👤 Poh Ying Lim

Climate change creates major challenges in livestock industry, making chickens vulnerable to heat stress because they can tolerate a narrow range of temperatures. Heat stress disrupts metabolic and physiological homeostasis, leading to reduced growth, productivity, reproduction, and immune function, thereby threatening the economic viability of poultry farming. This review explores the multifaceted impacts of heat stress on poultry, including physiological responses, production performance, and immune function. Recent advances in transcriptomic and genomic research have shed light on the molecular mechanisms underlying heat stress resilience in poultry. Key genes such as HSP70, HSP90, HSP27, and HSP47 are significantly upregulated under heat stress, playing vital roles in protein folding, preventing aggregation, and protecting cellular integrity. Additionally, genes like SOD and CAT enhance antioxidant defenses, mitigating oxidative damage. Genes such as RB1CC1, BAG3, and TRMT1L regulate apoptosis and oxidative stress, promoting cell survival. In the liver, CCK, DIO3, and ANGPTL4 improve energy homeostasis and reduce metabolism-related heat production, while BMP10 and MYH7 in the heart contribute to cardiac adaptation during thermal stress. Genetic adaptations such as the Naked neck, Frizzle, and Dwarf gene provide intrinsic thermotolerance by reducing feather mass, altering feather structure, and minimizing body size, thereby improving heat dissipation. These genetic traits, combined with transcriptomic insights into heat resilience genes, offer opportunities for developing heat-tolerant chicken breeds. By integrating molecular genetics, transcriptomics, and management strategies, this review highlights the importance of selective breeding programs to enhance poultry thermotolerance. Future research should focus on leveraging indigenous breeds, advanced molecular tools, and nutritional interventions to mitigate the effects of rising global temperatures. Enhancing heat stress resilience in poultry is imperative to ensure sustainable production and global food security in this climate change. Show less

Apolipoprotein B [apoB] and lipoprotein(a) [Lp(a)] concentrations are the two prime lipoprotein indices recommended by some expert consensus to assess and manage cardiovascular risk. However, their distributions, associations, inter-relationships, and clinical relevance remain un-investigated in the majority of Asian populations, particularly among healthcare workers. The distributions and relationships of serum Lp(a), apoB, and other lipid biomarker concentrations in 1,927 Asian consenting healthcare workers across ethnicities, sexes, and body mass index (BMI) were analysed. The percentage of apoB content of Lp(a) relative to apoB particle concentrations (Lp(a)-to-apoB proportion) was calculated. Participants’ mean age was 39.4 years, mostly females (79.7%). Ethnicities were Chinese (57.2%), Malay (16.9%), Indian (9.2%), Filipino (12.8%) and others (3.8%). Distribution of Lp(a) was positively skewed to the right for all ethnicities. The median Lp(a) was 16.4 nmol/L (IQR 7.9, 41.8) and ranged between < 7 to 470 nmol/L. The proportion of participants with Lp(a) ≥ 75 nmol/L was 13.9%, and with Lp(a) ≥ 125 nmol/L was 7.8%. Multivariable linear regression analysis showed that being female, older age, and Indian ethnicity were associated with higher Lp(a) levels, whereas being male, older age, Indian ethnicity, and higher BMI were associated with higher mean apoB levels. In this cohort, 11.4% of individuals had Lp(a)-to-apoB proportion > 5%, whilst 3.3% had Lp(a)-to-apoB proportion of > 10%. Among individuals with Lp(a) ≥ 250 nmol/L, the median Lp(a)-to-apoB proportion was 14.9% (IQR 12.6,19.7). Across Lp(a) deciles, the Lp(a)-to-apoB proportions were inversely correlated with LDL-C, non-HDL-C, remnant cholesterol, and triglyceride concentrations. Abnormal Lp(a) (≥ 75 nmol/L) was found in 13.9% of a predominantly female Asian healthcare cohort. In individuals with Lp(a) ≥ 250 nmol/L, Lp(a) particles contributed to the circulating apoB levels by a median of 15%. These findings support the notion that Lp(a) should be integrated into routine lipid assessment in Asian populations, including healthcare workers. clinicaltrial.gov NCT06304415. The online version contains supplementary material available at 10.1186/s12944-026-02912-7. Show less

