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Buffering of stomach acid by antacids is a well-established symptomatic therapy for heartburn. In addition, preparations from prickly pear (Opuntia ficus-indica) have been shown to reduce tissue damage in experimental gastritis models and to attenuate gastrointestinal discomfort in patients. Both active principles have been included in a fixed-combination product for symptomatic treatment of heartburn containing carbonate antacids (CaCO3 and MgCO3) and an extract from Opuntia ficus-indica cladodes. The aim of the study was to characterize the acid neutralization and esophageal cell protective activities of the product and its individual active ingredients in a set of in vitro assays. Acid neutralization was assessed in a simulated stomach model. Protective activity of individual constituents and in combination was analyzed in an esophageal cell line (COLO-680 N) exposed to low pH and deoxycholic acid to simulate acidic and non-acidic reflux challenge. The combination product protected cells against low pH mediated cytotoxicity via acid neutralization by carbonates. Opuntia extract itself and the combination product attenuated bile acid-induced cell irritation as measured by reduced release of proinflammatory interleukin-6 and -8. In conclusion, addition of Opuntia extract to a mineral antacid provides dual protection against acidic and non-acidic simulated reflux challenge. [ABSTRACT FROM AUTHOR]

Artificial intelligence-guided closed-loop experimentation has emerged as a promising method for optimization of objective functions1,2, but the substantial potential of this traditionally black-box approach to uncovering new chemical knowledge has remained largely untapped. Here we report the integration of closed-loop experiments with physics-based feature selection and supervised learning, denoted as closed-loop transfer (CLT), to yield chemical insights in parallel with optimization of objective functions. CLT was used to examine the factors dictating the photostability in solution of light-harvesting donor–acceptor molecules used in a variety of organic electronics applications, and showed fundamental insights including the importance of high-energy regions of the triplet state manifold. This was possible following automated modular synthesis and experimental characterization of only around 1.5% of the theoretical chemical space. This physics-informed model for photostability was strengthened using multiple experimental test sets and validated by tuning the triplet excited-state energy of the solvent to break out of the observed plateau in the closed-loop photostability optimization process. Further applications of CLT to additional materials systems support the generalizability of this strategy for augmenting closed-loop strategies. Broadly, these findings show that combining interpretable supervised learning models and physics-based features with closed-loop discovery processes can rapidly provide fundamental chemical insights.Integration of closed-loop experiments with physics-based feature selection and supervised learning, denoted as closed-loop transfer, yields chemical insights in parallel with optimization of objective functions. [ABSTRACT FROM AUTHOR]

Enabling the examination of cell-cell relationships in tissue, spatially resolved omics technologies have revolutionised our perspectives on cancer biology. Clinically, the development of immune checkpoint inhibitors (ICI) has advanced cancer therapeutics. However, a major challenge of effective implementation is the identification of predictive biomarkers of response. In this review we examine the potential added predictive value of spatial biomarkers of response to ICI beyond current clinical benchmarks. [ABSTRACT FROM AUTHOR]

The multi-staged XENON program at INFN Laboratori Nazionali del Gran Sasso aims to detect dark matter with two-phase liquid xenon time projection chambers of increasing size and sensitivity. The XENONnT experiment is the latest detector in the program, planned to be an upgrade of its predecessor XENON1T. It features an active target of 5.9 tonnes of cryogenic liquid xenon (8.5 tonnes total mass in cryostat). The experiment is expected to extend the sensitivity to WIMP dark matter by more than an order of magnitude compared to XENON1T, thanks to the larger active mass and the significantly reduced background, improved by novel systems such as a radon removal plant and a neutron veto. This article describes the XENONnT experiment and its sub-systems in detail and reports on the detector performance during the first science run. [ABSTRACT FROM AUTHOR]

Droughts pose serious threats to the agricultural sector, especially in rainfed-dominated agricultural regions like those in Argentina's Humid Pampas. This region was recently impacted by slow-evolving and long-lasting droughts as well as by flash droughts, resulting in losses reaching thousands of millions of US dollars. Improvements of drought early warning systems are essential, particularly given the projected increase in drought frequency and severity over southern South America. The spatial and temporal relationship between precipitation deficits, soil moisture and vegetation health anomalies are crucial for better understanding and representation of the agricultural droughts and their impacts. In this context, the Combined Drought Indicator (CDI) considers the causal and time-lagged relationship of these three variables. The study's objective is twofold: (1) Analyze the time-lagged response between precipitation deficits, soil moisture and satellite fAPAR anomalies; and (2) Evaluate the CDI's capability to characterize the severity of drought events on the Humid Pampas against agricultural yield estimations and simulations, as well as agricultural emergency declarations. The correlation among the variables shows strong spatial variability. The highest Pearson correlation values (r > 0.42) are observed over parts of the Humid Pampas for time lags of 0, 10, and 20 days between the variables. Although the CDI has limitations, such as its coarse spatial resolution and monthly temporal resolution of precipitation data, it effectively tracks the progression of major drought events in the region. The CDI's performance aligns well with estimations and simulations of soybean and corn yields, as well as official declarations of agricultural emergencies. Insights from this study also provide a basis for discussing potential improvements to the CDI. This study highlights the global and regional significance of evaluating and enhancing the CDI for effective drought monitoring, emphasizing the role of collaborative efforts for future advancements in drought early warning systems. [ABSTRACT FROM AUTHOR]

Introduction: Burkitt lymphoma (BL) is an aggressive non-Hodgkin lymphoma associated with Plasmodium falciparum and Epstein-Barr virus, both of which affect metabolic pathways. The metabolomic patterns of BL is unknown. Materials and methods: We measured 627 metabolites in pre-chemotherapy treatment plasma samples from 25 male children (6–11 years) with BL and 25 cancer-free area- and age-frequency-matched male controls from the Epidemiology of Burkitt Lymphoma in East African Children and Minors study in Uganda using liquid chromatography-tandem mass spectrometry. Unconditional, age-adjusted logistic regression analysis was used to estimate odds ratios (ORs) and their 95% confidence intervals (CIs) for the BL association with 1-standard deviation increase in the log-metabolite concentration, adjusting for multiple comparisons using false discovery rate (FDR) thresholds and Bonferroni correction. Results: Compared to controls, levels for 42 metabolite concentrations differed in BL cases (FDR < 0.001), including triacylglyceride (18:0_38:6), alpha-aminobutyric acid (AABA), ceramide (d18:1/20:0), phosphatidylcholine ae C40:6 and phosphatidylcholine C38:6 as the top signals associated with BL (ORs = 6.9 to 14.7, P < 2.4✕10− 4). Two metabolites (triacylglyceride (18:0_38:6) and AABA) selected using stepwise logistic regression discriminated BL cases from controls with an area under the curve of 0.97 (95% CI: 0.94, 1.00). Conclusion: Our findings warrant further examination of plasma metabolites as potential biomarkers for BL risk/diagnosis. [ABSTRACT FROM AUTHOR]

