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Video 3. Differential Interference Contrast (DIC)/fluorescence time-lapse microscopy images of a mitotic MCF10A treated with DMSO (vehicle). Hoechst 33258 was used to stain chromatin. Images were collected every 30 s.

Video 1. Fluorescence images from time-lapse confocal microscopy using a laser-scanning confocal microscope of a mitotic U2OS cell transiently expressing pmTurquoise2-tagged- α-tubulin (red) treated with DMSO (vehicle). Images were collected every 30 s.

In addition to its cytosolic function, γ-tubulin is a chromatin-associated protein. Reduced levels of nuclear γ-tubulin increase the activity of E2 promoter-binding factors (E2F) and raise the levels of retinoblastoma (RB1) tumor suppressor protein. In tumor cells lacking RB1 expression, decreased γ-tubulin levels induce cell death. Consequently, impairment of the nuclear activity of γ-tubulin has been suggested as a strategy for targeted chemotherapy of RB1-deficient tumors; thus, tubulin inhibitors were tested to identify compounds that interfere with γ-tubulin. Interestingly, citral increased E2F activity but impaired microtubule dynamics while citral analogues, such citral dimethyl acetal (CDA), increased E2F activity without affecting microtubules. The cytotoxic effect of CDA on tumor cells was attenuated by increased expression of either RB1 or γ-tubulin, and increased by reduced levels of either RB1 or γ-tubulin. Mechanistic study, in silico and in vitro, demonstrated that CDA prevents GTP binding to γ-tubulin and suggested that the FDA-approved drug dimethyl fumarate is also a γ-tubulin inhibitor. Finally, in vivo growth of xenograft tumors carrying defects in the RB1 signaling pathway were inhibited by CDA treatment. These results demonstrate that inhibition of γ-tubulin has the potential to specifically target tumor cells and may aid in the design of safer and more efficient chemotherapeutic regimes.Implications: The in vivo antitumorigenic activity of γ-tubulin inhibitors paves the way for the development of a novel broad range targeted anticancer therapy that causes fewer side effects. Mol Cancer Res; 13(7); 1073–82. ©2015 AACR.

Supplementary material and methods. Contains legends to supplementary Figures and movies and supplementary methods.

The endothelial vascular permeability barrier has an important role throughout the body's extensive vasculature, and its disruption leads to vascular hyperpermeability (leakage), which is associated with numerous medical conditions. In the lung, vascular hyperpermeability can lead to pulmonary edema and acute respiratory distress syndrome (ARDS), the most severe and deadly complication of viral and bacterial infections, trauma and radiation exposure. There is currently no pharmacological treatment for ARDS with the only approved options being focused on supportive care. The development of effective treatments for ARDS has a potential to turn infectious diseases such as bacterial and viral pneumonia (including COVID-19) into manageable conditions, saving lives and providing a new tool to combat future epidemics. Strategies that aim to protect and augment the vascular endothelial barrier are important avenues to consider as potential treatments for ARDS and other conditions underlined by vascular hyperpermeability. We propose the activation of the MAPKAPK2 (MK2) kinase pathway as a new approach to augment the endothelial barrier and prevent or reverse ARDS and other conditions characterized by vascular barrier dysfunction.

BackgroundNephrolithiasis (NL) is a complex multifactorial disease affecting up to 10%–20% of the human population and causing a significant burden on public health systems worldwide. It results from a combination of environmental and genetic factors. Hyperoxaluria is a major risk factor for NL.MethodsWe used a whole exome-based approach in a patient with calcium oxalate NL. The effects of the mutation were characterised using cell culture and in silico analyses.ResultsWe identified a rare heterozygous missense mutation (c.1519C>T/p.R507W) in theSLC26A6gene that encodes a secretory oxalate transporter. This mutation cosegregated with hyperoxaluria in the family. In vitro characterisation of mutant SLC26A6 demonstrated that Cl−-dependent oxalate transport was dramatically reduced because the mutation affects both SLC26A6 transport activity and membrane surface expression. Cotransfection studies demonstrated strong dominant-negative effects of the mutant on the wild-type protein indicating that the phenotype of patients heterozygous for this mutation may be more severe than predicted by haploinsufficiency alone.ConclusionOur study is in line with previous observations made in the mouse showing thatSLC26A6inactivation can cause inherited enteric hyperoxaluria with calcium oxalate NL. Consistent with an enteric form of hyperoxaluria, we observed a beneficial effect of increasing calcium in the patient’s diet to reduce urinary oxalate excretion.

