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PubMed2026

Secondary metabolite profiling of rare Micromonospora spp. from cold desert of NW Himalayas via multi-omics analysis.

INTRODUCTION: The genus Micromonospora is a prolific producer of specialized metabolites with pharmacological and agronomic relevance. Natural products derived from the genus Micromonospora have a distinctive chemical diversity and enormous therapeutic potential, thus represent a potential source for drugs and drug leads. OBJECTIVE: To explore the biosynthetic potential of four Micromonospora strains isolated from cold desert of NW Himalayas through genome mining and to correlate predicted biosynthetic gene clusters with chemical features detected by untargeted LC-HRMS metabolomics. METHOD: High-quality genomes were annotated for BGCs and matched against untargeted LC-HRMS features (peak picking, alignment, and annotation to chemical classes). Each isolate was grown in triplicate, and fermented broth was pooled for further metabolomic studies. RESULTS: By integrating genomic and metabolomic approaches, specialized biosynthetic gene clusters and strain-based putative metabolite classes were identified. LRS1 showed elevated xanthines (RiPP/siderophore), LRS3 had phenolic glycosides (hybrid PKS/NRPS), LRS4 showed 70-fold hydroxycinnamate enrichment (Type II PKS), and LRS5 displayed p-benzoquinone enrichment (Type III PKS). The metabolite profile of each strain aligned with its predicted biosynthetic gene cluster composition. CONCLUSION: Under a single growth regime, each Micromonospora strain exhibits a distinct metabolomic profile. This metabologenomics workflow can be further explored to isolate specialized metabolites with potential therapeutic and agricultural value.

Micromonospora↗
PubMed1979

Ixodid ticks of Barun Glacier region (the Nepal Himalaya).

During the 3rd Czechoslovak mountaineering expedition to the Himalaya in the spring 1973 ticks of the family Ixodidae were collected from small mammals and additionally from pastured sheep, and humans. The tick material represented the following species: Ixodes (P.) ovatus Neumann, 1899, Ixodes (I.) acutitarsus (Karsch, 1880) and Haemaphysalis (A.) aponommoides Warburton, 1921. Ecological and zoogeographical characteristics of the ticks found are given and their potential medical importance is discussed.

Animals↗
PubMed2026

Safety, tolerability, and efficacy of RIPK1 inhibitor, SAR443820, in amyotrophic lateral sclerosis (HIMALAYA): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: RIPK1, a protein regulating inflammatory signalling and cell death, is implicated in amyotrophic lateral sclerosis (ALS) pathophysiology. SAR443820 is a selective, oral, CNS-penetrant, reversible RIPK1 inhibitor. We aimed to evaluate the safety, tolerability, and efficacy of SAR443820 in participants with ALS. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 2 trial was conducted at 63 clinical sites in 13 countries (Belgium, Canada, China, France, Germany, Italy, Japan, the Netherlands, Poland, Spain, Sweden, the UK, and the USA). Adults (aged 18-80 years) with a diagnosis of possible ALS, clinically probable ALS, clinically probable laboratory-supported ALS, or clinically definite ALS, in accordance with the revised El Escorial World Federation of Neurology criteria, were randomly assigned (2:1) by use of a stratified block design (blocks of three) to receive either 20 mg SAR443820 orally twice per day or matching placebo in the 24-week double-blind period. Randomisation was done centrally using interactive response technology and stratified by geographical region of trial site, region of ALS onset, use of riluzole, use of edaravone, and use of the combination of sodium phenylbutyrate and taurursodiol. Participants, care providers, investigators, and outcomes assessors were masked to trial intervention. The primary outcome was a change in ALS Functional Rating Scale Revised (ALSFRS-R) total score from baseline to week 24 and was calculated for all participants who had an ALSFRS-R total score available at baseline and at week 24. Safety analyses included all randomly assigned participants receiving one dose or more of trial intervention. This trial is registered with ClinicalTrials.gov (NCT05237284) and was terminated early. FINDINGS: Between April 13, 2022, and July 17, 2023, 397 participants were screened and 305 randomly assigned to SAR443820 (n=203) or placebo (n=102); six were excluded from the primary analysis due to missing baseline ALSFRS-R values. Mean age was 56·9 years (SD 11·5); 183 (60%) participants were male and 122 (40%) were female. Least squares mean change in ALSFRS-R from baseline to week 24 was -6·73 (95% CI -7·48 to -5·98) for SAR443820 group (n=169) and -6·32 (-7·36 to -5·27) for placebo group (n=87). There was no statistically significant difference between the study groups (least squares mean difference -0·41 [95% CI -1·71 to 0·88]). Participants in the SAR443820 group had higher incidence of adverse events (171 [85%] of 202 vs placebo 80 [78%] of 102) and treatment discontinuations (28 [14%] of 202 vs placebo five [5%] of 102), with elevated hepatic enzymes being the most common cause. Nine deaths occurred in the double-blind period (seven [3%] of 202 in the SAR443820 group and two [2%] of 102 in the placebo group); none was attributed to SAR443820. INTERPRETATION: SAR443820 did not show clinical benefit and was associated with higher hepatic enzyme increase, indicating that further clinical development of SAR443820 in ALS is not warranted. FUNDING: Sanofi.

