Predicting drought stress under climate change in the Southern Central Highlands of Vietnam.

In the Southern Central Highlands of Vietnam, droughts occur more frequently, causing significant damage and impacting the region's socio-economic development. During the dry season, rivers, streams, and reservoirs often face limited water availability, exacerbated in recent years by increasing drought severity. Recognizing the escalating severity of droughts, the study offers a novel contribution by conducting a comprehensive analysis of surface water resource distribution in Lam Dong province, focusing on assessing water demand for agricultural production, a crucial factor in ensuring sustainable crop growth. Two scenarios, Current-2020 (SC1) and Climate Change-2025 (SC2), are simulated, with SC2 based on climate change and sea level rise scenarios provided by the Ministry of Natural Resources and Environment (MONRE). These scenarios are integrated into the MIKE-NAM and MIKE-HYDRO basin models, allowing for a thorough assessment of the water balance of Lam Dong province. Furthermore, the study utilizes the Keetch-Byram Drought Index (KBDI) to measure drought severity, revealing prevalent dry and moderately droughty conditions in highland districts with rainfall frequency ranging from 50 to 85%. Severe drought conditions occur with a rainfall frequency of 95%, indicating an increased frequency and geographic scope of severe droughts. Additionally, the study highlights that under abnormally dry conditions, water demand for the winter-spring crop is consistently met at 100%, decreasing to 85%, 80%, and less than 75% for moderate, severe, and extreme droughts, respectively. These findings offer insights into future drought conditions in the Lam Dong province and their potential impact on irrigation capacity, crucial for adaptation strategies.

Transcriptional regulation of CYR61 and CTGF by LM98: a synthetic YAP-TEAD inhibitor that targets in-vitro vasculogenic mimicry in glioblastoma cells.

Glioblastoma (GBM) is a highly angiogenic malignancy of the central nervous system that resists standard antiangiogenic therapy, in part because of an alternative process to angiogenesis termed vasculogenic mimicry. Intricately linked to GBM, dysregulation of the Hippo signaling pathway leads to overexpression of YAP/TEAD and several downstream effectors involved in therapy resistance. Little is known about whether vasculogenic mimicry and the Hippo pathway intersect in the GBM chemoresistance phenotype. This study seeks to investigate the expression patterns of Hippo pathway regulators within clinically annotated GBM samples, examining their involvement in vitro regarding vasculogenic mimicry. In addition, it aims to assess the potential for pharmacological targeting of this pathway. In-silico analysis of the Hippo signaling members YAP1, TEAD1, AXL, NF2, CTGF, and CYR61 transcript levels in low-grade GBM and GBM tumor tissues was done by Gene Expression Profiling Interactive Analysis. Gene expression was analyzed by real-time quantitative PCR from human U87, U118, U138, and U251 brain cancer cell lines and in clinically annotated brain tumor cDNA arrays. Transient gene silencing was performed with specific small interfering RNA. Vasculogenic mimicry was assessed using a Cultrex matrix, and three-dimensional capillary-like structures were analyzed with Wimasis. CYR61 and CTGF transcript levels were elevated in GBM tissues and were further induced when in-vitro vasculogenic mimicry was assessed. Silencing of CYR61 and CTGF, or treatment with a small-molecule TEAD inhibitor LM98 derived from flufenamic acid, inhibited vasculogenic mimicry. Silencing of SNAI1 and FOXC2 also altered vasculogenic mimicry and reduced CYR61/CTGF levels. Pharmacological targeting of the Hippo pathway inhibits in-vitro vasculogenic mimicry. Unraveling the connections between the Hippo pathway and vasculogenic mimicry may pave the way for innovative therapeutic strategies.

Assessing coastal vulnerability at the village level using a robust framework, the example of Canacona in South Goa, India.

