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Sulfur-containing natural products (S-containing NPs) exhibit diverse chemical structures and biosynthetic machineries. Unraveling the intricate chemistry of S-incorporation requires innovative and multidisciplinary approaches. In this review, we surveyed the landscape of S-containing NP biosynthetic machineries, classified the S-incorporation chemistry into four distinct classes, and highlighted each of the four classes with representative examples from recent studies. All highlighted chemistry has been correlated to the genes encoding the biosynthetic machineries of the S-containing NPs, which open new opportunities to discover S-containing NPs through genome mining. These examples should inspire the community to explore uncharted territories in NP research, promoting further advancements in both novel S-containing NP discovery and S-incorporation chemistry., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Rotaviruses are the most frequent agents associated with diarrhoea in children worldwide. Analysis of mobility of the 11 segments of genomic RNA by polyacrylamide gel electrophoresis (PAGE) yields a pattern which is characteristic for a particular rotavirus isolate. The group A rotaviruses can be further characterized by analysis of VP7 and VP4 genes specificities, responsible for rotavirus classification into G and P genotypes, respectively. The aim of the present study was to determine the evolution of group A Rotavirus strains circulating in Tunisia over a 3-year period (2005-2007)., Material and Methods: A total of 1503 stool samples collected from children less than five years old, consulting or hospitalised in Tunisia for diarrhoea between 2005 and 2007, were screened for the presence of group A Rotaviruses. Rotavirus-positive specimens were further analyzed by PAGE and G/P-genotyped by multiplex semi-nested RT-PCR., Results: Rotaviruses were detected in 323 stool samples over 1503 (21 %). Long electropherotypes predominated in Tunisia during the whole period of study (N=158 vs N=82 short electropherotypes). VP7 genotyping showed the cocirculation of five different genotypes: G1, G2, G3, G4 and G9. VP4 typing detected four different P-genotypes: P[8], P[4], P[6] and P[11]. Rotavirus strains with G3P[8] specificity were predominating in Tunisia in 2005 and 2006, replaced by G2P[4] strains in 2007., (Copyright © 2009 Elsevier Masson SAS. All rights reserved.)

Background: Rotaviruses are the most frequent agents associated with diarrhoea in children worldwide. Analysis of mobility of the 11 segments of genomic RNA by polyacrylamide gel electrophoresis (PAGE) yields a pattern which is characteristic for a particular rotavirus isolate. The group A rotaviruses can be further characterized by analysis of VP7 and VP4 genes specificities, responsible for rotavirus classification into G and P genotypes, respectively. The aim of the present study was to detect a relationship between electropherotype pattern and molecular characteristics of the rotavirus strains., Material and Methods: Were analyzed 278 rotavirus-positive specimens by PAGE and G/P-genotyped by multiplex semi-nested RT-PCR. Pearson's correlation tests were used for statistical analysis., Results: Twelve different electropherotypes were visualized, eight with a long profile (186 cases) and four with a short one (87 cases). Concerning VP7 types, G2 viral strains were found to be predominant and were detected in 91 specimens (32.7%). Strains with G1, G3, G4, G8 and G9 specificities were detected in 62 (22.3%), 82 (29.5%), 13 (4.7%), two (0.7%) and seven cases (2.5%), respectively. The results of VP4 genotyping showed a predominance of P[8] genotype which comprised half of the strains identified (139 cases, 50%). VP4 P[4], P[6] and P[11] were found in 83 (29.9%), 31 (11.1%) and 11 (4.0%) specimens, respectively. A high rate of mixed strains was also found (1.8% mixed electropherotypes, 7.6% G-mixed and 5% P-mixed strains). Electropherotype pattern of rotavirus strains was significantly correlated with VP7 genotype (p=0.018) and with VP4 genotype specificities (p<0.001)., (Copyright © 2009 Elsevier Masson SAS. All rights reserved.)