Humans↗
PubMed2026

Efficacy and Safety of Durvalumab plus Tremelimumab for Unresectable Hepatocellular Carcinoma: A Real-World Multicenter Observational Study.

Introduction: Durvalumab plus tremelimumab (Durva/Treme) improved survival in the HIMALAYA trial for unresectable hepatocellular carcinoma (HCC), but real-world evidence remains limited. This study aimed to evaluate clinical outcomes of Durva/Treme in routine practice. Methods: This retrospective multicenter study included patients with unresectable or advanced HCC who received Durva/Treme through the Expanded Access Program in Thailand between August 2023 and November 2025. Treatment outcomes and adverse events (AEs) were analyzed and descriptively compared with the HIMALAYA trial. Results: Fifty patients were included; median age was 62 years and 80% were male. Etiologies included hepatitis B (44%), hepatitis C (30%), and nonviral liver disease (26%). Most patients had Child-Pugh A (92%), while 24% had macrovascular invasion, including five with Vp4 portal vein involvement. The objective response rate (ORR) and disease control rate (DCR) were 12% and 60%, respectively. Among 43 patients meeting HIMALAYA eligibility criteria, ORR and DCR were 12% and 56%, respectively. With a median follow-up of 28.9 months, median progression-free survival (mPFS) and overall survival (mOS) were 4.6 and 10.5 months in the overall cohort, and 6.9 and 14.0 months in the HIMALAYA-eligible subgroup. Any-grade AEs occurred in 76% of patients, with grade ≥ 3 AEs in 24%. Hepatitis was the most common toxicity (48% overall; 14% grade ≥ 3). Conclusions: Durva/Treme demonstrated clinically meaningful activity with manageable toxicity in unresectable HCC. Outcomes among HIMALAYA-eligible patients were broadly consistent with the pivotal trial, supporting the feasibility of this regimen in routine clinical practice.

Aged↗
PubMed2026

Inference of Genetic Structure and the Process of Population Formation in Nepalese Native Goats Using Uniparental and Genome-Wide Markers.

Nepal is a small, landlocked country with marked elevational variation from the Terai plains to the Himalayas. Here, four indigenous goat populations (Chyangra, Sinhal, Khari, and Terai) are raised at different elevations. This study aimed to clarify the genetic structure of these populations and how they are formed and propagated across the Himalayan region. We analyzed 136 Nepalese goats using mitochondrial (mt) DNA D-loop and sex-determining region Y (SRY) 3'-untranslated region (UTR) sequences, as well as 50 K SNP array data. The mtDNA haplogroups D (0.162) and G (0.03) were detected only in Chyangra, whereas haplogroup B was predominant in Sinhal (0.42), followed by Khari (0.260). Regarding SRY haplotypes, Y2B was detected in all populations, whereas Y1AB (0.42) was found only in Chyangra. Genome-wide SNP analysis showed that Chyangra was genetically related to Tibetan and Central Asian goats, while Terai resembled South Asian goats. Interestingly, Sinhal formed a distinct cluster, whereas Khari exhibited an admixed genetic structure. These findings suggest that Nepalese goats originate from at least three ancestral lineages and that an additional migration route may have existed through the southern Himalayas.

