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The development of effective receptor-targeted nonviral vectors for use in vivo is complicated by a number of technical problems. One of these is the low efficiency of the conjugation procedures used to couple protein ligands to the DNA condensing carrier molecules. We have made and characterized a multi-domain protein (SPKR)[sub 4]inv, that is designed to target plasmid DNA to β[sub 1] integrins in remodeling tissue. It contains a nonspecific DNA-binding domain (SPKR)[sub 4], a rigid α-helical linker, and the C-terminal β[sub 1] integrin binding domain (aa 793-987) of the Yersinia pseudotuberculosis invasin protein. (SPKR)[sub 4]inv could be purified at high yields using a bacterial expression system. We show that (SPKR)[sub 4]inv binds with high affinity to both plasmid DNA and β[sub 1] integrins. In a cell attachment assay, the apparent affinity of (SPKR)[sub 4]inv for β[sub 1] integrins is three orders of magnitude higher than that of the synthetic peptide integrin ligand RGDS. (SPKR)[sub 4]inv-plasmid complexes are not active in an in vitro transfection assay. However, transfection efficiencies of plasmid complexes with a cationic lipid micelle (DOTAP/Tween-20) or a cationic polymer (polyethylenimine), are significantly increased in combination with (SPKR)[sub 4]inv. (SPKR)[sub 4]inv-mediated transfection can be inhibited by a soluble form of β[sub 1] integrin, which is evidence for its receptor specificity. In conclusion, (SPKR)[sub 4]inv allows β[sub 1] integrin-specific targeting of plasmid-carrier complexes, while avoiding inefficient and cumbersome coupling chemistry. The modular design of the expression vector allows production of similar multi-domain proteins with a different affinity. The further development of such complexes for use in vivo is discussed. [ABSTRACT FROM AUTHOR]

Kitaev chains in quantum dot-superconductor arrays are a promising platform for the realization of topological superconductivity. As recently demonstrated, even a two-site chain can host Majorana zero modes known as "poor man's Majorana". Harnessing the potential of these states for quantum information processing, however, requires increasing their robustness to external perturbations. Here, we form a two-site Kitaev chain using Yu-Shiba-Rusinov states in proximitized quantum dots. By deterministically tuning the hybridization between the quantum dots and the superconductor, we observe poor man's Majorana states with a gap larger than 70 μeV. The sensitivity to charge fluctuations is also greatly reduced compared to Kitaev chains made with non-proximitized dots. The systematic control and improved energy scales of poor man's Majorana states realized with Yu-Shiba-Rusinov states will benefit the realization of longer Kitaev chains, parity qubits, and the demonstration of non-Abelian physics., (© 2024. The Author(s).)

We study the current-phase relation (CPR) of an InSb-Al nanowire Josephson junction in parallel magnetic fields up to 700 mT. At high magnetic fields and in narrow voltage intervals of a gate under the junction, the CPR exhibits π shifts. The supercurrent declines within these gate intervals and shows asymmetric gate voltage dependence above and below them. We detect these features sometimes also at zero magnetic field. The observed CPR properties are reproduced by a theoretical model of supercurrent transport via interference between direct transmission and a resonant localized state.

The formation of a topological superconducting phase in a quantum-dot-based Kitaev chain requires nearest neighbor crossed Andreev reflection and elastic cotunneling. Here, we report on a hybrid InSb nanowire in a three-site Kitaev chain geometry-the smallest system with well-defined bulk and edge-where two superconductor-semiconductor hybrids separate three quantum dots. We demonstrate pairwise crossed Andreev reflection and elastic cotunneling between both pairs of neighboring dots and show sequential tunneling processes involving all three quantum dots. These results are the next step toward the realization of topological superconductivity in long Kitaev chain devices with many coupled quantum dots.

Semiconductor nanowires coupled to superconductors can host Andreev bound states with distinct spin and parity, including a spin-zero state with an even number of electrons and a spin-1/2 state with odd-parity. Considering the difference in spin of the even and odd states, spin-filtered measurements can reveal the underlying ground state. To directly measure the spin of single-electron excitations, we probe an Andreev bound state using a spin-polarized quantum dot that acts as a bipolar spin filter, in combination with a non-polarized tunnel junction in a three-terminal circuit. We observe a spin-polarized excitation spectrum of the Andreev bound state, which can be fully spin-polarized, despite strong spin-orbit interaction in the InSb nanowires. Decoupling the hybrid from the normal lead causes a current blockade, by trapping the Andreev bound state in an excited state. Spin-polarized spectroscopy of hybrid nanowire devices, as demonstrated here, is proposed as an experimental tool to support the observation of topological superconductivity., (© 2023. The Author(s).)