Progressive supranuclear palsy (PSP) is a heterogeneous neurodegenerative disease characterised by the accumulation of misfolded 4-repeat tau within neurones and glial cells. There are limited longitudinal data on pathologically confirmed PSP patients with phenotypes other than classic Richardson's syndrome (RS) and the pathomechanisms responsible for the broad variability in clinical phenotype and progression are not well understood. An unresolved question in this context is whether distinct spatiotemporal patterns of tau pathology propagation exist within the clinicopathological spectrum of PSP. We included 241 consecutive, pathologically confirmed patients with PSP from the Queen Square Brain Bank for Neurological Disorders (2010-2022). Phenotyping was performed based on clinical features present within the first 3 years from symptom onset according to the Movement Disorder Society (MDS) criteria, and specific clinical features and disease milestones were recorded. Genotyping was performed using Illumina NeuroBooster and NeuroChip arrays and MAPT haplotype, APOE genotype, TRIM11 rs564309 and SLC2A13 rs2242367 single nucleotide polymorphism data were collated. Tissue sections from eight brain regions, mounted on glass slides, were immunostained for hyperphosphorylated tau and digitised using whole-slide scanning. Forty-one anatomical regions of interest were manually segmented, and total tau pathology burden was quantified using an automated, machine learning-based algorithm. The associations between survival and both clinicogenetic features and regional tau pathology burden were modelled using Cox regression and generalised linear models, respectively and the Subtype and Stage Inference (SuStaIn) algorithm was used to identify subgroups with distinct progression patterns. We have identified: (i) several clinical predictors of survival in PSP and the relationship between regional tau pathology burden and survival; (ii) novel anatomical reference standards for the expected distribution of tau pathology across MDS-defined PSP phenotypes, including region-specific white matter involvement in patients with corticobasal syndrome and speech/language variants; (iii) associations potentially linking biological sex, MAPT haplotype and TDP-43 co-pathology to clinical phenotype and regional tau pathology burden; (iv) patterns of covariance in regional tau pathology implicating inter-regional connectivity in tau spreading; and (v) three distinct spatiotemporal patterns of tau pathology progression: one characterised by initial involvement of subcortical grey matter followed by rostral spread to cortical regions and two characterised by early, simultaneous involvement of subcortical grey matter and cortical regions. Taken together, these results indicate that PSP clinicopathological heterogeneity is mediated by propagation of tau pathology along anatomically connected networks and via intrinsic regional susceptibility mechanisms, possibly influenced by sex, genetic factors and co-pathology. Show less

Plant-based diets have been linked to slower cognitive decline, but data on long-term dietary changes and from diverse populations are limited. The primary aim of this study was to examine plant-based dietary patterns and their change over time in relation to Alzheimer disease and related dementias (ADRDs). This prospective longitudinal analysis of the Multiethnic Cohort Study, based in Hawaii and California (primarily Los Angeles County), included data on African American, Japanese American, Latino, Native Hawaiian, and White participants who completed food frequency questionnaires at baseline (1993-1996; age 45-75 years) and at 10-year follow-up (2003-2008) and whose Medicare claims were linked to identify incident ADRDs. A priori indices for the overall plant-based diet index (PDI), the healthful plant-based diet index (hPDI), and the unhealthful plant-based diet index (uPDI) were analyzed in Cox regression models for ADRD. The analysis included 92,849 participants (mean age 59.2 years, 55.1% female, 21,478 with ADRDs) for the baseline diet and 45,065 participants (8,360 with ADRDs) for the 10-year dietary change. For the baseline diet, comparing the highest vs lowest quintile, PDI and hPDI were associated with 12% (hazard ratio [HR] 0.88; 95% CI 0.85-0.92) and 7% (HR 0.93; 95% CI 0.89-0.97) lower risks of ADRD, respectively, whereas uPDI was related to a 6% higher risk (HR 1.06; 95% CI 1.01-1.10). For the dietary change over time, the strongest association with ADRD was observed for uPDI rather than for PDI or hPDI. Compared with those with a stable score (<0.5 SD change), participants with a large increase in uPDI (≥1 SD) showed a 25% higher risk (HR 1.25; 95% CI 1.15-1.36) and those with a large decrease in uPDI showed an 11% lower risk (HR 0.89; 95% CI 0.84-0.94). The associations between the plant-based diet indices and ADRD were generally similar by age group (<60 vs ≥60 years at baseline), race and ethnicity, or These findings suggest that adopting plant-based diets, specifically refraining from low-quality plant-based diets, even at an older age, is associated with a lower risk of ADRDs. Show less

Dementia in Lewy body diseases (LBD) is common and arises through heterogeneous and incompletely understood pathways. Evidence suggests contributions from genetic factors, including APOE ε4 genotype, co-pathology including concomitant Alzheimer's disease pathology and hypoperfusion related to orthostatic hypotension. However, the relative impact of these factors remains unclear. To address this, we analysed 399 post-mortem brains from LBD cases comprising Parkinson's disease, Parkinson's disease dementia and dementia with Lewy bodies, and controls, integrating APOE genotype, clinical data and assessment of ischaemic pathology alongside large-scale digital pathology quantification. We established an image analysis pipeline utilising machine learning to enable automated, standardised measurement of α-synuclein, amyloid-β, and phosphorylated tau burden across multiple brain regions. Quantitative pathology strongly correlated with semi-quantitative ratings and outperformed conventional staging in predicting dementia. Across multiple analytical approaches, APOE ε3 and ε4 carriers showed distinct dementia risk profiles. APOE ε3 carriers developed dementia at lower quantitative α-synuclein and amyloid-β thresholds than ε4 carriers, although overall dementia risk was dominated by ε4 genotype, consistent with ε4 both promoting greater pathology accumulation and modifying the threshold for dementia onset. Orthostatic hypotension and ischaemic pathology increased dementia risk only in ε3 carriers with low Lewy and Alzheimer's proteinopathy burden, while male sex further modulated dementia risk for this subgroup. The Subtype and Stage Inference (SuStaIn) algorithm identified four trajectories of Lewy pathology progression. Two corresponded to recognised patterns, one brainstem-first and the other with early amygdala and concomitant brainstem involvement. Two further patterns showed early cortical involvement, one with early cingulate cortex involvement together with brainstem pathology and the other starting in neocortex before limbic and brainstem involvement. Co-pathology progression modelling identified subtypes with early predominance of amyloid-β, phosphorylated tau, or α-synuclein, and showed that Lewy subtypes follow two propagation trajectories in opposite directions. Together, these findings demonstrate that integrating quantitative pathology with genotype and clinical data reveals distinct yet overlapping pathways to dementia in LBD, refining disease progression models and providing a basis for genotype- and pathology-informed patient stratification in therapeutic trials. Show less

