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Caspases are a family of cysteine-dependent proteases with important cellular functions in inflammation and apoptosis, while also implicated in human diseases. Classical chemical tools to study caspase functions lack selectivity for specific caspase family members due to highly conserved active sites and catalytic machinery. To overcome this limitation, we targeted a non-catalytic cysteine residue (C264) unique to caspase-6 (C6), an enigmatic and understudied caspase isoform. Starting from disulfide ligands identified in a cysteine trapping screen, we used a structure-informed covalent ligand design to produce potent, irreversible inhibitors (3a) and chemoproteomic probes (13-t) of C6 that exhibit unprecedented selectivity over other caspase family members and high proteome selectivity. This approach and the new tools described will enable rigorous interrogation of the role of caspase-6 in developmental biology and in inflammatory and neurodegenerative diseases.

1. SUMMARY Introduction Evidence is limited on how the onset of health conditions affects tobacco/nicotine use. We report analyses from adults in the U.S. PATH study relating changes in established cigarette and/or e-cigarette use between Waves 1 and 4 to onset of conditions in Waves 2 or 3. Methods Nine conditions had sufficient onsets for analysis. The main analyses adjusted for sex and age. Additional analyses excluded other tobacco/nicotine product users, controlled for more variables, restricted changes in one product to never users of the other, or restricted attention to changes occurring after onset of the condition. Results In the main analyses, onset of each condition predicted significantly increased overall e-cigarette initiation rates, with highest odds ratios (OR) for any major respiratory condition (2.86, 95% confidence interval (CI) 2.10–3.90) and cancer (2.51, 1.52–4.14). Each onset also predicted higher cigarette smoking initiation rates, but ORs were lower than for e-cigarette initiation, and only significant for any cardiovascular condition (1.65, 1.31–2.08), high blood pressure (1.34, 1.13–1.58), and any major smoking-related condition (1.35, 1.12–1.62). For quitting smoking only six conditions showed increased ORs, significant only for high cholesterol (1.29, 1.02–1.62). The additional analyses generally confirmed these patterns. Relationships with re-initiating cigarettes or becoming dual users of cigarettes and e-cigarettes were inconsistent. Onset of conditions also tended to reduce amount smoked by smokers. Conclusions While PATH is nationally representative, its sample size does not always allow precise estimates. There is concern about accuracy of statements by some older participants claiming to be Wave 1 never smokers but Wave 4 ever smokers. Nevertheless the previously unreported association between onset of the health conditions and e-cigarette initiation (which mainly occurs in Wave 1 cigarette smokers) appears real. [Contrib. Tob. Nicotine Res. 32 (2023) 1–10]

Intersex/Disorders/Differences of sex development conditions have been recognized for millennia. An organized approach was adopted in the 1960–70s using the philosophy that gender identity was fluid and malleable. Consequences of this approach were the lack of disclosure, stigmatization, and excessive surgery to “normalize” the genitalia. Often this led to quality of life issues for those patients. There have been many modifications in approach since then to avoid the problems noted. There is consensus on many of these changes (e.g. disclosure) but continued controversy on others (e.g. the benefits of early surgery). This review summarizes the historical context and the current areas of consensus and controversy.

As surface water resources become more intensely used, and occasionally non-useable, consideration of non-conventional water resources for anthropogenic use has become more prevalent. Potentially critical non-conventional water sources include flooded mine-pit lakes. However, water in these lakes can contain potentially problematic concentrations of contaminants of concern. We evaluated the potential use of elevated sulphate (SO4) mining-influenced waters with low to non-detect metals concentrations for irrigation of wild rice (Zizania palustris L.; WR), a culturally and economically important species. Two flow-through in-situ paddies were developed adjacent to two mine-pit lakes with differing chemical water characteristics; specifically, Pit A contained ≈350 mg SO4 L−1 and Pit C contained ≈1350 mg SO4 L−1. Throughout the course of multiple consecutive growing seasons, no adverse WR responses to these mining-influenced water exposures were observed. Based on data and observations from this study, potential use of mining-influenced waters containing elevated SO4 as the primary contaminant for appropriate irrigation purposes is supported. However, site-specific conditions and potential environmental risks must be considered prior to use of mining-influenced waters for anthropogenic applications.

Cancer is the second leading cause of death worldwide. Traditional approaches, such as surgery, chemotherapy, and radiotherapy have been the main cancer therapeutic modalities in recent years. Cancer immunotherapy is a novel therapeutic modality that potentiates the immune responses of patients against malignancy. Immune checkpoint proteins expressed on T cells or tumor cells serve as a target for inhibiting T cell overactivation, maintaining the balance between self-reactivity and autoimmunity. Tumors essentially hijack the immune checkpoint pathway in order to survive and spread. Immune checkpoint inhibitors (ICIs) are being developed as a result to reactivate the anti-tumor immune response. Recent advances in nanotechnology have contributed to the development of successful, safe, and efficient anticancer drug systems based on nanoparticles. Nanoparticle-based cancer immunotherapy overcomes numerous challenges and offers novel strategies for improving conventional immunotherapies. The fundamental and physiochemical properties of nanoparticles depend on various cancer therapeutic strategies, such as chemotherapeutics, nucleic acid-based treatments, photothermal therapy, and photodynamic agents. The review discusses the use of nanoparticles as carriers for delivering immune checkpoint inhibitors and their efficacy in cancer combination therapy.