The laborious and time-consuming nature of systematic review production hinders the dissemination of up-to-date evidence synthesis. Well-performing natural language processing (NLP) tools for systematic reviews have been developed, showing promise to improve efficiency. However, the feasibility and value of these technologies have not been comprehensively demonstrated in a real-world review. We developed an NLP-assisted abstract screening tool that provides text inclusion recommendations, keyword highlights, and visual context cues. We evaluated this tool in a living systematic review on SARS-CoV-2 seroprevalence, conducting a quality improvement assessment of screening with and without the tool. We evaluated changes to abstract screening speed, screening accuracy, characteristics of included texts, and user satisfaction. The tool improved efficiency, reducing screening time per abstract by 45.9% and decreasing inter-reviewer conflict rates. The tool conserved precision of article inclusion (positive predictive value; 0.92 with tool vs. 0.88 without) and recall (sensitivity; 0.90 vs. 0.81). The summary statistics of included studies were similar with and without the tool. Users were satisfied with the tool (mean satisfaction score of 4.2/5). We evaluated an abstract screening process where one human reviewer was replaced with the tool's votes, finding that this maintained recall (0.92 one-person, one-tool vs. 0.90 two tool-assisted humans) and precision (0.91 vs. 0.92) while reducing screening time by 70%. Implementing an NLP tool in this living systematic review improved efficiency, maintained accuracy, and was well-received by researchers, demonstrating the real-world effectiveness of NLP in expediting evidence synthesis., (© 2023 The Authors. Research Synthesis Methods published by John Wiley & Sons Ltd.)

Semiconducting nanowire Josephson junctions represent an attractive platform to investigate the anomalous Josephson effect and detect topological superconductivity. However, an external magnetic field generally suppresses the supercurrent through hybrid nanowire junctions and significantly limits the field range in which the supercurrent phenomena can be studied. In this work, we investigate the impact of the length of InSb-Al nanowire Josephson junctions on the supercurrent resilience against magnetic fields. We find that the critical parallel field of the supercurrent can be considerably enhanced by reducing the junction length. Particularly, in 30 nm long junctions supercurrent can persist up to 1.3 T parallel field─approaching the critical field of the superconducting film. Furthermore, we embed such short junctions into a superconducting loop and obtain the supercurrent interference at a parallel field of 1 T. Our findings are highly relevant for multiple experiments on hybrid nanowires requiring a magnetic-field-resilient supercurrent.

