👤 Mohd Akhtar

Psychedelic compounds such as psilocybin, Lysergic Acid Diethylamide (LSD), N,Ndimethyltryptamine (DMT), and 3,4-methylenedioxymethamphetamine (MDMA) are emerging as novel therapeutics for neuropsychiatric disorders, including depression, Post-Traumatic Stress Disorder (PTSD), and addiction. Acting primarily through serotonin 5-HT2A receptor agonism, they activate intracellular cascades involving Brain-Derived Neurotrophic Factor (BDNF), Tropomyosin receptor kinase B (TrkB), and the mammalian target of rapamycin (mTOR) pathway, leading to enhanced neuroplasticity and synaptogenesis. Recent evidence demonstrates direct TrkB binding and sustained cortical remodeling, underlying their rapid and durable antidepressant effects. Advanced Drug Delivery Systems (DDS)-including liposomes, Solid Lipid Nanoparticles (SLNs), and Poly(lactic-co-glycolic acid) (PLGA) carriers-are being engineered to achieve controlled, braintargeted, and stimuli-responsive release while minimizing systemic toxicity. Integration with microfluidic fabrication, Artificial Intelligence (AI)-based dosing, and non-invasive routes such as intranasal and transdermal delivery improves precision and patient adherence. By merging neuropharmacology with materials science, these innovations are redefining psychedelic-assisted therapy through enhanced safety, personalized dosing, and translational potential for central nervous system disorders. Show less

Diabetic nephropathy (DN) is a chronic renal complication characterized by persistent proteinuria, glomerular hypertrophy, impaired filtration capacity, and progressive renal fibrosis, ultimately leading to a gradual decline in kidney function. DN remains one of the leading causes of end-stage renal disease worldwide, contributing substantially to morbidity and mortality. Although the precise etiology of DN is not fully elucidated, its development is closely linked to prolonged hyperglycemia, renal hyperfiltration, accumulation of advanced glycation end products (AGEs), activation of pro-inflammatory cytokines, and oxidative stress-mediated injury. These pathogenic events involve multiple diabetes-associated pathways, including protein kinase C activation and increased reactive oxygen species (ROS) generation. O-linked β-N-acetylglucosamine (O-GlcNAc) modification is a dynamic post-translational protein modification that is significantly upregulated in DN and plays a critical role in regulating cellular signaling pathways associated with disease initiation and progression. This review summarizes current evidence on the role of O-GlcNAcylation in modulating molecular mechanisms underlying DN. Furthermore, Angiopoietin-like 4 (ANGPTL4) has emerged as a key regulator of lipid metabolism through inhibition of lipoprotein lipase and interactions with integrins, influencing vascular permeability, oxidative stress, and tissue remodeling. Increasing evidence suggests that ANGPTL4 plays a pivotal role in DN onset and progression. Show less

Cecal microbiota plays an essential role in chicken health. However, its contribution to fat metabolism, particularly in abdominal fat deposition, which is a severe problem in the poultry industry, is still unclear. Here, chickens at 1, 4, and 12 months of age with significantly (p < 0.05) higher and lower abdominal fat deposition were selected to elucidate fat metabolism. A significantly (p < 0.05) higher mRNA expression of fat anabolism genes (ACSL1, FADS1, CYP2C45, ACC, and FAS), a significantly (p < 0.05) lower mRNA expression of fat catabolism genes (CPT-1 and PPARα) and fat transport gene APOAI in liver/abdominal fat of high abdominal fat deposition chickens indicated that an unbalanced fat metabolism leads to excessive abdominal fat deposition. Parabacteroides, Parasutterella, Oscillibacter, and Anaerofustis were found significantly (p < 0.05) higher in high abdominal fat deposition chickens, while Sphaerochaeta was higher in low abdominal fat deposition chickens. Further, Spearman correlation analysis indicated that the relative abundance of cecal Parabacteroides, Parasutterella, Oscillibacter, and Anaerofustis was positively correlated with abdominal fat deposition, yet cecal Sphaerochaeta was negatively correlated with fat deposition. Interestingly, transferring fecal microbiota from adult chickens with low abdominal fat deposition into one-day-old chicks significantly (p < 0.05) decreased Parabacteroides and fat anabolism genes, while markedly increased Sphaerochaeta (p < 0.05) and fat catabolism genes (p < 0.05). Our findings might help to assess the potential mechanism of cecal microbiota regulating fat deposition in chicken production. Show less

