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Studies have demonstrated the positive impact of the Learning Assistant (LA) model on student learning across various disciplines, demographics, and course types. In order to investigate the effect of exposure to the LA program on student learning and success in a large Chemistry course, a pilot was launched in one of two sections of General Chemistry II at Florida Atlantic University (FAU) in spring 2020, with the addition of LAs as the sole experimental variable. The researchers hypothesized that the LA model positively impacts equity in the classroom with increased learning gains across student demographics. A t-test was used to determine the significance in differences between student exam scores in the LA and non-LA section. The researchers found that student learning was significantly higher in the LA section versus the non-LA section (p < 0.01). Students participating in the LA section (N = 275) had stronger outcomes than students in the non-LA section (N = 290). In addition, students in the LA section were more likely to pass the course, enroll in the subsequent (Organic Chemistry) course within one year, and were more likely to be retained at the institution. These success rates held for all students, particularly for students historically underrepresented in chemistry.

Interconnect resistance and reliability have emerged as critical factors limiting the performance of advanced CMOS circuits. With the slowdown of transistor scaling, interconnect scaling has become the primary driver of continued circuit miniaturization. The associated scaling challenges for interconnects are expected to further intensify in future CMOS technology nodes. As interconnect dimensions approach the 10 nm scale, the limitations of conventional Cu dual-damascene metallization are becoming increasingly difficult to overcome, spurring over a decade of focused research into alternative metallization schemes. The selection of alternative metals is a highly complex process, requiring consideration of multiple criteria, including resistivity at reduced dimensions, reliability, thermal performance, process technology readiness, and sustainability. This Tutorial introduces the fundamental criteria for benchmarking and selecting alternative metals and reviews the current state of the art in this field. It covers materials nearing adoption in high-volume manufacturing, materials currently under active research, and potential future directions for fundamental study. While early alternatives to Cu metallization have recently been introduced in commercial CMOS devices, the search for the optimal interconnect metal remains ongoing. [ABSTRACT FROM AUTHOR]

IntroductionPatients with cirrhosis undergoing liver transplantation frequently exhibit systemic inflammation, coagulation derangements, and edema, indicating endothelial dysfunction. This syndrome may worsen after ischemia–reperfusion injury of the liver graft, coincident with organ dysfunction that worsens patient outcomes. Little is known about changes in endothelial permeability during liver transplantation. We hypothesized that sera from these patients would increase permeability in cultured human endothelial cells ex vivo.MethodsAdults with cirrhosis presenting for liver transplantation provided consent for blood collection during surgery. Sera were prepared at five time points spanning the entire operation. The barrier function of human pulmonary microvascular endothelial cells in culture was assessed by transendothelial resistance measured using the ECIS ZΘ system. Confluent cells from two different endothelial cell donors were stimulated with human serum from liver transplant patients. Pooled serum from healthy men and purified inflammatory agonists served as controls. The permeability response to serum was quantified as the area under the normalized resistance curve. Responses were compared between time points and analyzed for associations with clinical characteristics of liver transplant patients and their grafts.ResultsLiver transplant sera from all time points during surgery-induced permeability in both endothelial cell lines. The magnitude of permeability change was heterogeneous between patients, and there were differences in the effects of sera on the two endothelial cell lines. In one of the cell lines, the severity of liver disease was associated with greater permeability at the start of surgery. In the same cell line, serum collected 15 min after liver reperfusion induced significantly more permeability as compared to that collected at the start of surgery. Early postreperfusion sera from patients undergoing living donor transplants induced more permeability than sera from deceased donor transplants. Sera from two exemplary cases of patients on preoperative dialysis, and one patient with an unexpectedly long warm ischemia time of the liver graft, induced exaggerated and prolonged endothelial permeability.DiscussionSerum from patients with cirrhosis undergoing liver transplantation induces permeability of cultured human pulmonary microvascular endothelial cells. Increased endothelial permeability during liver transplantation may contribute to organ injury and present a target for future therapeutics.