Climate change poses a significant threat to coastal regions worldwide. This study presents and applies a modified Coastal Vulnerability Index (CVI) to assess coastal vulnerability at the village level, focusing on Canacona, a taluka in South Goa, India. It adapts the existing CVI methodology by incorporating additional variables to better represent the various dimensions of vulnerability, resulting in 21 variables split into a Physical Vulnerability Index (PVI) and a Social Vulnerability Index (SoVI). The results show spatial variability in coastal vulnerability across the studied villages, with Agonda and Nagercem-Chaudi found to be highly vulnerable and Loliem to be the least vulnerable. A hydrological modeling approach is also used to compare the CVI of every village with their susceptibility to inundation due to rising sea levels. The results demonstrate the influence of local factors on vulnerability, challenging previous taluka-level assessments given the scale upon which adaptation typically takes place.

Development of HC-258, a Covalent Acrylamide TEAD Inhibitor That Reduces Gene Expression and Cell Migration.

The transcription factor YAP-TEAD is the downstream effector of the Hippo pathway which controls cell proliferation, apoptosis, tissue repair, and organ growth. Dysregulation of the Hippo pathway has been correlated with carcinogenic processes. A co-crystal structure of TEAD with its endogenous ligand palmitic acid (PA) as well as with flufenamic acid (FA) has been disclosed. Here we report the development of HC-258, which derives from FA and possesses an oxopentyl chain that mimics a molecule of PA as well as an acrylamide that reacts covalently with TEAD's cysteine. HC-258 reduces the CTGF, CYR61, AXL, and NF2 transcript levels and inhibits the migration of MDA-MB-231 breast cancer cells. Co-crystallization with hTEAD2 confirmed that HC-258 binds within TEAD's PA pocket, where it forms a covalent bond with its cysteine.

Development of LM-41 and AF-2112, two flufenamic acid-derived TEAD inhibitors obtained through the replacement of the trifluoromethyl group by aryl rings.

The Hippo pathway regulates organ size and tissue homeostasis by controlling cell proliferation and apoptosis. The YAP-TEAD transcription factor, the downstream effector of the Hippo pathway, regulates the expression of genes such as CTGF, Cyr61, Axl and NF2. Aberrant Hippo activity has been identified in multiple types of cancers. Flufenamic acid (FA) was reported to bind in a liphophilic TEAD palmitic acid (PA) pocket, leading to reduction of the expression of Axl and NF2. Here, we show that the replacement of the trifluoromethyl moiety in FA by aromatic groups, directly connected to the scaffold or separated by a linker, leads to compounds with better affinity to TEAD. Co-crystallization studies show that these compounds bind similarly to FA, but deeper within the PA pocket. Our studies identified LM-41 and AF-2112 as two TEAD binders that strongly reduce the expression of CTGF, Cyr61, Axl and NF2. LM-41 gave the strongest reduction of migration of human MDA-MB-231 breast cancer cells.

Synthesis of 1-Methylcyclopropyl Aryl Ethers from Phenols Using an Alkenylation-Cyclopropanation Sequence.

1-Methylcyclopropyl aryl ethers (McPAEs) can be viewed as cyclized derivatives of their O-tert-butyl counterparts. Although these compounds can find use in medicinal chemistry, they are much less represented in the literature than their aryl cyclopropyl ether analogues. McPAEs are generally prepared via an SNAr reaction using 1-methylcyclopropanol. However, this method works exclusively with highly deactivated arenes. We report herein a two-step sequence to access McPAEs consisting of the 1-methylvinylation of phenols followed by cyclopropanation of the corresponding 1-methylvinyl aryl ethers. Isomeric mono- and dimethyl analogues were also prepared using this sequence.

On the Barton Copper-Catalyzed C3-Arylation of Indoles using Triarylbismuth bis(trifluoroacetate) Reagents.

Invited for this month's cover are the collaborating groups of Prof. Alexandre Gagnon at the Université du Québec à Montréal in Canada, and Dr. Claire McMullin at the University of Bath in the UK. The cover picture represents the "Chasse-galerie", a popular French-Canadian tale published by the author Honoré Beaugrand in 1892, adapted with landmarks from Montréal, London, and Bath. The aryl groups are being transferred from a pentavalent triarylbismuth reagent to the C3 position of an indole via a copper-catalyzed C-H activation mechanism. Cover designed by Lysanne Arseneau. More information can be found in the Research Article by Claire L. McMullin, Alexandre Gagnon, and co-workers.