50K SNP↗
PubMed2025

Unraveling evolutionary pathways: allopolyploidization and introgression in polyploid Prunus (Rosaceae).

Allopolyploidization, resulting from hybridization and subsequent whole-genome duplication (WGD), is a fundamental mechanism driving evolutionary diversification across various lineages within the Tree of Life. The polyploid Prunus (Rosaceae), significant for its economic and agricultural value, provides an ideal model for investigating the evolutionary dynamics associated with allopolyploidy. In this study, we utilized deep genome skimming (DGS) data to demonstrate a comprehensive analytical framework for elucidating the underlying allopolyploidy that includes a newly adapted tool (DGS-Tree2GD) tailored explicitly for accurately detecting WGD events. Additionally, we introduced two methods to evaluate the contribution of incomplete lineage sorting (ILS) to lineage diversification. Phylogenomic discordance analyses revealed that allopolyploidization, rather than ILS, played a dominant role in the origin and dynamics of polyploid Prunus. Moreover, we inferred that the uplift of the Himalayas from the Middle to Late Miocene was a key driver in the rapid diversification of the Maddenia clade, an endemic group in East Asia. This geological event facilitated extensive hybridization and allopolyploidization, particularly the introgression between the Himalayas-Hengduan and Central-Eastern China clades. This case study demonstrates the robustness and efficacy of our analytical approach in precisely identifying WGD events and elucidating the evolutionary mechanisms underlying allopolyploidization in polyploid Prunus.

Polyploidy↗
PubMed2026

Mitotic karyotyping and FISH mapping of the gender-specific locus indicate an advanced XY system in Hippophae rhamnoides.

Hippophae rhamnoides ssp. turkestanica, a subdioecious plant inhabiting the cold desert of the Indian Himalaya, has gained immense recognition for its nutritional and medicinal values. In recent years, the plant species has proven to be a suitable system to understand the evolution of dioecy. Despite its biological significance, the cytogenetics of this dioecious plant is unclear due to various conflicting accounts of its X-Y chromosome system, particularly the length of Y-chromosome. In this study, we resolved these ambiguities through comprehensive cytogenetic analyses across diverse western Himalayan populations. Using morphometric analysis and fluorescence in situ hybridization (FISH) with a gender-specific marker (HRMSSR), we confirmed homomorphic XX chromosomes in females and heteromorphic sex-chromosomes in males with a notably smaller Y-chromosome. The investigation also revealed a predominant somatic chromosome number of 2n = 24, although minor deviations (2n = 18, 20, 22) appeared at the seed level. These findings highlight an evolutionarily advanced sex-chromosome system. This first detailed cytogenetic investigation of Himalayan Seabuckthorn provides critical insights into the chromosomal architecture, laying a crucial foundation for future evolutionary, genomic, and conservation studies in the species.

Chromosome Mapping↗
PubMed1976

The incidence, importance, and prophylaxis of acute mountain sickness.

Acute mountain sickness (A.M.S.) and its severe complications, high-altitude pulmonary oedema (H.A.P.O.) and cerebral oedema (C.O.), were studied in 278 unacclimatised hikers at 4243 m altitude at Pheriche in the Himalayas of Nepal. The overall incidence of A.M.S. was 53%, the incidence being increased in the young and in those who flew to 2800 m, climbed fast, and spent fewer nights acclimatising en route. It was unrelated to sex, to previous altitude experience, to the load carried, and to recent respiratory infections. The severity of A.M.S. was inversely related to age (independent of rate of ascent) and the highest altitude attained, and was highly ocrrelated with speed of ascent. There were 7 cases of H.A.P.O. and 5 with the more intractable C.O. and, of these 12, 11 had flown in, 9 had spent only one night at Pheriche, and none were on acetazolamide. 11 required evacuation. Acetazolamide, compared in a double-blind study with a placebo and also compared with no tablets at all, reduced both the incidence and the severity of A.M.S. in those who flew to 2800 m but not in those who hiked up to that altitude. Prevention consists in slow ascent, rapid recognition of warning signs, and prompt descent to avoid progression.