Cells rely on a diverse repertoire of genes for maintaining homeostasis, but the transcriptional networks underlying their expression remain poorly understood. The MOF acetyltransferase-containing Non-Specific Lethal (NSL) complex is a broad transcription regulator. It is essential in Drosophila, and haploinsufficiency of the human KANSL1 subunit results in the Koolen-de Vries syndrome. Here, we perform a genome-wide RNAi screen and identify the BET protein BRD4 as an evolutionary conserved co-factor of the NSL complex. Using Drosophila and mouse embryonic stem cells, we characterise a recruitment hierarchy, where NSL-deposited histone acetylation enables BRD4 recruitment for transcription of constitutively active genes. Transcriptome analyses in Koolen-de Vries patient-derived fibroblasts reveals perturbations with a cellular homeostasis signature that are evoked by the NSL complex/BRD4 axis. We propose that BRD4 represents a conserved bridge between the NSL complex and transcription activation, and provide a new perspective in the understanding of their functions in healthy and diseased states. Show less

Predictive genetic screening of relatives of patients with hypertrophic cardiomyopathy (HCM) caused by sarcomere protein (SP) gene mutations is current standard of care, but there are few data on long-term outcomes in mutation carriers without HCM. The aim of this study was to determine the incidence of new HCM diagnosis in SP mutation carriers. This was a retrospective analysis of adult and pediatric SP mutation carriers identified during family screening who did not fulfill diagnostic criteria for HCM at first evaluation. The authors evaluated 285 individuals from 156 families (median age 14.2 years [interquartile range: 6.8 to 31.6 years], 141 [49.5%] male individuals); 145 (50.9%) underwent cardiac magnetic resonance (CMR). Frequency of causal genes was as follows: MYBPC3 n = 123 (43.2%), MYH7 n = 69 (24.2%), TNNI3 n = 39 (13.7%), TNNT2 n = 34 (11.9%), TPM1 n = 9 (3.2%), MYL2 n = 6 (2.1%), ACTC1 n = 1 (0.4%), multiple mutations n = 4 (1.4%). Median follow-up was 8.0 years (interquartile range: 4.0 to 13.3 years) and 86 (30.2%) patients developed HCM; 16 of 50 (32.0%) fulfilled diagnostic criteria on CMR but not echocardiography. Estimated HCM penetrance at 15 years of follow-up was 46% (95% confidence interval [CI]: 38% to 54%). In a multivariable model adjusted for age and stratified for CMR, independent predictors of HCM development were male sex (hazard ratio [HR]: 2.91; 95% CI: 1.82 to 4.65) and abnormal electrocardiogram (ECG) (HR: 4.02; 95% CI: 2.51 to 6.44); TNNI3 variants had the lowest risk (HR: 0.19; 95% CI: 0.07 to 0.55, compared to MYBPC3). Following a first negative screening, approximately 50% of SP mutation carriers develop HCM over 15 years of follow-up. Male sex and an abnormal ECG are associated with a higher risk of developing HCM. Regular CMR should be considered in long-term screening. Show less

While nuclear lamina abnormalities are hallmarks of human diseases, their interplay with epigenetic regulators and precise epigenetic landscape remain poorly understood. Here, we show that loss of the lysine acetyltransferase MOF or its associated NSL-complex members KANSL2 or KANSL3 leads to a stochastic accumulation of nuclear abnormalities with genomic instability patterns including chromothripsis. SILAC-based MOF and KANSL2 acetylomes identified lamin A/C as an acetylation target of MOF. HDAC inhibition or acetylation-mimicking lamin A derivatives rescue nuclear abnormalities observed in MOF-deficient cells. Mechanistically, loss of lamin A/C acetylation resulted in its increased solubility, defective phosphorylation dynamics and impaired nuclear mechanostability. We found that nuclear abnormalities include EZH2-dependent histone H3 Lys 27 trimethylation and loss of nascent transcription. We term this altered epigenetic landscape "heterochromatin enrichment in nuclear abnormalities" (HENA). Collectively, the NSL-complex-dependent lamin A/C acetylation provides a mechanism that maintains nuclear architecture and genome integrity. Show less

The functionality of chromatin is tightly regulated by post-translational modifications that modulate transcriptional output from target loci. Among the post-translational modifications of chromatin, reversible ε-lysine acetylation of histone proteins is prominent at transcriptionally active genes. Lysine acetylation is catalyzed by lysine acetyltransferases (KATs), which utilize the central cellular metabolite acetyl-CoA as their substrate. Among the KATs that mediate lysine acetylation, males absent on the first (MOF/KAT8) is particularly notable for its ability to acetylate histone 4 lysine 16 (H4K16ac), a modification that decompacts chromatin structure. MOF and its non-specific lethal (NSL) complex members have been shown to localize to gene promoters and enhancers in the nucleus, as well as to microtubules and mitochondria to regulate key cellular processes. Highlighting their importance, mutations or deregulation of NSL complex members has been reported in both human neurodevelopmental disorders and cancer. Based on insight gained from studies in human, mouse, and Drosophila model systems, this review discusses the role of NSL-mediated lysine acetylation in a myriad of cellular functions in both health and disease. Through these studies, the importance of the NSL complex in regulating core transcriptional and signaling networks required for normal development and cellular homeostasis is beginning to emerge. Show less

