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Background: From January 2002 to May 2004, 28 puffer fish poisoning (PFP) cases in Florida, New Jersey, Virginia, and New York were linked to the Indian River Lagoon (IRL) in Florida. Saxitoxins (STXs) of unknown source were first identified in fillet remnants from a New Jersey PFP case in 2002. Methods: We used the standard mouse bioassay (MBA), receptor binding assay (RBA), mouse neuroblastoma cytotoxicity assay (MNCA), Ridascreen ELISA, MIST Alert assay, HPLC, and liquid chromatography-mass spectrometry (LC-MS) to determine the presence of STX, decarbamoyl STX (dc-STX), and N-sulfocarbamoyl (B1) toxin in puffer fish tissues, clonal cultures, and natural bloom samples of Pyrodinium bahamense from the IRL. Results: We found STXs in 516 IRL southern (Sphoeroides nephelus), checkered (Sphoeroides testudineus), and bandtail (Sphoeroides spengleri) puffer fish. During 36 months of monitoring, we detected STXs in skin, muscle, and viscera, with concentrations up to 22,104 ug STX equivalents (eq)/100 g tissue (action level, 80 µg STX eq/100 g tissue) in ovaries. Puffer fish tissues, clonal cultures, and natural bloom samples of P. bahamense from the IRL tested toxic in the MBA, RBA, MNCA, Ridascreen ELISA, and MIST Alert assay and positive for STX, dc-STX, and B1 toxin by HPLC and LC-MS. Skin mucus of IRL southern puffer fish captive for 1-year was highly toxic compared to Florida Gulf coast puffer fish. Therefore, we confirm puffer fish to be a hazardous reservoir of STXs in Florida's marine waters and implicate the dinoflagellate P. bahamense as the putative toxin source. Conclusions: Associated with fatal paralytic shellfish poisoning (PSP) in the Pacific but not known to be toxic in the western Atlantic, P. bahamense is an emerging public health threat. We propose characterizing this food poisoning syndrome as saxitoxin puffer fish poisoning (SPFP) to distinguish it from PFP, which is traditionally associated with tetrodotoxin, and from PSP caused by STXs in shellfish.

The discovery of ferrocene nearly 70 years ago marked the genesis of metallocene chemistry. Although the ferrocenium cation was discovered soon afterwards, a derivatized ferrocenium dication was only isolated in 2016 and the monoanion of ferrocene has only been observed in low-temperature electrochemical studies. Here we report the isolation of a derivatized ferrocene anion in the solid state as part of an isostructural family of 3d metallocenates, which consist of anionic complexes of a metal centre (manganese, iron or cobalt) sandwiched between two bulky Cpttt ligands (where Cpttt is {1,2,4-C5H2tBu3}). These thermally and air-sensitive complexes decompose rapidly above −30 °C; however, we were able to characterize all metallocenates by a wide range of physical techniques and ab initio calculations. These data have allowed us to map the electronic structures of this metallocenate family, including an unexpected high-spin S = 3/2 ground state for the 19e− derivatized ferrocene anion.Unlike ferrocene and its cationic counterpart ferrocenium, the ferrocene monoanion is an unusual species that has been observed through low-temperature electrochemical studies. Now, a family of isostructural 3d metallocenates has been isolated that consists of a manganocene, a cobaltocene and a high-spin ferrocene anion stabilized by cyclopentadienyl ligands bearing bulky aliphatic groups.

Gene expression is a heritable cellular phenotype that defines the function of a cell and can lead to diseases in case of misregulation. In order to detect genetic variations affecting gene expression, we performed association analysis of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) with gene expression measured in 869 lymphoblastoid cell lines of the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort in cis and in trans. We discovered that 3,534 genes (false discovery rate (FDR) = 5%) are affected by an expression quantitative trait locus (eQTL) in cis and 48 genes are affected in trans. We observed that CNVs are more likely to be eQTLs than SNPs. In addition, we found that variants associated to complex traits and diseases are enriched for trans-eQTLs and that trans-eQTLs are enriched for cis-eQTLs. As a variant affecting both a gene in cis and in trans suggests that the cis gene is functionally linked to the trans gene expression, we looked specifically for trans effects of cis-eQTLs. We discovered that 26 cis-eQTLs are associated to 92 genes in trans with the cis-eQTLs of the transcriptions factors BATF3 and HMX2 affecting the most genes. We then explored if the variation of the level of expression of the cis genes were causally affecting the level of expression of the trans genes and discovered several causal relationships between variation in the level of expression of the cis gene and variation of the level of expression of the trans gene. This analysis shows that a large sample size allows the discovery of secondary effects of human variations on gene expression that can be used to construct short directed gene regulatory networks.