Determining apolipoprotein E (APOE) ε4 allele status, a key genetic risk factor for Alzheimer's disease (AD), requires molecular genotyping infrastructure not widely accessible beyond specialized centers. A fully automated high-throughput apoE E4 proteotyping immunoassay was evaluated for clinical performance (460 participants across three cohorts) and analytical validity. Concordance with polymerase chain reaction (PCR)-based genotyping and measures of analytical validity were reported. The apoE E4 immunoassay demonstrated 99.6% (95% confidence interval [CI]: 98.4% to 99.9%) concordance with PCR-based APOE ε4 genotype results across the pooled clinical cohort; 100.0% (95% CI: 97.1% to 100.0%) in those with AD (N = 127) and 99.4% (95% CI: 97.8% to 99.8%) in those without AD (333). The assay met analytical validity criteria for E4 isoform specificity, interference, precision, and stability. The apoE E4 immunoassay demonstrated high concordance with PCR-based genotyping and robust analytical validity, offering an accessible alternative for APOE ε4 zygosity assessment. A novel high-throughput plasma-based proteotyping immunoassay for APOE ε4 zygosity classification was developed and evaluated for clinical performance and analytical validity. The apoE E4 immunoassay demonstrated high concordance (99.6%) with PCR-based APOE ε4 genotyping across a diverse international cohort, and a robust analytical profile. An apoE E4 immunoassay may offer a more cost-effective and accessible alternative to DNA genotyping approaches currently used for AD risk evaluation and anti-amyloid treatment decisions. Show less

Alzheimer's disease (AD) is the leading cause of dementia, characterized by the deposition of amyloid-β plaques and neurofibrillary tangles composed of hyperphosphorylated tau. Seizures have also emerged as a prevalent clinical feature of AD and are associated with APOE4, the major genetic risk factor of AD. However, the mechanism by which APOE4 induces seizures and neuronal hyperexcitability is incompletely understood. We discovered that human APOE4 targeted replacement mice showed increased seizure severity and seizure-induced death at 5.5-7 but not 2-3 months of age compared to APOE3 mice using the kainic acid model of status epilepticus which preferentially arises from the hippocampus. While Tau burden alone did not alter seizure susceptibility in mice, APOE4 together with Tau burden enhanced seizure severity in female mice. Notably, APOE4 was associated with decreased hippocampal levels of sodium/potassium-ATPase, ATP-generating glycolytic enzymes, including phosphoglycerate kinase 1 (PGK1) and pyruvate kinase M, and ATP. While inhibition of Na Show less

Diabetes is a major risk factor for diabetic encephalopathy (DE), which is closely associated with sporadic Alzheimer's disease. Folic acid (FA) receptor signaling can suppress generation of neuropathogenic amyloid-beta (Aβ) induced by high extracellular glucose, suggesting that enhanced activation of this pathway could be a therapeutic strategy against DE-associated dementia, but the precise molecular signaling mechanisms are unclear. We report that high glucose levels increased the expression of amyloid precursor protein (APP) and β-secretase (BACE1) in cultured neurons and concomitantly induced amyloidogenesis, while FA treatment suppressed high glucose-stimulated expression of APP and BACE1, Aβ release, and accumulation of mitochondrial reactive oxygen species. Expression of nuclear factor erythroid 2-related factor 2 (Nrf2) was minimal under high glucose conditions, but was significantly upregulated together with downstream antioxidant enzymes following FA co-treatment. High glucose stimulation also increased folate receptor 1 (FOLR1) mRNA expression, suggesting a compensatory protective response. While treatment with 5-methyltetrahydrofolate (5-MTHF), the activated form of folate, did not significantly alter high glucose-induced upregulation of APP and BACE1, knockdown of FOLR1 mRNA reduced high glucose-stimulated Nrf2 expression and further augmented APP and BACE1 expression under high glucose conditions. Treatment with the STAT3 inhibitor 5'15-DPP also abolished high glucose-stimulated Nrf2 expression and increased APP and BACE1 expression levels. These findings indicate that FA/FOLR1 activation suppresses high glucose-induced amyloidogenesis by mitigating mitochondrial oxidative stress via STAT3/Nrf2 pathway signaling. In conclusion, present study suggests that the FA/FOLR1/STAT3/Nrf2 pathway is an effective therapeutic target for DE. Show less