On the Barton Copper-Catalyzed C3-Arylation of Indoles using Triarylbismuth bis(trifluoroacetate) Reagents.

We disclose herein our detailed investigation into the Barton copper-promoted C3-arylation of indoles using triarylbismuth bis(trifluoroacetates). The arylation of unsubstituted 1H-indole using Barton's conditions gave a low yield of the C3-arylated indole, along with small amounts of the product of double C2/C3-arylation and traces of the product of C2 arylation. On the contrary, the arylation of indoles blocked at the C2 position is highly efficient, affording the desired products of C3-arylation in good to excellent yields. The reaction operates under simple conditions, shows good substrate scope, excellent functional group compatibility, and allows the transfer of electron-neutral or deficient aryl groups. Computational studies propose a mechanism involving a trifluoroacetate-assisted C-H activation step.

Zoning the suitability of the western Mekong Delta for paddy rice cultivation and aquaculture under current and future environmental conditions.

Ca Mau and Kien Giang, the two provinces of the Mekong Delta bordering the Gulf of Thailand, are facing major environmental challenges affecting the agriculture and aquaculture sectors upon which many livelihoods in this region depend on. This study maps the suitability of these two provinces for paddy rice cultivation and shrimp farming according to soil characteristics and current and future environmental conditions for variables found to significantly influence the yield of those two sectors, i.e., the level of saltwater intrusion, water availability for rainfed agriculture, and the length of the growing period. Future environmental conditions were simulated using the MIKE 11 hydrodynamic model forced by four hydrodynamic scenarios, each one representing different extents of saltwater intrusion during both the dry and rainy seasons, while also considering the availability of water resources for rainfed agriculture. The suitability zoning was performed using a GIS-based analytic hierarchy process (AHP) approach, resulting in the categorisation of the land according to four suitability levels for each sector. The analysis reveals that paddy rice cultivation will become more suitable to Kien Giang province while shrimp farming will be more suitable to Ca Mau province if the simulated future environmental conditions materialise. A suitability analysis is essential for optimal utilisation of the land. The approach presented in this study will inform the regional economic development master plan and provide guidance to other delta regions experiencing severe environmental changes and wishing to consider potential future climatic and sea level changes, and their associated impacts, in their land use planning.

Region of freshwater influence (ROFI) and its impact on sediment transport in the lower Mekong Delta coastal zone of Vietnam.

The delta of the Mekong River is one of the largest in the world, with the Mekong River carrying a large amount of sediments in its Region of Freshwater Influence (ROFI). This study investigates the flow structure and movement of both suspended and bedload sediments in the ROFI of the Lower Mekong Delta (LMD) in order to identify areas prone to sediment accretion and erosion. This is accomplished by applying the three-dimensional Coastal and Regional Ocean COmmunity (CROCO) model and then calculating the sediment budget of different stretches of the coastline. The model outputs, depicting areas experiencing sediment accretion and erosion along the coastline of the LMD, are then compared against observations obtained during the period 1990-2015 and demonstrate the ability of the model to identify areas particularly prone to erosion and where preventive actions against coastal erosion should focus.

Design and Synthesis of LM146, a Potent Inhibitor of PB1 with an Improved Selectivity Profile over SMARCA2.

PB1 is a bromodomain-containing protein hypothesized to act as the nucleosome-recognition subunit of the PBAF complex. Although PB1 is a key component of the PBAF chromatin remodeling complex, its exact role has not been elucidated due to the lack of potent and selective inhibitors. Chemical probes that target specific bromodomains within the complex would constitute highly valuable tools to characterize the function and therapeutic pertinence of PB1 and of each of its bromodomains. Here, we report the design and synthesis of lead compound LM146, which displays strong stabilization of the second and fifth bromodomains of PB1 as shown by DSF. LM146 does not interact with bromodomains outside of sub-family VIII and binds to PB1(2), PB1(5), and SMARCA2B with K D values of 110, 61, and 2100 nM, respectively, providing a ∼34-fold selectivity profile for PB1(5) over SMARCA2.