Key message: Annual stem CO2 efflux increases with stem wood production rates and are inhibited by daily moisture stress. Abstract: Tropical forests cycle a large amount of CO2 between the land and atmosphere, with a substantial portion of the return flux due tree respiratory processes. However, in situ estimates of woody tissue respiratory fluxes and carbon use efficiencies (CUEW) and their dependencies on physiological processes including stem wood production (Pw) and transpiration in tropical forests remain scarce. Here, we synthesize monthly Pw and daytime stem CO2 efflux (ES) measurements over 1 year from 80 trees with variable biomass accumulation rates in the central Amazon. On average, carbon flux to woody tissues, expressed in the same stem area normalized units as ES, averaged 0.90 ± 1.2µmolm−2s−1 for Pw, and 0.55 ± 0.33µmolm−2s−1 for daytime ES. A positive linear correlation was found between stem growth rates and stem CO2 efflux, with respiratory carbon loss equivalent to 15 ± 3% of stem carbon accrual. CUEW of stems was non-linearly correlated with growth and was as high as 77–87% for a fast-growing tree. Diurnal measurements of stem CO2 efflux for three individuals showed a daytime reduction of ES by 15–50% during periods of high sap flow and transpiration. The results demonstrate that high daytime ES fluxes are associated with high CUEW during fast tree growth, reaching higher values than previously observed in the Amazon Basin (e.g., maximum CUEW up to 77–87%, versus 30–56%). The observations are consistent with the emerging view that diurnal dynamics of stem water status influences growth processes and associated respiratory metabolism.

This file contains Supplementary Figures S1 and S2 legends

Nrh protein expression in healthy and tumoral tissues (A) Nrh protein expression in human healthy tissues. Immunohistochemistry on tissue array (B) Nrh expression assessed by western blot in cell lysate of liver cancer. (NAT) normal adjacent tissue.

AAC-11 is an antiapoptotic protein that is upregulated in most cancer cells. Increased expression of AAC-11 confers a survival advantage when cancer cells are challenged with various stresses and contributes to tumor invasion and metastases, whereas its deregulation reduces resistance to chemotherapeutic drugs. The antiapoptotic effect of AAC-11 may be clinically relevant as its expression correlates with poor prognosis in several human cancers. Thus, inactivation of AAC-11 might constitute an attractive approach for developing cancer therapeutics. We have developed an AAC-11–derived cell-penetrating peptide, herein named RT53, mimicking in part the heptad leucine repeat region of AAC-11, which functions as a protein–protein interaction module, and that can prevent AAC-11 antiapoptotic properties. In this study, we investigated the anticancer effects of RT53. Our results indicate that RT53 selectively kills cancer cells while sparing normal cells. RT53 selectively inserts into the membranes of cancer cells, where it adopts a punctate distribution and induces membranolysis and release of danger-associated molecular pattern molecules. Systemic administration of RT53 inhibited the growth of preexisting BRAF wild-type and V600E mutant melanoma xenograft tumors through induction of apoptosis and necrosis. Toxicological studies revealed that repetitive injections of RT53 did not produce significant toxicity. Finally, RT53-killed B16F10 cells induced tumor growth inhibition in immunocompetent mice following a rechallenge with live cancer cells of the same type. Collectively, our data demonstrate that RT53 possesses tumor-inhibitory activity with no toxicity in mice, suggesting its potential as a therapeutic agent for the treatment of melanoma and probably other cancers. Cancer Res; 76(18); 5479–90. ©2016 AACR.

Time-lapse imaging of dTAT-NDP action on CAL-51 breast cancer cell line

Fig. S8. Mechanism for irradiation-free dTAT peptide internalization Fig; S9. dTAT peptide treatment increases apoptosis of tumor cells in vivo

Drug resistance and metastatic relapse remain a top challenge in breast cancer treatment. In this study, we present preclinical evidence for a strategy to eradicate advanced breast cancers by targeting the BCL-2 homolog Nrh/BCL2L10, which we discovered to be overexpressed in >45% of a large cohort of breast invasive carcinomas. Nrh expression in these tumors correlated with reduced metastasis-free survival, and we determined it to be an independent marker of poor prognosis. Nrh protein localized to the endoplasmic reticulum. Mechanistic investigations showed that Nrh made BH4 domain–dependent interactions with the ligand-binding domain of the inositol-1,4,5-triphosphate receptor (IP3R), a type 1/3 Ca2+ channel, allowing Nrh to negatively regulate ER-Ca2+ release and to mediate antiapoptosis. Notably, disrupting Nrh/IP3R complexes by BH4 mimetic peptides was sufficient to inhibit the growth of breast cancer cells in vitro and in vivo. Taken together, our results highlighted Nrh as a novel prognostic marker and a candidate therapeutic target for late stage breast cancers that may be addicted to Nrh.Significance: These findings offer a comprehensive molecular model for the activity of Nrh/BCL2L10, a little studied antiapoptotic molecule, prognostic marker, and candidate drug target in breast cancer. Cancer Res; 78(6); 1404–17. ©2018 AACR.

