Explore the vast range of titles available.

Background. Natural killer (NK) cells are an integral part of the innate immune system. They have been suggested to play an important role in both defense against viral hepatitis and the pathogenesis of other liver diseases. Methods. NK cells from 134 individuals including patients with acute hepatitis B and C as well as chronic hepatitis B, C, and delta (D) patients were studied. Results. Infection with viral hepatitis was associated with increased frequencies of NK cells in the peripheral blood; that NK cells showed a less activated phenotype and were compromised in cytolotytic function and cytokine production in all viral hepatitis infections: Hepatitis virus infections did not alter NK cell differentiation, and the activity and severity of liver disease were reflected by alterations of NK cell surface receptors as demonstrated by principal component analysis. Conclusion. NK cell phenotypic and functional alterations can equally be observed in HBV, HCV, and HDV infections. Instead, patterns of NK cell alterations differ in acute and chronic infections. Thus, our data suggest a common mechanism in the alteration of NK cell phenotype and function with unique variations that depend on disease activity rather than virus-specific factors.

The SARS-CoV-2 RNA-dependent RNA polymerase coordinates viral RNA synthesis as part of an assembly known as the replication–transcription complex (RTC) 1 . Accordingly, the RTC is a target for clinically approved antiviral nucleoside analogues, including remdesivir 2 . Faithful synthesis of viral RNAs by the RTC requires recognition of the correct nucleotide triphosphate (NTP) for incorporation into the nascent RNA. To be effective inhibitors, antiviral nucleoside analogues must compete with the natural NTPs for incorporation. How the SARS-CoV-2 RTC discriminates between the natural NTPs, and how antiviral nucleoside analogues compete, has not been discerned in detail. Here, we use cryogenic-electron microscopy to visualize the RTC bound to each of the natural NTPs in states poised for incorporation. Furthermore, we investigate the RTC with the active metabolite of remdesivir, remdesivir triphosphate (RDV-TP), highlighting the structural basis for the selective incorporation of RDV-TP over its natural counterpart adenosine triphosphate 3 , 4 . Our results explain the suite of interactions required for NTP recognition, informing the rational design of antivirals. Our analysis also yields insights into nucleotide recognition by the nsp12 NiRAN (nidovirus RdRp-associated nucleotidyltransferase), an enigmatic catalytic domain essential for viral propagation 5 . The NiRAN selectively binds guanosine triphosphate, strengthening proposals for the role of this domain in the formation of the 5′ RNA cap 6 . Cryo-EM is used to visualize the SARS-CoV-2 RTC bound to each of the natural NTPs as well as remdesivir triphosphate (RDV-TP) in states poised for incorporation, explaining the interactions required for NTP recognition and RDV-TP selectivity.

Molecular-logic based computation (MLBC) has grown by accumulating many examples of combinational logic gates and a few sequential variants. In spite of many inspirations being available in biology, there are virtually no examples of MLBC in chemistry where sequential and combinational operations are integrated. Here we report a simple alcohol-ketone redox interconversion which switches a macrocycle between a large or small cavity, with erect aromatic walls which create a deep hydrophobic space or with collapsed walls respectively. Small aromatic guests can be captured or released in an all or none manner upon chemical command. During capture, the fluorescence of the alcohol macrocycle is quenched via fluorescent photoinduced electron transfer switching, meaning that its occupancy state is self-indicated. This represents a chemically-driven RS Flip-Flop, one of whose outputs is fed into an INHIBIT gate. Processing of outputs from memory stores is seen in the injection of packaged neurotransmitters into synaptic clefts for onward neural signalling. Overall, capture-release phenomena from discrete supermolecules now have a Boolean basis. While many processes in biological cells can be understood in terms of molecular logic gates that process information sequentially and combinationally, the design and construction of such devices in the laboratory are unknown. Here the authors achieve this by the reversibly-controlled capture and release of guest molecules from host containers.