Elongation of very long-chain fatty acid (Elovl) proteins plays pivotal functions in the biosynthesis of the physiologically essential long-chain polyunsaturated fatty acids (LC-PUFA). Polychaetes have important roles in marine ecosystems, contributing not only to nutrient recycling but also exhibiting a distinctive capacity for biosynthesizing LC-PUFA. To expand our understanding of the LC-PUFA biosynthesis in polychaetes, this study conducted a thorough molecular and functional characterization of Elovl occurring in the model organism Platynereis dumerilii. We identify six Elovl in the genome of P. dumerilii. The sequence and phylogenetic analyses established that four Elovl, identified as Elovl2/5, Elovl4 (two genes) and Elovl1/7, have putative functions in LC-PUFA biosynthesis. Functional characterization confirmed the roles of these elongases in LC-PUFA biosynthesis, demonstrating that P. dumerilii possesses a varied and functionally diverse complement of Elovl that, along with the enzymatic specificities of previously characterized desaturases, enables P. dumerilii to perform all the reactions required for the biosynthesis of the LC-PUFA. Importantly, we uncovered that one of the two Elovl4-encoding genes is remarkably long in comparison with any other animals' Elovl, which contains a C terminal KH domain unique among Elovl. The distinctive expression pattern of this protein in photoreceptors strongly suggests a central role in vision.

Abstract Background Programmed ventricular stimulation (PVS) during electrophysiological study (EPS), is a globally accepted tool for risk stratification of sudden cardiac death (SCD) in some specific clinical situations. The aim of this study was to evaluate the prognosis of ventricular arrhythmia induction in a cohort of patients with syncope of undetermined origin (SUO). Methods This is a historical cohort study in a population of patients with SUO referred for EPS between the years 2008–2021. In this interval, 575 patients underwent the procedure. Results Patients with induced ventricular arrhythmias had a higher occurrence of structural heart disease (36.7% vs. 76.5%), ischemic heart disease (28.2 vs. 57.1%), heart failure (15.5% vs. 34.4%), and lower left ventricular ejection fraction (59.16% vs. 47.51%), when compared to the outcome with a negative study. PVS triggered ventricular arrhythmias in 98 patients, 62 monomorphic and 36 polymorphic. During a median follow‐up of 37.6 months, 100 deaths occurred. Only the induction of sustained ventricular arrhythmias showed a significant association with the primary outcome (all‐cause mortality) with a p value

Introduction Catecholamine vasopressors such as norepinephrine are the standard drugs used to maintain mean arterial pressure during liver transplantation. At high doses, catecholamines may impair organ perfusion. Angiotensin II is a peptide vasoconstrictor that may improve renal perfusion pressure and glomerular filtration rate, a haemodynamic profile that could reduce acute kidney injury. Angiotensin II is approved for vasodilatory shock but has not been rigorously evaluated for treatment of hypotension during liver transplantation. The objective is to assess the efficacy of angiotensin II as a second-line vasopressor infusion during liver transplantation. This trial will establish the efficacy of angiotensin II in decreasing the dose of norepinephrine to maintain adequate blood pressure. Completion of this study will allow design of a follow-up, multicentre trial powered to detect a reduction of organ injury in liver transplantation.Methods and analysis This is a double-blind, randomised clinical trial. Eligible subjects are adults with a Model for End-Stage Liver Disease Sodium Score ≥25 undergoing deceased donor liver transplantation. Subjects are randomised 1:1 to receive angiotensin II or saline placebo as the second-line vasopressor infusion. The study drug infusion is initiated on reaching a norepinephrine dose of 0.05 µg kg-1 min-1 and titrated per protocol. The primary outcome is the dose of norepinephrine required to maintain a mean arterial pressure ≥65 mm Hg. Secondary outcomes include vasopressin or epinephrine requirement and duration of hypotension. Safety outcomes include incidence of thromboembolism within 48 hours of the end of surgery and severe hypertension. An intention-to-treat analysis will be performed for all randomised subjects receiving the study drug. The total dose of norepinephrine will be compared between the two arms by a one-tailed Mann-Whitney U test.Ethics and dissemination The trial protocol was approved by the local Institutional Review Board (#20–30948). Results will be posted on ClinicalTrials.gov and published in a peer-reviewed journal.Trial registration number ClinicalTrials.govNCT04901169