Copper-Promoted N-Arylation of the Imidazole Side Chain of Protected Histidine by Using Triarylbismuth Reagents.

The N-arylation of the side chain of histidine by using triarylbismuthines is reported. The reaction is promoted by copper(II) acetate in dichloromethane at 40 °C under oxygen in the presence of diisopropylethylamine and 1,10-phenanthroline and allows the transfer of aryl groups with substituents at any position of the aromatic ring. The reaction shows excellent functional group tolerance and is applicable to dipeptides where the histidine is located at the N terminus. A histidine-guided backbone N-H arylation was observed in dipeptides where the histidine occupies the C terminus.

Development of LM98, a Small-Molecule TEAD Inhibitor Derived from Flufenamic Acid.

The YAP-TEAD transcriptional complex is responsible for the expression of genes that regulate cancer cell growth and proliferation. Dysregulation of the Hippo pathway due to overexpression of TEAD has been reported in a wide range of cancers. Inhibition of TEAD represses the expression of associated genes, demonstrating the value of this transcription factor for the development of novel anti-cancer therapies. We report herein the design, synthesis and biological evaluation of LM98, a flufenamic acid analogue. LM98 shows strong affinity to TEAD, inhibits its autopalmitoylation and reduces the YAP-TEAD transcriptional activity. Binding of LM98 to TEAD was supported by 19 F-NMR studies while co-crystallization experiments confirmed that LM98 is anchored within the palmitic acid pocket of TEAD. LM98 reduces the expression of CTGF and Cyr61, inhibits MDA-MB-231 breast cancer cell migration and arrests cell cycling in the S phase during cell division.

Synthesis of NVS-BPTF-1 and evaluation of its biological activity.

BPTF (bromodomain and PHD finger containing transcription factor) is a multidomain protein that plays essential roles in transcriptional regulation, T-cell homeostasis and stem cell pluripotency. As part of the chromatin remodeling complex hNURF (nucleosome remodeling factor), BPTF epigenetic reader subunits are particularly important for BPTF cellular function. Here we report the synthesis of NVS-BPTF-1, a previously reported highly potent and selective BPTF-bromodomain inhibitor. Evaluation of the impact of the inhibition of BPTF-bromodomain using NVS-BPTF-1 on selected proteins involved in the antigen processing pathway revealed that exclusively targeting BPTF-bromodomain is insufficient to observe an increase of PSMB8, PSMB9, TAP1 and TAP2 proteins.

Correlates of Coronary Artery Calcification Prevalence and Severity in Patients With Heterozygous Familial Hypercholesterolemia.

BACKGROUND: Determinants of coronary artery calcification (CAC) prevalence and severity in heterozygous familial hypercholesterolemia (HeFH) remain understudied. The objective of this cross-sectional study was to investigate correlates of CAC in patients with HeFH. METHODS: A CAC score was calculated by a noncontrast computed tomography scan in women (n = 68) and men (n = 78) with genetically defined HeFH. We classified CAC prevalence and severity using 3 categories: CAC score = 0 Agatston Unit (AU), CAC score = 1-100 AU, and CAC score > 100 AU. Information on potential correlates of CAC including familial and personal health history, cardiovascular risk factors, lipid-lowering medication, and lifestyle habits was collected. RESULTS: A total of 95 patients had prevalent CAC. Independent correlates of CAC prevalence and severity included age (odds ratio [OR] per 10 years: 5.06, 95% confidence interval [CI]: 3.19, 7.93, P < 0.0001), family history of premature cardiovascular disease (OR: 3.88, 95% CI: 1.71, 8.81, P = 0.001), male sex (OR: 3.40, 95% CI: 1.49, 7.78, P = 0.004), statin use (OR: 15.5, 95% CI: 1.89, 126, P = 0.01), diet quality assessed with the Alternative Healthy Eating Index score (OR per 1 standard deviation: 0.59, 95% CI: 0.39, 0.90, P = 0.01), ever smoking (OR: 3.06, 95% CI: 1.20, 7.81, P = 0.02), receptor-negative genotype (OR: 3.17, 95% CI: 1.16, 8.66, P = 0.02), lipoprotein(a) year-score (OR per 1 standard deviation of log-transformed year-score: 1.53, 95% CI: 0.99, 2.36, P = 0.05). CONCLUSIONS: In individuals with HeFH, age, family history of premature cardiovascular disease, sex, statin use, diet quality, smoking status, the LDLR genotype, and lipoprotein(a) concentrations were independently associated with CAC prevalence and severity.