Ira Hall, Donald Conrad, the GTEx consortium and colleagues identify 23,602 high-confidence structural variants (SVs) and 24,884 cis expression quantitative trait loci (eQTLs) across 13 human tissues. They estimate that SVs are the causal variant at 3.5–6.8% of eQTLs and identify 789 SVs predicted to directly alter gene expression, most of which are noncoding variants in regulatory elements. Structural variants (SVs) are an important source of human genetic diversity, but their contribution to traits, disease and gene regulation remains unclear. We mapped cis expression quantitative trait loci (eQTLs) in 13 tissues via joint analysis of SVs, single-nucleotide variants (SNVs) and short insertion/deletion (indel) variants from deep whole-genome sequencing (WGS). We estimated that SVs are causal at 3.5–6.8% of eQTLs—a substantially higher fraction than prior estimates—and that expression-altering SVs have larger effect sizes than do SNVs and indels. We identified 789 putative causal SVs predicted to directly alter gene expression: most (88.3%) were noncoding variants enriched at enhancers and other regulatory elements, and 52 were linked to genome-wide association study loci. We observed a notable abundance of rare high-impact SVs associated with aberrant expression of nearby genes. These results suggest that comprehensive WGS-based SV analyses will increase the power of common- and rare-variant association studies.

Anti-malarial artemisinin-based combination therapies (ACTs) might be losing efficacy in east Africa, with the spread of artemisinin partial resistance and reduced partner drug activity. Our trial aimed to measure the efficacies of artemether–lumefantrine, artesunate–amodiaquine, dihydroartemisinin–piperaquine, and artesunate–pyronaridine in three sites in Uganda. This randomised, open-label, phase 4 clinical trial was carried out at three sites in the Agago, Arua, and Busia districts of Uganda. Children aged 6 months to 10 years with uncomplicated Plasmodium falciparum malaria were randomly assigned to receive either artemether–lumefantrine (20 mg artemether; 120 mg lumefantrine; twice a day for 3 days) in all sites or dihydroartemisinin–piperaquine (40 mg dihydroartemisinin and 320 mg piperaquine, once a day for 3 days) in Agago, artesunate–amodiaquine (25 mg artesunate and 67·5 mg amodiaquine for children <9 kg or 50 mg artesunate and 135 mg amodiaquine for children ≥9 kg, once a day for 3 days) in Busia; and artesunate–pyronaridine (60 mg artesunate and 180 mg pyronaridine for children >15 kg or 20 mg artesunate and 60 mg pyronaridine for children <15 kg, once a day for 3 days) in Arua, with follow-up to 42 days. Participants were not blinded to group assignments; however, investigators and those assessing outcome were masked. The primary outcome was parasitaemia, assessed by microscopy, either uncorrected or PCR-corrected to distinguish recrudescence from new infection. All participants who received the treatment per protocol and were not lost to follow-up were included in the primary outcome. All participants who were randomly allocated to treatment groups were included in the safety analyses. This study is registered with the Pan African Clinical Trials Registry, number PACTR202301796134887, and is complete. Between Nov 7, 2022, and March 24, 2023, 808 participants (437 [54%] female) were enrolled and assigned to treatment groups; 15 (2%) were lost to follow-up and 793 (98%) completed follow-up. The uncorrected adequate clinical and parasitological response for artemether–lumefantrine was 87 (51·8%; 95% CI 44·0–59·5) of 168 participants in Arua, 88 (51·8%; 44·0–59·4) of 170 and Busia, and 131 (79·4%; 72·3–85·1) of 165 in Agago. This response for artemether–lumefantrine was lower than that of the other ACTs at all sites: 97 (98·0%; 92·2–99·6) of 99 for dihydroartemisinin–piperaquine in Agago, 95 (99·0%; 93·5–99·9) of 96 for artesunate–amodiaquine in Busia, and 73 (73·7%; 63·8–81·8) of 99 for artesunate–pyronaridine in Arua. PCR-corrected 28-day efficacies were 88 (81·5%; 72·6–88·1) of 108 for artemether–lumefantrine and 95 (100%; 95·2–100·0) of 95 for artesunate–amodiaquine in Busia; 131 (97·0%; 92·1–99·0) of 135 for artemether–lumefantrine and 97 (100%; 95·3–100·0) of 97 for dihydroartemisinin–piperaquine in Agago; and 87 (82·1%; 73·2–88·6) of 106 for artemether–lumefantrine and 73 (92·4%; 83·6–96·9) of 79 for artesunate–pyronaridine in Arua. All regimens were well tolerated. The most common adverse events were upper respiratory tract infection, diarrhoea, and anaemia. None of the reported adverse events were attributed to the study drugs. There were two serious adverse events, both cases of severe malaria in Arua, one in each of the treatment groups. Parasite clearance half-lives were prolonged with parasites carrying the PfK13 Cys469Tyr (median 4·2 h; IQR 3·4–4·9) and Ala675Val (4·9 h; 3·4–5·7) mutations compared with wild-type parasites (2·8 h; 2·3–3·6; p<0·0001). Artemether–lumefantrine was associated with a higher risk of recurrent malaria than other antimalarial combinations tested, and K13 mutations were associated with delayed parasite clearance. Changes in first-line therapy for uncomplicated malaria must be considered in response to suboptimal efficacy of artemether–lumefantrine. US President's Malaria Initiative, US Agency for International Development, through the Uganda Malaria Reduction Activity and the National Institutes of Health (AI075045 and AI117001). For the Swahili translation of the abstract see Supplementary Materials section.

