Hexapeptides from mammalian inhibitory hormone hunt activate and inactivate nematode reproduction

© 2022 Hart et al. This is an open access article distributed under the terms of the Creative Commons Attribution License. https://creativecommons.org/licenses/by/4.0/Background: Biopurification has been used to disclose an evolutionarily conserved inhibitory reproductive hormone involved in tissue mass determination. A (rat) bioassay-guided physicochemical fractionation using ovine materials yielded via Edman degradation a 14-residue amino acid (aa) sequence. As a 14mer synthetic peptide (EPL001) this displayed antiproliferative and reproduction-modulating activity, while representing only a part of the native polypeptide. Even more unexpectedly, a scrambled-sequence control peptide (EPL030) did likewise. Methods: Reproduction has been investigated in the nematode Steinernema siamkayai, using a fermentation system supplemented with different concentrations of exogenous hexapeptides. Peptide structure-activity relationships have also been studied using prostate cancer and other mammalian cells in vitro, with peptides in solution or immobilized, and via the use of mammalian assays in vivo and through molecular modelling. Results: Reproduction increased (x3) in the entomopathogenic nematode Steinernema siamkayai after exposure to one synthetic peptide (IEPVFT), while fecundity was reduced (x0.5) after exposure to another (KLKMNG), both effects being dose-dependent. These hexamers are opposite ends of the synthetic peptide KLKMNGKNIEPVFT (EPL030). Bioactivity is unexpected as EPL030 is a control compound, based on a scrambled sequence of the test peptide MKPLTGKVKEFNNI (EPL001). EPL030 and EPL001 are both bioinformatically obscure, having no convincing matches to aa sequences in the protein databases. EPL001 has antiproliferative effects on human prostate cancer cells and rat bone marrow cells in vitro. Intracerebroventricular infusion of EPL001 in sheep was associated with elevated growth hormone in peripheral blood and reduced prolactin. The highly dissimilar EPL001 and EPL030 nonetheless have the foregoing biological effects in common in mammalian systems, while being divergently pro- and anti-fecundity respectively in the nematode Caenorhabditis elegans. Peptides up to a 20mer have also been shown to inhibit the proliferation of human cancer and other mammalian cells in vitro, with reproductive upregulation demonstrated previously in fish and frogs, as well as nematodes. EPL001 encodes the sheep neuroendocrine prohormone secretogranin II (sSgII), as deduced on the basis of immunoprecipitation using an anti-EPL001 antibody, with bespoke bioinformatics. Six sSgII residues are key to EPL001’s bioactivity: MKPLTGKVKEFNNI. A stereospecific bimodular tri-residue signature is described involving simultaneous accessibility for binding of the side chains of two specific trios of amino acids, MKP & VFN. An evolutionarily conserved receptor is conceptualised having dimeric binding sites, each with ligand-matching bimodular stereocentres. The bioactivity of the 14mer control peptide EPL030 and its hexapeptide progeny is due to the fortuitous assembly of subsets of the novel hormonal motif, MKPVFN, a default reproductive and tissue-building OFF signal.Peer reviewe

The First Direct Detection of Kirkwood Transitions in Concentrated Aqueous Electrolytes using Small Angle X-ray Scattering

Ion-ion correlations, screening, and equilibrium bulk structure in various concentrated electrolytes are investigated using synchrotron small angle X-ray scattering (SAXS), theory, and molecular simulation. Utilizing SAXS measurements we provide estimates of the Kirkwood Transition (KT) for a variety of aqueous electrolytes (NaCl, CaCl$_2$, SrCl$_2$, and ErCl$_3$). The KT may be defined as the concentration above which the ion-ion correlations cease to decay exponentially with a single length scale given by the Debye length $\lambda_{\rm D}$ and develop an additional length scale, $d=2\pi/Q_0$ that reflects the formation of local domains of charge. Theoretical models of the KT have been known for decades for highly idealized models of electrolytes, but experimental verification of KT in real electrolytes has yet to be confirmed. Herein, we provide consistent theoretical and experimental estimates of both the inverse screening lengths $a_0$ and inverse domain size, $Q_0$ for the aforementioned electrolyte systems. Taken together, $a_0$ and $Q_0$ are known descriptors of the KT and provide a view into the complexity of ion-ion interaction beyond the well-accepted Debye-H\"{u}ckel limit. Our findings suggest a picture of interaction for real electrolytes that is more general than that found in idealized models that is manifest in the precise form of the non-local response function that we estimate through the interpretation of the experimental SAXS signal. Importantly, the additional complexity of describing ion-ion interaction of real electrolytes will implicate the short-range ion-ion interactions that can only be computed via molecular simulation and provide a quantitative approach to describe electrolyte phenomena beyond Debye-H\"{u}ckel theory.Comment: 3