Background: Benign anastomotic stricture is a recognized complication following esophagectomy. Laparoscopic gastric ischemic preconditioning (LGIP) prior to esophagectomy has been associated with decreased anastomotic leak rates; however, its effect on stricture and the need for subsequent endoscopic intervention is not well studied. Methods: This was a case-control study at an academic medical center using consecutive patients undergoing oncologic esophagectomies (July 2012–July 2022). Our institution initiated an LGIP protocol on 1 January 2021. The primary outcome was the occurrence of stricture within 1 year of esophagectomy, while secondary outcomes were stricture severity and frequency of interventions within the 6 months following stricture. Bivariable comparisons were performed using Chi-square, Fisher's exact, or Mann–Whitney U tests. Multivariable regression controlling for confounders was performed to generate risk-adjust odds ratios and to identify the independent effect of LGIP. Results: Of 253 esophagectomies, 42 (16.6%) underwent LGIP prior to esophagectomy. There were 45 (17.7%) anastomotic strictures requiring endoscopic intervention, including three patients who underwent LGIP and 42 who did not. Median time to stricture was 144 days. Those who underwent LGIP were significantly less likely to develop anastomotic stricture (7.1% vs. 19.9%; p = 0.048). After controlling for confounders, this difference was no longer significant (odds ratio 0.46, 95% confidence interval 0.14–1.82; p = 0.29). Of those who developed stricture, there was a trend toward less severe strictures and decreased need for endoscopic dilation in the LGIP group (all p < 0.20). Conclusion: LGIP may reduce the rate and severity of symptomatic anastomotic stricture following esophagectomy. A multi-institutional trial evaluating the effect of LGIP on stricture and other anastomotic complications is warranted. [ABSTRACT FROM AUTHOR]

Hydrogen borrowing is an attractive and sustainable strategy for carbon–carbon bond formation that enables alcohols to be used as alkylating reagents in place of alkyl halides. However, despite intensive efforts, limited functional group tolerance is observed in this methodology, which we hypothesize is due to the high temperatures and harsh basic conditions often employed. Here we demonstrate that room temperature and functional group tolerant hydrogen borrowing can be achieved with a simple iridium catalyst in the presence of substoichiometric base without an excess of reagents. Achieving high yields necessitates the application of anaerobic conditions to counteract the oxygen sensitivity of the catalytic iridium hydride intermediate, which otherwise leads to catalyst degradation. Substrates containing heteroatoms capable of complexing the catalyst exhibit limited room temperature reactivity, but the application of moderately higher temperatures enables extension to a broad range of medicinally relevant nitrogen rich heterocycles. These newly developed conditions allow alcohols possessing functional groups that were previously incompatible with hydrogen borrowing reactions to be employed. Hydrogen borrowing is a method that allows common alcohols to serve as alkylating agents but is often associated with high temperatures and relatively harsh reaction conditions leading to limited scope. Here, the authors present a hydrogen borrowing method that proceeds at lower temperatures under iridium catalysis, enabling broad substrate scope. [ABSTRACT FROM AUTHOR]

The neurocranium (braincase) is one of the defining vertebrate characters. Housing the brain and other key sensory organs, articulating with the jaws and contributing to the shape of the anteriormost portion of the body, the braincase is undoubtedly of great functional importance. Through studying relationships between braincase shape and ecology we can gain an improved understanding of form-function relationships in extant and fossil taxa. Elasmobranchii (sharks and rays) represent an important case study of vertebrate braincase diversity as their neurocranium is simplified and somewhat decoupled from other components of the cranium relative to other vertebrates. Little is known about the associations between ecology and braincase shape in this clade. In this study we report patterns of mosaic cranial evolution in Elasmobranchii that differ significantly from those present in other clades. The degree of evolutionary modularity also differs between Selachii and Batoidea. In both cases innovation in the jaw suspension appears to have driven shifts in patterns of integration and modularity, subsequently facilitating ecological diversification. Our results confirm the importance of water depth and biogeography as drivers of elasmobranch cranial diversity and indicate that skeletal articulation between the neurocranium and jaws represents a major constraint upon the evolution of braincase shape in vertebrates. [ABSTRACT FROM AUTHOR]

In this study, a large-scale laboratory testing apparatus was developed to investigate the effect of different helical shapes on the helical pile installation and the axial compression loading bearing pressure. The various helical shapes were designed using 3D printing technology. The high strength Polylactic acid Plus (PLA-Plus) material was used for printing different helical shapes. The helical pile's installation was accomplished by coupling the shaft of the helical pile to a torque engine that rotates the helical pile in the soil. After installing the pile to a predetermined depth, compression loading tests were conducted on helical piles under a constant strain rate. The results illustrate that the helix shape has a significant influence on the performance of the helical pile. The multi-pitch helix produces an 18% increase in bearing pressure compared to the traditional helix. The helix diameter has exhibited a significant influence on the helical pile bearing pressure. Moreover, an empirical equation was proposed to estimate the coefficient of torque ( K t ) using the helical pile embedment area for measuring the bearing capacity and installation torque of the helical pile. [ABSTRACT FROM AUTHOR]