CONTEXTE: Les déterminants de la prévalence et de la sévérité de la calcification des artères coronaires (CAC) dans l'hypercholestérolémie familiale hétérozygote (HFHe) demeurent peu étudiés. L'objectif de cette étude transversale était d'identifier les corrélats de la CAC chez des patients atteints d'HFHe. MÉTHODOLOGIE: Un score calcique coronarien (SCC) a été calculé par un examen de tomodensitométrie sans contraste chez des femmes (n = 68) et des hommes (n = 78) avec HFHe génétiquement définie. Nous avons classé la prévalence et la gravité de la CAC en trois catégories : SCC = 0 unité d'Agatston (UA), SCC = 1 à 100 UA et SCC > 100 UA. Des renseignements ont été recueillis sur des corrélats potentiels de la CAC, dont les antécédents médicaux familiaux et personnels, les facteurs de risque cardiovasculaire, les médicaments hypolipidémiants et les habitudes de vie. RÉSULTATS: Au total, 95 patients présentaient une CAC. Les corrélats indépendants de la prévalence et de la gravité de la CAC comprenaient l'âge (rapport de cotes [RC] par tranche de 10 ans : 5,06; intervalle de confiance [IC] à 95 % : 3,19 à 7,93; p < 0,0001), des antécédents familiaux de maladie cardiovasculaire précoce (RC : 3,88; IC à 95 % : 1,71 à 8,81; p = 0,001), le sexe masculin (RC : 3,40; IC à 95 % : 1,49 à 7,78; p = 0,004), l'emploi de statines (RC : 15,5; IC à 95 % : 1,89 à 126; p = 0,01), la qualité du régime alimentaire évaluée selon le score AHEI (Alternative Healthy Eating Index) (RC par écart-type : 0,59; IC à 95 % : 0,39 à 0,90; p = 0,01), le tabagisme (RC : 3,06; IC à 95 % : 1,20 à 7,81; p = 0,02), le génotype récepteur-négatif (RC : 3,17; IC à 95 % : 1,16 à 8,66; p = 0,02) et le score lipoprotéine(a)-année (RC par écart-type du score-année transformé en logarithme : 1,53; IC à 95 % : 0,99 à 2,36; p = 0,05). CONCLUSIONS: Chez les personnes atteintes d'HFHe, l'âge, les antécédents familiaux de maladie cardiovasculaire précoce, le sexe, l'emploi de statines, la qualité du régime alimentaire, le statut de tabagisme, le génotype du LDLR et les concentrations de lipoprotéine(a) ont été associés de façon indépendante à la prévalence et à la gravité de la CAC.

Can nature-based solutions contribute to water security in Bhopal?

Bhojtal, a large man-made lake bordering the city of Bhopal (Madhya Pradesh state, central India), is important for the city's water supply, connoted the lifeline of the city. Despite the dry though not arid and markedly seasonal climate, soil impermeability hampers infiltration into the complex geology underlying the Bhojtal catchment. Rural communities in the catchment are nonetheless high dependent on underlying aquifers. This paper develops baseline understanding of trends in the ecology, water quality and uses of Bhojtal, discussing their implications for the long-term wellbeing of the Bhopal city region. It highlights increasing dependency on water diverted from out-of-catchment sources, and also abstraction across the Bhojtal catchment in excess of replenishment that is depressing groundwater and contributing to reported declining lake level and water quality. Despite some nature-based management initiatives, evidence suggests little progress in haltering on-going groundwater depression and declines in lake water level and quality. Significant declines in ecosystem services produced by Bhojtal are likely without intervention, a major concern given the high dependency of people in the Bhopal region on Bhojtal for their water supply and socio-economic and cultural wellbeing. Over-reliance on appropriation of water from increasingly remote sources is currently compensating for lack of attention to measures protecting or regenerating local resources that may provide greater resilience and regional self-sufficiency. Improved knowledge of catchment hydrogeology on a highly localised scale could improve the targeting and efficiency of water harvesting and other management interventions in the Bhojtal catchment, and their appropriate hybridisation with engineered solutions, protecting the catchment from unintended impacts of water extraction or increasing its carrying capacity, and also providing resilience to rising population and climate change. Ecosystem service assessment provides useful insights into the breadth of benefits of improved management of Bhojtal and its catchment.

