Biology subjects

Sultana, F.

Publications and source records attributed to Sultana, F..

8 recordsLinked to original sources

bioRxiv2026

A patient-derived LMX1B variant causes tissue-specific manifestations of nail-patella syndrome in mice

Nail-patella syndrome (NPS) is a multisystem disorder caused by pathogenic variants in LMX1B and is characterized by dysplasia of the nails and patellae as well as extraskeletal complications such as progressive nephropathy and glaucoma. We generated a CRISPR/Cas9 knock-in mouse carrying the R252Q substitution, corresponding to a human LMX1B variant associated with renal-predominant disease. Phenotypic analysis revealed that homozygous mice were viable, but they displayed marked growth retardation and severe bilateral ocular opacity. Interestingly, while this model exhibited clear skeletal and ocular defects, the renal phenotype was relatively mild, although increased urinary albumin excretion, focal glomerular basement membrane abnormalities, and subtle changes in renal gene expression were detected. Beyond the classical NPS hallmarks, mutant mice also displayed midbrain morphological abnormalities, suggesting broader developmental consequences of this LMX1B variant. This patient-derived variant model not only recapitulates the pleiotropic features of NPS but also demonstrates organ-specific susceptibility to the R252Q substitution, providing a foundation for elucidating the complex molecular mechanisms underlying multisystem disease.

genetics↗

bioRxiv2026

Erythroferrone Modulates Osteoblast-Osteoclast Crosstalk During Bone Remodeling

Erythroferrone (ERFE) secretion inhibits hepcidin expression by sequestering several bone morphogenetic protein (BMP) family members to increase iron availability for erythropoiesis. Recent evidence demonstrates that ERFE is also expressed in osteoblasts and osteoclasts and Erfe-/- mice display low-bone-mass arising from increased bone resorption despite a concomitant increase in bone formation. To mechanistically dissect how bone-derived ERFE exerts an osteoprotective effect, we first created Erfefl/fl mice, which were then crossed with Col2.3-Cre mice to generate osteoblast-selective Erfe mutants (or Erfefl/fl;Col2.3-Cre mice). We now demonstrate that ERFE derived from osteoblasts is not responsible for the decreased BMD noted in Erfe-/- mice, revealing enhanced BMD during anabolic stress in Erfefl/fl;Col2.3-Cre mice. Consistently, in contrast to global ERFE loss, osteoblast-selective ERFE loss does not increase osteoclasts in vivo. Furthermore, our results demonstrate that ERFE loss in osteoblasts induces osteoclast Erfe expression in co-culture experiments in vitro. Finally, the osteoclastogenesis gene program is induced in co-culture with osteoblasts only when ERFE is lost in osteoclasts. Taken together, our finding provide strong evidence of osteoclast-derived ERFE as a central osteoprotective regulator of bone mass, its loss resulting in net bone loss in Erfe-/- mice. BRIEF SUMMARYLoss of erythroferrone derived from osteoclasts enhances osteoclastogenesis resulting in accelerated bone loss. SIGNIFICANCE STATEMENTCanonical erythroferrone (ERFE) function includes hepcidin suppression through bone morphogenic proteins (BMPs) sequestration, establishing the rationale for ERFE-mediated regulation of bone homeostasis. We previously showed that global ERFE loss controls bone mass. Here, we report that osteoclast-derived ERFE is a major regulator of osteoclastogenesis. For this, we crossed Erfefl/fl with Col2.3-Cre mice to generate osteoblast-selective Erfe mutants, demonstrating that osteoblast-derived ERFE does not recapitulate bone loss found in global ERFE knockout mice. In contrast, bone mineral density is enhanced during anabolic stress in Erfefl/fl;Col2.3-Cre mice. Finally, we document that osteoclast ERFE loss enhances osteoclastogenesis in co-culture with osteoblasts. Together, the data provide compelling evidence that osteoclast-derived ERFE modulates communication between osteoblasts and osteoclasts.

cell biology↗

bioRxiv2025

Distribution and environmental drivers of multi-functional community traits in the Sundarbans mangrove forest