Recruitment and retention of patients with acute pancreatitis (AP) in clinical studies can be challenging. While some obstacles are similar to other clinical conditions, some are unique to AP. Identifying potential barriers early and developing targeted solutions can help optimize recruitment and retention in AP studies. Such preemptive and detailed planning can help prospective, longitudinal studies focusing on exocrine and endocrine complications of AP in accurately measuring outcomes. This manuscript highlights the challenges in recruitment and retention strategies in AP studies and reviews available resources to create opportunities to address them. We describe the multifaceted approach used by the Recruitment and Retention Committee of the Type 1 Diabetes in Acute Pancreatitis Consortium (T1DAPC), which builds upon earlier experiences to develop a recruitment and retention plan for the DREAM (Diabetes RElated to Acute pancreatitis and its Mechanisms) study.

Niobium samples cut from large-grain discs with residual resistivity ratio ranging between 60 and 300 were mechanically polished and subjected to chemical treatments similar to those applied during the fabrication of superconducting radio-frequency cavities for particle accelerators. Pitting occurred during the chemical treatments and the pit density was higher in the samples of lower purity. Electropolishing resulted in the lowest density of pits, regardless of sample purity, compared to buffered chemical polishing. A correlation between high pit density and grains with 100 orientation of the exposed surface was found, however, no such correlation emerged with respect to the dislocation density.

Pelvic exenteration (PE) has become the standard of care for locally advanced and recurrent rectal cancer. The high short-term morbidity reported from this procedure is well established; however, longer term complications of such radical surgery and their management have not been fully addressed. This study aimed to investigate the incidence, indications and outcomes of long-term (more than 90-day) reoperative surgery in this group of patients, with a focus on the empty pelvis syndrome (EPS).Clinical data were extracted from a prospectively maintained database, with additional data pertaining to indications, operative details and outcomes of reoperative surgery obtained from electronic medical records. Patients were excluded if reoperative surgery was endoscopic or radiologically guided, was for the investigation or treatment of recurrent disease, or was clearly unrelated to previous surgery.Of 716 patients who underwent PE, 75 (11%) required 101 reoperative abdominal or perineal procedures, 52 (51%) of which were in 40 (6%) patients for complications of EPS. This group were more likely to have undergone a total PE (65% vs. 43%; P 0.01) with either major bony (70% vs. 50%; P 0.01) and/or nerve (40% vs. 25%; P = 0.03) resections at index exenteration. The patho-anatomy, surgical management and outcomes of these patients are described herein, considering separately complications of entero-cutaneous fistula, entero-perineal fistula, small bowel obstruction and local management of perineal wound complications.Six per cent of PE patients will require re-intervention for the management of EPS. Reliable strategies for preventing EPS remain elusive; however, surgical management is feasible with acceptable short-term outcomes with the optimum strategy to be selected on an individual patient basis.

Acute pancreatitis (AP) is a disease characterized by an acute inflammatory phase followed by a convalescent phase. Diabetes mellitus (DM) was historically felt to be a transient phenomenon related to acute inflammation; however, it is increasingly recognized as an important late and chronic complication. There are several challenges that have prevented precisely determining the incidence rate of DM following AP and understanding the underlying mechanisms. The Diabetes RElated to Acute Pancreatitis and its Mechanisms (DREAM) Study is a prospective cohort study designed to address these and other knowledge gaps to provide the evidence needed to screen for, prevent, and treat DM following AP. In the following article, we summarize literature regarding the epidemiology of DM following AP, and provide the rationale and an overview of the DREAM study.

Summary Background Smoking is associated with cancer and cardio-respiratory mortality. Reducing smoking prevalence will lead to fewer deaths and more life-years. Here, we estimate the impact of hypothetical introduction of reduced-risk products (heat-not-burn products and e-cigarettes) in Germany from 1995 to 2015 on mortality from lung cancer, chronic obstructive pulmonary disease, ischaemic heart disease, and stroke in men and women aged 30–79 years. Methods We used a previously described population health impact model, with individuals with a defined baseline cigarette smoking distribution followed under a “Null Scenario”, with reduced-risk products never introduced, and various “Alternative Scenarios” where they are. Transition probabilities allow product use to change annually, with the individual product histories allowing estimation of risks, relative to never users, which are then used to estimate reductions in deaths and life-years lost for each Alternative Scenario. Results In the Null Scenario, we estimated 852,000 deaths from cigarette smoking (42,600 per year), with 8.61 million life-years lost. Had everyone ceased smoking in 1995, and with no use of reduced-risk products, these numbers would reduce by 217,000 and 2.88 million. Compared to the Null Scenario, the estimated reductions would be 159,000 and 2.06 million with an immediate complete switch to heat-not-burn products and 179,000 and 2.34 million with 50% of smokers immediately switching to heat-not-burn products and 50% to e-cigarettes. In four Scenarios with a more gradual switch, the estimated decreases were 39,800–81,000 deaths and 0.50–1.05 million life-years, representing 17.5%–37.5% of the effect of immediate cessation in 1995. These estimates assume that switching to heat-not-burn products and e-cigarettes involves risk decreases of 80% and 95% of those from quitting, respectively. The reductions in mortality would be greater with more diseases and a wider age range considered or with a longer follow-up period, as the decreases increased markedly with time. Various limitations are discussed, none affecting the conclusion that introducing these new products into Germany in 1995 could have substantially reduced deaths and life-years lost. Conclusions Deaths from cigarette smoking could be substantially reduced not only by cessation but additionally by switching to reduced-risk products. Respective public health campaigns might increase such switching.

