Sixteen years of bathymetry and waves at San Diego beaches.

Sustained, quantitative observations of nearshore waves and sand levels are essential for testing beach evolution models, but comprehensive datasets are relatively rare. We document beach profiles and concurrent waves monitored at three southern California beaches during 2001-2016. The beaches include offshore reefs, lagoon mouths, hard substrates, and cobble and sandy (medium-grained) sediments. The data span two energetic El Niño winters and four beach nourishments. Quarterly surveys of 165 total cross-shore transects (all sites) at 100 m alongshore spacing were made from the backbeach to 8 m depth. Monthly surveys of the subaerial beach were obtained at alongshore-oriented transects. The resulting dataset consists of (1) raw sand elevation data, (2) gridded elevations, (3) interpolated elevation maps with error estimates, (4) beach widths, subaerial and total sand volumes, (5) locations of hard substrate and beach nourishments, (6) water levels from a NOAA tide gauge (7) wave conditions from a buoy-driven regional wave model, and (8) time periods and reaches with alongshore uniform bathymetry, suitable for testing 1-dimensional beach profile change models

MCL-1 is essential for survival but dispensable for metabolic fitness of FOXP3+ regulatory T cells

FOXP3+ regulatory T (Treg) cells are essential for maintaining immunological tolerance. Given their importance in immune-related diseases, cancer and obesity, there is increasing interest in targeting the Treg cell compartment therapeutically. New pharmacological inhibitors that specifically target the prosurvival protein MCL-1 may provide this opportunity, as Treg cells are particularly reliant upon this protein. However, there are two distinct isoforms of MCL-1; one located at the outer mitochondrial membrane (OMM) that is required to antagonize apoptosis, and another at the inner mitochondrial membrane (IMM) that is reported to maintain IMM structure and metabolism via ATP production during oxidative phosphorylation. We set out to elucidate the relative importance of these distinct biological functions of MCL-1 in Treg cells to assess whether MCL-1 inhibition might impact upon the metabolism of cells able to resist apoptosis. Conditional deletion of Mcl1 in FOXP3+ Treg cells resulted in a lethal multiorgan autoimmunity due to the depletion of the Treg cell compartment. This striking phenotype was completely rescued by concomitant deletion of the apoptotic effector proteins BAK and BAX, indicating that apoptosis plays a pivotal role in the homeostasis of Treg cells. Notably, MCL-1-deficient Treg cells rescued from apoptosis displayed normal metabolic capacity. Moreover, pharmacological inhibition of MCL-1 in Treg cells resistant to apoptosis did not perturb their metabolic function. We conclude that Treg cells require MCL-1 only to antagonize apoptosis and not for metabolism. Therefore, MCL-1 inhibition could be used to manipulate Treg cell survival for clinical benefit without affecting the metabolic fitness of cells resisting apoptosis

Theoretical and experimental analysis of the photoluminescence and photoluminescence excitation spectroscopy spectra of m\textit{m}-plane InGaN/GaN quantum wells

We present a combined theoretical and experimental analysis of the optical properties of $\textit{m}$-plane InGaN/GaN quantum wells. The sample was studied by photoluminescence and photoluminescence excitation spectroscopy at low temperature. The spectra show a large Stokes shift between the lowest exciton peak in the excitation spectra and the peak of the photoluminescence spectrum. This behavior is indicative of strong carrier localization effects. These experimental results are complemented by tight-binding calculations, accounting for random alloy fluctuations and Coulomb effects. The theoretical data explain the main features of the experimental spectra. Moreover, by comparison with calculations based on a virtual crystal approximation, the importance of carrier localization effects due to random alloy fluctuations is explicitly shown.This work was supported by Science Foundation Ireland (Project No. 13/SIRG/2210) and the United Kingdom Engineering and Physical Sciences Research Council (Grant Agreement Nos. EP\J001627\1 and EP\J003603\1). S.S. acknowledges computing resources provided by the SFI/HEA Irish Centre for High-End Computing. R.A.O. and F.T. acknowledge the support of the European Research Council under the European Community's 7th Framework Programme (FP7/2007–2013)/ERC Grant Agreement No. 279361 (MACONS)