Alzheimer's disease (AD) and neuroblastoma are distinct conditions that affect the nervous system. However, they share some molecular similarities, particularly concerning the amyloid precursor protein (APP) and related pathways. While previous studies have demonstrated a correlation between neurodegenerative diseases and various tumors, the causality and direction of their relationship remain unclear. Oleacein, one of the most abundant polyphenols in Extra Vergin Olive Oil (EVOO) may exert neuroprotective and/or antitumor effects. In this study, we explored the effects of the polyphenol oleacein, obtained by a simple and efficient sustainable semi-synthesis starting from natural oleuropein, on AD-related genes in SHSY5Y, a human neuroblastoma cell line, and in 3Tg-iAstro cells, immortalized astrocytes from the hippocampus of 3xTg-AD mice, to identify potential shared biological pathways. Show less

Aberrant deposition of β-amyloid (Aβ) and hyperphosphorylated tau, along with neuroinflammation, are key drivers of Alzheimer's disease (AD) pathology. Here, we identify ramalin, a natural antioxidant, as a promising therapeutic agent that alleviates AD pathology by modulating β-site APP cleaving enzyme 1 (BACE1), histone deacetylase 6 (HDAC6), and the mitogen-activated protein kinases (MAPK) pathway. Ramalin reduced BACE1 protein levels, independently of its transcription, translation, or enzymatic activity, an effect mediated by inhibition of HDAC6. Consistently, HDAC6 knockout similarly decreased BACE1 levels, highlighting HDAC6 as a key regulator of BACE1. Ramalin further suppressed neuroinflammatory responses by downregulating inducible nitric oxide synthase (iNOS) and the NLR family pyrin domain containing 3 (NLRP3) inflammasome. In AD mouse models, ramalin treatment significantly attenuated neuroinflammation, Aβ plaque burden, and tau hyperphosphorylation, while improving cognitive performance. Notably, ramalin reversed Aβ oligomer-induced synaptic transmission impairment and restored synaptic vesicle recycling in hippocampal neurons. Transcriptomic analysis identified modulation of the MAPK pathway, with reduced phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) implicated in tau pathology. These findings establish ramalin as a disease-modifying intervention that provides neuroprotection through concurrent regulation of BACE1, HDAC6, and MAPK signaling pathway. Collectively, our findings highlight ramalin as a compelling disease-modifying candidate with the potential to drive a breakthrough approach targeting AD pathology. Show less

Lipoprotein lipase (LPL) is a blood vessel lipase that regulates and removes plasma lipoprotein triglycerides from blood circulation. It is important in the control of hypertriglyceridemia. LPL dysregulation can lead to hypertriglyceridemia and increase the risk of atherosclerosis cardiovascular disease. Therefore, the biochemical characterization of LPL could help understand the LPL dysregulation mechanism. However, active LPL enzyme acquisition via bacterial expression is challenging, as studies have reported that LPL could only be co-expressed in the presence of a chaperone. Therefore, this work intends to investigate the possibility of bacterial expression of human LPL (hLPL) with active lipase activity. The hLPL protein has been produced in SHuffle® T7 cells, and the optimal refolding conditions of the hLPL protein have been described here. The addition of 4% glycerol, 0.5-M NaCl, and 0.5-mM CaCl Show less

We aimed to investigate whether maternal and fetal genetic predispositions to insulin deficiency and resistance affect offspring fetal growth through distinct pathways in multi-ethnic populations. In 5065 multi-ethnic mother-infant pairs, we examined the conditional associations of maternal and fetal partitioned polygenic risk scores (pPRSs) for type 2 diabetes-related pathways with fetal growth outcomes, including birthweight, sum of skinfold thicknesses (SSF), large-for-gestational-age (LGA) births and small-for-gestational-age (SGA) births. Two-sample Mendelian randomisation (2SMR) in Europeans was performed for triangulation. Exposures were eight type 2 diabetes-related pathways (n=1,812,017), eight beta cell function indices (n=26,356) and two insulin sensitivity indices (n=53,657). Outcomes were maternal and fetal genetically determined birthweight (n=406,063). Mediation analysis was used to assess the mediation effects of maternal glucose levels and BMI on maternal genetic effects and of cord blood C-peptide on fetal genetic effects. Co-localisation analyses were performed to test for shared causal variants. Fetal type 2 diabetes polygenic risk score (PRS) and pPRSs for lipodystrophy-related insulin resistance and impaired fasting glucose (IFG)-related insulin deficiency were associated with lower birthweight and SSF, while maternal type 2 diabetes PRS and pPRSs for IFG-related insulin deficiency and obesity-related insulin resistance were associated with higher offspring birthweight, SSF and LGA. These associations were consistent across five ethnic groups. Maternal post-load hyperglycaemia mediated 44.2% and 34.2% of the effects of type 2 diabetes PRS and IFG pPRS, respectively, while maternal BMI mediated 43.4% of the effect of Obesity pPRS. 2SMR found consistent results in Europeans and further revealed that fetal insulin sensitivity index and corrected insulin response were associated with higher birthweight. Some loci with shared causal variants acted through multiple pathways, including CDKAL1, TCF7L2, ADCY5 and MACF1. Reduced fetal growth may be driven by lipodystrophy-related insulin resistance and IFG-related insulin deficiency pathways. Targeting pregnant women with high type 2 diabetes PRS/pPRS and prescribing interventions to reduce their post-load hyperglycaemia and BMI may help reduce offspring risk of LGA. Show less