Summary Background We previously estimated the impact of introducing heat-not-burn products and e-cigarettes in Germany on smoking-related disease mortality in men and women aged 30–79 years between 1995 and 2015. Here, we estimate the impact by socioeconomic group. Methods Individuals with a defined baseline cigarette smoking distribution were followed under a “Null Scenario” (no reduced-risk products) and “Alternative Scenarios” (reduced-risk products introduced). Transition probabilities allowed estimation of annual product use changes, with individual product histories used to estimate reductions in deaths and life-years lost. Here, however, individuals were classified into two socioeconomic groups defined by income and education, with allowance for variation by group in initial smoking prevalence and the probability of changing product use, or of changing socioeconomic group. Results With no allowance for socioeconomic group, deaths would have reduced by 217,000 (from 852,000 for continued smoking) had everyone immediately ceased smoking in 1995 and by 40,000 to 179,000 had one or two types of reduced-risk products – the heat-not-burn product and the e-cigarette – been adopted by smokers to varying extents. With such allowance, we estimate substantial drops in each socioeconomic group. Where all cigarette smokers switched immediately, half of them to heat-not-burn products, half to e-cigarettes, the estimated drops in deaths were 60,000 in group A (higher socioeconomic group) and 122,000 in group B (lower), about 82% of the drops associated with immediate cessation (73,000 in A and 148,000 in B). With more gradual conversion, the drops were 26,648 in A and 53,000 in B, about 35% of those from cessation. The drops in deaths and life-years saved were about 2 and 1.5 times higher in group B, respectively, associated with its greater numbers, older age, and higher smoking prevalence. The estimated reductions would increase upon considering more diseases, a wider age range, or longer follow-up. Methodological limitations would not affect the conclusion that introducing these products in 1995 in Germany could have substantially reduced deaths and life-years lost in both groups, more so in B. Conclusions Although cessation is optimal for reducing mortality, switching to reduced-risk products also provides substantial health gains. A public health approach encouraging lower socioeconomic group smokers to switch to reduced-risk products could diminish smoking-related health inequalities relative to continued smoking.

Previously we presented our initial findings from a 9-patient rapid autopsy pilot for metastatic breast cancer (MBC). At the time of procurement, one third of subjects exhibited clinically unidentified diseased sites in organs not commonly associated with breast cancer metastases, including ovary, kidney, and pancreas. In two other instances, “resolved” bone specimens (as measured by absence of FTG uptake in PET/CT imaging) were later determined to be >30% tumor positive when assessed by a pathologist. We now expand upon these findings in a more in-depth exploration of the presence of micro-metastases in presumed tumor-negative tissues. A subset of tumor-free tissues were selected from each patient (average of 10 specimens per patient). All selected specimens were negative by clinical imaging, appeared grossly normal at procurement, and were reported to be tumor negative by H&E assessment by a clinical pathologist. We included organs both commonly and uncommonly involved in MBC, including lung, bone, spleen, pancreas, kidney, and non-tumor draining lymph nodes. Tissues were stained for one or more of the markers, pan-cytokeratin, GATA-3, HMFG, MUC1, and ER (if patient was previously ER+), depending on tissue type. Of the 87 total specimens assessed, we identified micro-metastases in 13 specimens from 4 individual patients. Across these 4 patients, micro-metastases were found in lung, bone, pancreas, spleen, and several non-tumor draining lymph nodes. While lung and bone are commonly involved in MBC and these results are not entirely surprising, pancreas and spleen involvement is extraordinarily rare. Further surprising was the identification of micro-metastases in several lymph nodes that were not located anatomically downstream from a disease-involved organ. Image patterns demonstrate tumor cell infiltration into the lymph node within the subcapsular sinus. Presence of micro-metastases in tumor-negative tissue did not correlate with tumor hormone status or cancer type (e.g. lobular vs DCIS). Combined with our previous findings, we now report unexpected and clinically undiagnosed disease involvement in 6/9, or two-thirds, of our patients. Based on these findings, we hypothesize that cancer stem cells and/or micro-metastases are present throughout the body, in all tissue types, and that their ability to grow into tumors is regulated by the local immune microenvironment. Lastly, the differing roles and mechanics of lymphatic vs hematological spread in metastatic disease has long been discussed. Our findings provide strong evidence for cancer dissemination through the lymphatics system. Further study is necessary to better understand the timing of metastatic spread, whether systemic dissemination occurs early or later in disease, and if conducive metastatic or pre-metastatic niches are already present throughout the body at the time of primary diagnosis or if these permissive environments develop slowly overtime. Citation Format: Eliza R. Bacon, Kena Ihle, Colt Egelston, Weihua Guo, Diana Simons, Dan Schmolze, Christina Wei, Lusine Tumyan, Peter P Lee, James R. Waisman. Insights from rapid autopsy shed light on mechanisms of cancer dissemination in metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-06-01.