Background: Rotavirus gastroenteritis causes many deaths in infants in sub-Saharan Africa. Because rotavirus vaccines have proven effective in developed countries but had not been tested in developing countries, we assessed efficacy of a pentavalent rotavirus vaccine against severe disease in Ghana, Kenya, and Mali between April, 2007, and March, 2009., Methods: In our multicentre, double-blind, placebo-controlled trial, undertaken in rural areas of Ghana and Kenya and an urban area of Mali, we randomly assigned infants aged 4-12 weeks without symptoms of gastrointestinal disorders in a 1:1 ratio to receive three oral doses of pentavalent rotavirus vaccine 2 mL or placebo at around 6 weeks, 10 weeks, and 14 weeks of age. Infants with HIV infection were not excluded. Randomisation was done by computer-generated randomisation sequence in blocks of six. We obtained data for gastrointestinal symptoms from parents on presentation to health-care facilities and clinical data were obtained prospectively by clinicians. The primary endpoint was severe rotavirus gastroenteritis (Vesikari score >or=11), detected by enzyme immunoassay, arising 14 days or more after the third dose of placebo or vaccine to end of study (March 31, 2009; around 21 months of age). Analysis was per protocol; infants who received scheduled doses of vaccine or placebo without intervening laboratory-confirmed naturally occurring rotavirus disease earlier than 14 days after the third dose and had complete clinical and laboratory results were included in the analysis. This study is registered with ClinicalTrials.gov, number NCT00362648., Findings: 5468 infants were randomly assigned to receive pentavalent rotavirus vaccine (n=2733) or placebo (n=2735). 2357 infants assigned to vaccine and 2348 assigned to placebo were included in the per-protocol analysis. 79 cases of severe rotavirus gastroenteritis were reported in 2610.6 person-years in the vaccine group, compared with 129 cases in 2585.9 person-years in the placebo group, resulting in a vaccine efficacy against severe rotavirus gastroenteritis of 39.3% (95% CI 19.1-54.7, p=0.0003 for efficacy >0%). Median follow-up in both groups was 527 days starting 14 days after the third dose of vaccine or placebo was given. 42 (1.5%) of 2723 infants assigned to receive vaccine and 45 (1.7%) of 2724 infants assigned to receive placebo had a serious adverse event within 14 days of any dose. The most frequent serious adverse event was gastroenteritis (vaccine 17 [0.6%]; placebo 17 [0.6%])., Interpretation: Pentavalent rotavirus vaccine is effective against severe rotavirus gastroenteritis in the first 2 years of life in African countries with high mortality in infants younger than 5 years. We support WHO's recommendation for adoption of rotavirus vaccine into national expanded programmes on immunisation in Africa., Funding: PATH (GAVI Alliance grant) and Merck., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Background: Rotavirus vaccine has proved effective for prevention of severe rotavirus gastroenteritis in infants in developed countries, but no efficacy studies have been done in developing countries in Asia. We assessed the clinical efficacy of live oral pentavalent rotavirus vaccine for prevention of severe rotavirus gastroenteritis in infants in Bangladesh and Vietnam., Methods: In this multicentre, double-blind, placebo-controlled trial, undertaken in rural Matlab, Bangladesh, and urban and periurban Nha