Background and Aims: Etiological risk factors for cirrhosis have changed in the last decade. It remains unclear to what extent these trends in cirrhosis risk factors have changed HCC risk., Approach and Results: We used data from two contemporary, prospective multiethnic cohorts of patients with cirrhosis: the Texas Hepatocellular Carcinoma Consortium Cohort and the Houston Veterans Administration Cirrhosis Surveillance Cohort. Patients with cirrhosis were enrolled from seven US centers and followed until HCC diagnosis, transplant, death, or June 30, 2021. We calculated the annual incidence rates for HCC and examined the effects of etiology, demographic, clinical, and lifestyle factors on the risk of HCC. We included 2733 patients with cirrhosis (mean age 60.1 years, 31.3% women). At enrollment, 19.0% had active HCV, 23.3% had cured HCV, 16.1% had alcoholic liver disease, and 30.1% had NAFLD. During 7406 person-years of follow-up, 135 patients developed HCC at an annual incidence rate of 1.82% (95% CI, 1.51-2.13). The annual HCC incidence rate was 1.71% in patients with cured HCV, 1.32% in patients with alcoholic liver disease, and 1.24% in patients with NAFLD cirrhosis. Compared to patients with NAFLD, the risk of progression to HCC was 2-fold higher in patients with cured HCV (HR, 2.04; 95% CI, 1.24-3.35). Current smoking (HR, 1.63; 95% CI, 1.01-2.63) and overweight/obesity (HR, 1.79; 95% CI, 1.08-2.95) were also associated with HCC risk., Conclusions: HCC incidence among patients with cirrhosis was lower than previously reported. HCC risk was variable across etiologies, with higher risk in patients with HCV cirrhosis and lower risk in those with NAFLD cirrhosis. Current smoking and overweight/obesity increased HCC risk across etiologies., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background: Polygenic risk scores (PRS) hold the promise to refine prognostication in hepatocellular cancer (HCC). The few available HCC PRS include germline risk variants identified among individuals of mostly European ancestry, but data are lacking on the transportability of these PRS in multiethnic U.S patients with cirrhosis from multiple etiologies., Methods: We used data from 1644 patients with cirrhosis enrolled in two prospective cohort studies in the U.S. Patients were followed until HCC diagnosis, death, liver transplantation, or last study visit through June 30, 2021. The high-risk variants in PNPLA3-MBOAT7-TM6SF2-GCKR were combined in a PRS and we evaluated its association with HCC. Discriminatory accuracy was assessed using the C-statistic., Results: During 4,759 person-years of follow-up, 93 patients developed HCC. Mean age was 59.8 years, 68.6% were male, 27.2% Hispanic, 25.1% non-Hispanic Black, 25.7% had NAFLD, 42.1% had heavy alcohol use, and 19.5% had active HCV. HCC risk increased by 134% per unit increase in PRS (HR = 2.30; 95% CI, 1.35-3.92). Compared to cirrhosis patients in the lowest tertile of the PRS, those in the highest tertile had 2-fold higher risk of HCC (HR = 2.05; 95% CI, 1.22-3.44). The PRS alone had modest discriminatory ability (C-statistic = 0.58; 95% CI, 0.52-0.63); however, adding PRS to a predictive model with traditional HCC risk factors had a C-statistic of 0.70 (95% CI, 0.64-0.76), increasing from 0.68 without the PRS (p = 0.0012)., Conclusions: Our findings suggest that PRS may enhance risk prediction for HCC in contemporary U.S. cirrhosis patients., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Dr. Singal consults for Genentech, AstraZeneca, Bayer, Eisai, Exelixis, BMS, Exact Sciences, Fujifilm Medical Sciences, Glycotest, and GRAIL. Dr. Marrero consults for Glycotest. Dr. Loo advises Gilead. All other authors declare no conflicts of interest., (Copyright: © 2023 Thrift et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Majorana bound states constitute one of the simplest examples of emergent non-Abelian excitations in condensed matter physics. A toy model proposed by Kitaev shows that such states can arise at the ends of a spinless p-wave superconducting chain 1 . Practical proposals for its realization 2,3 require coupling neighbouring quantum dots (QDs) in a chain through both electron tunnelling and crossed Andreev reflection 4 . Although both processes have been observed in semiconducting nanowires and carbon nanotubes 5-8 , crossed-Andreev interaction was neither easily tunable nor strong enough to induce coherent hybridization of dot states. Here we demonstrate the simultaneous presence of all necessary ingredients for an artificial Kitaev chain: two spin-polarized QDs in an InSb nanowire strongly coupled by both elastic co-tunnelling (ECT) and crossed Andreev reflection (CAR). We fine-tune this system to a sweet spot where a pair of poor man's Majorana states is predicted to appear. At this sweet spot, the transport characteristics satisfy the theoretical predictions for such a system, including pairwise correlation, zero charge and stability against local perturbations. Although the simple system presented here can be scaled to simulate a full Kitaev chain with an emergent topological order, it can also be used imminently to explore relevant physics related to non-Abelian anyons., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

In most naturally occurring superconductors, electrons with opposite spins form Cooper pairs. This includes both conventional s-wave superconductors such as aluminium, as well as high-transition-temperature, d-wave superconductors. Materials with intrinsic p-wave superconductivity, hosting Cooper pairs made of equal-spin electrons, have not been conclusively identified, nor synthesized, despite promising progress 1-3 . Instead, engineered platforms where s-wave superconductors are brought into contact with magnetic materials have shown convincing signatures of equal-spin pairing 4-6 . Here we directly measure equal-spin pairing between spin-polarized quantum dots. This pairing is proximity-induced from an s-wave superconductor into a semiconducting nanowire with strong spin-orbit interaction. We demonstrate such pairing by showing that breaking a Cooper pair can result in two electrons with equal spin polarization. Our results demonstrate controllable detection of singlet and triplet pairing between the quantum dots. Achieving such triplet pairing in a sequence of quantum dots will be required for realizing an artificial Kitaev chain 7-9 ., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

