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Missense mutations in p53 are severely deleterious and occur in over 50% of all human cancers. The majority of these mutations are located in the inherently unstable DNA-binding domain (DBD), many of which destabilize the domain further and expose its aggregation-prone hydrophobic core, prompting self-assembly of mutant p53 into inactive cytosolic amyloid-like aggregates. Screening an oligopyridylamide library, previously shown to inhibit amyloid formation associated with Alzheimer’s disease and type II diabetes, identified a tripyridylamide, ADH-6, that abrogates self-assembly of the aggregation-nucleating subdomain of mutant p53 DBD. Moreover, ADH-6 targets and dissociates mutant p53 aggregates in human cancer cells, which restores p53’s transcriptional activity, leading to cell cycle arrest and apoptosis. Notably, ADH-6 treatment effectively shrinks xenografts harboring mutant p53, while exhibiting no toxicity to healthy tissue, thereby substantially prolonging survival. This study demonstrates the successful application of a bona fide small-molecule amyloid inhibitor as a potent anticancer agent. Amyloid aggregation of mutant p53 contributes to its loss of tumor suppressor function and oncogenic gain-of-function. Here, the authors use a protein mimetic to abrogate mutant p53 aggregation and rescue p53 function, which inhibits cancer cell proliferation in vitro and halts tumor growth in vivo.

Key messageRIN4 homologs from important crop species differ in their ability to prevent ectopic activity of the nucleotide binding-leucine rich repeat resistance protein, RPS2.Pathogens deploy virulence effectors to perturb host processes. Plants utilize intracellular resistance (R) proteins to recognize pathogen effectors either by direct interaction or indirectly via effector-mediated perturbations of host components. RPM1-INTERACTING PROTEIN4 (RIN4) is a plant immune regulator that mediates the indirect activation of multiple, independently evolved R-proteins by multiple, unrelated effector proteins. One of these, RPS2 (RESISTANT TO P. SYRINGAE2), is activated upon cleavage of Arabidopsis (At)RIN4 by the Pseudomonas syringae effector AvrRpt2. To gain insight into the AvrRpt2-RIN4-RPS2 defense-activation module, we compared the function of AtRIN4 with RIN4 homologs present in a diverse range of plant species. We selected seven homologs containing conserved features of AtRIN4, including two NOI (Nitrate induced) domains, each containing a predicted cleavage site for AvrRpt2, and a C-terminal palmitoylation site predicted to mediate membrane tethering of the proteins. Palmitoylation-mediated tethering of AtRIN4 to the plasma membrane and cleavage by AvrRpt2 are required for suppression and activation of RPS2, respectively. While all seven homologs are localized at the plasma membrane, only four suppress RPS2 when transiently expressed in Nicotiana benthamiana. All seven homologs are cleaved by AvrRpt2 and, for those homologs that are able to suppress RPS2, cleavage relieves suppression of RPS2. Further, we demonstrate that the membrane-tethered, C-terminal AvrRpt2-generated cleavage fragment is sufficient for the suppression of RPS2. Lastly, we show that the membrane localization of RPS2 is unaffected by its suppression or activation status.

Plant nucleotide-binding, leucine-rich-repeat (NLR) immune receptors recognize pathogen effectors and activate immunity. The NLR RPS2 recognizes AvrRpt2, a Pseudomonas effector that promotes virulence by proteolytically cleaving a membrane-tethered host protein, RIN4. RIN4 cleavage by AvrRpt2 generates fragments that activate RPS2. A model for RPS2 activation by RIN4 destruction is consistent with the ectopic activity of RPS2 in plants lacking RIN4 but does not explain the link between AvrRpt2’s virulence activity and RPS2 activation. We found that non-membrane-tethered RIN4 derivatives are potent cytosolic activators of RPS2. Activation of RPS2 by these RIN4 derivatives, like AvrRpt2-induced activation, and unlike ectopic activation in the absence of RIN4, requires the defense signaling protein NDR1. Cleavage products of RIN4 produced by AvrRpt2 play contrasting roles in the activation of RPS2, with the membrane-tethered C-terminal fragment suppressing RPS2 and the non-membrane-tethered internal fragment, dependent on compatibility with the C-terminal fragment, overcoming its suppression of RPS2. Non-membrane tethered derivatives of RIN4 activate RPS2-induced cell death Activation of RPS2 by non-membrane-tethered derivatives of RIN4 requires NDR1 AvrRpt2-induced cleavage fragments of RIN4 play contrasting roles in RPS2 activation