Quantifying the hydration structure of sodium and potassium ions: taking additional steps on Jacob's Ladder

The ability to reproduce the experimental structure of water around the sodium and potassium ions is a key test of the quality of interaction potentials due to the central importance of these ions in a wide range of important phenomena. Here, we simulate the Na+ and K+ ions in bulk water using three density functional theory functionals: (1) the generalized gradient approximation (GGA) based dispersion corrected revised Perdew, Burke, and Ernzerhof functional (revPBE-D3) (2) the recently developed strongly constrained and appropriately normed (SCAN) functional (3) the random phase approximation (RPA) functional for potassium. We compare with experimental X-ray diffraction (XRD) and X-ray absorption fine structure (EXAFS) measurements to demonstrate that SCAN accurately reproduces key structural details of the hydration structure around the sodium and potassium cations, whereas revPBE-D3 fails to do so. However, we show that SCAN provides a worse description of pure water in comparison with revPBE-D3. RPA also shows an improvement for K+, but slow convergence prevents rigorous comparison. Finally, we analyse cluster energetics to show SCAN and RPA have smaller fluctuations of the mean error of ion-water cluster binding energies compared with revPBE-D3

Coherent Detector Arrays for Millimeter and Submillimeter Astronomy

Progress in many areas of astronomy requires large-area surveys and observations of extended objects. This includes the cosmic microwave background, nearby galaxies, the Milky Way, and regions of star-forming regions within our galaxy. The ability to carry out such studies is critically dependent on the development of affordable high-sensitivity focal plane arrays, for both spectral line and continuum observations. We discuss a program for the next decade to develop such technology for ground-based and spacebased millimeter and submillimeter astronomy. Appropriate technologies exist, but significant effort is required to make the transition from simply replicating individual pixels to approaching focal plane array design in an integrated fashion from feeds to spectrometers for spectral analysis. This advance is essential to realize the full potential of major new ground-based, suborbital, and future space facilities, and is relevant to the RMS and EOS panels. The recommended budget for this activity is $65M

546 Results from Phase Ib study of tebentafusp (tebe) in combination with durvalumab (durva) and/or tremelimumab (treme) in metastatic cutaneous melanoma (mCM)

BackgroundTebe, a T cell receptor fused to an anti-CD3 effector, can redirect T cells to target gp100+ cells and in Ph3, demonstrated overall survival (OS) benefit as monotherapy in metastatic uveal melanoma. In Ph2, any tumor shrinkage (44% of patients) was a better predictor of OS than response rate. In Ph1, Tebe had monotherapy activity in mCM, also a gp100+ tumor, with 1-year OS ~74% in PD-1 naïve mCM. A Ph1 dose escalation of tebe with durva (anti-PD-L1) and/or treme (anti-CTLA4) was conducted in pre-treated mCM [NCT02535078], with nearly all patients having prior PD1-treatment, and where recently reported therapies have 1-yr OS of ~55%.MethodsHeavily pre-treated HLA-A2+ mCM patients received weekly IV tebe alone (Arm 4) or with increasing doses of durva and/or treme (Arm 1–3) administered IV monthly starting day 15 of each cycle. Primary objective was to identify RP2D of combination therapy. Secondary objectives included adverse events (AE) and efficacy.Results112 pts received ≥1 tebe dose. Median age was 59, 77% were ECOG 0, and 37% were BRAFm (of which 71% received prior BRAFi/MEKi). 91% of pts were 2L+, while 74% were 3L+. 103 (92%) received prior PD-1 inhibitor, of which 87% also received prior ipilimumab. 43 pts received tebe + durva (Arm 1), 13 received tebe + treme (Arm 2), 29 received triplet therapy (Arm 3), and 27 received tebe alone (Arm 4). Maximum target doses of tebe (68 mcg) + durva (20 mg/kg) and treme (1 mg/kg) were tolerated. MTD was not formally identified for any arm. Two DLTs occurred: prolonged grade 3 rash (Arm 1) and grade 2 diarrhea leading to treatment delay (Arm 2). Related AEs that were Grade ≥3 or led to discontinuations were: 44%/0% (Arm 1), 23%/0% (Arm2), 38%/7% (Arm3), 26%/4% (Arm 4). There were no treatment-related deaths.In prior PD-1 pts, tumor shrinkage occurred in 36% and 1-yr OS was 68%. Of 51 evaluable PD-1 resistant pts (best response CR/PR/SD to prior PD1), tumor shrinkage occurred in 28% and 1-yr OS was 73% (figure 1). In 35 evaluable PD-1 refractory pts (prior best response PD), tumor shrinkage occurred in 49% and 1-yr OS was 61%. For 38 prior PD-1 pts who received ≥10mg/kg durva, 1-yr OS was 81%.Abstract 546 Figure 1% tumor change from baseline in evaluable patients with known response to prior PD1 exposureConclusionsTebe with anti-PD-L1 and/or anti-CTLA4 had an acceptable safety profile. Tebe + durva demonstrated durable tumor shrinkage and promising 1-yr OS rates in prior-PD1 treated mCM relative to recent reports.Trial RegistrationNCT02535078Ethics ApprovalThe institutional review board or independent ethics committee at each center approved the trial. The trial was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines

The seeding of ice algal blooms in Arctic pack ice: The multiyear ice seed repository hypothesis

Source at http://dx.doi.org/10.1002/2016JG003668 During the Norwegian young sea ICE expedition (N-ICE2015) from January to June 2015 the pack ice in the Arctic Ocean north of Svalbard was studied during four drifts between 83° and 80°N. This pack ice consisted of a mix of second year, fi rst year, and young ice. The physical properties and ice algal community composition was investigated in the three different ice types during the winter-spring-summer transition. Our results indicate that algae remaining in sea ice that survived the summer melt season are subsequently trapped in the upper layers of the ice column during winter and may function as an algal seed repository. Once the connectivity in the entire ice column is established, as a result of temperature-driven increase in ice porosity during spring, algae in the upper parts of the ice are able to migrate toward the bottom and initiate the ice algal spring bloom. Furthermore, this algal repository might seed the bloom in younger ice formed in adjacent leads. This mechanism was studied in detail for the dominant ice diatom Nitzschia frigida . The proposed seeding mechanism may be compromised due to the disappearance of older ice in the anticipated regime shift toward a seasonally ice-free Arctic Ocean

ATAF1 transcription factor directly regulates abscisic acid biosynthetic gene NCED3 in Arabidopsis thaliana.

ATAF1, an Arabidopsis thaliana NAC transcription factor, plays important roles in plant adaptation to environmental stress and development. To search for ATAF1 target genes, we used protein binding microarrays and chromatin-immunoprecipitation (ChIP). This identified T[A,C,G]CGT[A,G] and TT[A,C,G]CGT as ATAF1 consensus binding sequences. Co-expression analysis across publicly available microarray experiments identified 25 genes co-expressed with ATAF1. The promoter regions of ATAF1 co-expressors were significantly enriched for ATAF1 binding sites, and TTGCGTA was identified in the promoter of the key abscisic acid (ABA) phytohormone biosynthetic gene NCED3. ChIP-qPCR and expression analysis showed that ATAF1 binding to the NCED3 promoter correlated with increased NCED3 expression and ABA hormone levels. These results indicate that ATAF1 regulates ABA biosynthesis

Leads in Arctic pack ice enable early phytoplankton blooms below snow-covered sea ic

publishedVersio

Patient characteristics associated with retrospectively self-reported treatment outcomes following psychological therapy for anxiety or depressive disorders - a cohort of GLAD study participants

Background: Progress towards stratified care for anxiety and depression will require the identification of new predictors. We collected data on retrospectively self-reported therapeutic outcomes in adults who received psychological therapy in the UK in the past ten years. We aimed to replicate factors associated with traditional treatment outcome measures from the literature. Methods: Participants were from the Genetic Links to Anxiety and Depression (GLAD) Study, a UK-based volunteer cohort study. We investigated associations between retrospectively self-reported outcomes following therapy, on a five-point scale (global rating of change; GRC) and a range of sociodemographic, clinical and therapy-related factors, using ordinal logistic regression models (n = 2890). Results: Four factors were associated with therapy outcomes (adjusted odds ratios, OR). One sociodemographic factor, having university-level education, was associated with favourable outcomes (OR = 1.37, 95%CI: 1.18, 1.59). Two clinical factors, greater number of reported episodes of illness (OR = 0.95, 95%CI: 0.92, 0.97) and higher levels of personality disorder symptoms (OR = 0.89, 95%CI: 0.87, 0.91), were associated with less favourable outcomes. Finally, reported regular use of additional therapeutic activities was associated with favourable outcomes (OR = 1.39, 95%CI: 1.19, 1.63). There were no statistically significant differences between fully adjusted multivariable and unadjusted univariable odds ratios. Conclusion: Therapy outcome data can be collected quickly and inexpensively using retrospectively self-reported measures in large observational cohorts. Retrospectively self-reported therapy outcomes were associated with four factors previously reported in the literature. Similar data collected in larger observational cohorts may enable detection of novel associations with therapy outcomes, to generate new hypotheses, which can be followed up in prospective studies