Focal segmental glomerulosclerosis (FSGS) is a histological lesion with many causes, including inherited genetic defects, with significant proteinuria being the predominant clinical finding at presentation. Mutations in COL4A3 and COL4A4 are known to cause Alport syndrome (AS), thin basement membrane nephropathy, and to result in pathognomonic glomerular basement membrane (GBM) findings. Secondary FSGS is known to develop in classic AS at later stages of the disease. Here, we present seven families with rare or novel variants in COL4A3 or COL4A4 (six with single and one with two heterozygous variants) from a cohort of 70 families with a diagnosis of hereditary FSGS. The predominant clinical finding at diagnosis was proteinuria associated with hematuria. In all seven families, there were individuals with nephrotic-range proteinuria with histologic features of FSGS by light microscopy. In one family, electron microscopy showed thin GBM, but four other families had variable findings inconsistent with classical Alport nephritis. There was no recurrence of disease after kidney transplantation. Families with COL4A3 and COL4A4 variants that segregated with disease represent 10% of our cohort. Thus, COL4A3 and COL4A4 variants should be considered in the interpretation of next-generation sequencing data from such patients. Furthermore, this study illustrates the power of molecular genetic diagnostics in the clarification of renal phenotypes.

Objective To determine if first trimester fetal growth is associated with birth weight, duration of pregnancy, and the risk of delivering a small for gestational age infant.Design Prospective cohort study of 38 033 pregnancies between 1999 and 2003.Setting 15 centres representing major regions of the United States.Participants 976 women from the original cohort who conceived as the result of assisted reproductive technology, had a first trimester ultrasound measurement of fetal crown-rump length, and delivered live singleton infants without evidence of chromosomal or congenital abnormalities. First trimester growth was expressed as the difference between the observed and expected size of the fetus, expressed as equivalence to days of gestational age.Main outcome measures Birth weight, duration of pregnancy, and risk of delivering a small for gestational age infant.Results For each one day increase in the observed size of the fetus, birth weight increased by 28.2 (95% confidence interval 14.6 to 41.2) g. The association was substantially attenuated by adjustment for duration of pregnancy (adjusted coefficient 17.1 (6.6 to 27.5) g). Further adjustments for maternal characteristics and complications of pregnancy did not have a significant effect. The risk of delivering a small for gestational age infant decreased with increasing size in the first trimester (odds ratio for a one day increase 0.87, 0.81 to 0.94). The association was not materially affected by adjustment for maternal characteristics or complications of pregnancy.Conclusion Variation in birth weight may be determined, at least in part, by fetal growth in the first 12 weeks after conception through effects on timing of delivery and fetal growth velocity.

Natural Killer (NK) cells contribute to HIV control in adults, but HLA-B-mediated T-cell activity has a more substantial impact on disease outcome. However, the HLA-B molecules influencing immune control in adults have less impact on paediatric infection. To investigate the contribution NK cells make to immune control, we studied >300 children living with HIV followed over two decades in South Africa. In children, HLA-B alleles associated with adult protection or disease-susceptibility did not have significant effects, whereas Bw4 (p = 0.003) and low HLA-A expression (p = 0.002) alleles were strongly associated with immunological and viral control. In a comparator adult cohort, Bw4 and HLA-A expression contributions to HIV disease outcome were dwarfed by those of protective and disease-susceptible HLA-B molecules. We next investigated the immunophenotype and effector functions of NK cells in a subset of these children using flow cytometry. Slow progression and better plasma viraemic control were also associated with high frequencies of less terminally differentiated NKG2A+NKp46+CD56 dim NK cells strongly responsive to cytokine stimulation and linked with the immunogenetic signature identified. Future studies are indicated to determine whether this signature associated with immune control in early life directly facilitates functional cure in children.

Direct-acting antivirals (DAAs) have dramatically improved the management of chronic hepatitis C (CHC). In this study, we investigated the effects of hepatitis C virus clearance on markers of systemic inflammation measured in plasma samples from CHC patients before, during and after DAA therapy. We identified a plasma soluble protein profile associated with CHC. Successful DAA therapy rapidly normalised the plasma inflammatory milieu, with the notable exception of soluble (s)CD163, a marker of macrophage activation, which remained elevated after viral clearance and segregated patients with high and low levels of cirrhosis. Patients who received DAA in combination with Ribavirin maintained elevated levels of CXCL10, consistent with an immune-stimulatory role of Ribavirin. As anticipated, DAA-treated patients experienced durable improvement in liver fibrosis measurements. Interestingly, pre-treatment levels of fatty acid-binding protein 4 (FABP4) were inversely associated with reduction of APRI and FIB-4 scores during treatment. Together, these results support the notion of a rapid restoration of many aspects of the inflammatory state in CHC patients in response to DAA therapy. Furthermore, the associations with sCD163 and FABP4 warrant further investigation into the role of macrophages in residual liver disease and fibrosis resolution after viral clearance.