In superconducting quantum circuits, aluminum is one of the most widely used materials. It is currently also the superconductor of choice for the development of topological qubits. However, aluminum-based devices suffer from poor magnetic field compatibility. Herein, this limitation is resolved by showing that adatoms of heavy elements (e.g., platinum) increase the critical field of thin aluminum films by more than a factor of two. Using tunnel junctions, it is shown that the increased field resilience originates from spin-orbit scattering introduced by Pt. This property is exploited in the context of the superconducting proximity effect in semiconductor-superconductor hybrids, where it is shown that InSb nanowires strongly coupled to Al/Pt films can maintain superconductivity up to 7 T. The two-electron charging effect is shown to be robust against the presence of heavy adatoms. Additionally, non-local spectroscopy is used in a three-terminal geometry to probe the bulk of hybrid devices, showing that it remains free of sub-gap states. Finally, it is demonstrated that proximitized semiconductor states maintain their ability to Zeeman-split in an applied magnetic field. Combined with the chemical stability and well-known fabrication routes of aluminum, Al/Pt emerges as the natural successor to Al-based systems and is a compelling alternative to other superconductors, whenever high-field resilience is required., (© 2022 The Authors. Advanced Materials published by Wiley-VCH GmbH.)

Background and Aims: NAFLD is characterized by insulin resistance and dysregulated lipid and glucose metabolism. Saroglitazar, a dual peroxisome proliferator activated receptor-α/γ agonist, improves insulin sensitivity, and lipid and glycemic parameters. Saroglitazar improved NASH histology in animal studies. In this randomized controlled clinical trial, we evaluated the efficacy and safety of saroglitazar in patients with NAFLD/NASH., Approach and Results: A total of 106 patients with NAFLD/NASH with alanine aminotransferase (ALT) ≥ 50 U/L at baseline and body mass index ≥25 kg/m 2 were randomized in a 1:1:1:1 ratio to receive placebo or saroglitazar 1 mg, 2 mg, or 4 mg for 16 weeks. The primary efficacy endpoint was percentage change from baseline in ALT levels at week 16. Liver fat content (LFC) was assessed by MRI proton density fat fraction. The least-squares mean percent change from baseline in ALT at week 16 was -25.5% (5.8), -27.7% (5.9), and -45.8% (5.7), with saroglitazar 1 mg, 2 mg, and 4 mg, respectively, versus 3.4% (5.6) in placebo (P < 0.001 for all). Compared with placebo, saroglitazar 4 mg improved LFC (4.1% [5.9] vs. -19.7% [5.6]), adiponectin (-0.3 μg/mL [0.3] vs. 1.3 μg/mL [0.3]), homeostatic model assessment-insulin resistance (-1.3 [1.8] vs. -6.3 [1.7]), and triglycerides (-5.3 mg/dL [10.7] vs. -68.7 mg/dL [10.3]) (P < 0.05 for all). Saroglitazar 4 mg also improved lipoprotein particle composition and size and reduced lipotoxic lipid species. Saroglitazar was well-tolerated. A mean weight gain of 1.5 kg was observed with saroglitazar 4 mg versus 0.3 kg with placebo (P = 0.27)., Conclusions: Saroglitazar 4 mg significantly improved ALT, LFC, insulin resistance, and atherogenic dyslipidemia in participants with NAFLD/NASH. (ClinicalTrials.gov identifier: NCT03061721.)., (© 2021 by the American Association for the Study of Liver Diseases.)

The realization of hybrid superconductor-semiconductor quantum devices, in particular a topological qubit, calls for advanced techniques to readily and reproducibly engineer induced superconductivity in semiconductor nanowires. Here, we introduce an on-chip fabrication paradigm based on shadow walls that offers substantial advances in device quality and reproducibility. It allows for the implementation of hybrid quantum devices and ultimately topological qubits while eliminating fabrication steps such as lithography and etching. This is critical to preserve the integrity and homogeneity of the fragile hybrid interfaces. The approach simplifies the reproducible fabrication of devices with a hard induced superconducting gap and ballistic normal-/superconductor junctions. Large gate-tunable supercurrents and high-order multiple Andreev reflections manifest the exceptional coherence of the resulting nanowire Josephson junctions. Our approach enables the realization of 3-terminal devices, where zero-bias conductance peaks emerge in a magnetic field concurrently at both boundaries of the one-dimensional hybrids., (© 2021. The Author(s).)