Plant nucleotide-binding, leucine-rich repeat (NLR) immune receptors recognize pathogen effectors and activate defense. NLR genes can be non-functional in distantly related plants (restricted taxonomic functionality, RTF). Here, we enable Solanaceae NLR gene function in rice, soybean and Arabidopsis by co-delivering sensor NLR genes with their cognate NRC-type helper NLRs. In soybean protoplasts and in Arabidopsis plants, Solanum americanum Rpi-amr1, Rpi-amr3 and pepper Bs2 sensor NLRs confer cognate effector responsiveness if co-expressed with NRC helper NLRs. Rice carrying pepper Bs2 and NRCs recognizes the conserved effector, AvrBs2, and resists an important pathogen, Xanthomonas oryzae pv. oryzicola for which no resistance gene is available in rice. Rice lines carrying sensor and helper NLR genes otherwise resemble wild-type, with unaltered basal resistance or field fitness. Thus, interfamily co-transfer of sensor and helper NLRs can broaden utility of sensor NLRs, extending the tools available to control diseases of rice, soybean, Brassicas and other crops.Competing Interest StatementThe authors have declared no competing interest.

Plants encounter diverse pathogens and have evolved a two-layered innate immune system to detect pathogen molecules and activate defense mechanisms that restrict infection. Most cloned plant Resistance (R) genes encode NLR immune receptors. NLR genes are often found in clusters of paralogs with sequence and copy number variation; whether these NLR clusters evolve in response to single or multiple pathogens has been unclear. We report here the isolation of a Phytophthora capsici resistance gene, Rpc2, along with a novel P. infestans resistance gene, Rpi-amr5, from two Solanum americanum accessions. These orthologous genes reside in the Rpi-amr1 cluster, which has previously been associated with resistance to P. infestans. By screening RXLR effector libraries of P. infestans and P. capsici, we identified multiple effectors recognized by both NLRs. Our findings highlight the complexity of NLR clusters and evolution driven by interactions with multiple pathogens. This work will underpin efforts to elevate resistance against Phytophthora pathogens and enhances our understanding of NLR evolution.

Missense mutations in p53 are severely deleterious and occur in over 50% of all human cancers. The vast majority of these mutations are located in the inherently unstable DNA-binding domain (DBD), many of which destabilize the domain further and expose its aggregation-prone hydrophobic core, prompting self-assembly of mutant p53 into inactive cytosolic amyloid-like aggregates. Screening an oligopyridylamide library, previously shown to inhibit amyloid formation associated with Alzheimer's disease and type II diabetes, identified a tripyridylamide, ADH-6, that potently abrogates self-assembly of the aggregation-nucleating subdomain of mutant p53 DBD. Moreover, ADH-6 effectively targets and dissociates mutant p53 aggregates in human cancer cells, which restores p53's transcriptional activity, leading to cell cycle arrest and apoptosis. Notably, ADH-6 treatment substantially shrinks xenografts harboring mutant p53 and prolongs survival, while exhibiting no toxicity to healthy tissue. This study demonstrates the first successful application of a bona fide small-molecule amyloid inhibitor as an anticancer agent. Competing Interest Statement The authors have declared no competing interest.

Land use and land cover (LULC) change has been one of the most immense and perceptible transformations of the earth’s surface. Evaluating LULC change at varied spatial scales is imperative in wide range of perspectives such as environmental conservation, resource management, land use planning, and sustainable development. This work aims to examine the land use and land cover changes in the Kashmir valley between the time periods from 1992–2001–2015 using a set of compatible moderate resolution Landsat satellite imageries. Supervised approach with maximum likelihood classifier was adopted for the classification and generation of LULC maps for the selected time periods. Results reveal that there have been substantial changes in the land use and cover during the chosen time periods. In general, three land use and land cover change patterns were observed in the study area: (1) consistent increase of the area under marshy, built-up, barren, plantation, and shrubs; (2) continuous decrease in agriculture and water; (3) decrease (1992–2001) and increase (2001–2015) in forest and pasture classes. In terms of the area under each LULC category, most significant changes have been observed in agriculture (−), plantation (+), built-up (+), and water (−); however, with reference to percent change within each class, the maximum variability was recorded in built-up (198.45%), plantation (87.98%), pasture (− 71%), water (− 48%) and agriculture (− 28.85%). The massive land transformation is largely driven by anthropogenic actions and has been mostly adverse in nature, giving rise to multiple environmental issues in the ecologically sensitive Kashmir valley.