Ischemia-reperfusion (I/R) injury, resulting from transient or permanent cerebral vessel occlusion, triggers oxidative stress, neuroinflammation, and blood-brain barrier (BBB) disruption, leading to progressive neuronal damage and cognitive decline. The hippocampus, due to its high metabolic demand and susceptibility to oxidative stress, is particularly vulnerable to I/R-induced injury. This study evaluated the neuroprotective effects of α-lipoic acid (α-LA), a potent antioxidant, using bilateral common carotid arteries occlusion/reperfusion (BCCAO/R) mouse model and an oxygen-glucose deprivation/reoxygenation in vitro model. In BCCAO/R mice, α-LA improved spatial memory without affecting motor activity and restored hippocampal tight junction proteins (Claudin-5 and Occludin) and antioxidant enzyme expression, indicating BBB stabilization and oxidative stress reduction. Although synaptic proteins (BDNF and PSD-95) were not restored, cognitive improvements suggest alternative protective mechanisms. In HT22 cells, α-LA decreased intracellular reactive oxygen species levels, enhanced viability, and inhibited apoptosis via decreased PARP cleavage and caspase-3 activation. These protective effects were linked to the activation of the Nrf2/ARE signaling pathway and the upregulation of its downstream antioxidant targets. Overall, α-LA demonstrated marked neuroprotective effects in ischemic models by reducing oxidative stress, preserving BBB integrity, and restoring hippocampal function, positioning it as a promising therapeutic candidate for ischemic brain injury. Show less

Transcranial direct current stimulation (tDCS) is a promising non-invasive intervention for mild cognitive impairment (MCI). This prospective study investigated the relationship between optimized electrical field (EF) strength of tDCS and white matter (WM) microstructural changes in 55 individuals with MCI. Magnetic resonance imaging (MRI)-based computational modeling was used to optimize EF strength targeting the left dorsolateral prefrontal cortex (DLPFC). Diffusion tensor imaging (DTI) assessed WM integrity through fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD). Higher EF strength was significantly associated with increased FA and reduced MD and RD in specific left-lateralized tracts, including the anterior thalamic radiation, corticospinal tract, inferior fronto-occipital fasciculus, and inferior longitudinal fasciculus. These EF-dependent WM changes were moderated by Alzheimer's disease (AD)-related factors. Greater WM plasticity was observed in Aβ-positive individuals, APOE ε4 non-carriers, and BDNF Met non-carriers. Moreover, APOE ε4 status significantly moderated the relationship between EF strength and executive function; in non-carriers, stronger EF strength was associated with improved Stroop performance, potentially reflecting enhanced WM integrity in the right superior longitudinal fasciculus. However, no significant associations were observed between EF-sensitive tracts and short-term cognitive changes in the full sample, suggesting that structural modifications may precede functional improvements or require longer follow-up. These findings emphasize the importance of individual AD-related factors in shaping neuromodulatory responses. They also support the need for longitudinal, sham-controlled studies to clarify the clinical implications of EF strength in personalized tDCS for MCI. Show less

The Gold Coast criteria permit diagnosis of amyotrophic lateral sclerosis (ALS) even without upper motor neuron (UMN) signs. However, whether ALS patients with UMN signs (ALSwUMN) and those without (ALSwoUMN) share similar characteristics and prognoses remains unclear. This study compared clinical features, disease progression, electrophysiological findings, biomarker profiles, imaging parameters, and survival between these groups. ALS patients diagnosed according to the Gold Coast criteria were classified into ALSwUMN (n = 51) and ALSwoUMN (n = 20) groups. We evaluated clinical data, motor evoked potentials (MEP), and serum biomarkers, including cardiac Troponin T, neurofilament light chain, glial fibrillary acidic protein, and brain-derived neurotrophic factor. Imaging parameters, including cortical thickness and white matter volume, were also evaluated. Survival was analyzed using the Kaplan-Meier method. The groups showed broadly similar clinical features, disease progression, and biomarker profiles. Abnormal MEPs were more frequent in ALSwUMN (94.0%) than in ALSwoUMN (63.2%, p = 0.017). Both groups demonstrated cortical thinning in the precentral and entorhinal regions compared to healthy controls. ALSwUMN exhibited thinning in the lateral orbitofrontal, insular, and temporal pole regions, while ALSwoUMN showed thinning in the pars opercularis. White matter volume was reduced in both groups in the thalamus, cerebellum, and amygdala, with additional brainstem atrophy in ALSwUMN. No significant survival difference was observed. Despite minor distinctions in electrophysiological and imaging findings, ALSwoUMN had overall comparable clinical profiles and outcomes to ALSwUMN. These findings support recognizing ALSwoUMN within the ALS spectrum under the Gold Coast criteria. Show less

Introduction: Pathogenic heterozygous melanocortin-4 receptor (MC4R) variants are the most common cause of monogenic obesity, affecting central satiety and appetite regulatory areas of the brain. Case Presentations: We report a pedigree with a pathogenic MC4R variant (c.380C>T, p.Ser127Leu). In the proband with obesity (BMI 35 kg/m2) and severe insulin resistance, use of combination of semaglutide and naltrexone-bupropion was successful in reducing insulin requirements and weight. His adult monozygotic twin daughters both had childhood-onset obesity; however, weight trajectories differed. Twin 1 had a peak BMI of 29.1 kg/m2, which decreased to 19.7 kg/m2 with intensive exercise and diet control without weight-lowering medication. Twin 2 had a sedentary lifestyle and epilepsy and had a peak BMI of 30.1 kg/m2; she responded well to naltrexone-bupropion and BMI decreased to 26 kg/m2. Conclusion: The manifestation of obesity, even in cases of monogenic obesity, can vary significantly due to the influence of environmental and lifestyle factors.

