The Roles of Climate Change and Climate Variability in the 2017 Atlantic Hurricane Season

The 2017 hurricane season was extremely active with six major hurricanes, the third most on record. The sea-surface temperatures (SSTs) over the eastern Main Development Region (EMDR), where many tropical cyclones (TCs) developed during active months of August/September, were approximately 0.96 degrees Centigrade above the 1901-2017 average (warmest on record): about 0.42 degrees Centigrade from a long-term upward trend and the rest (around 80 percent) attributed to the Atlantic Meridional Mode (AMM). The contribution to the SST from the North Atlantic Oscillation over the EMDR was a weak warming, while that from ENSO was negligible. Nevertheless, ENSO, the NAO, and the AMM all contributed to favorable wind shear conditions, while the AMM also produced enhanced atmospheric instability. Compared with the strong hurricane years of 2005-2010, the ocean heat content (OHC) during 2017 was larger across the tropics, with higher SST anomalies over the EMDR and Caribbean Sea. On the other hand, the dynamical/thermodynamical atmospheric conditions, while favorable for enhanced TC activity, were less prominent than in 2005-2010 across the tropics. The results suggest that unusually warm SST in the EMDR together with the long fetch of the resulting storms in the presence of record-breaking OHC were key factors in driving the strong TC activity in 2017

Predicting gene essentiality in Caenorhabditis elegans by feature engineering and machine-learning

Defining genes that are essential for life has major implications for understanding critical biological processes and mechanisms. Although essential genes have been identified and characterised experimentally using functional genomic tools, it is challenging to predict with confidence such genes from molecular and phenomic data sets using computational methods. Using extensive data sets available for the model organism Caenorhabditis elegans, we constructed here a machine-learning (ML)-based workflow for the prediction of essential genes on a genome-wide scale. We identified strong predictors for such genes and showed that trained ML models consistently achieve highly-accurate classifications. Complementary analyses revealed an association between essential genes and chromosomal location. Our findings reveal that essential genes in C. elegans tend to be located in or near the centre of autosomal chromosomes; are positively correlated with low single nucleotide polymorphim (SNP) densities and epigenetic markers in promoter regions; are involved in protein and nucleotide processing; are transcribed in most cells; are enriched in reproductive tissues or are targets for small RNAs bound to the argonaut CSR-1. Based on these results, we hypothesise an interplay between epigenetic markers and small RNA pathways in the germline, with transcription-based memory; this hypothesis warrants testing. From a technical perspective, further work is needed to evaluate whether the present ML-based approach will be applicable to other metazoans (including Drosophila melanogaster) for which comprehensive data set (i.e. genomic, transcriptomic, proteomic, variomic, epigenetic and phenomic) are available

Proteomic analysis of Oesophagostomum dentatum (Nematoda) during larval transition, and the effects of hydrolase inhibitors on development

In this study, in vitro drug testing was combined with proteomic and bioinformatic analyses to identify and characterize proteins involved in larval development of Oesophagostomum dentatum, an economically important parasitic nematode. Four hydrolase inhibitors ο-phenanthroline, sodium fluoride, iodoacetamide and 1,2-epoxy-3-(pnitrophenoxy)-propane (EPNP) significantly inhibited (≥90%) larval development. Comparison of the proteomic profiles of the development-inhibited larvae with those of uninhibited control larvae using two-dimensional gel electrophoresis, and subsequent MALDI-TOF mass spectrometric analysis identified a down-regulation of 12 proteins inferred to be involved in various larval developmental processes, including post-embryonic development and growth. Furthermore, three proteins (i.e. intermediate filament protein B, tropomyosin and peptidyl-prolyl cis-trans isomerase) inferred to be involved in the moulting process were down-regulated in moulting- and development-inhibited O. dentatum larvae. This first proteomic map of O. dentatum larvae provides insights in the protein profile of larval development in this parasitic nematode, and significantly improves our understanding of the fundamental biology of its development. The results and the approach used might assist in developing new interventions against parasitic nematodes by blocking or disrupting their key biological pathways