Anal squamous cell carcinoma (ASCC) is associated with immunosuppression and infection with human papillomavirus (HPV). Response to standard chemoradiotherapy (CRT) varies considerably. A comprehensive molecular characterization of CRT resistance is lacking, and little is known about the interplay between tumor immune contexture, host immunity, and immunosuppressive and/or immune activating effects of CRT. Patients with localized ASCC, treated with CRT at three different sites of the German Cancer Consortium (DKTK) were included. Patient cohorts for molecular analysis included baseline formalin fixed paraffin embedded biopsies for immunohistochemistry (n = 130), baseline RNA sequencing (n = 98), peripheral blood immune profiling (n = 47), and serum cytokine measurement (n = 35). Gene set enrichment analysis showed that pathways for IFNγ, IFNα, inflammatory response, TNFα signaling via NF-κB, and EMT were significantly enriched in poor responders (all p < 0.001). Expression of interferon-induced transmembrane protein 1 (IFITM1), both on mRNA and protein levels, was associated with reduced Freedom from locoregional failure (FFLF, p = 0.037) and freedom from distant metastasis (FFDM, p = 0.014). An increase of PD-L1 expression on CD4+ T-cells (p < 0.001) and an increase in HLA-DR expression on T-cells (p < 0.001) was observed in the peripheral blood after CRT. Elevated levels of regulatory T-cells and CXCL2 were associated with reduced FFLF (p = 0.0044 and p = 0.004, respectively). Inflammatory pathways in tissue in line with elevated levels of regulatory T-cells and CXCL2 in peripheral blood are associated with resistance to CRT. To counteract this resistance mechanism, the RADIANCE randomized phase-2 trial currently tests the addition of the immune checkpoint inhibitor durvalumab to standard CRT in locally advanced ASCC. [ABSTRACT FROM AUTHOR]

Optogenetics has transformed studies of neural circuit function, but remains challenging to apply to non-human primates (NHPs). A major challenge is delivering intense, spatiotemporally-precise, patterned photostimulation across large volumes in deep tissue. Such stimulation is critical, for example, to modulate selectively deep-layer corticocortical feedback circuits. To address this need, we have developed the Utah Optrode Array (UOA), a 10×10 glass needle waveguide array fabricated atop a novel opaque optical interposer, and bonded to an electrically addressable µLED array. In vivo experiments with the UOA demonstrated large-scale, spatiotemporally precise, activation of deep circuits in NHP cortex. Specifically, the UOA permitted both focal (confined to single layers/columns), and widespread (multiple layers/columns) optogenetic activation of deep layer neurons, as assessed with multi-channel laminar electrode arrays, simply by varying the number of activated µLEDs and/or the irradiance. Thus, the UOA represents a powerful optoelectronic device for targeted manipulation of deep-layer circuits in NHP models. A novel device for selective large-scale optogenetic manipulation of the deep layers of cortical circuits in non-human primates is presented and validated using electrophysiological recordings and c-fos imaging in macaque visual cortex. [ABSTRACT FROM AUTHOR]

Despite increasing risks from sea-level rise (SLR) and storms, US coastal communities continue to attract relatively high-income residents, and coastal property values continue to rise. To understand this seeming paradox and explore policy responses, we develop the Coastal Home Ownership Model (C-HOM) and analyze the long-term evolution of coastal real estate markets. C-HOM incorporates changing physical attributes of the coast, economic values of these attributes, and dynamic risks associated with storms and flooding. Resident owners, renters, and non-resident investors jointly determine coastal property values and the policy choices that influence the physical evolution of the coast. In the coupled system, we find that subsidies for coastal management, such as beach nourishment, tax advantages for high-income property owners, and stable or increasing property values outside the coastal zone all dampen the effects of SLR on coastal property values. The effects, however, are temporary and only delay precipitous declines as total inundation approaches. By removing subsidies, prices would more accurately reflect risks from SLR but also trigger more coastal gentrification, as relatively high-income owners enter the market and self-finance nourishment. Our results suggest a policy tradeoff between slowing demographic transitions in coastal communities and allowing property markets to adjust smoothly to risks from climate change. Subsidies for coastal management and tax advantages for high-income property owners dampen the negative effects of climate risks on coastal property values. Without subsidies or tax advantages market prices better reflect climate risks, but coastal gentrification could accelerate. [ABSTRACT FROM AUTHOR]

The rapid advancement of 9 Be + ion-based quantum computing is creating a high demand for scalable and specialized laser sources. For this purpose, laser radiation at 313 nm is necessary which is generated by frequency doubling of 626 nm laser emission. Laser sources in this spectral region lack simplicity and need to be miniaturized. We carry out a systematic improvement of room temperature semiconductor laser structures emitting at 626 nm. They are based on a GaInP single quantum well embedded in AlGaInP grown on GaAs. We first investigate the structure theoretically and determine its limits and optima. We select the three most promising quantum well combinations, which are grown by metal-organic vapor-phase epitaxy. Furthermore, we fabricate broad-area lasers with dimensions of 1600 μ m × 100 μ m. All structures show laser operation around 626 nm. We are able to achieve a threshold current density of 721 A/cm2, a slope of 0.384 mW/mA and total maximum output power of 708 mW under pulsed excitation. Based on these results, we believe that quantum computing focusing on beryllium ions will highly benefit from these results. [ABSTRACT FROM AUTHOR]

Significant progress in our knowledge of Beringian biodiversity and in the technologies available for biodiversity research has been made in the several decades since a comprehensive biogeographic synthesis of Beringian freshwater fishes was compiled and published in 1986. Further, the fish fauna of Beringia and, more broadly, of high latitude freshwater systems of the northern hemisphere face some of the most intense well documented effects of global climate change. Here we synthesize current understanding of how the dynamic spatial and ecological landscapes of Pleistocene glaciations have shaped the distribution of taxonomic and genetic diversity in fish faunas of Beringia. Through a more complete integration of knowledge obtained in studies of fishes in Russian drainages, we aimed to identify promising strategies to test alternative biogeographic hypotheses on the roles played by the Bering land bridge, paleorivers and glacial history in intercontinental faunal movement. We focus on freshwater fishes of the Bering Strait region, which live in an environment that is premised on extreme instability and profound changes in long-term connectivity for fishes and offers opportunities to assess long-term evolutionary trends in both speciation and life history variation. Such information is critical for both our scientific understanding of evolutionary processes in fishes and valuable for those tasked with the challenges of management and conservation of natural resources in this expansive, dynamic and remote region. We provide an overview of Beringian freshwater ichthyofauna and examine genetic differentiation among population units within these lineages. We also examine evidence for how long population units have been separated based on historic glacially-related separations and the more recent marine barrier of the Bering Strait that constrains freshwater or diadromous species based on their ability to disperse in salt water. Our review concludes on how Arctic and sub-Arctic fishes may adapt and persist in their dynamic environment considering low genetic diversity, the role of adaptive introgression, and epigenetic variation. We find that Beringian fishes may poorly fit traditional taxonomic categories and the designation of conservation units below the species level may be of great practical application. Furthermore, as hybridization is documented to increase in the Arctic, the use of this process for ecological monitoring may also be of high utility with Beringian fishes. [ABSTRACT FROM AUTHOR]