IL6 is a pleiotropic cytokine with both pro- and anti-inflammatory properties, which acts directly on cancer cells to promote their survival and proliferation. Elevated serum IL6 levels negatively correlate with survival of cancer patients, which is generally attributed to the direct effects of IL6 on cancer cells. How IL6 modulates the host immune response in cancer patients is unclear. Here, we show the IL6 signaling response in peripheral blood T cells is impaired in breast cancer patients and is associated with blunted Th17 differentiation. The mechanism identified involved downregulation of gp130 and IL6Rα in breast cancer patients and was independent of plasma IL6 levels. Importantly, defective IL6 signaling in peripheral blood T cells at diagnosis correlated with worse relapse-free survival. These results indicate that intact IL6 signaling in T cells is important for controlling cancer progression. Furthermore, they highlight a potential for IL6 signaling response in peripheral blood T cells at diagnosis as a predictive biomarker for clinical outcome of breast cancer patients. Cancer Res; 77(5); 1119–26. ©2016 AACR.

Figure S1: Endocrine-resistant MCF-7 cells demonstrate sensitivity to TRAIL Figure S2: Endocrine-resistant CSCs demonstrate sensitivity to TRIAL. Figure S3: Primary-derived patient samples. Figure S4: Endocrine-resistant primary and PDX tumour cells are sensitive to TRAIL. Figure S5: Mechanism of endocrine-resistant tumour cell sensitivity to TRAIL.

Purpose: One third of ER-positive breast cancer patients who initially respond to endocrine therapy become resistant to treatment. Such treatment failure is associated with poor prognosis and remains an area of unmet clinical need. Here, we identify a specific posttranslational modification that occurs during endocrine resistance and which results in tumor susceptibility to the apoptosis-inducer TRAIL. This potentially offers a novel stratified approach to targeting endocrine-resistant breast cancer.Experimental Design: Cell line and primary-derived xenograft models of endocrine resistance were investigated for susceptibility to TRAIL. Tumor viability, cancer stem cell (CSC) viability (tumorspheres), tumor growth kinetics, and metastatic burden were assessed. Western blots for the TRAIL-pathway inhibitor, c-FLIP, and upstream regulators were performed. Results were confirmed in primary culture of 26 endocrine-resistant and endocrine-naïve breast tumors.Results: Breast cancer cell lines with acquired resistance to tamoxifen (TAMR) or faslodex were more sensitive to TRAIL than their endocrine-sensitive controls. Moreover, TRAIL eliminated CSC-like activity in TAMR cells, resulting in prolonged remission of xenografts in vivo. In primary culture, TRAIL significantly depleted CSCs in 85% endocrine-resistant, compared with 8% endocrine-naïve, tumors, whereas systemic administration of TRAIL in endocrine-resistant patient-derived xenografts reduced tumor growth, CSC-like activity, and metastases. Acquired TRAIL sensitivity correlated with a reduction in intracellular levels of c-FLIP, and an increase in Jnk-mediated phosphorylation of E3-ligase, ITCH, which degrades c-FLIP.Conclusions: These results identify a novel mechanism of acquired vulnerability to an extrinsic cell death stimulus, in endocrine-resistant breast cancers, which has both therapeutic and prognostic potential. Clin Cancer Res; 24(10); 2452–63. ©2018 AACR.