. Show less

JOURNAL/nrgr/04.03/01300535-202512000-00030/figure1/v/2025-01-31T122243Z/r/image-tiff Studies have shown that vascular dysfunction is closely related to the pathogenesis of Alzheimer's disease. The middle temporal gyrus region of the brain is susceptible to pronounced impairment in Alzheimer's disease. Identification of the molecules involved in vascular aberrance of the middle temporal gyrus would support elucidation of the mechanisms underlying Alzheimer's disease and discovery of novel targets for intervention. We carried out single-cell transcriptomic analysis of the middle temporal gyrus in the brains of patients with Alzheimer's disease and healthy controls, revealing obvious changes in vascular function. CellChat analysis of intercellular communication in the middle temporal gyrus showed that the number of cell interactions in this region was decreased in Alzheimer's disease patients, with altered intercellular communication of endothelial cells and pericytes being the most prominent. Differentially expressed genes were also identified. Using the CellChat results, AUCell evaluation of the pathway activity of specific cells showed that the obvious changes in vascular function in the middle temporal gyrus in Alzheimer's disease were directly related to changes in the vascular endothelial growth factor (VEGF)A-VEGF receptor (VEGFR) 2 pathway. AUCell analysis identified subtypes of endothelial cells and pericytes directly related to VEGFA-VEGFR2 pathway activity. Two subtypes of middle temporal gyrus cells showed significant alteration in AD: endothelial cells with high expression of Erb-B2 receptor tyrosine kinase 4 (ERBB4 high ) and pericytes with high expression of angiopoietin-like 4 (ANGPTL4 high ). Finally, combining bulk RNA sequencing data and two machine learning algorithms (least absolute shrinkage and selection operator and random forest), four characteristic Alzheimer's disease feature genes were identified: somatostatin ( SST ), protein tyrosine phosphatase non-receptor type 3 ( PTPN3 ), glutinase ( GL3 ), and tropomyosin 3 ( PTM3 ). These genes were downregulated in the middle temporal gyrus of patients with Alzheimer's disease and may be used to target the VEGF pathway. Alzheimer's disease mouse models demonstrated consistent altered expression of these genes in the middle temporal gyrus. In conclusion, this study detected changes in intercellular communication between endothelial cells and pericytes in the middle temporal gyrus and identified four novel feature genes related to middle temporal gyrus and vascular functioning in patients with Alzheimer's disease. These findings contribute to a deeper understanding of the molecular mechanisms underlying Alzheimer's disease and present novel treatment targets. Show less

The present study explored for the first time the blood-based proteomic signature that could potentially distinguish older adults with and without cognitive frailty (CF). The participants were recruited under the Malaysian Elders Longitudinal Research (MELoR) study. Cognition and physical frailty were determined using the Montreal Cognitive Assessment (MoCA) and Fried's criteria, respectively. The differential protein expression in the blood samples (38 CF vs 40 robust) were then determined using the Sequential Window Acquisition of All Theoretical Mass Spectra (SWATH) analysis. A total of 294 proteins were found to be differentially expressed in the CF group as opposed to the robust group. Considering proteins with fold change (FC) ≥  ± 2 and p-values < 0.05, 13 proteins were significantly upregulated and nine proteins significantly downregulated in the CF group when compared to the robust group. Subsequent correlation analysis identified nine dysregulated proteins, namely APOA1, APOA2, APOA4, APOC1, APOE, GPX3, RBP4, SERPINC1 and TTR, to exhibit significantly and moderately strong correlations with parameters of cognitive and/or frailty assessments. These proteins could potentially serve as useful proteomic signature of CF given their sensitivity > 78%, specificity > 75%, accuracy > 80% and area under the curve (AUC) > 0.8. The major biological pathways that could be potentially dysregulated by the nine proteins were associated with lipid metabolism and the retinoid system. The present findings warrant further validation in future studies that involve a larger cohort. Show less

Type 2 diabetes mellitus (T2DM) is known to adversely impact brain health, leading to cognitive decline and brain tissue volume reduction. This study aimed to assess the damage to gray-white matter junction tissue volume (gwJTV) in T2DM patients with and without carotid artery plaques, and its association with various metabolic parameters. We conducted a cross-sectional study involving 69 T2DM patients, employing three-dimensional T1-weighted MRI scans to measure brain tissue volumes, particularly gwJTV, and analyzing blood samples for metabolic parameters. Voxel-based (VBA) and region-of-interest (ROI) analyses of gwJTV were performed to evaluate the group difference with and without carotid artery plaques and to determine correlations to metabolic biomarkers. Voxel-based and region-of-interest analyses revealed that participants with carotid plaques had lower gwJTV than those without at the specific brain area. ROI results study further demonstrated positive associations between gwJTV and metabolic parameters such as AST, ApoB, and LDL, and negative associations with C-peptide, creatinine, and hsCRP. Our findings suggest that gwJTV could be a valuable imaging biomarker for monitoring brain and vascular health in T2DM patients, particularly those affected by carotid atherosclerosis. Show less