Mangrove forests are vital blue-carbon ecosystems, playing a crucial role in global carbon storage, climate regulation, and biodiversity conservation. However, escalating environmental threats, particularly salinity intrusion, necessitate a deeper understanding of their functional dynamics to inform effective conservation and restoration strategies. This study examines the distribution of multi-functional community traits (MFCT) and their environmental drivers across mangrove functional groups (pioneer, mid-successional, climax) along salinity gradients in the Sundarbans, the worlds largest mangrove forest. Using data from 62 plots, nine functional traits from 17 mangrove species were analysed to evaluate MFCT diversity and its environmental determinants. Results revealed distinct variations in MFCT diversity, with mid-successional species exhibiting the highest trait diversity (64.0 {+/-} 1.58), followed by climax (51.3 {+/-} 2.09) and pioneer groups (50.2 {+/-} 2.26). Climax species demonstrated resilience to salinity increases (R{superscript 2} = 0.29, p < 0.001), whereas mid-successional and pioneer groups were negatively affected (R{superscript 2} = 0.22, p < 0.001 and R{superscript 2} = 0.17, p < 0.001). Annual precipitation exerted contrasting effects, reducing diversity in climax species (R{superscript 2} = 0.25, p < 0.001) but enhancing it in mid-successional (R{superscript 2} = 0.22, p < 0.001) and pioneer groups (R{superscript 2} = 0.06, p = 0.05). Notably, MFCT values remained stable across salinity gradients, underscoring the ecosystems functional resilience. These findings highlight mid-successional species as keystones in sustaining mangrove multifunctionality and resilience under environmental stressors. Prioritizing these species in conservation and restoration efforts can mitigate the impacts of salinity intrusion and climate variability. By integrating the MFCT framework, resource managers can develop targeted restoration strategies to enhance ecosystem functionality and long-term stability. These insights provide a critical foundation for policymakers to align global mangrove conservation with adaptive management strategies, reinforcing coastal resilience, biodiversity conservation, and climate change mitigation.

ecology↗

bioRxiv2024

Gender-specific Single Transcript Level Atlas of Vasopressin and its Receptor (AVPR1a) in the Mouse Brain

Vasopressin (AVP), a nonapeptide synthesized predominantly by magnocellular hypothalamic neurons, is conveyed to the posterior pituitary via the pituitary stalk, where AVP is secreted into the circulation. Known to regulate blood pressure and water homeostasis, it also modulates diverse social behaviors, such as pair-bonding, social recognition and cognition in mammals including humans. Importantly, AVP modulates social behaviors in a sex-specific manner, perhaps, due to sex differences in the distribution in the brain of AVP and its main receptor AVPR1a. There is a corpus of integrative studies for the expression of AVP and AVPR1a in various brain regions, and their functions in modulating central and peripheral actions. In order to purposefully address sexually dimorphic and novel roles of AVP on central and peripheral functions through its AVPR1a, we utilized RNAscope to map Avp and Avpr1a single transcript expression in the mouse brain. As the most comprehensive atlas of AVP and AVPR1a in the mouse brain, this compendium highlights the importance of newly identified AVP/AVPR1a neuronal nodes that may stimulate further functional studies.

neuroscience↗

bioRxiv2024

Faster amylin aggregation on fibrillar collagen hastens diabetic progression through β cell death and loss of function

Amyloid deposition of the neuroendocrine peptide amylin in islet tissues is a hallmark of type 2 diabetes (T2DM), leading to {beta}-cell toxicity through nutrient deprivation, membrane rupture and apoptosis. Though accumulation of toxic amylin aggregates in islet matrices is well documented, the role of the islet extracellular matrix in mediating amylin aggregation and its pathological consequences remains elusive. Here, we address this question by probing amylin interaction with collagen I (Col I)--whose expression in the islet tissue increases during diabetes progression. By combining multiple biophysical techniques, we show that hydrophobic, hydrophilic & cation-{pi} interactions regulate amylin binding to Col I, with fibrillar collagen driving faster amylin aggregation. Amylin-entangled Col I matrices containing high amounts of amylin induce death and loss of function of INS1E {beta}-cells. Together, our results illustrate how amylin incorporation in islet matrices through amylin-Col interactions drives T2DM progression by impacting {beta}-cell viability and insulin secretion.

biophysics↗

bioRxiv2024

Gene-Dose-Dependent Reduction Fshr Expression Improves Spatial Memory Deficits in Alzheimer's Mice

Alzheimers disease (AD) is a major progressive neurodegenerative disorder of the aging population. High post-menopausal levels of the pituitary gonadotropin follicle-stimulating hormone (FSH) are strongly associated with the onset of AD, and we have shown recently that FSH directly activates the hippocampal Fshr to drive AD-like pathology and memory loss in mice. To establish a role for FSH in memory loss, we used female 3xTg;Fshr+/+, 3xTg;Fshr+/- and 3xTg;Fshr-/- mice that were either left unoperated or underwent sham surgery or ovariectomy at 8 weeks of age. Unoperated and sham-operated 3xTg;Fshr-/-mice were implanted with 17{beta}-estradiol pellets to normalize estradiol levels. Morris Water Maze and Novel Object Recognition behavioral tests were performed to study deficits in spatial and recognition memory, respectively, and to examine the effects of Fshr depletion. 3xTg;Fshr+/+mice displayed impaired spatial memory at 5 months of age; both the acquisition and retrieval of the memory were ameliorated in 3xTg;Fshr-/- mice and, to a lesser extent, in 3xTg;Fshr+/- mice-- thus documenting a clear gene-dose-dependent prevention of hippocampal-dependent spatial memory impairment. At 5 and 10 months, sham-operated 3xTg;Fshr-/- mice showed better memory performance during the acquisition and/or retrieval phases, suggesting that Fshr deletion prevented the progression of spatial memory deficits with age. However, this prevention was not seen when mice were ovariectomized, except in the 10-month-old 3xTg;Fshr-/-mice. In the Novel Object Recognition test performed at 10 months, all groups of mice, except ovariectomized 3xTg;Fshr-/- mice showed a loss of recognition memory. Consistent with the neurobehavioral data, there was a gene-dose-dependent reduction mainly in the amyloid {beta}40 isoform in whole brain extracts. Finally, serum FSH levels <8 ng/mL in 16-month-old APP/PS1 mice were associated with better retrieval of spatial memory. Collectively, the data provide compelling genetic evidence for a protective effect of inhibiting FSH signaling on the progression of spatial and recognition memory deficits in mice, and lay a firm foundation for the use of an FSH-blocking agent for the early prevention of cognitive decline in postmenopausal women.