Recurrent copy-number alterations, mutations, and transcript fusions of the genes encoding CDKs/cyclins are characterized in >10,000 tumors. Genomic alterations of CDKs/cyclins are dominantly driven by copy number aberrations. In contrast to cell-cycle-related CDKs/cyclins, which are globally amplified, transcriptional CDKs/cyclins recurrently lose copy numbers across cancers. Although mutations and transcript fusions are relatively rare events, CDK12 exhibits recurrent mutations in multiple cancers. Among the transcriptional CDKs, CDK7 and CDK12 show the most significant copy number loss and mutation, respectively. Their genomic alterations are correlated with increased sensitivities to DNA-damaging drugs. Inhibition of CDK7 preferentially represses the expression of genes in the DNA-damage-repair pathways and impairs the activity of homologous recombination. Low-dose CDK7 inhibitor treatment sensitizes cancer cells to PARP inhibitor-induced DNA damage and cell death. Our analysis provides genomic information for identification and prioritization of drug targets for CDKs and reveals rationales for treatment strategies., Competing Interests: Declaration of Interests Drs. Lin Zhang, Xiaowen Hu, and Youyou Zhang report having received research funding from Bristol-Myers Squibb/Celgene and Prelude Therapeutics., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Benign recurrent intrahepatic cholestasis represents a rare class of autosomal recessive chronic cholestasis disorders, usually presenting with recurrent episodes of intense pruritus and jaundice. We report a 27-year-old woman presenting with benign recurrent intrahepatic cholestasis type 2 due to heterozygosity in ABCB11. Interestingly, she was also found to be heterozygous in cystic fibrosis transmembrane conductance regulator, NPHP4 , and A1ATD ( SERPINA1 ), which may explain the severe nature of her disease expression because heterozygosity in each of these genes has been associated with cholestasis. Finally, she exhibited a response to steroids that may have implications for future treatment of bile salt export pump-related diseases., (© 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Background: Thrombocytopenia (TCP), a common complication of chronic liver disease (CLD), can cause uncontrolled bleeding during procedures. As such, CLD patients with TCP and platelet counts <50,000/μL often receive prophylactic platelet transfusions before invasive procedures. However, platelet transfusions are associated with clinical complications, which may result in increased healthcare utilization and costs. Objective: This retrospective database analysis describes the clinical and economic burden in CLD patients with TCP, CLD patients without TCP, and CLD patients with TCP who receive platelet transfusions. Methods: Adult CLD patients with or without TCP were identified in the IBM MarketScan Commercial Claims and Medicare Supplemental data from 1 January 2012 to 31 December 2015. CLD patients with or without TCP were propensity-score matched (1:1) for the analysis of annual healthcare utilization and costs. Platelet transfusions among CLD patients with TCP were identified using procedure codes. Results: Of the 601,626 patients with CLD, 8,292 (1.4%) patients with TCP were matched to patients without TCP. Among CLD patients with TCP, 981 (11.8%) patients received ≥1 platelet transfusions and met inclusion/exclusion criteria. Compared to patients without TCP, CLD patients with TCP had more complications, including higher prevalence of neutropenia (11.4% vs 2.9%) and bleeding events (21.4% vs 10.9%), greater resource utilization including greater average hospital admissions (1.2 vs 0.7, p  < .01), greater average ER visits (2.1 vs 1.3, p  < .01), higher average outpatient office visits (20.1 vs 18.4, p  < .01), and higher average healthcare costs including total costs ( p  < .01), inpatient costs ( p  < .01), ER visit costs ( p  < .01), and outpatient office visit costs ( p  < .01). The mean annual total costs in CLD and TCP patients with platelet transfusions were $206,396. Conclusions: CLD patients with TCP, and particularly those who received platelet transfusions, experienced significantly greater clinical and economic burden compared to CLD patients without TCP. Safer and more cost-effective treatments to increase platelets are necessary.