Sustainable development is South Asia's main objective and energy plays a vital role in achieving this objective. The main objective of this study was to use econometric tools to examine the impacts of renewable and non-renewable energy on sustainable development in South Asia using time series data over the period 1995–2019. First, the panel unit root tests were used to look for the unit root in each data series. Some of the data series were stationary at the level, while others were stationary at the first difference. Second, the panel ARDL technique was used to examine the short-term and long-term impacts of renewable and non-renewable energy on sustainable development. The panel ARDL results reveal that renewable and non-renewable energies have considerable long-term beneficial influence on sustainable development in South Asia. Third, several preliminary tests were used to confirm the reliability, stability and predictability of the panel ARDL parameters. The results of these diagnostic tests indicated that the parameters of the panel ARDL model are stable, predictable and reliable in the long term. Finally, the study outlined how various policy approaches can be used to drive sustainable development.

The Fauzderhat coast of Chattogram (Bangladesh) is increasingly affected anthropogenic pressures, necessitating an understanding of its ecological conditions to inform effective ecosystem management. Despite this urgency, the local succession patterns and environmental impacts on macrobenthic communities remain poorly understood. This study examines the saltmarsh bed macrobenthos in Fauzderhat, documenting 81,724 individuals from 54 species. These include ten families and twenty-two species of annelids, ten and twelve species of arthropods, and ten and eleven species of mollusks, as well as six and nine species from different phyla. Seasonality showed significantly different patterns of changes, with the number of species and abundance peaking during the monsoon (53 species) and post-monsoon (21,969) conditions, respectively, and being lowest in the post-monsoon condition (39 species) and winter (18,265 individuals). Species richness, diversity, and evenness were significantly higher in monsoon and lower in post-monsoon conditions, with the differences being only significant in the former. Cluster analysis and line graphs indicated that average species abundance was lowest post-monsoon, increased through the winter and pre-monsoon conditions, then declined again during monsoon conditions. SIMPER analysis revealed the highest dissimilarity between pre-monsoon and post-monsoon conditions while winter and post-monsoon conditions showed the lowest dissimilarity of microbenthic assemblages. Correlation coefficients showed the macrobenthos were positively correlated with soil salinity, dissolved oxygen, and pH, while they were negatively correlated with sand, Inundation Period, and nutrients. CCA showed that monsoon conditions (higher water temperature, inundation period, and tidal height) created unfavorable environments for most species, except for several species. Conversely, winter favored species like M. oligobranchia. Post-monsoon nutrient levels increased stress, reducing species presence, while pre-monsoon conditions supported balanced diversity.

ObjectiveThis meta-analysis aims to compare the clinical outcomes of the no-touch (NT) and conventional (CON) vein harvesting techniques in patients undergoing coronary artery bypass grafting (CABG).MethodsWe conducted a systematic review and meta-analysis following the guidelines of the Cochrane Handbook and PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) statement. We searched PubMed, Embase and Web of Science for randomised controlled trials (RCTs) comparing NT and CON vein harvesting techniques in CABG patients. Data were extracted on primary outcomes (graft failure incidence per patient, graft occlusion incidence per patient and leg infection) and secondary outcomes (revascularisation, all-cause death, myocardial infarction). Statistical analysis was performed using Review Manager V.5.4, with risk ratios (RRs) calculated for binary outcomes.ResultsSeven RCTs involving 4176 patients were included. The NT group showed a significantly lower risk of graft failure incidence per patient (RR=0.74, p=0.0001) and graft occlusion incidence per patient (RR=0.62, p=0.0002) compared with the CON group. However, the NT group had a higher risk of leg infection (RR=1.91, p<0.00001). No significant differences were observed between groups for revascularisation (p=0.46), all-cause death (p=0.87), or myocardial infarction (p=0.95).ConclusionsThe no-touch vein harvesting technique is associated with reduced graft failure incidence per patient and graft occlusion incidence per patient compared with conventional harvesting techniques in CABG, though it increases the risk of leg infection. These findings suggest NT as a preferable technique for improving graft patency but highlight the need for caution regarding leg infection.PROSPERO registration numberCRD42025646500.