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Inhibition of the eIF4A RNA helicase with silvestrol and related compounds is emerging as a powerful anti-cancer strategy. We find that a synthetic silvestrol analogue (CR-1-31 B) has nanomolar activity across many cancer cell lines. It is especially active against aggressive MYC+/BCL2+ B cell lymphomas and this likely reflects the eIF4A-dependent translation of both MYC and BCL2. We performed a genome-wide CRISPR/Cas9 screen and identified mechanisms of resistance to this new class of therapeutics. We identify three negative NRF2 regulators (KEAP1, CUL3, CAND1) whose inactivation is sufficient to cause CR1-31-B resistance. NRF2 is known to alter the oxidation state of translation factors and cause a broad increase in protein production. We find that NRF2 activation particularly increases the translation of some eIF4A-dependent mRNAs and restores MYC and BCL2 production. We know that NRF2 functions depend on removal of sugar adducts by the frutosamine-3-kinase (FN3K). Accordingly, loss of FN3K results in NRF2 hyper-glycation and inactivation and resensitizes cancer cells to eIF4A inhibition. Together, our findings implicate NRF2 in the translation of eIF4A-dependent mRNAs and point to FN3K inhibition as a new strategy to block NRF2 functions in cancer.

The eIF4E translation initiation factor has oncogenic properties and concordantly, the inhibitory eIF4E-binding protein (4EBP1) is considered a tumor suppressor. The exact molecular effects of 4EBP1 activation in cancer are still unknown. Surprisingly, 4EBP1 is a target of genomic copy number gains (Chr. 8p11) in breast and lung cancer. We noticed that 4EBP1 gains are genetically linked to gains in neighboring genes, including WHSC1L1 and FGFR1. Our results show that FGFR1 gains act to attenuate the function of 4EBP1 via PI3K-mediated phosphorylation at Thr37/46, Ser65, and Thr70 sites. This implies that not 4EBP1 but instead FGFR1 is the genetic target of Chr. 8p11 gains in breast and lung cancer. Accordingly, these tumors show increased sensitivity to FGFR1 and PI3K inhibition, and this is a therapeutic vulnerability through restoring the tumor-suppressive function of 4EBP1. Ribosome profiling reveals genes involved in insulin signaling, glucose metabolism, and the inositol pathway to be the relevant translational targets of 4EBP1. These mRNAs are among the top 200 translation targets and are highly enriched for structure and sequence motifs in their 5′UTR, which depends on the 4EBP1-EIF4E activity. In summary, we identified the translational targets of 4EBP1-EIF4E that facilitate the tumor suppressor function of 4EBP1 in cancer.

Cancer cells adapt their metabolic activities to support growth and proliferation. However, increased activity of metabolic enzymes is not usually considered an initiating event in the malignant process. Here, we investigate the possible role of the enzyme serine hydroxymethyltransferase-2 (SHMT2) in lymphoma initiation. localizes to the most frequent region of copy number gains at chromosome 12q14.1 in lymphoma. Elevated expression of cooperates with in lymphoma development; loss or inhibition of impairs lymphoma cell survival. SHMT2 catalyzes the conversion of serine to glycine and produces an activated one-carbon unit that can be used to support -adenosyl methionine synthesis. SHMT2 induces changes in DNA and histone methylation patterns leading to promoter silencing of previously uncharacterized mutational genes, such as and Together, our findings reveal that amplification of in cooperation with is sufficient in the initiation of lymphomagenesis through epigenetic tumor suppressor silencing.

Background India accounts for more than two-third of mortality due to non-communicable diseases (NCDs) in south-east Asia. The burden is high in Karnataka, one of the largest states in southern India. There is a need for integration of disease prevention, health promotion, treatment and care within the national program at primary level. A public-private partnership initiative explored evidence gaps to inform a health system based, integrated NCD programme across care continuum with a focus on hypertension and diabetes. Methods The study was conducted during 2017–18 in urban parts of Mysore city, covering a population of 58,000. Mixed methods were used in the study; a population-based screening to estimate denominators for those with disease and at risk; cross-sectional surveys to understand distribution of risk factors, treatment adherence and out of pocket expenses; facility audits to assess readiness of public and private facilities; in-depth interviews and focus group discussions to understand practices, myths and perceptions in the community. Chi-square tests were used to test differences between the groups. Framework analysis approach was used for qualitative analysis. Results Twelve and 19% of the adult population had raised blood sugar and blood pressure, respectively, which increased with age, to 32 and 44% for over 50 years. 11% reported tobacco consumption; 5.5%, high alcohol consumption; 40%, inadequate physical activity and 81%, inappropriate diet consumption. These correlated strongly with elderly age and poor education. The public facilities lacked diagnostics and specialist services; care in the private sector was expensive. Qualitative data revealed fears and cultural myths that affected treatment adherence. The results informed intervention design across the NCD care continuum. Conclusions The study provides tools and methodology to gather evidence in designing comprehensive NCD programmes in low and middle income settings. The study also provides important insights into public-private partnership driving effective NCD care at primary care level.

