger volumes within brain regions associated with pain sensation and affective processing, which may reflect pain chronification. SIGNIFICANCE STATEMENT The pathophysiology of chronic pain in Gulf War veterans is understudied and not well understood. In a large sample of Gulf War veterans, we report veterans with chronic musculoskeletal pain have smaller gray matter volumes in brain regions associated with pain regulation and larger volumes in regions associated with pain sensitivity compared with otherwise healthy Gulf War veterans. Gray matter volumes in regions of pain regulation were significantly associated with pain symptoms and encompassed the observed group brain volume differences. These results are suggestive of deficient pain modulation that may contribute to pain chronification.

Photonic Time crystals (PTC) arise in time-modulated media when the frequency of modulation of permittivity is on the order of twice the frequency of light and are manifested by the generation and amplification of so-called time reversed waves propagating in the direction opposite to the incoming light. Superficially, the observed phenomenon bears resemblance to the widely known phenomena of optical parametric generation (OPG) and amplification (OPA) using second or third order optical nonlinearities. I show that while indeed the same physical mechanism underpins both PTC and OPA , the difference arises from the boundary conditions. Thus , while dispersion for both PTC and OPA exhibit the same bandgap in momentum space, only in the case of PTC can one have propagation in that bandgap with exponential amplification. I also show that PTC can be engineered with both second and third order nonlinearities, and that rather unexpectedly, modulating permittivity on the ultrafast (few fs) rate is not a necessity, and that one can emulate all the PTC features using materials with a few picoseconds response time commensurate with the propagation time through the medium.

ImportanceClinical guidelines for patients with heart failure with reduced ejection fraction (HFrEF) strongly recommend treatment with a sodium-glucose cotransporter-2 inhibitor (SGLT2i) to reduce cardiovascular mortality or HF hospitalization. Nationwide adoption of SGLT2i for HFrEF in the US is unknown.ObjectiveTo characterize patterns of SGLT2i use among eligible US patients hospitalized for HFrEF.Design, Setting, and ParticipantsThis retrospective cohort study analyzed 49 399 patients hospitalized for HFrEF across 489 sites in the Get With The Guidelines–Heart Failure (GWTG-HF) registry between July 1, 2021, and June 30, 2022. Patients with an estimated glomerular filtration rate less than 20 mL/min/1.73 m2, type 1 diabetes, and previous intolerance to SGLT2i were excluded.Main Outcomes and MeasuresPatient-level and hospital-level prescription of SGLT2i at hospital discharge.ResultsOf 49 399 included patients, 16 548 (33.5%) were female, and the median (IQR) age was 67 (56-78) years. Overall, 9988 patients (20.2%) were prescribed an SGLT2i. SGLT2i prescription was less likely among patients with chronic kidney disease (CKD; 4550 of 24 437 [18.6%] vs 5438 of 24 962 [21.8%]; P P P P Conclusions and RelevanceIn this study, prescription of SGLT2i at hospital discharge among eligible patients with HFrEF was low, including among patients with comorbid CKD and T2D who have multiple indications for therapy, with substantial variation among US hospitals. Further efforts are needed to overcome implementation barriers and improve use of SGLT2i among patients with HFrEF.

Foldy is a cloud-based application that allows non-expert scientists to easily access and utilize advanced AI-based structural biology tools, including AlphaFold and DiffDock. Built on Kubernetes, it can be deployed by universities, departments, and labs without requiring hardware resources, but can also be configured to utilize available computers. Foldy enables scientists to predict the structure of proteins and complexes up to 3000 amino acids, visualize Pfam annotations, and dock ligands with AutoDock Vina and DiffDock.Our manuscript describes the user interface and deployment considerations of Foldy, as well as some of our applications. By democratizing access to sophisticated AI-based tools, Foldy can facilitate life science research and promote the wider adoption of structural bioinformatics tools. Our work demonstrates that even the most advanced tools can be made accessible to a broad audience through user-friendly platforms like Foldy, and we believe it will be a valuable resource for researchers across scientific disciplines. The public structures available on the Lawrence Berkeley Labs Foldy deployment can be viewed athttps://foldy.lbl.gov.Author SummaryFoldy is a cloud-based application that enables scientists to use AI-based structural biology tools such as AlphaFold and DiffDock without software expertise. Built on Kubernetes, it can be set up by universities, departments, and labs with no need for hardware resources. Foldy can predict the structure of proteins and complexes up to 3000 amino acids, visualize Pfam annotations, and dock ligands with AutoDock Vina and DiffDock. Our public structures can be viewed athttps://foldy.lbl.gov.Our manuscript highlights the user interface, deployment considerations, and product applications of Foldy. It’s an accessible solution for researchers who are not software experts and can handle the traffic of thousands of users and hundreds of thousands of protein structures and docked ligands. This makes advanced AI-based tools more widely available, paving the way for accelerating life science research.By developing an easy-to-use platform, our work demonstrates that even the most sophisticated AI-based tools can be made accessible to a wide audience. Foldy enables more scientists to draw from the rapidly growing field of structural biology, making it a valuable tool for researchers across scientific disciplines. We look forward to its adoption by the scientific community.