Differences in transcription between free-living and CO_2-activated third-stage larvae of Haemonchus contortus

Background: The disease caused by Haemonchus contortus, a blood-feeding nematode of small ruminants, is of major economic importance worldwide. The infective third-stage larva (L3) of this gastric nematode is enclosed in a cuticle (sheath) and, once ingested with herbage by the host, undergoes an exsheathment process that marks the transition from the free-living (L3) to the parasitic (xL3) stage. This study explored changes in gene transcription associated with this transition and predicted, based on comparative analysis, functional roles for key transcripts in the metabolic pathways linked to larval development. Results: Totals of 101,305 (L3) and 105,553 (xL3) expressed sequence tags (ESTs) were determined using 454 sequencing technology, and then assembled and annotated; the most abundant transcripts encoded transthyretin-like, calcium-binding EF-hand, NAD(P)-binding and nucleotide-binding proteins as well as homologues of Ancylostoma-secreted proteins (ASPs). Using an in silico-subtractive analysis, 560 and 685 sequences were shown to be uniquely represented in the L3 and xL3 stages, respectively; the transcripts encoded ribosomal proteins, collagens and elongation factors (in L3), and mainly peptidases and other enzymes of amino acid catabolism (in xL3). Caenorhabditis elegans orthologues of transcripts that were uniquely transcribed in each L3 and xL3 were predicted to interact with a total of 535 other genes, all of which were involved in embryonic development. Conclusion: The present study indicated that some key transcriptional alterations taking place during the transition from the L3 to the xL3 stage of H. contortus involve genes predicted to be linked to the development of neuronal tissue (L3 and xL3), formation of the cuticle (L3) and digestion of host haemoglobin (xL3). Future efforts using next-generation sequencing and bioinformatic technologies should provide the efficiency and depth of coverage required for the determination of the complete transcriptomes of different developmental stages and/or tissues of H. contortus as well as the genome of this important parasitic nematode. Such advances should lead to a significantly improved understanding of the molecular biology of H. contortus and, from an applied perspective, to novel methods of intervention

Systolic blood pressure, cardiovascular outcomes and efficacy and safety of sacubitril/valsartan (LCZ696) in patients with chronic heart failure and reduced ejection fraction: results from PARADIGM-HF

Background: Compared to heart failure patients with higher systolic blood pressure (SBP), those with lower SBP have a worse prognosis. To make matters worse, the latter patients often do not receive treatment with life-saving therapies that might lower blood pressure further. We examined the association between SBP and outcomes in the Prospective Comparison of angiotensin receptor-neprilysin inhibitor (ARNI) with an angiotensin-converting enzyme (ACE) inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure trial (PARADIGM-HF), as well as the effect of sacubitril/valsartan, compared with enalapril, according to baseline SBP. Methods: We analysed the effect of treatment on SBP and on the primary composite outcome (cardiovascular death or heart failure hospitalization), its components and all-cause death. We examined baseline SBP as a categorical (<110, 110 to < 120, 120 to < 130, 130 to < 140 and ≥140 mmHg) and continuous variable, as well as average in-trial SBP and time-updated SBP. Findings: All-cause and cardiovascular mortality rates were highest in patients with the lowest SBP whereas there was a U-shaped relationship between SBP and the rate of heart failure hospitalization. The benefit of sacubitril/valsartan over enalapril was consistent across all baseline SBP categories for all outcomes. For example, the sacubitril/valsartan versus enalapril hazard ratio for the primary endpoint was 0.88 (95%CI 0.74–1.06) in patients with a baseline SBP <110 mmHg and 0.81 (0.65–1.02) for those with a SBP ≥140 mmHg (P for interaction = 0.55). Symptomatic hypotension, study drug dose-reduction and discontinuation were more frequent in patients with a lower SBP. Interpretation: In PARADIGM-HF, patients with lower SBP at randomization, notably after tolerating full doses of both study drugs during a run-in period, were at higher risk but generally tolerated sacubitril/valsartan and had the same relative benefit over enalapril as patients with higher baseline SBP

Structural and Functional Analysis of a β2-Adrenergic Receptor Complex with GRK5.