Background The Jawadhi Hills region in Tamil Nadu, India, is home to predominantly tribal communities facing severe health challenges, including high infant and maternal mortality. Data on disability within these populations are limited. This study aimed to estimate the prevalence of disability and examine associated factors in this region. Methods A census was conducted across 395 hamlets in the Tiruvannamalai and Vellore districts. Trained field workers collected data on sociodemographic characteristics, health status, and living conditions using a structured questionnaire. Disability was assessed in individuals aged five years and above using the Washington Group Short Set on Functioning (WG-SS). Results Among 58,598 individuals aged ≥ 5 years, the prevalence of perceived functional disability, defined as “a lot of difficulty” or “unable to do” in ≥ 1 domain, or “some difficulty” in ≥ 2 domains, was 2.89% (95% CI: 2.75%–3.03%). Moderate to severe disability was most commonly reported in the domains of mobility (1.64%, 95% CI: 1.54% − 1.75%.), vision (0.89%, 95% CI: 0.81% − 0.96%), and hearing (0.70%, 95% CI: 0.63% − 0.77%). The highest prevalence of disability was observed in the ≥ 85 years age group (33.59%). Logistic regression showed that increasing age, lower educational attainment, unemployment, chronic conditions (diabetes, hypertension), caste, and poor housing conditions were significantly associated with higher odds of disability. Conclusions This is the first census-based estimate of disability in a tribal population in the Jawadhi Hills. The findings reveal a notable burden of mobility-related impairments and strong links between disability and social disadvantage. The results support the integration of disability assessment into existing health programs, particularly those addressing non-communicable diseases, and call for expanded access to rehabilitation services in tribal areas.

As many as four exotic whiteflies of Neotropical origin have been reported from different coconut-growing regions in India in rapid succession in the last four years. The spiralling whitefly, Aleurodicus dispersus Russell was the earliest reported invasive species on coconut from Kerala in 1996. The rugose spiralling whitefly, Aleurodicus rugioperculatus Martin was first reported in 2016 followed by three species (Paraleyrodes bondari, Paraleyrodes minei and Aleurotrachelus atratus) in 2019. At present, all are found to coexist on coconut in South India. In such combined incidences, one species occupies the breeding and feeding niche of another under optimum weather parameters and attempts to displace one or more of its competitors. The Bondar’s nesting whitefly, P. bondari is associated with rugose spiralling whitefly in most districts of Kerala and Tamil Nadu, whereas the nesting whitefly P. minei is interlinked with A. rugioperculatus in Kasaragod, Kerala, and also found to co-occur with the palm whitefly, A. atratus in Mandya, Karnataka. In Kayamkulam, Kerala, P. bondari, P. minei and A. rugioperculatus co-lived for a brief period during 2018. Due to the incursion and subsequent coexistence of these exotic whiteflies which share more or less the same niche with similar habits on coconut, it is imperative to identify them correctly for carrying out further studies on their bioecology, population dynamics and management. Hence an illustrated diagnostic account of these exotic whiteflies is given here to facilitate their visual identification by economic entomologists and field workers. The COI sequences of these exotic whiteflies are also given to enable rapid confirmation of the field diagnosis.

Field occurrence of the exotic neotropical nesting whitefly, Paraleyrodes minei Iaccarino in association with Bondar’s nesting whitefly, Paraleyrodes bondari Peracchi on coconut leaflets is reported from Kerala, India. These coconut palms were previously infested by the rugose spiralling whitefly, Aleurodicus rugioperculatus Martin, which was reported from Kerala and Tamil Nadu during 2016. P. minei closely resembles P. bondari, but is devoid of the oblique grey bands on the wings and it constructs loosely woven, woolly wax nests. Female P. minei are white, but males are smoky grey. Cockhead-like male aedeagus with two thin appendixes projected downwards is the unique feature for species-level identification of P. minei. Detection of three non-native whiteflies of neotropical origin infesting coconut palms in India within a span of two years suggests their simultaneous introduction. Invasive potential of P. minei due to its polyphagous nature and short lifecycle calls upon strict policy frameworks in exchange of planting materials. Domestic quarantine should be strictly enforced in the country to avoid spread of this pest to other coconut-growing regions.

The octopus of the genus Tremoctopus from the Arabian Sea has not been investigated in the past. This study reports on the rare pelagic octopus Tremoctopus gracilis from the south-eastern Arabian Sea. Twenty females with dorsal mantle lengths (DML) ranging between 62 and 160 mm and weighing between 31 and 719 g were examined. These specimens were collected from commercial fishing grounds, and amongst them was a single mature female with 12,618 oocytes in the ovary (size varied from 0.61 to 1.67 mm (mean = 1.13 mm). The detailed morphometric and morphological characteristics were recorded, and the specimens were identified up to the genus level. Further molecular species identification was carried out through mitochondrial markers (COI & 16S rRNA). Phylogenetic analysis, based on partial sequences of the above markers, generated a single clade that included sequences from the Indian and Pacific Oceans, including those misidentified as Tremoctopus violaceus from the Pacific. Evolutionary divergence estimation revealed a high inter-specific genetic divergence from T. violaceus sequences in the Mediterranean Sea and Atlantic Ocean, thus confirming the Tremoctopus species in our study as T. gracilis and authenticated that GenBank sequences of T. violaceus from the Pacific Ocean are indeed T. gracilis .