Synthesis of aryl cyclopropyl sulfides through copper-promoted S-cyclopropylation of thiophenols using cyclopropylboronic acid.

The copper-promoted S-cyclopropylation of thiophenols using cyclopropylboronic acid is reported. The procedure operates under simple conditions to afford the corresponding aryl cyclopropyl sulfides in moderate to excellent yields. The reaction tolerates substitution in ortho-, meta- and para-substitution as well as electron-donating and electron-withdrawing groups. The S-cyclopropylation of a thiophenol was also accomplished using potassium cyclopropyl trifluoroborate.

Synthesis of NSC 106084 and NSC 14778 and evaluation of their DNMT inhibitory activity.

DNA methylation is an epigenetic modification that is performed by DNA methyltransferases (DNMTs) and that leads to the transfer of a methyl group from S-adenosylmethionine (SAM) to the C5 position of cytosine. This transformation results in hypermethylation and silencing of genes such as tumor suppressor genes. Aberrant DNA methylation has been associated with the development of many diseases, including cancer. Inhibition of DNMTs promotes the demethylation and reactivation of epigenetically silenced genes. NSC 106084 and 14778 have been reported to inhibit DNMTs in the micromolar range. We report herein the synthesis of NSC 106084 and 14778 and the evaluation of their DNMT inhibitory activity. Our results indicate that while commercial NSC 14778 is moderately active against DNMT1, 3A/3L and 3B/3L, resynthesized NSC 14778 is inactive under our assay conditions. Resynthesized 106084 was also found to be inactive.

Peak vertical force in a stabilized canine cranial cruciate deficient stifle model: A one-year follow-up.

This study aimed to describe the peak vertical force (PVF) over a 1-year period in a stabilized canine cranial cruciate deficient stifle model. Our hypothesis was that PVF would be restored to Baseline (intact) at the end of the follow-up. Fifteen (> 20 kg) mixed-breed dogs were included in this study. Cranial cruciate ligament was transected on Day (D) 0 followed by lateral suture stabilization at D28. Peak vertical force was acquired at D-1, D14, D26, D91, D210 and D357. When compared to Baseline, the PVF was significantly decreased at D14, D26, and D91. Values at D210 and D357 were not statistically different to Baseline. This study suggests a return to normal baseline peak vertical force in a canine cranial cruciate deficient stifle model when lateral suture stabilization has been performed 28 days after surgical transection.

Le but de cette étude était de rapporter, chez un modèle canin stabilisé suite à une déficience du genou induite par section transversale du ligament croisé crânial (LCC), l'évolution du pic de force vertical (PFV) sur une année. Notre hypothèse était que le PFV serait normalisé à la fin de la période de suivi.Quinze (> 20 kg) chiens croisés ont été inclus dans l'étude. L'instabilité du genou a été induite par section transversale du ligament croisé crânial au Jour (J) 0, suivie par la stabilisation par suture latérale à J28. Le PFV a été acquis à J−1, J14, J26, J91, J210, et J357.Lorsque comparé à J0, le PFV était significativement diminué à J14, J26 et J91. Les valeurs du PFV à J210 et J357 n'étaient pas différentes qu'à J0.Cette étude suggère le retour des valeurs normales du pic de force verticale chez un modèle d'instabilité induite du genou lorsque la stabilisation a été réalisée 28 jours après la section transversale du ligament croisé crânial.(Traduit par les auteurs).