Background RNA sequencing (RNA-Seq) has emerged as a powerful approach for the detection of differential gene expression with both high-throughput and high resolution capabilities possible depending upon the experimental design chosen. Multiplex experimental designs are now readily available, these can be utilised to increase the numbers of samples or replicates profiled at the cost of decreased sequencing depth generated per sample. These strategies impact on the power of the approach to accurately identify differential expression. This study presents a detailed analysis of the power to detect differential expression in a range of scenarios including simulated null and differential expression distributions with varying numbers of biological or technical replicates, sequencing depths and analysis methods. Results Differential and non-differential expression datasets were simulated using a combination of negative binomial and exponential distributions derived from real RNA-Seq data. These datasets were used to evaluate the performance of three commonly used differential expression analysis algorithms and to quantify the changes in power with respect to true and false positive rates when simulating variations in sequencing depth, biological replication and multiplex experimental design choices. Conclusions This work quantitatively explores comparisons between contemporary analysis tools and experimental design choices for the detection of differential expression using RNA-Seq. We found that the DESeq algorithm performs more conservatively than edgeR and NBPSeq. With regard to testing of various experimental designs, this work strongly suggests that greater power is gained through the use of biological replicates relative to library (technical) replicates and sequencing depth. Strikingly, sequencing depth could be reduced as low as 15% without substantial impacts on false positive or true positive rates.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

To increase understanding of the genomic landscape of acral melanoma, a rare form of melanoma occurring on palms, soles or nail beds, whole genome sequencing of 87 tumors with matching transcriptome sequencing for 63 tumors was performed. Here we report that mutational signature analysis reveals a subset of tumors, mostly subungual, with an ultraviolet radiation signature. Significantly mutated genes are BRAF, NRAS , NF1 , NOTCH2 , PTEN and TYRP1 . Mutations and amplification of KIT are also common. Structural rearrangement and copy number signatures show that whole genome duplication, aneuploidy and complex rearrangements are common. Complex rearrangements occur recurrently and are associated with amplification of TERT , CDK4 , MDM2 , CCND1 , PAK1 and GAB2 , indicating potential therapeutic options. Acral melanoma occurs on the soles of the feet, palms of the hands and in nail beds. Here, the authors reports the genomic landscape of 87 acral melanomas and find that some tumors harbor a UV signature and that the tumors are diverse at the levels of mutational signatures, structural aberrations and copy number signatures.

Background Malignant pleural mesothelioma (MPM) has a poor overall survival with few treatment options. Whole genome sequencing (WGS) combined with the immune features of MPM offers the prospect of identifying changes that could inform future clinical trials. Methods We analysed somatic mutations from 229 MPM samples, including previously published data and 58 samples that had undergone WGS within this study. This was combined with RNA-seq analysis to characterize the tumour immune environment. Results The comprehensive genome analysis identified 12 driver genes, including new candidate genes. Whole genome doubling was a frequent event that correlated with shorter survival. Mutational signature analysis revealed SBS5/40 were dominant in 93% of samples, and defects in homologous recombination repair were infrequent in our cohort. The tumour immune environment contained high M2 macrophage infiltrate linked with MMP2 , MMP14 , TGFB1 and CCL2 expression, representing an immune suppressive environment. The expression of TGFB1 was associated with overall survival. A small subset of samples (less than 10%) had a higher proportion of CD8 T cells and a high cytolytic score, suggesting a ‘hot’ immune environment independent of the somatic mutations. Conclusions We propose accounting for genomic and immune microenvironment status may influence therapeutic planning in the future.

Salt marshes can sequester large amounts of carbon in sediments, but the relation between carbon storage and exportation remains poorly understood. Groundwater exchange can flush sediment carbon to surface waters and potentially reduce storage. In this study, we estimated groundwater fluxes and associated carbon fluxes using a radon (222Rn) mass balance and sediment carbon burial rates using lead (210Pb) in a pristine salt marsh (North Inlet, SC, USA). We used δ13C to trace carbon origins. We found that groundwater releases large amounts of carbon to the open ocean. These groundwater fluxes have the potential to export 7.2 ± 5.5 g m−2 of dissolved inorganic carbon (DIC), 0.2 ± 0.2 g m−2 of dissolved organic carbon (DOC) and 0.7 ± 0.5 g m−2 of carbon dioxide (CO2) per day. The fluxes exceed the average surface water CO2 emissions (0.6 ± 0.2 g m−2 day−1) and the average sediment carbon burial rates (0.17 ± 0.09 g m−2 day−1). The δ13C results suggest that groundwater carbon originated from salt marsh soils, while the sediment carbon source is derived from salt marsh vegetation. We propose that the impact of salt marshes in carbon cycling depends not only on their capacity to bury carbon in sediments, but also on their high potential to export carbon to the ocean via groundwater pathways.