Trang, Vietnam, infants aged 4-12 weeks without symptoms of gastrointestinal disorders were randomly assigned (1:1) to receive three oral doses of pentavalent rotavirus vaccine 2 mL or placebo at around 6 weeks, 10 weeks, and 14 weeks of age, in conjunction with routine infant vaccines including oral poliovirus vaccine. Randomisation was done by computer-generated randomisation sequence in blocks of six. Episodes of gastroenteritis in infants who presented to study medical facilities were reported by clinical staff and from parent recollection. The primary endpoint was severe rotavirus gastroenteritis (Vesikari score >or=11) arising 14 days or more after the third dose of placebo or vaccine to end of study (March 31, 2009; around 21 months of age). Analysis was per protocol; infants who received scheduled doses of vaccine or placebo without intervening laboratory-confirmed naturally occurring rotavirus disease earlier than 14 days after the third dose and had complete clinical and laboratory results were included in the analysis. This study is registered with ClinicalTrials.gov, number NCT00362648., Findings: 2036 infants were randomly assigned to receive pentavalent rotavirus vaccine (n=1018) or placebo (n=1018). 991 infants assigned to pentavalent rotavirus vaccine and 978 assigned to placebo were included in the per-protocol analysis. Median follow up from 14 days after the third dose of placebo or vaccine until final disposition was 498 days (IQR 480-575). 38 cases of severe rotavirus gastroenteritis (Vesikari score >or=11) were reported during more than 1197 person-years of follow up in the vaccine group, compared with 71 cases in more than 1156 person years in the placebo group, resulting in a vaccine efficacy of 48.3% (95% CI 22.3-66.1) against severe disease (p=0.0005 for efficacy >0%) during nearly 2 years of follow-up. 25 (2.5%) of 1017 infants assigned to receive vaccine and 20 (2.0%) of 1018 assigned to receive placebo had a serious adverse event within 14 days of any dose. The most frequent serious adverse event was pneumonia (vaccine 12 [1.2%]; placebo 15 [1.5%])., Interpretation: In infants in developing countries in Asia, pentavalent rotavirus vaccine is safe and efficacious against severe rotavirus gastroenteritis, and our results support expanded WHO recommendations to promote its global use., Funding: PATH (GAVI Alliance grant) and Merck., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Vascular endothelial dysfunction is thought to play a prominent role in systemic anthrax pathogenesis. We examined the effect of anthrax lethal toxin (LTx), a key virulence factor of Bacillus anthracis, on the expression of vascular cell adhesion molecule-1 (VCAM-1) on normal and cytokine-stimulated human lung microvascular endothelial cells. Confluent endothelial monolayers were treated with lethal factor (LF), protective antigen (PA), or both (LTx) in the presence or absence of tumor necrosis factor-alpha (TNFalpha). LTx enhanced cytokine-induced VCAM-1 expression and monocyte adhesion. LTx alone had no effect on VCAM-1 expression. LF, PA or the combination of a catalytically inactive mutant LF and PA failed to enhance cytokine-induced VCAM-1 expression. Treatment with inhibitors of mitogen-activated protein kinase kinases (MEKs) and mitogen-activated protein kinases did not reproduce the VCAM-1 enhancement effect of LTx, a known MEK metalloprotease, suggesting LTx-mediated MEK cleavage may not be a contributing factor.