BackgroundPrevious research studies have demonstrated that medical content image retrieval can play an important role by assisting dermatologists in skin lesion diagnosis. However, current state-of-the-art approaches have not been adopted in routine consultation, partly due to the lack of interpretability limiting trust by clinical users. ObjectiveThis study developed a new image retrieval architecture for polarized or dermoscopic imaging guided by interpretable saliency maps. This approach provides better feature extraction, leading to better quantitative retrieval performance as well as providing interpretability for an eventual real-world implementation. MethodsContent-based image retrieval (CBIR) algorithms rely on the comparison of image features embedded by convolutional neural network (CNN) against a labeled data set. Saliency maps are computer vision–interpretable methods that highlight the most relevant regions for the prediction made by a neural network. By introducing a fine-tuning stage that includes saliency maps to guide feature extraction, the accuracy of image retrieval is optimized. We refer to this approach as saliency-enhanced CBIR (SE-CBIR). A reader study was designed at the University Hospital Zurich Dermatology Clinic to evaluate SE-CBIR’s retrieval accuracy as well as the impact of the participant’s confidence on the diagnosis. ResultsSE-CBIR improved the retrieval accuracy by 7% (77% vs 84%) when doing single-lesion retrieval against traditional CBIR. The reader study showed an overall increase in classification accuracy of 22% (62% vs 84%) when the participant is provided with SE-CBIR retrieved images. In addition, the overall confidence in the lesion’s diagnosis increased by 24%. Finally, the use of SE-CBIR as a support tool helped the participants reduce the number of nonmelanoma lesions previously diagnosed as melanoma (overdiagnosis) by 53%. ConclusionsSE-CBIR presents better retrieval accuracy compared to traditional CBIR CNN-based approaches. Furthermore, we have shown how these support tools can help dermatologists and residents improve diagnosis accuracy and confidence. Additionally, by introducing interpretable methods, we should expect increased acceptance and use of these tools in routine consultation.

Many essential proteins require pyridoxal 5'-phosphate, the active form of vitamin B6, as a cofactor for their activity. These include enzymes important for amino acid metabolism, one-carbon metabolism, polyamine synthesis, erythropoiesis, and neurotransmitter metabolism. A third of all mammalian pyridoxal 5'-phosphate-dependent enzymes are localized in the mitochondria; however, the molecular machinery involved in the regulation of mitochondrial pyridoxal 5'-phosphate levels in mammals remains unknown. In this study, we used a genome-wide CRISPR interference screen in erythroleukemia cells and organellar metabolomics to identify the mitochondrial inner membrane protein SLC25A38 as a regulator of mitochondrial pyridoxal 5'-phosphate. Loss of SLC25A38 causes depletion of mitochondrial, but not cellular, pyridoxal 5'-phosphate, and impairs cellular proliferation under both physiological and low vitamin B6 conditions. Metabolic changes associated with SLC25A38 loss suggest impaired mitochondrial pyridoxal 5'-phosphate-dependent enzymatic reactions, including serine to glycine conversion catalyzed by serine hydroxymethyltransferase-2 as well as ornithine aminotransferase. The proliferation defect of SLC25A38-null K562 cells in physiological and low vitamin B6 media can be explained by the loss of serine hydroxymethyltransferase-2-dependent production of one-carbon units and downstream de novo nucleotide synthesis. Our work points to a role for SLC25A38 in mitochondrial pyridoxal 5'-phosphate accumulation and provides insights into the pathology of congenital sideroblastic anemia. Pyridoxal 5'-phosphate (PLP, vitamin B6) is crucial for various metabolic processes. Here, the authors identified SLC25A38 as a key regulator of mitochondrial PLP levels using a genome-wide CRISPRi screen and organellar metabolomics, with insights into congenital sideroblastic anemia. [ABSTRACT FROM AUTHOR]

The renal actions of parathyroid hormone (PTH) promote 1,25-vitamin D generation; however, the signaling mechanisms that control PTH-dependent vitamin D activation remain unknown. Here, we demonstrated that salt-inducible kinases (SIKs) orchestrated renal 1,25-vitamin D production downstream of PTH signaling. PTH inhibited SIK cellular activity by cAMP-dependent PKA phosphorylation. Whole-tissue and single-cell transcriptomics demonstrated that both PTH and pharmacologic SIK inhibitors regulated a vitamin D gene module in the proximal tubule. SIK inhibitors increased 1,25-vitamin D production and renal Cyp27b1 mRNA expression in mice and in human embryonic stem cell–derived kidney organoids. Global- and kidney-specific Sik2/Sik3 mutant mice showed Cyp27b1 upregulation, elevated serum 1,25-vitamin D, and PTH-independent hypercalcemia. The SIK substrate CRTC2 showed PTH and SIK inhibitor–inducible binding to key Cyp27b1 regulatory enhancers in the kidney, which were also required for SIK inhibitors to increase Cyp27b1 in vivo. Finally, in a podocyte injury model of chronic kidney disease–mineral bone disorder (CKD-MBD), SIK inhibitor treatment stimulated renal Cyp27b1 expression and 1,25-vitamin D production. Together, these results demonstrated a PTH/SIK/CRTC signaling axis in the kidney that controls Cyp27b1 expression and 1,25-vitamin D synthesis. These findings indicate that SIK inhibitors might be helpful for stimulation of 1,25-vitamin D production in CKD-MBD.