A comparative study of Tam3 and Ac transposition in transgenic tobacco and petunia plants

Transposition of the Anthirrinum majus Tam3 element and the Zea mays Ac element has been monitored in petunia and tobacco plants. Plant vectors were constructed with the transposable elements cloned into the leader sequence of a marker gene. Agrobacterium tumefaciens-mediated leaf disc transformation was used to introduce the transposable element constructs into plant cells. In transgenic plants, excision of the transposable element restores gene expression and results in a clearly distinguishable phenotype. Based on restored expression of the hygromycin phosphotransferase II (HPTII) gene, we established that Tam3 excises in 30% of the transformed petunia plants and in 60% of the transformed tobacco plants. Ac excises from the HPTII gene with comparable frequencies (30%) in both plant species. When the β-glucuronidase (GUS) gene was used to detect transposition of Tam3, a significantly lower excision frequency (13%) was found in both plant species. It could be shown that deletion of parts of the transposable elements Tam3 and Ac, removing either one of the terminal inverted repeats (TIR) or part of the presumptive transposase coding region, abolished the excision from the marker genes. This demonstrates that excision of the transposable element Tam3 in heterologous plant species, as documented for the autonomous element Ac, also depends on both properties. Southern blot hybridization shows the expected excision pattern and the reintegration of Tam3 and Ac elements into the genome of tobacco plants.

Targeting tumour re-wiring by triple blockade of mTORC1, epidermal growth factor, and oestrogen receptor signalling pathways in endocrine-resistant breast cancer

Background Endocrine therapies are the mainstay of treatment for oestrogen receptor (ER)-positive (ER+) breast cancer (BC). However, resistance remains problematic largely due to enhanced cross-talk between ER and growth factor pathways, circumventing the need for steroid hormones. Previously, we reported the anti-proliferative effect of everolimus (RAD001-mTORC1 inhibitor) with endocrine therapy in resistance models; however, potential routes of escape from treatment via ERBB2/3 signalling were observed. We hypothesised that combined targeting of three cellular nodes (ER, ERBB, and mTORC1) may provide enhanced long-term clinical utility. Methods A panel of ER+ BC cell lines adapted to long-term oestrogen deprivation (LTED) and expressing ESR1wt or ESR1Y537S, modelling acquired resistance to an aromatase-inhibitor (AI), were treated in vitro with a combination of RAD001 and neratinib (pan-ERBB inhibitor) in the presence or absence of oestradiol (E2), tamoxifen (4-OHT), or fulvestrant (ICI182780). End points included proliferation, cell signalling, cell cycle, and effect on ER-mediated transactivation. An in-vivo model of AI resistance was treated with monotherapies and combinations to assess the efficacy in delaying tumour progression. RNA-seq analysis was performed to identify changes in global gene expression as a result of the indicated therapies. Results Here, we show RAD001 and neratinib (pan-ERBB inhibitor) caused a concentration-dependent decrease in proliferation, irrespective of the ESR1 mutation status. The combination of either agent with endocrine therapy further reduced proliferation but the maximum effect was observed with a triple combination of RAD001, neratinib, and endocrine therapy. In the absence of oestrogen, RAD001 caused a reduction in ER-mediated transcription in the majority of the cell lines, which associated with a decrease in recruitment of ER to an oestrogen-response element on the TFF1 promoter. Contrastingly, neratinib increased both ER-mediated transactivation and ER recruitment, an effect reduced by the addition of RAD001. In-vivo analysis of an LTED model showed the triple combination of RAD001, neratinib, and fulvestrant was most effective at reducing tumour volume. Gene set enrichment analysis revealed that the addition of neratinib negated the epidermal growth factor (EGF)/EGF receptor feedback loops associated with RAD001. Conclusions Our data support the combination of therapies targeting ERBB2/3 and mTORC1 signalling, together with fulvestrant, in patients who relapse on endocrine therapy and retain a functional ER

Reduced ventral cingulum integrity and increased behavioral problems in children with isolated optic nerve hypoplasia and mild to moderate or no visual impairment.