Acetazolamide↗
PubMed2025

Genomic Insights Into Local Adaptation Across Heterogeneous Understory Habitats and Climate Change Vulnerability.

Understanding adaptive evolution and survival risks in understory herbs is crucial for the effective conservation of biodiversity. How environmental gradients shape species local adaptation patterns is not well understood, nor is how populations of understory herbs respond to a changing climate. In this study, we conducted population genomic analyses of Adenocaulon himalaicum (Asteraceae) with a pan-East Asian distribution, representing a good model for dominant understory herbs to elucidate adaptation mechanisms in heterogeneous forest ecosystems. Based on 34,398 putatively neutral single nucleotide polymorphisms (SNPs) across 27 populations, we identified three genetic lineages accompanied by high levels of genetic differentiation between populations. Our isolation by environment results (IBE) indicated a significant effect of environmental gradients on genomic variation of A. himalaicum (r = 0.18, p = 0.03). To decompose the relative contributions of climate, geography and population structure in explaining genetic variance, our partial RDA found that the prominent contribution of environmental effects (climatic and soil variables) explained 29% and 36% of the neutral and adaptive genetic variation, respectively. Using two genotype-environment association (GEA) methods, we identified 13 SNPs as candidates for core climate-related adaptation loci, with two of these loci further validated by qRT-PCR experiments. Projections of spatiotemporal genomic vulnerability under different future climate scenarios revealed that populations in the southeastern edge of the Himalayas, near the Sichuan Basin, the southernmost region of Northeast China and the northern Korean Peninsula, as well as northern Japan, were identified as the most vulnerable and should be prioritised for conservation. Therefore, our current study provides the genomic foundations for conservation and management strategies to elucidate how these understory herbs cope with future climate changes.

Climate Change↗
PubMed1979

Birmingham Medical Research Expeditionary Society 1977 Expedition: Psychological aspects of acute mountain sickness.

In order to assess the importance of personality and expectations in the development of Acute Mountain Sickness (AMS), 3 standard personality questionnaires and a Mountain Sickness Anticipation Questionnaire were completed by all of the 17 BMRES expedition members before their departure for the Himalayas. AMS could not be predicted with these tests and its occurrence, when assessed either by clinical interview or by peer review, bore no significant relationship to personality. For comparison daily self-assessment of the signs and symptoms of AMS were also conducted throughout the expedition, using graduated and graphic rating scales. The results were found to be unreliable and dependent upon personality factors. These findings have implications for those assessing others at high altitude.

Adult↗
PubMed2024

Variable resource allocation pattern, biased sex-ratio, and extent of sexual dimorphism in subdioecious Hippophae rhamnoides.

Evolutionary maintenance of dioecy is a complex phenomenon and varies by species and underlying pathways. Also, different sexes may exhibit variable resource allocation (RA) patterns among the vegetative and reproductive functions. Such differences are reflected in the extent of sexual dimorphism. Though rarely pursued, investigation on plant species harbouring intermediate sexual phenotypes may reveal useful information on the strategy pertaining to sex-ratios and evolutionary pathways. We studied H. rhamnoides ssp. turkestanica, a subdioecious species with polygamomonoecious (PGM) plants, in western Himalaya. The species naturally inhabits a wide range of habitats ranging from river deltas to hill slopes. These attributes of the species are conducive to test the influence of abiotic factors on sexual dimorphism, and RA strategy among different sexes. The study demonstrates sexual dimorphism in vegetative and reproductive traits. The sexual dimorphism index, aligned the traits like height, number of branches, flower production, and dry-weight of flowers with males while others including fresh-weight of leaves, number of thorns, fruit production were significantly associated with females. The difference in RA pattern is more pronounced in reproductive traits of the male and female plants, while in the PGM plants the traits overlap. In general, habitat conditions did not influence either the extent of sexual dimorphism or RA pattern. However, it seems to influence secondary sex-ratio as females show their significant association with soil moisture. Our findings on sexual dimorphism and RA pattern supports attributes of wind-pollination in the species. The observed extent of sexual dimorphism in the species reiterates limited genomic differences among the sexes and the ongoing evolution of dioecy via monoecy in the species. The dynamics of RA in the species appears to be independent of resource availability in the habitats as the species grows in a resource-limited and extreme environment.