The intrinsic and acquired resistance to PD-1/PD-L1 immune checkpoint blockade is an important challenge for patients and clinicians because no reliable tool has been developed to predict individualized response to immunotherapy. In this study, we demonstrate the translational relevance of an ex vivo functional assay that measures the tumor cell killing ability of patient-derived CD8 T and NK cells (referred to as “cytotoxic lymphocytes,” or CLs) isolated from the peripheral blood of patients with renal cell carcinoma. Patient-derived PBMCs were isolated before and after nephrectomy from patients with renal cell carcinoma. We compared the efficacy of U.S. Food and Drug Administration (FDA)-approved PD-1/PD-L1 inhibitors (pembrolizumab, nivolumab, atezolizumab) and a newly developed PD-L1 inhibitor (H1A Ab) in eliciting cytotoxic function. CL activity was improved at 3 mo after radical nephrectomy compared with baseline, and it was associated with higher circulating levels of tumor-reactive effector CD8 T cells (CD11ahighCX3CR1+GZMB+). Treatment of PBMCs with FDA-approved PD-1/PD-L1 inhibitors enhanced tumor cell killing activity of CLs, but a differential response was observed at the individual-patient level. H1A demonstrated superior efficacy in promoting CL activity compared with FDA-approved PD-1/PD-L1 inhibitors. PBMC immunophenotyping by mass cytometry revealed enrichment of effector CD8 T and NK cells in H1A-treated PBMCs and immunosuppressive regulatory T cells in atezolizumab-treated samples. Our study lays the ground for future investigation of the therapeutic value of H1A as a next-generation immune checkpoint inhibitor and the potential of measuring CTL activity in PBMCs as a tool to predict individual response to immune checkpoint inhibitors in patients with advanced renal cell carcinoma.

Slope units are terrain partitions bounded by drainage and divide lines. They provide several advantages over gridded units in landslide-susceptibility modeling, such as better capturing terrain geometry, improved incorporation of geospatial landslide-occurrence data in different formats (e.g., point and polygon), and better accommodating the varying data accuracy and precision in landslide inventories. However, the use of slope units in regional (> 100 km2) landslide susceptibility studies remains limited due, in part, to prohibitive computational costs and/or poor reproducibility with current delineation methods. We introduce a computationally efficient algorithm for the parameter-free delineation of slope units. The algorithm uses geomorphic scaling laws to define the appropriate scaling of the slope units representative of hillslope processes, avoiding the costly parameter optimization procedures of other slope unit delineation methods. We then demonstrate how slope units enable more robust regional-scale landslide susceptibility maps.

SUMMARYThe function of many organs, including skeletal muscle, depends on its three-dimensional structure. Muscle regeneration therefore requires not only reestablishment of myofibers, but restoration of tissue architecture. Resident muscle stem cells (SCs) are essential for regeneration, but how SCs regenerate muscle architecture is largely unknown. We address this problem using genetic labeling of SCs and whole mount imaging to reconstruct in three dimensions muscle regeneration. Unexpectedly, we found that the residual basement membrane of necrotic myofibers is critical for promoting fusion and orienting regenerated myofibers and myofibers form via two distinct phases of fusion. Furthermore, the centralized myonuclei characteristic of regenerated myofibers are associated with myofibrillogenesis and permanently mark regenerated myofibers. Finally, we elucidate a new cellular mechanism for the formation of branched myofibers, a pathology characteristic of diseased muscle. We provide a new synthesis of the cellular events of regeneration and show these differ from those used during development.