I- Reagents and antibodies. Vectors. RNA preparation & RT-qPCR -II- Supplementary Table 1: Invasive breast carcinomas patient cohort characteristics -III- Supplementary Table 2: Correlation between Nrh protein expression and the clinicopathologic factors of breast cancer -IV- Supplementary Table 3: Multivariate analysis of clinical parameters predicting shorter DMFS -V- Legend of supplementary movie : Time-lapse imaging of dTAT-NDP action on CAL-51 breast cancer cell line

R code and eDNA input files to train a taxon-independent community index (TICI) for 53 riverine monitoring sites in New Zealand

While the sample of optical Type Ia Supernova (SN Ia) light curves (LCs) usable for cosmological parameter measurements surpasses 2000, the sample of published, cosmologically viable near-infrared (NIR) SN Ia LCs, which have been shown to be good "standard candles," is still $\lesssim$ 200. Here, we present high-quality NIR LCs for 83 SNe Ia ranging from $0.002 < z < 0.09$ as a part of the Dark Energy, H$_0$, and peculiar Velocities using Infrared Light from Supernovae (DEHVILS) survey. Observations are taken using UKIRT's WFCAM, where the median depth of the images is 20.7, 20.1, and 19.3 mag (Vega) for $Y$, $J$, and $H$-bands, respectively. The median number of epochs per SN Ia is 18 for all three bands ($YJH$) combined and 6 for each band individually. We fit 47 SN Ia LCs that pass strict quality cuts using three LC models, SALT3, SNooPy, and BayeSN and find scatter on the Hubble diagram to be comparable to or better than scatter from optical-only fits in the literature. Fitting NIR-only LCs, we obtain standard deviations ranging from 0.128-0.135 mag. Additionally, we present a refined calibration method for transforming 2MASS magnitudes to WFCAM magnitudes using HST CALSPEC stars that results in a 0.03 mag shift in the WFCAM $Y$-band magnitudes., 24 pages, 9 figures. Accepted by MNRAS

The use of disinfection and cleaning chemicals in several municipal facilities, such as swimming pools and drinking water treatment plants, causes the degradation of various types of wood, which leads to failures in equipment and the corresponding need for maintenance. This degradation creates added costs for municipalities, as well as the closure of certain facilities due to curative or preventive maintenance and, in many cases, public health issues, due to the water being contaminated with deteriorating products. Through a thorough study of the degradation effect on the products, more resistant materials can be found which are able to withstand these adversities and increase the lifespan of wood in regular contact with chemical agents. This is achievable by the determination of the cost-effectiveness of the substitute material to replace these components with alternative ones, with properties that better resist the deterioration effects promoted by aggressive environments. No studies have been found so far strictly focused on this matter. The objective of this study is to evaluate the degradation presented by two types of wood, beech and oak, which are exposed to the action of chlorine in municipal facilities. This degradation varies according to the chlorine content and the materials’ time of contact with the chemical agent, allowing the selection of new materials which will provide an extended lifetime of the components, reducing maintenance drastically, as well as costs for the facilities and the risk to public health. The performed experimental tests have shown that the oak wood has the best results regarding chlorine degradation resistance.

With the increased demand for sustainable, hypoallergenic products, plant surfactants are a promising, eco-friendly option for cleaning products due to their low toxicity or even the absence of toxicity. In the present study, surfactant-rich extracts from Chenopodium quinoa, Glycine max, and Malpighia emarginata were assessed for their stability, antioxidant capacity, toxic potential, and cleaning potential in shampoo formulations. The surfactants in the extracts were isolated and characterized by NMR, UV-Vis, and FTIR spectroscopy. The results demonstrated that the extracts remained stable within the temperature and pH ranges tested. The antioxidant properties were also determined. In the analysis of irritation potential, G. max and C. quinoa exhibited low toxicity and no toxicity, respectively. The cleaning potential analysis confirmed that the extracts could be used as primary surfactants. Seven shampoo formulations were developed, which showed potential to reduce surface tension to the range of 27.1–31.7 mN/m and interfacial tension to the range of 5.4–7.3 mN/m. The wettability, percentage of solids, density, pH, and dirt dispersion of the formulas were within standard ranges, and the sebum removal capacity of the seven formulations was similar to or even better than that of a commercial shampoo.

Additional file 1: Genealogical trees of to the 6 consanguineous MMA probands.

Additional file 5: Quantitative PCR results comparing relative expression of NOS3 mRNA in cells transfected with the wild type and with the M035 mutated cDNA.

Additional file 2: 3D structural analysis of the functional consequences of the eNOS p.C648R variant and sGC alpha1 subunit p.R593H variant.

Additional file 3: Candidate homozygous variants identified in the 6 consanguineous probands.

Additional file 4: NOS3 homozygous splice variant in M084 and NOS3 homozygous missense variant in M035.