BackgroundThe kidney vasculature is exquisitely structured to orchestrate renal function. Structural profiling of the vasculature in intact rodent kidneys, has provided insights into renal haemodynamics and oxygenation, but has never been extended to the human kidney beyond a few vascular generations. We hypothesised that synchrotron-based imaging of a human kidney would enable assessment of vasculature across the whole organ.MethodsAn intact kidney from a 63-year-old male was scanned using hierarchical phase-contrast tomography (HiP-CT), followed by semi-automated vessel segmentation and quantitative analysis. These data were compared to published micro-CT data of whole rat kidney.ResultsThe intact human kidney vascular network was imaged with HiP-CT at 25 μm voxels, representing a 20-fold increase in resolution compared to clinical CT scanners. Our comparative quantitative analysis revealed the number of vessel generations, vascular asymmetry and a structural organisation optimised for minimal resistance to flow, are conserved between species, whereas the normalised radii are not. We further demonstrate regional heterogeneity in vessel geometry between renal cortex, medulla, and hilum, showing how the distance between vessels provides a structural basis for renal oxygenation and hypoxia.ConclusionsThrough the application of HiP-CT, we have provided the first quantification of the human renal arterial network, with a resolution comparable to that of light microscopy yet at a scale several orders of magnitude larger than that of a renal punch biopsy. Our findings bridge anatomical scales, profiling blood vessels across the intact human kidney, with implications for renal physiology, biophysical modelling, and tissue engineering.SIGNIFICANCE STATEMENTHigh-resolution, three-dimensional, renal vasculature models are currently highly reliant on data obtained from rodent kidneys. Obtaining this information in a human kidney is difficult, given its size and scale. Here, we overcome this challenge through synchrotron-based imaging to profile the vasculature of an intact human kidney. Organ-wide vascular network metrics are shown to be largely conserved between human and rat kidneys. Regional and spatial heterogeneities between cortical, medullary, and hilar vascular architecture are revealed, highlighting a structural basis for renal oxygen gradients in humans. This is, to our knowledge, the first time the vasculature of a human kidney has been mapped in its entirety, with implications for understanding how the hierarchy of individual blood vessel segments collectively scales to renal function.

In this paper, we aim to provide a comprehensive overview of customer feedback literature, highlighting the burgeoning role of artificial intelligence (AI). Customer feedback has long been a valuable source of customer insights for businesses and market researchers. While previously survey focused, customer feedback in the digital age has evolved to be rich, interactive, multimodal, and virtually real time. Such explosion in feedback content has also been accompanied by a rapid development of AI and machine learning technologies that enable firms to understand and take advantage of these high-velocity data sources. Yet, some of the challenges with traditional surveys remain, such as self-selection concerns of who chooses to participate and what attributes they give feedback on. In addition, these new feedback channels face other unique challenges like review manipulation and herding effects due to their public and democratic nature. Thus, while the AI toolkit has revolutionized the area of customer feedback, extracting meaningful insights requires complementing it with the appropriate social science toolkit. We begin by touching upon conventional customer feedback research and chart its evolution through the years as the nature of available data and analysis tools develop. We conclude by providing recommendations for future questions that remain to be explored in this field.

Improving the scalability of tissue imaging throughput with bright, coherent X-rays requires identifying and mitigating artifacts resulting from the interactions between X-rays and matter. At synchrotron sources, long-term imaging of soft tissues in solution can result in gas bubble formation or cavitation, which dramatically compromises image quality and integrity of the samples. By combining in-line phase-contrast cineradiography withoperandogas chromatography, we were able to track the onset and evolution of high-energy X-ray-induced gas bubbles in ethanol-embedded soft tissue samples for tens of minutes (2 to 3 times the typical scan times). We demonstrate quantitatively that vacuum degassing of the sample during preparation can significantly delay bubble formation, offering up to a twofold improvement in dose tolerance, depending on the tissue type. However, once nucleated, bubble growth is faster in degassed than undegassed samples, indicating their distinct metastable states at bubble onset. Gas chromatography analysis shows increased solvent vaporization concurrent with bubble formation, yet the quantities of dissolved gases remain unchanged. Coupling features extracted from the radiographs with computational analysis of bubble characteristics, we uncover dose-controlled kinetics and nucleation site-specific growth. These hallmark signatures provide quantitative constraints on the driving mechanisms of bubble formation and growth. Overall, the observations highlight bubble formation as a critical, yet often overlooked hurdle in upscaling X-ray imaging for biological tissues and soft materials and we offer an empirical foundation for their understanding and imaging protocol optimization. More importantly, our approaches establish a top-down scheme to decipher the complex, multiscale radiation-matter interactions in these applications.Significance statementBetter probing the X-ray radiation dose limit of bubble formation in biological tissue and developing mitigation methods is essential for improving imaging techniques involving X-ray, such as synchrotron X-ray tomography or crystallography. Here, we combinedoperandogas chromatography with in-line X-ray phase-contrast radiography on human lung and brain tissue to investigate bubble formation under high-energy X-ray irradiation. We demonstrate that vacuum degassing delays bubble nucleation up to a factor two, depending on the tissue type. Gas chromatography analysis showed increased solvent vaporization during bubble formation; however, the quantities of dissolved gases remained unchanged. Moreover, depending on the nucleation site, bubble growth can be geometrically constrained by sample microstructure, which influence its dynamics.

Sentinel-1 is a synthetic aperture radar platform that provides free and open-source images of the Earth. A product type of Sentinel-1 is ground range detected (GRD), which records intensity while discarding phase information from the radar backscatter. Especially in cross-polarized GRD images, there are noticeable intensity changes throughout the image that are caused by amplifying the noise floor of the signal, which varies due to the nonuniform radiation pattern of the satellite's antenna. While Sentinel-1 has instrument processing facility (IPF) software to estimate the noise floor, even in the newer versions (3.1 or above) of the IPF software there are still instances where the estimates provided do not fit the actual noise floor in the image, which is particularly noticeable in transitions between adjacent subswaths. In this work, we propose a method that reduces the impact of the varying noise-floor throughout the image. The method models the intensity of the noise floor to be a power function of the radiation pattern power. The method divides the swath into several sections depending on the location of the local minimum and maximum of the radiation pattern power with respect to the range. The parameter estimation is portrayed as a geometric programming problem that is transformed into a linear programming problem by logarithmic transformation. Affine offsets are computed for each subswath by a weighted least squares approach. Vast improvement is found on extra-wide (EW) and interferometric wide (IW) Sentinel-1 modes over cross-polarized images. Code implementation is available at https://github.com/PeterQLee/sentinel1_denoise_rs.