Breast cancer is the second most common cancer worldwide. Chemotherapy often causes dyslipidemia and obesity in breast cancer patients. Monitoring lipid profiles and body mass index (BMI) is crucial to evaluate chemotherapy's metabolic side effects, identify interventions to mitigate them, and understand health risks linked to weight changes during treatment. Shenling Baizhu Powder (SLBZP), a traditional Chinese medicine (TCM), treats spleen-stomach ailments by boosting spleen function, enhancing qi, and reducing dampness. SLBZP has potential benefits in managing chemotherapy-induced dyslipidemia and improving overall metabolic health in cancer patients. This study retrospectively examined the effects of SLBZP on blood lipid levels and BMI in breast cancer patients undergoing adjuvant chemotherapy. This study reviewed the medical records of patients who were diagnosed with breast cancer at the Breast Surgery Department of Zhejiang Provincial Hospital of Traditional Chinese Medicine from January 2022 to December 2023. Based on the inclusion criteria, a total of 180 eligible patients were included and divided into an observational group (which received SLBZP) and a control group (which did not receive SLBZP) during chemotherapy. Patients' clinical data, including age at diagnosis, menopausal status, tumor location, smoking and drinking habits, tumor molecular type, tumor node metastasis (TNM) stage, chemotherapy drugs, targeted therapy, lipid levels, and BMI before and after chemotherapy, were collected. Statistical analyses were conducted using SPSS 25.0. After chemotherapy, the control group showed significant increases in total cholesterol (TC) (P=0.03), triglyceride (TG) (P=0.001), low-density lipoprotein cholesterol (LDL-C) (P=0.02), and apolipoprotein B (ApoB) (P=0.01) levels. In the observational group, the TC, TG, and LDL-C levels remained stable (P>0.05), but the high-density lipoprotein cholesterol (HDL-C) (P=0.001) and apolipoprotein A1 (ApoA1) (P<0.001) levels significantly decreased, and BMI (P=0.02) significantly increased. The subgroup analysis revealed that the taxane followed by anthracycline subgroup showed significant increases in BMI (P=0.007) and significant decreases in the HDL-C (P=0.007) and ApoA1 (P<0.001) levels, while the taxane subgroup showed a significant decrease in the HDL-C level post-chemotherapy (P=0.003). In the control group, the TG (P=0.002) and LDL-C (P=0.02) levels were significantly elevated in the taxane followed by anthracycline subgroup post-chemotherapy. No significant changes were observed in BMI or the other lipid indexes in the remaining chemotherapy drug regime subgroups (P>0.05). Chemotherapy increased the TC, TG, LDL-C, and ApoB levels in breast cancer patients, but SLBZP mitigated dyslipidemia. The patients who received SLBZP also showed increased BMI post-chemotherapy, which was likely due to reduced gastrointestinal side effects. Taxane-based chemotherapy drugs had greater effects on blood lipids and BMI, while anthracycline-based drugs did not significantly affect blood lipids and BMI. Show less

Alzheimer´s disease (AD) is dominated by a complex cellular pathology which involves most brain cell types with glial cells increasingly recognized as playing fundamental roles in neurodegeneration. Astrocytes, which perform essential functions in preserving brain homeostasis, present a reactive phenotype in the AD brains with still unknown consequences. In this study, we generated and characterized human induced pluripotent stem cell (hiPSC)-derived astrocytes from AD patients harboring the The online version contains supplementary material available at 10.1186/s12974-025-03607-z. Show less

Alzheimer's disease (AD) is the most prevalent neurodegenerative dementia, marked by progressive cognitive decline and memory impairment. Despite advances in therapeutic research, single-target-directed treatments often fall short in addressing the complex, multifactorial nature of AD. This arises from various pathological features, including amyloid-β (Aβ) aggregate deposition, metal ion dysregulation, oxidative stress, impaired neurotransmission, neuroinflammation, mitochondrial dysfunction, and neuronal cell death. This Show less

This study aims to explore the association between plasma metabolites and chronic kidney disease progression in individuals with type 2 diabetes. We performed a comprehensive metabolomic analysis in a prospective cohort study of 5144 multi-ancestral individuals with type 2 diabetes in Singapore, using eGFR slope as the primary outcome of kidney function decline. In addition, we performed genome-wide association studies on metabolites to assess how these metabolites could be genetically influenced by metabolite quantitative trait loci and performed colocalisation analysis to identify genes affecting both metabolites and kidney function. Elevated levels of 61 lipids with long unsaturated fatty acid chains such as phosphatidylethanolamines, triacylglycerols, diacylglycerols, ceramides and deoxysphingolipids were prospectively associated with more rapid kidney function decline. In addition, elevated levels of seven amino acids and three lipids in the plasma were associated with a slower decline in eGFR. We also identified 15 metabolite quantitative trait loci associated with these metabolites, within which variants near TM6SF2, APOE and CPS1 could affect both metabolite levels and kidney functions. Our study identified plasma metabolites associated with prospective renal function decline, offering insights into the underlying mechanism by which the metabolite abnormalities due to fatty acid oversupply might reflect impaired β-oxidation and associate with future chronic kidney disease progression in individuals with diabetes. Show less