Hemorrhage and pleural effusion are prominent pathological features of systemic anthrax infection. We examined the effect of anthrax lethal toxin (LT), a major virulence factor of Bacillus anthracis, on the barrier function of primary human lung microvascular endothelial cells. We also examined the distribution patterns of cytoskeletal actin and vascular endothelial-cadherin (VE-cadherin), both of which are involved in barrier function regulation. Endothelial monolayers cultured on porous membrane inserts were treated with the LT components lethal factor (LF) and protective antigen (PA) individually, or in combination. LT induced a concentration- and time-dependent decrease in transendothelial electrical resistance that correlated with increased permeability to fluorescently labeled albumin. LT also produced a marked increase in central actin stress fibers and significantly altered VE-cadherin distribution as revealed by immunofluorescence microscopy and cell surface enzyme-linked immunosorbent assay. Treatment with LF, PA, or the combination of an inactive LF mutant and PA did not alter barrier function or the distribution of actin or VE-cadherin. LT-induced barrier dysfunction was not dependent on endothelial apoptosis or necrosis. The present findings support a possible role for LT-induced barrier dysfunction in the vascular permeability changes accompanying systemic anthrax infection.

Purpose: Regression, a gradual partial or complete return to the myopic state, remains a common complication of excimer laser photorefractive keratectomy (PRK) and limits the predictability of refractive outcome, especially in high myopia. An estimated 10% to 20% of patients, therefore, request a repeat PRK procedure. This study was designed to provide patient selection criteria and guidelines for successful retreatment., Methods: One hundred six patients who had regressed were randomized to 1 of 4 retreatment groups comprising (1) those with minimal haze after their first PRK who received an exact retreatment; (2) those with minimal haze treated with a 50% deliberate overcorrection; (3) those with significant haze (> or = 2+ haze) given an exact retreatment; and (4) those with significant haze who received a 50% overcorrection. A Visx 20/20 laser was used in each case. Mean follow-up after retreatment was 12 months (range, 6-18 months)., Results: Deliberate overcorrection (groups 2 and 4) resulted in a statistically significantly better refractive outcome (P = 0.026 at 6 months). Analysis of variance showed that significant haze after the first PRK was the most important predictor of a poor outcome after retreatment, other factors being high original myopia, marked regression, and loss of best-corrected visual acuity., Conclusions: A retreatment PRK procedure for significant regression will reduce residual myopia significantly in the majority of patients, and a deliberate overcorrection (50%) reduces the chance of further regression. However, patients with high myopia who have regressed beyond approximately -3.50 diopters originally and who show significant anterior stromal haze (> 2+) should be retreated only with great caution, because of the risk of further regression, haze, and loss of visual acuity.

Background: Granular corneal dystrophy is a rare indication for corneal transplantation. Both penetrating and lamellar keratoplasty have been recommended, but because granular corneal dystrophy is known to recur within the donor material and multiple grafts may be necessary, the best surgical option has not been clearly established. The cellular cause of the dystrophy is unknown and the authors hypothesized that the rate and pattern of recurrence within lamellar and penetrating grafts might give clues to its etiology., Methods: The authors compared the visual outcome, rate, and pattern of recurrence after 20 penetrating keratoplasties and 11 lamellar keratoplasties for granular corneal dystrophy., Results: Penetrating keratoplasty and lamellar keratoplasty have a good visual outcome in granular corneal dystrophy. Visual acuities after both procedures were not statistically different. Recurrence of the dystrophy within the graft material was almost universal within 4 years. It first appeared centrally and superficially, occasionally adopting a vortex pattern suggesting epithelial involvement. The recurrence-free interval was independent of size and type of graft performed., Conclusion: The authors recommend lamellar keratoplasty as a primary procedure in managing visually disabling granular corneal dystrophy if the deposits are limited to the superficial cornea. This is particularly applicable in younger patients in whom multiple procedures may be necessary over a lifetime due to recurrence of the dystrophy, and the lower morbidity rate associated with lamellar keratoplasty becomes appreciable. Although granular corneal dystrophy generally is classified as a stromal dystrophy, the pattern of recurrence is more consistent with an epithelial or tear-borne abnormality than a disease of the stromal keratocyte.

Of a series of 201 corneal transplants for keratoconus over a 20-year period, 42 grafts (39 eyes of 38 patients) required further surgery because of intolerable astigmatism (range, -3 diopters [D] to -18 D; mean, 8.9 D). Relaxing incisions, compressive resuturing, and augmented relaxing incisions were the techniques used. All procedures resulted in a similar mean reduction in cylinder -3.6 to 5 D, but the outcome with augmented relaxing incisions was less predictable. Six grafts required two or more procedures for a satisfactory outcome. All patients had corrected visual acuity of 20/30 or better after surgery, and 75% had visual acuity of 20/20 or better. The cumulative time until 90% of the grafts had useful vision was 32 months after refractive surgery. Relaxing incisions offer the prospect of more rapid visual rehabilitation than compressive resuturing.

Graft survival in a previously reported cohort of patients recruited between 1967 and 1978 (10.6 years' mean follow-up) was reviewed and compared with that for a cohort recruited between 1979 and 1987 (3.8 years' mean follow-up). This allowed analysis of improved graft survival due to changes in management, introduced after critical review of the first group in 1978. The salient changes included transition from intracapsular to extracapsular cataract surgery (P = 0.001) and treatment of rejection episodes with antiviral prophylaxis. Extracapsular cataract surgery improved graft survival (P = 0.07) benefiting inflamed eyes which more frequently required concomitant surgery (P = 0.005). Survival of rejection episodes was improved by antiviral prophylaxis (P = 0.02), and the incidence of recurrent keratitis was reduced (P = 0.0005). The complete and prompt removal of loose sutures improved graft survival (P = 0.025). Long-term survival of first grafts was 70%, and management changes improved overall survival (P = 0.036) despite an increased number of eyes (P = 0.05) grafted when inflamed.