Introduction: Identification of liver disease during bariatric operations is an important task given the patients risk for occult fatty liver disease. Surgeon's accuracy of assessing for liver disease during an operation is poorly understood. The objective was to measure surgeons' performance on intra-operative visual assessment of the liver in a simulated environment. Methods: Liver images from 100 patients who underwent laparoscopic bariatric surgery and pre-operative ultrasound elastography between July 2020 and July 2021 were retrospectively evaluated. The perception of 15 surgeons regarding the degree of hepatic steatosis and fibrosis was collected in a simulated clinical environment by survey and compared to results determined by ultrasonographic exam. Results: The surgeons' ability to correctly identify the class of steatosis and fibrosis was poor (accuracy 61% and 59%, respectively) with a very weak correlation between the surgeon's predicted class and its true class (r = 0.17 and r = 0.12, respectively). When liver disease was present, surgeons completely missed its presence in 26% and 51% of steatosis and fibrosis, respectively. Digital image processing demonstrated that surgeons subjectively classified steatosis based on the "yellowness" of the liver and fibrosis based on texture of the liver, despite neither correlating with the true degree of liver disease. Conclusion: Laparoscopic visual assessment of the liver surface for identification of non-cirrhotic liver disease was found to be an inaccurate method during laparoscopic bariatric surgery. While validation studies are needed, the results suggest the clinical need for alternative approaches. [ABSTRACT FROM AUTHOR]

Multi-layered thermal barrier coatings (TBCs) are deposited on gas turbine metallic components to protect them against high temperatures, oxidation, and corrosion. However, TBCs have limited working temperatures and lifetimes due to their material properties. Several approaches are tested to increase TBC topcoats' phase stability and properties. Increasing entropy to stabilize phases is a concept introduced in 2004 and required decreasing the Gibbs free energy. Many high entropy ceramics are developed for structural and functional applications, and different types of high entropy oxides (HEOs) are promising TBC ceramics due to their unique characteristics. HEOs are single-phase solid solutions that contain five or more cations, usually a mixture of transition metals and rare-earth elements. Due to the cocktail effect, the final material has a different behavior from its constituents, making it a viable method to improve the properties of traditional materials. Generally, high entropy materials are characterized by three additional phenomena: sluggish diffusion, severe lattice distortion, and high entropy. A review of possible improvements in the lifetime of TBC topcoats using different HEOs in terms of their composition, properties, and stability is presented here. Different HEOs are then examined, and various thermophysical properties, high-temperature stability, and sintering resistance are discussed. [ABSTRACT FROM AUTHOR]

The precision in reconstructing events detected in a dual-phase time projection chamber depends on an homogeneous and well understood electric field within the liquid target. In the XENONnT TPC the field homogeneity is achieved through a double-array field cage, consisting of two nested arrays of field shaping rings connected by an easily accessible resistor chain. Rather than being connected to the gate electrode, the topmost field shaping ring is independently biased, adding a degree of freedom to tune the electric field during operation. Two-dimensional finite element simulations were used to optimize the field cage, as well as its operation. Simulation results were compared to 83 m Kr calibration data. This comparison indicates an accumulation of charge on the panels of the TPC which is constant over time, as no evolution of the reconstructed position distribution of events is observed. The simulated electric field was then used to correct the charge signal for the field dependence of the charge yield. This correction resolves the inconsistent measurement of the drift electron lifetime when using different calibrations sources and different field cage tuning voltages. [ABSTRACT FROM AUTHOR]

Purpose: Vascularized lymph node transfer (VLNT) entails the autologous relocation of lymph nodes to a lymphedematous region of the body, whereas lymphaticovenous anastomosis (LVA) creates a direct bypass between the lymphatic and venous system. Both techniques are meant to lastingly bolster the local lymphatic drainage capacity. This study compared safety and effectiveness of VLNT and LVA in patients with chronic breast cancer related lymphedema (BCRL). Methods: A retrospective cohort study was conducted using data from our encrypted database composed of patients with chronic BCRL who were treated with either VLNT or LVA and had a minimum follow-up of two years. Patient-specific variables analyzed included pre- and postoperative arm circumferences, lymphedema stages and postoperative complications. Results: A total of 105 patients met the inclusion criteria, of which 96 patients demonstrated a complete follow-up period of two years. The VLNT group displayed larger preoperative circumferential measurements, evident in both in the isolated examination of the affected arm, as well as when adjusted for the contralateral unaffected arm. Significant reduction in arm volume was achieved by both groups. However, VLNT demonstrated superior relative reduction rates than LVA, neutralizing any significant arm size disparities after 24 months. Surgery duration was slightly longer for VLNT than LVA. Postoperative complications, predominantly minor, were exclusively observed in the VLNT group. Conclusions: Both VLNT and LVA offer significant improvement for patients suffering from chronic BCRL. VLNT shows an even greater potential for improvement in more severe cases of BCRL, but involves a higher risk for (mostly minor) complications. [ABSTRACT FROM AUTHOR]

Recent years have seen revived interest in computer-assisted organic synthesis1,2. The use of reaction- and neural-network algorithms that can plan multistep synthetic pathways have revolutionized this field1,3–7, including examples leading to advanced natural products6,7. Such methods typically operate on full, literature-derived ‘substrate(s)-to-product’ reaction rules and cannot be easily extended to the analysis of reaction mechanisms. Here we show that computers equipped with a comprehensive knowledge-base of mechanistic steps augmented by physical-organic chemistry rules, as well as quantum mechanical and kinetic calculations, can use a reaction-network approach to analyse the mechanisms of some of the most complex organic transformations: namely, cationic rearrangements. Such rearrangements are a cornerstone of organic chemistry textbooks and entail notable changes in the molecule’s carbon skeleton8–12. The algorithm we describe and deploy at generates, within minutes, networks of possible mechanistic steps, traces plausible step sequences and calculates expected product distributions. We validate this algorithm by three sets of experiments whose analysis would probably prove challenging even to highly trained chemists: (1) predicting the outcomes of tail-to-head terpene (THT) cyclizations in which substantially different outcomes are encoded in modular precursors differing in minute structural details; (2) comparing the outcome of THT cyclizations in solution or in a supramolecular capsule; and (3) analysing complex reaction mixtures. Our results support a vision in which computers no longer just manipulate known reaction types1–7 but will help rationalize and discover new, mechanistically complex transformations.Computers equipped with a comprehensive knowledge-base of mechanistic steps augmented by physical-organic chemistry rules, as well as quantum mechanical and kinetic calculations, can use a reaction-network approach to analyse the mechanisms of cationic rearrangements. [ABSTRACT FROM AUTHOR]