Testes were associated with maleness from antiquity, and ancient societies had fanciful myths about the origins of the sexes and about fetal sexual development. 17th century anatomists developed the concept that mammals developed from eggs and discovered sperm in semen; in 1878, Hertwig observed sperm entering eggs (of sea urchins), establishing the cellular basis of sex development. Individuals with atypical genitalia were known clinically in the 17th century, with much debate about their origins, but by the late 19th century it was generally accepted that gonads determined sex, and that sex determined gender role. Testosterone was isolated in 1935, and Alfred Jost showed that both circulating testosterone and diffusible anti-Mullerian hormone were needed for male development. Patients with apparent androgen insensitivity were reported in 1937 and shown to be unresponsive to exogenous androgen by Lawson Wilkins in 1957; androgen receptor mutations were reported in 1989. Steroidogenic errors were associated with differences in sex development (DSDs) starting in the 1940s, and finding mutations in the responsible enzymes explained many forms of hyper- and hypo-androgenism in both sexes. Sex chromosomes were identified in the early 20th century; Y was associated with maleness, and the responsible SRY gene was identified in 1991. Early efforts to manage patients with DSDs were confounded by philosophical perspectives on the relative roles of prenatal biology versus postnatal environment. Approaches to natal sex assignment evolved in the later 20th century and now emphasize a team approach based on data, not guessing, parental involvement, cultural considerations, and the acknowledgement of uncertainty.

We propose a novel image analysis framework to automate analysis of X-ray microtomography images of sintering ceramics and glasses, using open-source toolkits and machine learning. Additive manufacturing (AM) of glasses and ceramics usually requires sintering of green bodies. Sintering causes shrinkage, which presents a challenge for controlling the metrology of the final architecture. Therefore, being able to monitor sintering in 3D over time (termed 4D) is important when developing new porous ceramics or glasses. Synchrotron X-ray tomographic imaging allows in situ, real-time capture of the sintering process at both micro and macro scales using a furnace rig, facilitating 4D quantitative analysis of the process. The proposed image analysis framework is capable of tracking and quantifying the densification of glass or ceramic particles within multiple volumes of interest (VOIs) along with structural changes over time using 4D image data. The framework is demonstrated by 4D quantitative analysis of bioactive glass ICIE16 within a 3D-printed scaffold. Here, densification of glass particles within 3 VOIs were tracked and quantified along with diameter change of struts and interstrut pore size over the 3D image series, delivering new insights on the sintering mechanism of ICIE16 bioactive glass particles in both micro and macro scales

The tribological performance of the piston assembly of an automotive engine is highly influenced by the complex flow mechanisms that supply lubricant to the upper piston rings. As well as affecting friction and wear, the oil consumption and emissions of the engine are strongly influenced by these mechanisms. There is a significant body of work that seeks to model these flows effectively. However, these models are not able to fully describe the flow of lubricant through the piston assembly. Some experimental studies indicate that droplets of lubricant carried in the gas flows through the piston assembly may account for some of this. This work describes an investigation into the nature of lubricant misting in a fired gasoline engine. Previous work in a laboratory simulator showed that the tendency of a lubricant to form mist is dependent on the viscosity of the lubricant and the type and concentration of viscosity modifier. The higher surface area-to-volume ratio of the lubricant if more droplets are formed or if the droplets are smaller is hypothesised to increase the degradation rate of the lubricant. The key work in the investigation was to measure the size distribution of the droplets in the crankcase of a fired gasoline engine. Droplets were extracted from the crankcase and passed through a laser diffraction particle sizer. Three characteristic droplet size ranges were observed: Spray sized (250–1000 μm); Major mist (30–250 μm); and Minor mist (0.1–30 μm). Higher base oil viscosity tended to reduce the proportion of mist-sized droplets. The viscoelasticity contributed by a polymeric viscosity modifier reduced the proportion of mist droplets, especially at high load.