Morphogen gradients can instruct cells about their position in a patterned tissue. Non-linear morphogen decay has been suggested to increase gradient precision by reducing the sensitivity to variability in the morphogen source. Here, we use cell-based simulations to quantitatively compare the positional error of gradients for linear and non-linear morphogen decay. While we confirm that non-linear decay reduces the positional error close to the source, the reduction is very small for physiological noise levels. Far from the source, the positional error is much larger for non-linear decay in tissues that pose a flux barrier to the morphogen at the boundary. In light of this new data, a physiological role of morphogen decay dynamics in patterning precision appears unlikely.

Two star‐shaped mesogens with a (meso‐tetraphenylporphinato) zinc (II) core and bithiophene conjugated arms with 3,4,5‐trisdodecyloxyphenyl periphery were synthesized. One of these molecules was decorated with four fullerenes via an aliphatic spacer. This is the sterically overcrowded compound with an octapodal morphology. The other star lacks the fullerenes and provides free space between the conjugated arms. This mesogen does not aggregate in solution, but in solid state it forms a hexagonal columnar and a highly ordered oblique helical columnar phase, while the octopus molecule assembles in an amorphous solid. Photophysical studies of the octapodal compound in solution and the solid thin film reveal the formation of J‐type aggregates, in which the interaction between donors (porphyrin) and acceptors (fullerene) dominates leading to absorption bands in the NIR region of the spectra. The mixture of both compounds results in a self‐assembly which is called the Click procedure. Fullerenes of the octopus nanosegregate in the pockets of the star mesogens generating hexagonal columnar structures with a regular stacking along the columnar axis. Thus providing free space is a tool to control the competition between supramolecular interactions and nanosegregation. Such liquid‐crystalline donor‐acceptor structures may play a role in future LC photovoltaic applications. [ABSTRACT FROM AUTHOR]

We present a novel machine learning-based approach to generate fast-executing virtual radiofrequency quadrupole (RFQ) particle accelerators using surrogate modelling. These could potentially be used as on-line feedback tools during beam commissioning and operation, and to optimize the RFQ beam dynamics design prior to construction. Since surrogate models execute orders of magnitude faster than corresponding physics beam dynamics simulations using standard tools like PARMTEQM and RFQGen, the computational complexity of the multi-objective optimization problem reduces significantly. Ultimately, this presents a computationally inexpensive and time efficient method to perform sensitivity studies and an optimization of the crucial RFQ beam output parameters like transmission and emittances. Two different methods of surrogate model creation (polynomial chaos expansion and neural networks) are discussed and the achieved model accuracy is evaluated for different study cases with gradually increasing complexity, ranging from a simple FODO cell example to the full RFQ optimization. We find that variations of the beam input Twiss parameters can be reproduced well. The prediction of the beam with respect to hardware changes, e.g., the electrode modulation, are challenging on the other hand. We discuss possible reasons for that and elucidate nevertheless existing benefits of the applied method to RFQ beam dynamics design.

Author(s): Charles H. Adelmann [sup.1] [sup.2] [sup.3] [sup.4] [sup.5] , Anna K. Traunbauer [sup.1] [sup.2] [sup.3] [sup.4] [sup.5] , Brandon Chen [sup.1] [sup.2] [sup.3] [sup.4] [sup.5] , Kendall J. Condon [...], Dozens of genes contribute to the wide variation in human pigmentation. Many of these genes encode proteins that localize to the melanosome--the organelle, related to the lysosome, that synthesizes pigment--but have unclear functions.sup.1,2. Here we describe MelanoIP, a method for rapidly isolating melanosomes and profiling their labile metabolite contents. We use this method to study MFSD12, a transmembrane protein of unknown molecular function that, when suppressed, causes darker pigmentation in mice and humans.sup.3,4. We find that MFSD12 is required to maintain normal levels of cystine--the oxidized dimer of cysteine--in melanosomes, and to produce cysteinyldopas, the precursors of pheomelanin synthesis made in melanosomes via cysteine oxidation.sup.5,6. Tracing and biochemical analyses show that MFSD12 is necessary for the import of cysteine into melanosomes and, in non-pigmented cells, lysosomes. Indeed, loss of MFSD12 reduced the accumulation of cystine in lysosomes of fibroblasts from patients with cystinosis, a lysosomal-storage disease caused by inactivation of the lysosomal cystine exporter cystinosin.sup.7-9. Thus, MFSD12 is an essential component of the cysteine importer for melanosomes and lysosomes. A rapid labelling and immunopurification-based method is used to isolate melanosomes and profile their labile metabolites, revealing that MFSD12 has a key role in cysteine import into melanosomes and lysosomes.