Introduction It is time to provide heavier defense systems to U.S. Navy hospital ships. They serve vital functions in both the military and emergency management spaces. They provide medical support for combat operations and can also convey the empathy and generosity of the American people when used in humanitarian assistance and disaster relief response. Hospital ships are often key to success in scenarios that require the international deployment of resources and medical expertise. Hospital ships serve a dual purpose and hence are subject to regulations that do not address all wartime mission requirements and necessary defensive capabilities. The current U.S. Navy’s interpretation of the Geneva Conventions regarding the visibility, lack of defensive capabilities, and inability to use encrypted communications needlessly endangers medical platforms and personnel in the modern environment. Methods The authors (including senior author F.M.B.—a recognized (International Health Law expert) reviewed relevant literature and have evaluated the policies of belligerent parties in past and current conflicts. These increasingly appear to target civilian infrastructure including medical facilities and may increase the risk to hospital ships. This demonstrable current hybrid warfare appears to include purposeful attacks on health care facilities and as such hospital ships should have additional defensive measures. Results Hybrid warfare and its focus on civilian infrastructure and health care targets are highly visible in the acts of both state and non-state actors and may encourage others to purposefully target health care facilities and personnel. Evidence of this is seen in the current Russian invasion of Ukraine, where since the invasion a year ago 1,218 Ukrainian health facilities have been damaged, including 540 damaged hospitals, 173 of which were totally destroyed and turned into “piles of stones.” Conclusions In today’s conflicted global environment, the clear identification of hospital ships leaving them relatively undefended and denying encrypted communication is the folly of a bygone era. Hospital ships may be targeted because they are brightly lit soft targets that can deliver a large payoff by their destruction. It is time to adapt to the global reality and move on from the tradition of painting hospital ships white, adorning them with red crosses, keeping them unarmed, maintaining open communications, and illuminating them at night. The increasing threats from hybrid warfare and unprincipled adversaries to medical platforms and providers of health care demonstrate that hospital ships must be capable of self-defense. The U.S. Navy is designing new platforms for medical missions and the debate, no matter how uncomfortable, must now occur among major decision-makers to make them more tactical and defensible.

IntroductionProposals for embodied metaphor and embodied cognition have suggested abstract concepts are understood indirectly through the simulation of previous sensory experiences in a different domain. While exceptions have been observed for sensory deficits and impairments that are common, such as vision and audition, it is commonly assumed that somatosensation (proprioception, haptic touch, pain, pressure, temperature, etc.) is fundamental for the comprehension of production of sensory metaphors and much abstract thought in general. In this way, our past sensory experiences are critical to our understanding not just of the world around us but also of our sense of selves. This would suggest that Kim, who was born without somatosensation, would have difficulty understanding, using, or even thinking about many abstract concepts typically linked to different sensory experiences through metaphor, including a creation of a sense of self.MethodsTo examine her comprehension of sensory metaphors, Kim was asked to select the best sensory idiomatic expression given its context. Her friends and family as well as a representative sample of individuals online were recruited to complete the survey as controls. Additionally, we transcribed and analyzed six hours of unprompted speech to determine if Kim spontaneously uses somatosensory metaphors appropriately.ResultsResults from the idiomatic expression survey indicate that Kim performs as well as controls despite lacking any previous direct sensory experiences of these concepts. Analysis of the spontaneous speech highlights that Kim appropriately uses tactile expressions in both their concrete sensory and abstract metaphorical meanings.DiscussionTaken together, these two studies demonstrate that what is lost in sensory experiences can be made up in linguistic experiences, as Kim's understanding of tactile words was acquired in the complete absence of somatosensory experiences. This study demonstrates that individuals can comprehend and use tactile language and metaphor without recruiting past somatosensory experiences, and thus challenges a strong definition of embodied cognition which requires sensory simulations in language comprehension and abstract thought.

Cytotoxic CD8+ T cells (CTL) are a crucial component of the immune system notable for their ability to eliminate rapidly proliferating malignant cells. However, the T-cell intrinsic factors required for human CTLs to accomplish highly efficient antitumor cytotoxicity are not well defined. By evaluating human CD8+ T cells from responders versus nonresponders to treatment with immune checkpoint inhibitors, we sought to identify key factors associated with effective CTL function. Single-cell RNA-sequencing analysis of peripheral CD8+ T cells from patients treated with anti–PD-1 therapy showed that cells from nonresponders exhibited decreased expression of the cytolytic granule-associated molecule natural killer cell granule protein-7 (NKG7). Functional assays revealed that reduced NKG7 expression altered cytolytic granule number, trafficking, and calcium release, resulting in decreased CD8+ T-cell–mediated killing of tumor cells. Transfection of T cells with NKG7 mRNA was sufficient to improve the tumor-cell killing ability of human T cells isolated from nonresponders and increase their response to anti–PD-1 or anti–PD-L1 therapy in vitro. NKG7 mRNA therapy also improved the antitumor activity of murine tumor antigen–specific CD8+ T cells in an in vivo model of adoptive cell therapy. Finally, we showed that the transcription factor ETS1 played a role in regulating NKG7 expression. Together, our results identify NKG7 as a necessary component for the cytotoxic function of CD8+ T cells and establish NKG7 as a T-cell–intrinsic therapeutic target for enhancing cancer immunotherapy.See related article by Li et al., p. 154.