Background To describe our institutional experience in the management of locally advanced primary, and recurrent pelvic sarcoma through pelvic exenteration (PE). Methods Patients undergoing PE for locally advanced primary or recurrent pelvic sarcoma between 2003 and 2017 were identified from a prospectively maintained database at a single quaternary referral hospital in Sydney, Australia were eligible for review. The primary outcomes measured were surgical resection margin and survival. Secondary outcome measures included 30-day morbidity, in hospital length of stay (LOS) and return to theatre. Results There were 29 patients who underwent PE for pelvic sarcoma during the study period, with 55% (n = 16) having advanced primary tumours and 45% (n = 13) having recurrent disease. The R0 resection rate was 52% (n = 15); and five-year-survival of 38% (n = 11). The R0 resection was noted to be higher in patients having primary advanced tumours (56%) compared to those with recurrent disease (46%), however this failed to reach statistical significance in this cohort. There was no recorded 30-day mortality. Grade 3 or higher Clavien-Dindo complications were uncommon (14%), but more likely in patients undergoing surgery for recurrent disease (75%). Conclusion In our cohort of patients with locally advanced and recurrent disease, more than 50% achieved an R0 resection. Recurrent disease makes R0 resection more difficult and can lead to higher morbidity, need for 30-day re-intervention and longer in hospital LOS. PE surgery remains the only curative option for locally advanced, and recurrent sarcoma in the pelvis, and can be performed with acceptable survival and morbidity outcomes.

This article considers cultural hybridity as a concept that helps interpret complex social phenomena found in various intercultural contexts in missions. The concept of cultural hybridity is better used as an analytic tool rather than an object of analysis in order for it to have an interpretive power. Adopting cultural hybridity in missiological research requires focusing on its active, dynamic, and processual nature found in the verb form, “hybridization,” rather than a stationary concept depicted by the noun form, “hybridity.” When using cultural hybridity in empirical studies, the mission researcher needs to develop a framework using the concept by immersing in the prior and current scholarly discussions, analyze social processes at multiple levels, utilize the hybridity theory in conjunction with other relevant social theories, and close the gap between the theory and data by focusing on how things work rather than forcing meanings out of the data. These practices may aid missiologists in their empirical research and increase their understanding of challenging intercultural issues.

The process of creating a Safe and Inclusive Church (SIC) Commission within the Anglican Church of the Province of SouthernAfrica (ACSA) is not unique in the Communion. This article seeks to explore ACSA’s specific journey to date, with a view to engaging the Communion in a learning partnership. While some of the process of establishing this ministry may be unique, there are places of commonality as we jointly grapple with the call of our Lord Jesus to continue to build the Kingdom of God in contemporary times. Most specifically, this process has highlighted a need for renewal of the Church in both our theological understanding and how we organize to best serve our call to preach the Good News. These theological and structural dimensions of ‘doing church’ speak deeply into our ‘being church’ and are at the heart of why dialogue is needed as a Communion. We offer this article as an invitation to continue discerning together how best to follow and serve our Lord and Saviour Jesus Christ by being His Body to a broken and wounded world.

Systematic review with meta-analysis of the epidemiological evidence in Europe, Israel, America and Australasia on smoking and COVID-19

Fucoidan is a sulfated polysaccharide, derived from various marine brown seaweeds, that has immunomodulatory effects. In this study, we analyzed the effects of five different fucoidans, which were extracted from Ascophyllum nodosum, Undaria pinnatifida, Macrocystis pyrifera, Fucus vesiculosus, and Ecklonia cava, on natural killer (NK) cell activation in mice. Among these, E. cava fucoidan (ECF) promoted an increase in the number of NK cells in the spleen and had the strongest effect on the activation of NK cells. Additionally, we observed that DC stimulation was required for NK cell activation and that ECF had the most potent effect on splenic dendritic cells (DC). Finally, ECF treatment effectively prevented infiltration of CT-26 carcinoma cells in the lungs of BALB/c mice in an NK cell dependent manner. Collectively, these results suggest that ECF could be a suitable candidate for enhancing NK cell-mediated anti-cancer immunity.

INTRODUCTION: For over 50 yr, investigators have studied the physiological adaptations of the human system during short- and long-duration spaceflight exposures. Much of the knowledge gained in developing health countermeasures for astronauts onboard the International Space Station demonstrate terrestrial applications. To date, a systematic process for translating these space applications to terrestrial human health has yet to be defined.METHODS: In the summer of 2017, a team of 38 international scientists launched the Bellagio ll Summit Initiative. The goals of the Summit were: 1) To identify space medicine findings and countermeasures with highest probability for future terrestrial applications; and 2) To develop a roadmap for translation of these countermeasures to future terrestrial application. The team reviewed public domain literature, NASA databases, and evidence books within the framework of the five-stage National Institutes of Health (NIH) translation science model, and the NASA two-stage translation model. Teams then analyzed and discussed interdisciplinary findings to determine the most significant evidence-based countermeasures sufficiently developed for terrestrial application.RESULTS: Teams identified published human spaceflight research and applied translational science models to define mature products for terrestrial clinical practice.CONCLUSIONS: The Bellagio ll Summit identified a snapshot of space medicine research and mature science with the highest probability of translation and developed a Roadmap of terrestrial application from space medicine-derived countermeasures. These evidence-based findings can provide guidance regarding the terrestrial applications of best practices, countermeasures, and clinical protocols currently used in spaceflight.Sides MB, Johnston SL III, Sirek A, Lee PH, Blue RS, Antonsen EL, Basner M, Douglas GL, Epstein A, Flynn-Evans EE, Gallagher MB, Hayes J, Lee SMC, Lockley SW, Monseur B, Nelson NG, Sargsyan A, Smith SM, Stenger MB, Stepanek J, Zwart SR; Bellagio II Team. Bellagio II report: terrestrial applications of space medicine research. Aerosp Med Hum Perform. 2021; 92(8):650669.