Patients with inflammatory breast cancer (IBC) have aggressive biology and relatively inferior responses to standard-of-care (SOC) therapies. Understanding the efficacy of SOC therapies in IBC is critical to optimize outcomes. Our objective was to assess the progression-free survival (PFS) of metastatic hormone receptor-positive HER2-negative/low (HR+HER2-) IBC patients treated with CDK4/6 inhibitors (CDKIs) and hormonal therapy (HT). Data from 58 IBC patients with metastatic HR + /HER2- IBC from a single institution were reviewed. The medians (95% confidence intervals) of overall survival (OS), PFS, and time on treatment (ToT) from the time of CDKI initiation were reported via the Kaplan‒Meier method. Differences were tested by the log-rank test. We identified 58 patients (including 16 with de novo stage IV disease). The median OS, PFS, and ToT in the total cohort were 26 (16, 37), 7 (5, 10), and 7 (5, 10) months (mos), respectively. No differences were observed between pre-menopausal patients and postmenopausal patients. The OS, PFS, and ToT rates at the initial diagnosis of Stage III later developing metastatic breast cancer (MBC, N = 42) and de novo IV (N = 16) patients were 19 (15, 34) vs 34 (21, NR), 7 (5, 14) vs 9 (6, NR), and 6 (5, 10) vs 9 (4, NR) mos, respectively (ns). OS, PFS, and ToT in patients receiving CDKI in the first-line vs second-line metastatic setting were 27 (19, 44) vs 17 (12, 39), 7 (5, 15) vs 6 (3, NR), and 7 (5, 15) vs 6 (3, 20) mos, respectively (ns). Among the patients initially diagnosed with stage III disease later progressing to MBC, brain metastases were observed in 12/42 patients. Thirty-eight patients underwent genomic testing either before CDKI treatment (N = 21) or at progression (N = 17). Among the 38 patients who underwent genomic testing, 34 had mutations, most commonly in TP53, PIK3CA, FGFR1, CCND1, and ARID1A. ESR1 mutations were present in 0% of the samples tested prior to CDKI treatment, and 29% of the samples tested at progression. Patients with metastatic HR+HER2- IBC demonstrated a shorter time on treatment suggesting shorter duration of response on CDKI + HT, which is markedly inferior to reported data for non-IBC patients from phase III trials. Show less

Growth factor induced receptor dimerization and activation of downstream pathways can modulate cell fate decisions. Here, we investigate the potential of de novo designed synthetic ligands, termed Novokines, to reprogram cell identity by inducing proximity of novel pairs of receptor subunits. We find that a design, H2F, that brings together HER2 (which has no known natural ligand) and the FGF receptor has potent signaling activity. H2F induces robust signaling and reprograms fibroblasts into myogenic cells. Unlike native FGF ligands, H2F selectively activates the MAPK pathway without engaging PLCγ-mediated Ca²⁺ signaling. FRET assays confirm H2F-mediated HER2-FGFR proximity, and phosphoproteomic analysis reveals activation of MAPK effectors. H2F-induced ERK phosphorylation is abolished in cells expressing a kinase-dead FGFR1 (K514M) mutant, confirming the requirement for FGFR catalytic activity. H2F treatment significantly increases myofiber formation from adult patient-derived primary myoblasts, demonstrating its capacity to promote myogenic regeneration. Our findings demonstrate that synthetic receptor pairings can rewire signaling outputs to drive regeneration, providing a programmable platform for cell fate engineering. Show less

The tumor microenvironment (TME) is a highly dynamic network shaped by immune, vascular, and stromal interactions, further modulated by extracellular factors. The high tumor heterogeneity complicates treatment due to evolving resistance. Biodynamic imaging (BDI), a 3D coherence-gated holography technique, quantifies intracellular motion to assess phenotypic responses to therapy. We applied BDI to prostate cancer (PCa) treated with IL-27-based combinations to evaluate the dynamic responses of immunotherapy. This study is the first to integrate BDI with RNA-seq to correlate physiological changes with gene expression. Using a subcutaneous PCa model, tumors were treated ex vivo with chemotherapy and immunomodulatory agents. BDI enabled capturing motion frequency shifts (0.01-12.5 Hz), while RNA-seq revealed the molecular changes in the tumors. IL-27 showed potential to modulate the immunologically "cold" TME and enhance therapeutic efficacy. This integrative approach offers a novel platform for evaluating combination strategies in PCa and may inform more effective treatment decisions. Show less

The immunoregulatory effects of probiotics have been widely studied, particularly in maintaining immune balance. Conventional in vitro functional screening of probiotics relies on fresh donor-derived primary immune cells, which often exhibit significant inter-individual and temporal variability, limiting reproducibility and interpretation. As an alternative, human-induced pluripotent stem cell (iPSC)-derived dendritic cells were co-cultured with five probiotic strains in the current study to evaluate their immunomodulatory interactions. To assess whether cytokines produced by probiotic-stimulated dendritic cells can influence T cell differentiation, human CD4 Show less