APOL1 G1 and G2 variants are established risk factors for nondiabetic kidney disease. The presence of two APOL1 risk variants in donor kidneys negatively impacts kidney allograft survival. Because of evolutionary pressure, the APOL1 risk variants have become common in people from Africa and in those with recent African ancestry. APOL1 risk variant proteins are expressed in kidney cells and can cause toxicity to these cells. In this issue of the JCI, Zhang, Sun, and colleagues show that recipient APOL1 risk variants negatively affect kidney allograft survival and T cell-mediated rejection rates, independent of donor APOL1 genotype or recipient ancestry. The authors provide evidence that APOL1 risk variants play an immunomodulatory role in T cells and NK cells in the setting of kidney transplantation. These findings have important clinical implications that require further investigation.

Background Many COL4A5 splice region variants have been described in patients with X-linked Alport syndrome, but few have been confirmed by functional analysis to actually cause defective splicing. We sought to demonstrate that a novel COL4A5 splice region variant in a family with Alport syndrome is pathogenic using functional studies. We also describe an alternative method of diagnosis. Methods Targeted next-generation sequencing results of an individual with Alport syndrome were analyzed and the results confirmed by Sanger sequencing in family members. A splicing reporter minigene assay was used to examine the variant’s effect on splicing in transfected cells. Plucked hair follicles from patients and controls were examined for collagen IV proteins using immunofluorescence microscopy. Results A novel splice region mutation in COL4A5 , c.1780-6T>G, was identified and segregated with disease in this family. This variant caused frequent skipping of exon 25, resulting in a frameshift and truncation of collagen α5(IV) protein. We also developed and validated a new approach to characterize the expression of collagen α5(IV) protein in the basement membranes of plucked hair follicles. Using this approach we demonstrated reduced collagen α5(IV) protein in affected male and female individuals in this family, supporting frequent failure of normal splicing. Conclusions Differing normal to abnormal transcript ratios in affected individuals carrying splice region variants may contribute to variable disease severity observed in Alport families. Examination of plucked hair follicles in suspected X-linked Alport syndrome patients may offer a less invasive alternative method of diagnosis and serve as a pathogenicity test for COL4A5 variants of uncertain significance.

Research Questions- What was the state of accounting information systems (AIS) faculty in accounting programs of US universities and colleges (hereafter, institutions) at the peak of Dotcom? What can the artificial intelligence (AI)-era accounting education learn from its Dotcom experience? Motivation- Accounting education environment during the Dotcom-led innovations and the current AI- and Generative AI (GenAI)-led innovations bears similarities in many respects. While AIS faculty teach AIS courses where students learn information systems (IS) concepts including technology, processes and internal controls in greater detail and depth relative to other accounting courses, our literature review suggests a paucity of research on AIS faculty, especially during the Dotcom-era. AIS faculty is an appropriate proxy for the IS and information technology (IT) skills of accounting graduates' market-ready quality. Therefore, we examine AIS faculty's institutional characteristics during the Dotcom-era and consider implications for the AI-era accounting education to minimize capacity gaps, technology gaps, and resource gaps. Idea- We analyze US accounting programs for AIS faculty's (i) individual features and (ii) association with institutional features. Data- We hand-collect data, from 1998-1999 Hasselback Accounting Faculty Directory (HAFD), which is just before the Dotcom's bust and reflects the culmination of a series of actions taken by accounting programs and accounting education during the Dotcom-era. HAFD, our primary data source, provides faculty and program information in sufficient detail and granularity. Tools- We use count data econometric models corresponding to Poisson and Negative Binomial (NEGBIN) processes, since our response variable (i.e., AIS faculty) and its proxies suggest that they approximate a Poisson probability distribution. Findings- We find that doctoral programs supplying AIS faculty are public institutions and mostly in the southern states. AIS faculty are (i) less in private institutions; (ii) less in professor ranks; (iii) proportionately more with a PhD and certified public accountant (CPA) credentials; and (iv) similar in gender split, vis-à-vis all accounting faculty. AIS faculty associate positively with total accounting faculty size, accreditation and public institutions, and negatively with the presence of a doctoral program in the department. Contribution- We contribute to the existing research stream that examines accounting program quality and faculty background which proxy graduate's market-readiness. At the theoretical and usefulness level, we contribute by using accounting education's Dotcom experience to identify specific implications for the AI-era. At the methodological level, we theorize the count-data econometric features of AIS faculty and consider its five proxies, each with a different theoretical significance to associate with its factors. Significance- We discuss significance of our results by posing questions to stir debate, dialogue and discussion for devising action-based strategies that are sustainable, inclusive and equitable.