Burkitt lymphoma (BL) is responsible for many childhood cancers in sub-Saharan Africa, where it is linked to recurrent or chronic infection by Epstein-Barr virus or Plasmodium falciparum. However, whether human leukocyte antigen (HLA) polymorphisms, which regulate immune response, are associated with BL has not been well investigated, which limits our understanding of BL etiology. Here we investigate this association among 4,645 children aged 0-15 years, 800 with BL, enrolled in Uganda, Tanzania, Kenya, and Malawi. HLA alleles are imputed with accuracy >90% for HLA class I and 85-89% for class II alleles. BL risk is elevated with HLA-DQA1*04:01 (adjusted odds ratio [OR] = 1.61, 95% confidence interval [CI] = 1.32-1.97, P = 3.71 × 10−6), with rs2040406(G) in HLA-DQA1 region (OR = 1.43, 95% CI = 1.26-1.63, P = 4.62 × 10−8), and with amino acid Gln at position 53 versus other variants in HLA-DQA1 (OR = 1.36, P = 2.06 × 10−6). The associations with HLA-DQA1*04:01 (OR = 1.29, P = 0.03) and rs2040406(G) (OR = 1.68, P = 0.019) persist in mutually adjusted models. The higher risk rs2040406(G) variant for BL is associated with decreased HLA-DQB1 expression in eQTLs in EBV transformed lymphocytes. Our results support the role of HLA variation in the etiology of BL and suggest that a promising area of research might be understanding the link between HLA variation and EBV control. A study of 4,645 children in four countries in East Africa, 800 with Burkitt lymphoma (BL), identifies an association between HLA-DQA1*04:01 and variant rs2040406(G) and elevated risk of BL in Africa. [ABSTRACT FROM AUTHOR]

The origin of vertebrate paired appendages is one of the most investigated and debated examples of evolutionary novelty1–7. Paired appendages are widely considered as key innovations that enabled new opportunities for controlled swimming and gill ventilation and were prerequisites for the eventual transition from water to land. The past 150 years of debate8–10 has been shaped by two contentious theories4,5: the ventrolateral fin-fold hypothesis9,10 and the archipterygium hypothesis8. The latter proposes that fins and girdles evolved from an ancestral gill arch. Although studies in animal development have revived interest in this idea11–13, it is apparently unsupported by fossil evidence. Here we present palaeontological support for a pharyngeal basis for the vertebrate shoulder girdle. We use computed tomography scanning to reveal details of the braincase of Kolymaspis sibirica14, an Early Devonian placoderm fish from Siberia, that suggests a pharyngeal component of the shoulder. We combine these findings with refreshed comparative anatomy of placoderms and jawless outgroups to place the origin of the shoulder girdle on the sixth branchial arch. These findings provide a novel framework for understanding the origin of the pectoral girdle. Our evidence clarifies the location of the presumptive head–trunk interface in jawless fishes and explains the constraint on branchial arch number in gnathostomes15. The results revive a key aspect of the archipterygium hypothesis and help reconcile it with the ventrolateral fin-fold model.Computed tomography analysis of the braincase of the Early Devonian placoderm fish Kolymaspis sibirica suggests a skeletal gill support was involved in the origin of the shoulder girdle and provides new evidence reconciling historic theories about the evolution of paired fins. [ABSTRACT FROM AUTHOR]

Background: Anastomotic leak after esophagectomy is associated with significant morbidity and mortality. Our institution began performing laparoscopic gastric ischemic preconditioning (LGIP) with ligation of the left gastric and short gastric vessels prior to esophagectomy in all patients presenting with resectable esophageal cancer. We hypothesized that LGIP may decrease the incidence and severity of anastomotic leak. Methods: Patients were prospectively evaluated following the universal application of LGIP prior to esophagectomy protocol in January 2021 until August 2022. Outcomes were compared with patients who underwent esophagectomy without LGIP from a prospectively maintained database from 2010 to 2020. Results: We compared 42 patients who underwent LGIP followed by esophagectomy with 222 who underwent esophagectomy without LGIP. Age, sex, comorbidities, and clinical stage were similar between groups. Outpatient LGIP was generally well tolerated, with one patient experiencing prolonged gastroparesis. Median time from LGIP to esophagectomy was 31 days. Mean operative time and blood loss were not significantly different between groups. Patients who underwent LGIP were significantly less likely to develop an anastomotic leak following esophagectomy (7.1% vs. 20.7%, p = 0.038). This finding persisted on multivariate analysis [odds ratio (OR) 0.17, 95% confidence interval (CI) 0.03–0.42, p = 0.029]. The occurrence of any post-esophagectomy complication was similar between groups (40.5% vs. 46.0%, p = 0.514), but patients who underwent LGIP had shorter length of stay [10 (9–11) vs. 12 (9–15), p = 0.020]. Conclusions: LGIP prior to esophagectomy is associated with a decreased risk of anastomotic leak and length of hospital stay. Further, multi-institutional studies are warranted to confirm these findings. [ABSTRACT FROM AUTHOR]

The spatial organization of the tumor microenvironment has a profound impact on biology and therapy response. Here, we perform an integrative single-cell and spatial transcriptomic analysis on HPV-negative oral squamous cell carcinoma (OSCC) to comprehensively characterize malignant cells in tumor core (TC) and leading edge (LE) transcriptional architectures. We show that the TC and LE are characterized by unique transcriptional profiles, neighboring cellular compositions, and ligand-receptor interactions. We demonstrate that the gene expression profile associated with the LE is conserved across different cancers while the TC is tissue specific, highlighting common mechanisms underlying tumor progression and invasion. Additionally, we find our LE gene signature is associated with worse clinical outcomes while TC gene signature is associated with improved prognosis across multiple cancer types. Finally, using an in silico modeling approach, we describe spatially-regulated patterns of cell development in OSCC that are predictably associated with drug response. Our work provides pan-cancer insights into TC and LE biology and interactive spatial atlases (http://www.pboselab.ca/spatial%5fOSCC/; http://www.pboselab.ca/dynamo%5fOSCC/) that can be foundational for developing novel targeted therapies. Oral squamous cell carcinoma is known to contain altered tumour cells within both the tumour core and leading edge. Here, the authors utilise spatial transcriptomics to characterise differences in gene expression and ligand-receptor architecture between areas of the tumour. [ABSTRACT FROM AUTHOR]