Hippophae↗
PubMed1979

[Mountain sickness or alpine climber's disease (author's transl)].

The symptoms of mountain sickness extend from slight malaise to severe clinical disease. From our own observations in the Himalayas the most serious symptoms appear at night, i. e. at less than the meximum height achieved and when physically at rest. The etiology is not completely clear; the reduced oxygen partial pressure at a height plays a principal role. Prophylactic measures are empirical, scientific methods are being worked on. Treatment is symptomatic, causal therapy consists of rapid removal from the height and oxygen respiration.

Adult↗
PubMedDate not supplied

[Anomalohimalaya lotozkyi sp. n., a new species of ixodid ticks from the Peter the First Range (Ixodoidea, Ixodidae)].

Anomalohimalaya lotozkyi sp. n., the second species of this genus, was found in Tadzhikistan, Peter I ridge, at the height of 2700 m above the sea level in rocky locality with xerophilous vegetation on Alticola argentatus. In June, 1977 there were found larvae and nymphs of the species. After feeding larvae and then nymphs females and males were obtained. All phases of the life cycle differ distinctly from those of the type species An. lama Hoog., Kais. et Mitch., 1970, from Himalayas. The diagnosis of the genus Anomalohimalaya is specified. This genus combines the characters of Haemaphysalis Koch and Rhipicephalus Koch and is of great significance for more precise definition of phylogeny of the subfamily Amblyomminae Banks.

Animals↗
PubMed2026

Genomic signatures of cold adaptation in a Himalayan drosophilid.

Drosophila nepalensis is a cold-adapted drosophilid endemic to the Himalayan region. Its ability to survive in harsh, cold conditions makes it a valuable Drosophila model for investigating how adaptation to thermal extremes may influence species persistence under future climate change. Here, we report the first de novo genome assembly of D. nepalensis, based on a hybrid sequencing strategy that combines Illumina short reads and Oxford Nanopore long reads. Illumina sequencing generated 49.88 million 150 bp paired-end reads (∼14.96 Gbp), while Nanopore sequencing produced 1.35 million long reads totaling ∼0.76 Gbp. The assembled genome spanned ∼178 Mb with an N50 of 83.6 kb and 98% BUSCO completeness, comparable to other well-annotated Drosophila genomes. Annotation identified 10,560 protein-coding genes, including transcription factor-rich and stress-related domains such as zinc fingers, WD40 repeats, and ankyrin motifs. Comparative orthology analysis across 6 Drosophila species identified 14,168 orthologous clusters, of which 9,173 were shared among all 6 species, indicating a conserved core genomic set across the sampled taxa. D. nepalensis showed 83 unique orthogroups and 50 singletons, suggesting some lineage-specific gene expansions associated with cold adaptation and endemicity, including families encoding caspase-family apoptotic regulators, chromatin remodeling proteins (HMGB/protamine-like), and SNARE-domain vesicle trafficking factors. Gene family evolution analysis revealed the highest expansions in the cold-tolerant Himalayan drosophilid, D. nepalensis, including significant expansions in serine protease, chaperone, and neurotransmitter transporter families, alongside dramatic contractions of core histone gene families, suggesting lineage-specific chromatin remodeling and ecological specialization.

Drosophila nepalensis↗