A major goal of biomedicine is to understand the function of every gene in the human genome. Loss-of-function mutations can disrupt both copies of a given gene in humans and phenotypic analysis of such 'human knockouts' can provide insight into gene function. Consanguineous unions are more likely to result in offspring carrying homozygous loss-of-function mutations. In Pakistan, consanguinity rates are notably high. Here we sequence the protein-coding regions of 10,503 adult participants in the Pakistan Risk of Myocardial Infarction Study (PROMIS), designed to understand the determinants of cardiometabolic diseases in individuals from South Asia. We identified individuals carrying homozygous predicted loss-of-function (pLoF) mutations, and performed phenotypic analysis involving more than 200 biochemical and disease traits. We enumerated 49,138 rare (<1% minor allele frequency) pLoF mutations. These pLoF mutations are estimated to knock out 1,317 genes, each in at least one participant. Homozygosity for pLoF mutations at PLA2G7 was associated with absent enzymatic activity of soluble lipoprotein-associated phospholipase A2; at CYP2F1, with higher plasma interleukin-8 concentrations; at TREH, with lower concentrations of apoB-containing lipoprotein subfractions; at either A3GALT2 or NRG4, with markedly reduced plasma insulin C-peptide concentrations; and at SLC9A3R1, with mediators of calcium and phosphate signalling. Heterozygous deficiency of APOC3 has been shown to protect against coronary heart disease; we identified APOC3 homozygous pLoF carriers in our cohort. We recruited these human knockouts and challenged them with an oral fat load. Compared with family members lacking the mutation, individuals with APOC3 knocked out displayed marked blunting of the usual post-prandial rise in plasma triglycerides. Overall, these observations provide a roadmap for a 'human knockout project', a systematic effort to understand the phenotypic consequences of complete disruption of genes in humans. Show less

A functional crosstalk between epigenetic regulators and metabolic control could provide a mechanism to adapt cellular responses to environmental cues. We report that the well-known nuclear MYST family acetyl transferase MOF and a subset of its non-specific lethal complex partners reside in mitochondria. MOF regulates oxidative phosphorylation by controlling expression of respiratory genes from both nuclear and mtDNA in aerobically respiring cells. MOF binds mtDNA, and this binding is dependent on KANSL3. The mitochondrial pool of MOF, but not a catalytically deficient mutant, rescues respiratory and mtDNA transcriptional defects triggered by the absence of MOF. Mof conditional knockout has catastrophic consequences for tissues with high-energy consumption, triggering hypertrophic cardiomyopathy and cardiac failure in murine hearts; cardiomyocytes show severe mitochondrial degeneration and deregulation of mitochondrial nutrient metabolism and oxidative phosphorylation pathways. Thus, MOF is a dual-transcriptional regulator of nuclear and mitochondrial genomes connecting epigenetics and metabolism. Show less

The evolutionary conserved NSL complex is a prominent epigenetic regulator controlling expression of thousands of genes. Here we uncover a novel function of the NSL complex members in mitosis. As the cell enters mitosis, KANSL1 and KANSL3 undergo a marked relocalisation from the chromatin to the mitotic spindle. By stabilizing microtubule minus ends in a RanGTP-dependent manner, they are essential for spindle assembly and chromosome segregation. Moreover, we identify KANSL3 as a microtubule minus-end-binding protein, revealing a new class of mitosis-specific microtubule minus-end regulators. By adopting distinct functions in interphase and mitosis, KANSL proteins provide a link to coordinate the tasks of faithful expression and inheritance of the genome during different phases of the cell cycle. Show less

The subunits of the nonspecific lethal (NSL) complex, which include the histone acetyltransferase MOF (males absent on the first), play important roles in various cellular functions, including transcription regulation and stem cell identity maintenance and reprogramming, and are frequently misregulated in disease. Here, we provide the first biochemical and structural insights into the molecular architecture of this large multiprotein assembly. We identified several direct interactions within the complex and show that KANSL1 acts as a scaffold protein interacting with four other subunits, including WDR5, which in turn binds KANSL2. Structural analysis of the KANSL1/WDR5/KANSL2 subcomplex reveals how WDR5 is recruited into the NSL complex via conserved linear motifs of KANSL1 and KANSL2. Using structure-based KANSL1 mutants in transgenic flies, we show that the KANSL1-WDR5 interaction is required for proper assembly, efficient recruitment of the NSL complex to target promoters, and fly viability. Our data clearly show that the interactions of WDR5 with the MOF-containing NSL complex and MLL/COMPASS histone methyltransferase complexes are mutually exclusive. We propose that rather than being a shared subunit, WDR5 plays an important role in assembling distinct histone-modifying complexes with different epigenetic regulatory roles. Show less