Purpose: Dysregulated expression of heat shock proteins (HSP) plays a fundamental role in tumor development and progression. Consequently, HSP90 may be an effective tumor target in oncology, including the treatment of gastrointestinal cancers. Methods: We carried out a systematic review of data extracted from clinicaltrials.gov and pubmed.gov, which included all studies available until January 1st, 2022. The published data was evaluated using primary and secondary endpoints, particularly with focus on overall survival, progression-free survival, and rate of stable disease. Results: Twenty trials used HSP90 inhibitors in GI cancers, ranging from phase I to III clinical trials. Most studies assessed HSP90 inhibitors as a second line treatment. Seventeen of the 20 studies were performed prior to 2015 and only few studies have results pending. Several studies were terminated prematurely, due to insufficient efficacy or toxicity. Thus far, the data suggests that HSP90 inhibitor NVP-AUY922 might improve outcome for colorectal cancer and gastrointestinal stromal tumors. Conclusion: It currently remains unclear which subgroup of patients might benefit from HSP90 inhibitors and at what time point these inhibitors may be beneficial. There are only few new or ongoing studies initiated during the last decade. [ABSTRACT FROM AUTHOR]

Purpose: Our aim is to describe the role of immune checkpoint inhibitors (ICI) in clinical practice by providing the patient and tumor characteristics as well as survival and toxicity rates by sex. Methods: We used electronic health records to identify patients treated at the Cancer Center of the University Hospital Bern, Switzerland between January 1, 2017 and June 16, 2021. Results: We identified 5109 patients, 689 of whom (13.5%) received at least one dose of ICI. The fraction of patients who were prescribed ICI increased from 8.6% in 2017 to 22.9% in 2021. ICI represented 13.2% of the anticancer treatments in 2017 and increased to 28.2% in 2021. The majority of patients were male (68.7%), who were older than the female patients (median age 67 vs. 61 years). Over time, adjuvant and first line treatments increased for both sexes. Lung cancer and melanoma were the most common cancer types in males and females. The incidence of irAEs was higher among females (38.4% vs. 28.1%) and lead more often to treatment discontination in females than in males (21.1% vs. 16.8%). Independent of sex, the occurrence of irAEs was associated with greater median overall survival (OS, not reached vs. 1.1 years). Female patients had a longer median OS than males (1.9 vs. 1.5 years). Conclusions: ICI play an increasingly important role in oncology. irAEs are more frequent in female patients and are associated with a longer OS. More research is needed to understand the association between patient sex and toxicity and survival. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-33 is a broad-acting alarmin cytokine that can drive inflammatory responses following tissue damage or infection and is a promising target for treatment of inflammatory disease. Here, we describe the identification of tozorakimab (MEDI3506), a potent, human anti-IL-33 monoclonal antibody, which can inhibit reduced IL-33 (IL-33red) and oxidized IL-33 (IL-33ox) activities through distinct serum-stimulated 2 (ST2) and receptor for advanced glycation end products/epidermal growth factor receptor (RAGE/EGFR complex) signalling pathways. We hypothesized that a therapeutic antibody would require an affinity higher than that of ST2 for IL-33, with an association rate greater than 107 M−1 s−1, to effectively neutralize IL-33 following rapid release from damaged tissue. An innovative antibody generation campaign identified tozorakimab, an antibody with a femtomolar affinity for IL-33red and a fast association rate (8.5 × 107 M−1 s−1), which was comparable to soluble ST2. Tozorakimab potently inhibited ST2-dependent inflammatory responses driven by IL-33 in primary human cells and in a murine model of lung epithelial injury. Additionally, tozorakimab prevented the oxidation of IL-33 and its activity via the RAGE/EGFR signalling pathway, thus increasing in vitro epithelial cell migration and repair. Tozorakimab is a novel therapeutic agent with a dual mechanism of action that blocks IL-33red and IL-33ox signalling, offering potential to reduce inflammation and epithelial dysfunction in human disease. [ABSTRACT FROM AUTHOR]

A low-energy electronic recoil calibration of XENON1T, a dual-phase xenon time projection chamber, with an internal 37 Ar source was performed. This calibration source features a 35-day half-life and provides two mono-energetic lines at 2.82 keV and 0.27 keV. The photon yield and electron yield at 2.82 keV are measured to be ( 32.3 ± 0.3 ) photons/keV and ( 40.6 ± 0.5 ) electrons/keV, respectively, in agreement with other measurements and with NEST predictions. The electron yield at 0.27 keV is also measured and it is ( 68. 0 - 3.7 + 6.3 ) electrons/keV. The 37 Ar calibration confirms that the detector is well-understood in the energy region close to the detection threshold, with the 2.82 keV line reconstructed at ( 2.83 ± 0.02 ) keV, which further validates the model used to interpret the low-energy electronic recoil excess previously reported by XENON1T. The ability to efficiently remove argon with cryogenic distillation after the calibration proves that 37 Ar can be considered as a regular calibration source for multi-tonne xenon detectors. [ABSTRACT FROM AUTHOR]

The salivary gland section in the 5th edition of the World Health Organization Classification of Head and Neck Tumours includes a description of several new entities. In addition, numerous tumor variants were described and new concepts proposed, most of which have been based on recent molecular discoveries. However, there are still some controversial issues that remain to be resolved, and some of them are discussed in this review. [ABSTRACT FROM AUTHOR]