neuroscience↗

bioRxiv2023

Development and Biophysical Characterization of a Humanized FSH-Blocking Monoclonal Antibody Therapeutic Formulated at an Ultra-High Concentration

Highly concentrated antibody formulations are oftentimes required for subcutaneous, self-administered biologics. Here, we report the creation of a unique formulation for our first-in- class FSH-blocking humanized antibody, MS-Hu6, which we propose to move to the clinic for osteoporosis, obesity, and Alzheimers disease. The studies were carried out using our Good Laboratory Practice (GLP) platform, compliant with the Code of Federal Regulations (Title 21, Part 58). We first used protein thermal shift, size exclusion chromatography, and dynamic light scattering to examine MS-Hu6 concentrations between 1 and 100 mg/mL. We found that thermal, monomeric, and colloidal stability of formulated MS-Hu6 was maintained at a concentration of 100 mg/mL. The addition of the antioxidant L-methionine and chelating agent disodium EDTA improved the formulations long-term colloidal and thermal stability. Thermal stability was further confirmed by Nano differential scanning calorimetry (DSC). Physiochemical properties of formulated MS-Hu6, including viscosity, turbidity, and clarity, conformed with acceptable industry standards. That the structural integrity of MS-Hu6 in formulation was maintained was proven through Circular Dichroism (CD) and Fourier Transform Infrared (FTIR) spectroscopy. Three rapid freeze-thaw cycles at -80{degrees}C/25{degrees}C or -80{degrees}C/37{degrees}C further revealed excellent thermal and colloidal stability. Furthermore, formulated MS-Hu6, particularly its Fab domain, displayed thermal and monomeric storage stability for more than 90 days at 4{degrees}C and 25{degrees}C. Finally, the unfolding temperature (Tm) for formulated MS-Hu6 increased by >4.80{degrees}C upon binding to recombinant FSH, indicating highly specific ligand binding. Overall, we document the feasibility of developing a stable, manufacturable and transportable MS-Hu6 formulation at a ultra-high concentration at industry standards. The study should become a resource for developing biologic formulations in academic medical centers.

bioengineering↗

bioRxiv2022

A Single Multipurpose FSH-Blocking Therapeutic for Osteoporosis and Obesity

Pharmacological and genetic studies over the past decade have established FSH as an actionable target for diseases affecting millions, notably osteoporosis, obesity and Alzheimers disease (AD). Blocking FSH action prevents bone loss, fat gain and AD-like features in mice. We recently developed a first-in-class, humanized, epitope-specific FSH blocking antibody, MS-Hu6, with a KD of 7.52 nM. Using a GLP-compliant platform, we now report the efficacy of MS-Hu6 in preventing obesity and osteoporosis in mice, and parameters of acute safety in monkeys. Biodistribution studies using 89Zr-labelled, biotinylated or unconjugated MS-Hu6 in mice and monkeys showed localization to bone, bone marrow and fat depots. MS-Hu6 displayed a {beta} phase t[1/2] of 13 days (316 hours) in humanized Tg32 mice, and bound endogenous FSH. We tested 215 variations of excipients using the protein thermal shift assay to generate a final formulation that rendered MS-Hu6 stable in solution upon freeze-thaw and at different temperatures, with minimal aggregation, and without self-, cross-, or hydrophobic interactions or appreciable binding to relevant human antigens. MS-Hu6 showed the same level of "humanness" as human IgG1 in silico, and was non-immunogenic in ELISPOT assays for IL-2 and IFN{gamma} in human peripheral blood mononuclear cell cultures. We conclude that MS-Hu6 is efficacious, durable and manufacturable, and is therefore poised for future human testing as a multipurpose therapeutic.

pharmacology and toxicology↗