Laser powder bed fusion (LPBF) can produce high-value metallic components for many industries; however, its adoption for safety-critical applications is hampered by the presence of imperfections. The interdependency between imperfections and processing parameters remains unclear. Here, the evolution of porosity and humps during LPBF using X-ray and electron imaging, and a high-fidelity multiphase process simulation, is quantified. The pore and keyhole formation mechanisms are driven by the mixing of high temperatures and high metal vapor concentrations in the keyhole is revealed. The irregular pores are formed via keyhole collapse, pore coalescence, and then pore entrapment by the solidification front. The mixing of the fast-moving vapor plume and molten pool induces a Kelvin-Helmholtz instability at the melt track surface, forming humps. X-ray imaging and a high-fidelity model are used to quantify the pore evolution kinetics, pore size distribution, waviness, surface roughness, and melt volume under single layer conditions. This work provides insights on key criteria that govern the formation of imperfections in LPBF and suggest ways to improve process reliability.

Objectives It is important to understand what variables influence change in predicted adult height (PAH) throughout GnRHa treatment for central precocious puberty (CPP) to individualize treatment decisions and optimize care. Methods Changes in PAH, chronological age (CA), bone age (BA), BA/CA, and height velocity (HV) were evaluated in girls with CPP throughout treatment with leuprolide acetate (n=77). A second analysis focused on changes in the 3 years preceding the first observed BA of ≥12 years. Relationships were characterized using plot inspection and linear mixed-effects analyses. Association between treatment duration and last assessed PAH was examined using multiple linear regression models. Results BA/CA and HV showed a nonlinear change during treatment, with the largest changes and improvement in PAH observed in the first 6–18 months. Rate of BA advancement tended to decrease more slowly in girls initiating treatment at a younger BA. On-treatment change in PAH was predicted by concurrent BA/CA change, HV, and BA, as well as CA at treatment initiation. Last assessed PAH was positively associated with longer treatment durations (primary/exploratory models cut-offs of ≥33/≥55 months). Conclusions These findings support individualized monitoring during GnRHa treatment. Initial response should be interpreted with caution until 6–18 months after treatment initiation and failure should not be assumed based on continued bone maturation in girls starting therapy at a younger age. Treatment cessation should not be automatically based on a diminishing change in PAH or HV, as ongoing treatment may result in continued increase or maintenance of PAH.

Communication between distant cells can be mediated by extracellular vesicles (EVs) that deliver proteins and RNAs to recipient cells. Little is known about how EVs are targeted to specific cell types. Here we identify the Drosophila cell-surface protein Stranded at second (Sas) as a targeting ligand for EVs. Full-length Sas is present in EV preparations from transfected Drosophila Schneider 2 (S2 cells). Sas is a binding partner for the Ptp10D receptor tyrosine phosphatase, and Sas-bearing EVs preferentially target to cells expressing Ptp10D. We used co-immunoprecipitation and peptide binding to show that the cytoplasmic domain (ICD) of Sas binds to dArc1. dArc1 and mammalian Arc are related to retrotransposon Gag proteins. They form virus-like capsids which encapsulate Arc and other mRNAs and are transported between cells via EVs. The Sas ICD contains a motif required for dArc1 binding that is shared by the mammalian and Drosophila amyloid precursor protein (APP) orthologs, and the Sas and APP ICDs also bind to mammalian Arc. Sas facilitates delivery of dArc1 capsids bearing dArc1 mRNA into distant Ptp10D-expressing recipient cells in vivo.

Astragalus membranaceus (A. membranaceus) is commonly used in various herbal formulations to treat several human and animal diseases. Polysaccharides, which are the major bioactive components in the A. membranaceus, exhibit various bioactive properties. However, the ability of A. membranaceus polysaccharides (APS) to activate the mucosal immune response has not been examined. We examined the effect of intranasal administration of APS on mucosal immune cell activation and the growth-inhibitory activity against pulmonary metastatic melanoma in mice by combination treatment with immune checkpoint blockade. The intranasal treatment of APS increased the number of lineage-CD11c+ dendritic cell (DCs) in the mesenteric lymph nodes (mLN) through the upregulation of CC-chemokine receptor 7 expression. Moreover, intranasal treatment of APS activated DCs, which further stimulated natural killer (NK) and T cells in the mLN. The APS/anti-PD-L1 antibody combination inhibited the pulmonary infiltration of B16 melanoma cells. The depletion of NK cells and CD8 T cells in mice mitigated the anti-cancer effect of this combination, thereby highlighting the critical role of NK cells and CD8 T cells in mediating anti-cancer immunity. These findings demonstrated that APS could be used as a topical mucosal adjuvant to enhance the immune check point inhibitor anti-cancer effect.