Environmental controls of species diversity represent a central research focus in evolutionary biology. In the marine realm, sharks are widely distributed, occupying mainly higher trophic levels and varied dietary preferences, mirrored by several morphological traits and behaviours. Recent comparative phylogenetic studies revealed that sharks present a fairly uneven diversification across habitats, from reefs to deep-water. We show preliminary evidence that morphological diversification (disparity) in the feeding system (mandibles) follows these patterns, and we tested hypotheses linking these patterns to morphological specialisation. We conducted a 3D geometric morphometric analysis and phylogenetic comparative methods on 145 specimens representing 90 extant shark species using computed tomography models. We explored how rates of morphological evolution in the jaw correlate with habitat, size, diet, trophic level, and taxonomic order. Our findings show a relationship between disparity and environment, with higher rates of morphological evolution in reef and deep-water habitats. Deep-water species display highly divergent morphologies compared to other sharks. Strikingly, evolutionary rates of jaw disparity are associated with diversification in deep water, but not in reefs. The environmental heterogeneity of the offshore water column exposes the importance of this parameter as a driver of diversification at least in the early part of clade history. Macroevolutionary analyses of shark mandible form and function reveal links between jaw shape disparity and habitat preference. [ABSTRACT FROM AUTHOR]

A comprehensive evaluation of the total burden of morbidity endured by cancer survivors remains unavailable. This study quantified the burden of 144 health conditions and critical care admissions across 26 adult cancers and treatment modalities in 243,767 adults. By age 60, top conditions ranked by fold difference (cumulative burden in survivors divided by cumulative burden in controls) were haematology, immunology/infection and pulmonary conditions. Patients who had all three forms of treatment (chemotherapy, radiotherapy and surgery) experienced a high cumulative burden of late morbidities compared with patients who received radiotherapy alone. The top five cancers with the highest cumulative burden of critical care admissions by age 60 were bone (12.4 events per 100 individuals [CI: 11.6-13.1]), brain (9.0 [7.5-10.5]), spinal cord and nervous system (7.2 [6.7-7.8]), testis (6.7 [4.9-8.4]) and Hodgkin lymphoma (4.4 [3.6-5.1]). Conditions that were associated with high excess years-of-life-lost were haematological conditions (9.6 years), pulmonary conditions (8.6 years) and immunological conditions or infections (7.8 years). As the population of cancer survivors continues to grow, our results indicate that it is important to tackle long-term health consequences through enacting data-driven policies. Here the authors evaluate the burden of 144 health conditions in adult cancer survivors, and show that the magnitude of late morbidities experienced by survivors varies according to the type of cancer and treatment, highlighting opportunities for optimising patient care [ABSTRACT FROM AUTHOR]

The control of tetrahedral carbon stereocentres remains a focus of modern synthetic chemistry and is enabled by their configurational stability. By contrast, trisubstituted nitrogen1, phosphorus2 and sulfur compounds3 undergo pyramidal inversion, a fundamental and well-recognized stereochemical phenomenon that is widely exploited4. However, the stereochemistry of oxonium ions—compounds bearing three substituents on a positively charged oxygen atom—is poorly developed and there are few applications of oxonium ions in synthesis beyond their existence as reactive intermediates5,6. There are no examples of configurationally stable oxonium ions in which the oxygen atom is the sole stereogenic centre, probably owing to the low barrier to oxygen pyramidal inversion7 and the perception that all oxonium ions are highly reactive. Here we describe the design, synthesis and characterization of a helically chiral triaryloxonium ion in which inversion of the oxygen lone pair is prevented through geometric restriction to enable it to function as a determinant of configuration. A combined synthesis and quantum calculation approach delineates design principles that enable configurationally stable and room-temperature isolable salts to be generated. We show that the barrier to inversion is greater than 110 kJ mol−1 and outline processes for resolution. This constitutes, to our knowledge, the only example of a chiral non-racemic and configurationally stable molecule in which the oxygen atom is the sole stereogenic centre.The design, synthesis and characterization of a helically chiral triaryloxonium ion is reported, which is an example of a chiral non-racemic and configurationally stable molecule in which the oxygen atom is the sole stereogenic centre. [ABSTRACT FROM AUTHOR]

Background: Oral ulcers represent a full thickness loss of the mucosal epithelium leading to exposure of the submucosal connective tissue. These are common and usually self-limited lesions, although they may sometimes result from neoplasms, most commonly squamous cell carcinoma. Lymphoproliferative disorders may be difficult to diagnose in apthous ulcers since they mimic reactive inflammation. Methods: This review presents ten rare oral lymphoid proliferations which should not be missed when assessing oral ulcer biopsies. Results: The ten lesions include several with diagnostic cells which look similar to the histiocytes of a reactive inflammatory ulcer, including Rosai–Dorfman disease, reticulohistiocytoma, Langerhans cell histiocytosis, and traumatic ulcerative granuloma. Other lesions, such as EBV-positive mucocutaneous ulcer, extranodal marginal zone lymphoma of mucosal-associated lymphoid tissue, and plasmablastic lymphoma have lymphoid and/or plasma cell differentiation that mimic the reactive lymphocytes and plasma cells found in reactive ulcers. Two dendritic cell lesions, follicular dendritic cell sarcoma and blastic plasmacytoid dendritic cell neoplasm, both have distinct phenotypes which are required to make an accurate diagnosis. Conclusion: Each of these lesions are diagnosed by evaluating their histology, along with their phenotypic profile, which is sometimes enhanced by pertinent molecular findings. [ABSTRACT FROM AUTHOR]

Purpose: A cornerstone of treatment for many cancers is the administration of platinum-based chemotherapies and/or ionizing radiation, which can be ototoxic. An accurate ototoxicity risk assessment would be useful for counseling, treatment planning, and survivorship follow-up in patients with cancer. Methods: This systematic review evaluated the literature on predictive models for estimating a patient's risk for chemotherapy-related auditory injury to accelerate development of computational approaches for the clinical management of ototoxicity in cancer patients. Of the 1195 articles identified in a PubMed search from 2010 forward, 15 studies met inclusion for the review. Conclusions: All but 1 study used an abstraction of the audiogram as a modeled outcome; however, specific outcome measures varied. Consistently used predictors were age, baseline hearing, cumulative cisplatin dose, and radiation dose to the cochlea. Just 5 studies were judged to have an overall low risk of bias. Future studies should attempt to minimize bias by following statistical best practices including not selecting multivariate predictors based on univariate analysis, validation in independent cohorts, and clearly reporting the management of missing and censored data. Future modeling efforts should adopt a transdisciplinary approach to define a unified set of clinical, treatment, and/or genetic risk factors. Creating a flexible model that uses a common set of predictors to forecast the full post-treatment audiogram may accelerate work in this area. Such a model could be adapted for use in counseling, treatment planning, and follow-up by audiologists and oncologists and could be incorporated into ototoxicity genetic association studies as well as clinical trials investigating otoprotective agents. Implications for Cancer Survivors: Improvements in the ability to model post-treatment hearing loss can help to improve patient quality of life following cancer care. The improvements advocated for in this review should allow for the acceleration of advancements in modeling the auditory impact of these treatments to support treatment planning and patient counseling during and after care. [ABSTRACT FROM AUTHOR]