To assess the prevalence of behavioral problems in children with isolated optic nerve hypoplasia, mild to moderate or no visual impairment, and no developmental delay. To identify white matter abnormalities that may provide neural correlates for any behavioral abnormalities identified

Durable Responses and Low Toxicity After Fast Off-Rate CD19 Chimeric Antigen Receptor-T Therapy in Adults With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia

PURPOSE Prognosis for adult B-cell acute lymphoblastic leukemia (B-ALL) is poor, and there are currently no licensed CD19 chimeric antigen receptor (CAR) therapeutics. We developed a novel second-generation CD19-CAR (CAT19-41BB-Z) with a fast off rate, designed for more physiologic T-cell activation to reduce toxicity and improve engraftment. We describe the multicenter phase I ALLCAR19 (NCT02935257) study of autologous CAT19-41BB-Z CAR T cells (AUTO1) in relapsed or refractory (r/r) adult B-ALL. METHODS Patients age ≥ 16 years with r/r B-ALL were eligible. Primary outcomes were toxicity and manufacturing feasibility. Secondary outcomes were depth of response at 1 and 3 months, persistence of CAR-T, incidence and duration of hypogammaglobulinemia and B-cell aplasia, and event-free survival and overall survival at 1 and 2 years. RESULTS Twenty-five patients were leukapheresed, 24 products were manufactured, and 20 patients were infused with AUTO1. The median age was 41.5 years; 25% had prior blinatumomab, 50% prior inotuzumab ozogamicin, and 65% prior allogeneic stem-cell transplantation. At the time of preconditioning, 45% had ≥ 50% bone marrow blasts. No patients experienced ≥ grade 3 cytokine release syndrome; 3 of 20 (15%) experienced grade 3 neurotoxicity that resolved to ≤ grade 1 within 72 hours with steroids. Seventeen of 20 (85%) achieved minimal residual disease–negative complete response at month 1, and 3 of 17 underwent allogeneic stem-cell transplantation while in remission. The event-free survival at 6 and 12 months was 68.3% (42.4-84.4) and 48.3% (23.1%-69.7%), respectively. High-level expansion (Cmax 127,152 copies/µg genomic DNA) and durable CAR-T persistence were observed with B-cell aplasia ongoing in 15 of 20 patients at last follow-up. CONCLUSION AUTO1 demonstrates a tolerable safety profile, high remission rates, and excellent persistence in r/r adult B-ALL. Preliminary data support further development of AUTO1 as a stand-alone treatment for r/r adult B-ALL

Granulation and microbial community dynamics in the chitosan-supplemented anaerobic treatment of wastewater polluted with organic solvents

The effect of chitosan on the development of granular sludge in upflow anaerobic sludge blanket reactors (UASB) when treating wastewater polluted with the organic solvents ethanol, ethyl acetate, and 1-ethoxy-2-propanol was evaluated. Three UASB reactors were operated for 219 days at ambient temperature with an organic loading rate (OLR) of between 0.3 kg COD m−3 d−1 and 20 kg COD m−3 d−1. One reactor was operated without the addition of chitosan, while the other two were operated with the addition of chitosan doses of 2.4 mg gVSS−1 two times. The three reactors were all able to treat the OLR tested with COD removal efficiencies greater than 90%. However, the time required to reach stable operation was considerably reduced in the chitosan-assisted reactors. The development of granules in the reactors with chitosan was accelerated and granules larger than 2000 μm were only observed in these reactors. In addition, these granules exhibited better physicochemical characteristics: the mean particle diameter (540 and 613 μm) was approximately two times greater than in the control reactor (300 μm), and the settling velocities exceeded 35 m h−1. The extracellular polymeric substances (EPS) in the reactors with the chitosan was found to be higher than in the control reactor. The protein-EPS content has been correlated with the granule size. The analyses of the microbial communities, performed through denaturing gradient gel electrophoresis and high-throughput sequencing, revealed that the syntrophic microorganisms belonging to genus Geobacter and the hydrogenotrophic methanogen Methanocorpusculum labreanum were predominant in the granules. Other methanogens like Methanosaeta species were found earlier in the chitosan-assisted reactors than in the control reactor