The phosphorylation of agonist-occupied G-protein-coupled receptors (GPCRs) by GPCR kinases (GRKs) functions to turn off G-protein signaling and turn on arrestin-mediated signaling. While a structural understanding of GPCR/G-protein and GPCR/arrestin complexes has emerged in recent years, the molecular architecture of a GPCR/GRK complex remains poorly defined. We used a comprehensive integrated approach of cross-linking, hydrogen-deuterium exchange mass spectrometry (MS), electron microscopy, mutagenesis, molecular dynamics simulations, and computational docking to analyze GRK5 interaction with the β2-adrenergic receptor (β2AR). These studies revealed a dynamic mechanism of complex formation that involves large conformational changes in the GRK5 RH/catalytic domain interface upon receptor binding. These changes facilitate contacts between intracellular loops 2 and 3 and the C terminus of the β2AR with the GRK5 RH bundle subdomain, membrane-binding surface, and kinase catalytic cleft, respectively. These studies significantly contribute to our understanding of the mechanism by which GRKs regulate the function of activated GPCRs. PAPERCLIP

Reconstruction of the insulin-like signalling pathway of Haemonchus contortus

Background: In the present study, we reconstructed the insulin/insulin-like growth factor 1 signalling (IIS) pathway for Haemonchus contortus, which is one of the most important eukaryotic pathogens of livestock worldwide and is related to the free-living nematode Caenorhabditis elegans. Methods: We curated full-length open-reading frames from assembled transcripts, defined the complement of genes that encode proteins involved in this pathway and then investigated the transcription profiles of these genes for all key developmental stages of H. contortus. Results: The core components of the IIS pathway are similar to their respective homologs in C. elegans. However, there is considerable variation in the numbers of isoforms between H. contortus and C. elegans and an absence of AKT-2 and DDL-2 homologs from H. contortus. Interestingly, DAF-16 has a single isoform in H. contortus compared with 12 in C. elegans, suggesting novel functional roles in the parasitic nematode. Some IIS proteins, such as DAF-18 and SGK-1, vary in their functional domains, indicating distinct roles from their homologs in C. elegans. Conclusions: This study paves the way for the further characterization of key signalling pathways in other socioeconomically important parasites and should help understand the complex mechanisms involved in developmental processes

The Haemonchus contortus kinome - a resource for fundamental molecular investigations and drug discovery

Background: Protein kinases regulate a plethora of essential signalling and other biological pathways in all eukaryotic organisms, but very little is known about them in most parasitic nematodes. Methods: Here, we defined, for the first time, the entire complement of protein kinases (kinome) encoded in the barber’s pole worm (Haemonchus contortus) through an integrated analysis of transcriptomic and genomic datasets using an advanced bioinformatic workflow. Results: We identified, curated and classified 432 kinases representing ten groups, 103 distinct families and 98 subfamilies. A comparison of the kinomes of H. contortus and Caenorhabditis elegans (a related, free-living nematode) revealed considerable variation in the numbers of casein kinases, tyrosine kinases and Ca^(2+) /calmodulin-dependent protein kinases, which likely relate to differences in biology, habitat and life cycle between these worms. Moreover, a suite of kinase genes was selectively transcribed in particular developmental stages of H. contortus, indicating central roles in developmental and reproductive processes. In addition, using a ranking system, drug targets (n = 13) and associated small-molecule effectors (n = 1517) were inferred. Conclusions: The H. contortus kinome will provide a useful resource for fundamental investigations of kinases and signalling pathways in this nematode, and should assist future anthelmintic discovery efforts; this is particularly important, given current drug resistance problems in parasitic nematodes