Background: Scoring systems have been proposed to select donation after circulatory death (DCD) donors and recipients for liver transplantation (LT). We hypothesized that complex scoring systems derived in large datasets might not predict outcomes locally.Methods: Based on 1-year DCD-LT graft survival predictors in multivariate logistic regression models, we designed, validated, and compared a simple index using the University of California, San Francisco (UCSF) cohort (n = 136) and a universal-comprehensive (UC)-DCD score using the United Network for Organ Sharing (UNOS) cohort (n = 5,792) to previously published DCD scoring systems.Results: The total warm ischemia time (WIT)-index included donor WIT (dWIT) and hepatectomy time (dHep). The UC-DCD score included dWIT, dHep, recipient on mechanical ventilation, transjugular-intrahepatic-portosystemic-shunt, cause of liver disease, model for end-stage liver disease, body mass index, donor/recipient age, and cold ischemia time. In the UNOS cohort, the UC-score outperformed all previously published scores in predicting DCD-LT graft survival (AUC: 0.635 vs. ≤0.562). In the UCSF cohort, the total WIT index successfully stratified survival and biliary complications, whereas other scores did not.Conclusion: DCD risk scores generated in large cohorts provide general guidance for safe recipient/donor selection, but they must be tailored based on non-/partially-modifiable local circumstances to expand DCD utilization.

Introduction: Tetralogy of Fallot (TOF) is a cyanotic congenital heart disease that has an incidence of sudden cardiac death of 0.2% per year, being arrhythmias the main cause of its occurrence. Objective: To compare characteristics of TOF patients referred for electrophysiological study (EPS) against those that were not (No-EPS). Method: Retrospective cohort with 215 patients (57.2% men; age = 29 ± 4) with corrected TOF (median of three years, ranging from 0.33 to 51) that underwent EPS between 2009-2020. The primary outcome was composed of death, implantable cardiac defibrillator (ICD) requirement and hospitalization. Results: Pre-syncope (EPS = 4.7%, No-EPS = 0%; p = 0.004), syncope (EPS = 7.1%, No-EPS = 1.7%; p = 0.056) and palpitations (EPS = 31%, No-EPS = 5.8%; p < 0.001) were symptoms that justified electrophysiological investigation. ICD was implanted in 24% of EPS and 0.6% of No-EPS (p=0.001). Twenty-six percent of the EPS group presented non-sustained ventricular tachycardia, while 0% in No-EPS (p = 0.012). The EPS group had more atrial fibrillation or atrial Flutter (35.7% vs. 6.9%; p < 0.001). The EPS patients had a wider QRS duration than the no-EPS group (171.12 ± 29.52 ms vs. 147 ± 29.77 ms; p < 0.001). Also, 26.2% of EPS performed ablation to correct macroreentrant atrial tachycardias. The incidence of primary outcome (death + ICD requirement + hospitalization) was higher in patients in the EPS group compared to the No-EPS group (p = 0.001). However, the total of seven deaths occurred during the clinical follow-up, but without differences between the groups (EPS = 4.7% vs. No-EPS = 2.8%; p = 0.480). Conclusion: EPS group had a profile of greater risk, more complex heart disease, and a greater occurrence of the primary outcome when compared to the No-EPS group.

Particle accelerators are complex facilities that produce large amounts of structured data and have clear optimization goals as well as precisely defined control requirements. As such they are naturally amenable to data-driven research methodologies. The data from sensors and monitors inside the accelerator form multivariate time series. With fast preemptive approaches being highly preferred in accelerator control and diagnostics, the application of data-driven time series forecasting methods is particularly promising. This review formulates the time series forecasting problem and summarizes existing models with applications in various scientific areas. Several current and future attempts in the field of particle accelerators are introduced. The application of time series forecasting to particle accelerators has shown encouraging results and promise for broader use, and existing problems such as data consistency and compatibility have started to be addressed.