Both current live, attenuated, and killed virus vaccines for bovine viral diarrhea virus (BVDV) have their limitations. Here, we report the development of a BVDV subunit vaccine by (i) the expression of a secreted form of a recombinant E2 glycoprotein using BHK21 cells and (ii) determination of the immune responses in mice. The E2 glycoprotein was modified by deletion of the C-terminal transmembrane anchor domain and fusion to a V5 epitope tag. This allowed detection using anti-V5 monoclonal antibodies together with simple purification of the expressed, secreted, form of E2 from the cell media. Furthermore, we genetically fused green fluorescent protein (GFP) linked to E2 via a Thosea asigna virus 2A (T2A) ribosome skipping sequence thereby creating a self-processing polyprotein [GFP-T2A-BVDV-E2trunk-V5], producing discrete [GFP-T2A] and [E2trunk-V5] translation products: GFP fluorescence acts, therefore, as a surrogate marker of E2 expression, BALB/c mice were inoculated with [E2trunk-V5] purified from cell media and both humoral and cellular immune responses were observed. Our antigen expression system provides, therefore, both (i) a simple antigen purification protocol together with (ii) a feasible strategy for further, large-scale, production of vaccines. [ABSTRACT FROM AUTHOR]

Purpose of Review: Bound to its high affinity receptor on mast cells and basophils, the IgE antibody molecule plays an integral role in the allergic reaction. Through interactions with the allergen, it provides the sensitivity and specificity parameters for cell activation and mediator release that produce allergic symptoms. Advancements in human hybridoma technologies allow for the generation and molecular definition of naturally occurring allergen-specific human IgE monoclonal antibodies. Recent Findings: A high-resolution structure of dust mite allergen Der p 2 in complex with Fab of the human IgE mAb 2F10 was recently determined using X-ray crystallography. The structure reveals the fine molecular details of IgE 2F10 binding its 750 Å2 conformational epitope on Der p 2. Summary: This review provides an overview of this major milestone in allergy, the first atomic resolution structure of an authentic human IgE epitope. The molecular insights that IgE epitopes provide will allow for structure-based design approaches to the development of novel diagnostics, antibody therapeutics, and immunotherapies. [ABSTRACT FROM AUTHOR]

A monoclonal antibody's (mAb) glycosylation pattern has a significant impact on its binding affinity to the FcγRIIIa receptor and thus on antibody-dependent cell-mediated cytotoxicity. However, to analyze the relation in cell cultures, complex sample preparation is required. In this study, we demonstrate the analytical capability of a two-dimensional liquid chromatography–mass spectrometry (2D-HPLC–HRMS) method to analyze the affinity of mAbs to the FcγRIIIa receptor while simultaneously characterizing the glycoforms involved. Results were comparable in purified samples and cell culture-free supernatants. This was demonstrated with the monoclonal antibodies adalimumab, pertuzumab, ustekinumab, tocilizumab and omalizumab. Our method hence renders extensive purification of mAb samples superfluous. [ABSTRACT FROM AUTHOR]

Harnessing the full complexity of optical fields requires the complete control of all degrees of freedom within a region of space and time—an open goal for present-day spatial light modulators, active metasurfaces and optical phased arrays. Here, we resolve this challenge with a programmable photonic crystal cavity array enabled by four key advances: (1) near-unity vertical coupling to high-finesse microcavities through inverse design; (2) scalable fabrication by optimized 300 mm full-wafer processing; (3) picometre-precision resonance alignment using automated, closed-loop 'holographic trimming'; and (4) out-of-plane cavity control via a high-speed μLED array. Combining each, we demonstrate the near-complete spatiotemporal control of a 64 resonator, two-dimensional spatial light modulator with nanosecond- and femtojoule-order switching. Simultaneously operating wavelength-scale modes near the space–bandwidth and time–bandwidth limits, this work opens a new regime of programmability at the fundamental limits of multimode optical control. Englund et al. demonstrate a programmable photonic crystal cavity array, enabling the spatiotemporal control of a 64 resonator, two-dimensional spatial light modulator with nanosecond- and femtojoule-order switching. [ABSTRACT FROM AUTHOR]

Coastal response to anthropogenic climate change is of central importance to the infrastructure and inhabitants in these areas. Despite being globally ubiquitous, the stability of rock coasts has been largely neglected, and the expected acceleration of cliff erosion following sea-level rise has not been tested with empirical data, until now. We have optimised a coastal evolution model to topographic and cosmogenic radionuclide data to quantify cliff retreat rates for the past 8000 years and forecast rates for the next century. Here we show that rates of cliff retreat will increase by up to an order of magnitude by 2100 according to current predictions of sea-level rise: an increase much greater than previously predicted. This study challenges conventional coastal management practices by revealing that even historically stable rock coasts are highly sensitive to sea-level rise and should be included in future planning for global climate change response. Results forecast that cliff retreat rates will increase by up to an order of magnitude by 2100 according to current predictions of sea-level rise, and reveal that even historically stable rock coasts are highly sensitive to sea-level rise. [ABSTRACT FROM AUTHOR]

Smoking is a leading risk factor for many of the top ten causes of death worldwide. Of the 1.3 billion smokers globally, 80% live in low- and middle-income countries, where the number of deaths due to tobacco use is expected to double in the next decade according to the World Health Organization. Genetic studies have helped to identify biological pathways for smoking behaviours, but have mostly focussed on individuals of European ancestry or living in either North America or Europe. We performed a genome-wide association study of two smoking behaviour traits in 10,558 men of African ancestry living in five African countries and the UK. Eight independent variants were associated with either smoking initiation or cessation at P-value < 5 × 10–6, four being monomorphic or rare in European populations. Gene prioritisation strategy highlighted five genes, including SEMA6D, previously described as associated with several smoking behaviour traits. These results confirm the importance of analysing underrepresented populations in genetic epidemiology, and the urgent need for larger genomic studies to boost discovery power to better understand smoking behaviours, as well as many other traits. [ABSTRACT FROM AUTHOR]