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Biology subjects

Suresh, S.

Publications and source records attributed to Suresh, S..

At least 37 records · Page 2Linked to original sources

Does local adaptation influence thermal responses in red coral populations across depth gradients? Transcriptomic insights for effective conservation.

Marine heatwaves (MHWs) pose significant threats to marine biodiversity, including Mediterranean octocorals. Using a common garden experiment, we test whether differential transcriptomic responses to thermal stress between shallow and mesophotic populations of Corallium rubrum are shaped by their adaptation to the local environment, i.e. local adaptation. Six individuals from one shallow (15m) and one mesophotic (48m) population were exposed to control (18{degrees}C) and thermal stress (25{degrees}C) treatments, with samples collected at day 0 (T0), day 5 (T5), and day 10 (T10) for RNA sequencing (N=36). We revealed 1,957 differentially expressed genes (DEGs) in response to heat stress. Mild transcriptomic responses were observed in the shallow population (441 DEGs) characterized by heat shock proteins (HSPs) and developmental regulation. Conversely, a stronger and extensive response was observed in the mesophotic population with more than twice as many DEGs (1,081), predominantly associated with enhanced stress and wound healing mechanisms. Temporal transcriptional shifts were larger between T5 to T10 in the mesophotic population (1,497 vs 241), while more stable in the shallow (265 vs 271). Additionally, 172 DEGs, including HSPs, apoptosis and collagen, were found in the shallow population under control conditions, indicating transcriptional frontloading. The contrasting thermal stress responses between populations suggest distinct adaptative strategies potentially driven by local adaptation. These insights challenge the deep refugia hypothesis that considered mesophotic populations as potential sources for recolonization and active restoration of shallow populations threatened by MHWs. Our results support the need to integrate population-specific adaptive responses into conservation and restoration strategies for C. rubrum.

molecular biology↗

Single-AAV CRISPR editing of skeletal muscle in non-human primates with NanoCas, an ultracompact nuclease

CRISPR gene editing is a transformative technology for addressing genetic diseases, but delivery constraints have largely limited its therapeutic applications to liver-targeted and ex vivo therapies. Here, we present the discovery and engineering of NanoCas, an ultracompact CRISPR nuclease capable of extending CRISPRs reach in vivo beyond liver targets. We experimentally screened 176 ultracompact CRISPR systems found in metagenomic data and applied protein engineering approaches to enhance the editing efficiency of NanoCas. The optimized NanoCas exhibits potent editing capabilities across various cell systems and tissues in vivo when administered via adeno-associated viral (AAV) vectors. This is accomplished despite NanoCas being approximately one-third the size of conventional CRISPR nucleases. In proof-of-concept experiments, we observed robust editing with our optimized NanoCas in mouse models targeting Pcsk9, a gene involved in cholesterol regulation, and targeting exon splice sites in dystrophin to address Duchenne muscular dystrophy (DMD) mutations. We further tested the efficacy of our NanoCas system in vivo in non-human primates (NHPs) resulting in editing levels above 30% in muscle tissues. The compact size of NanoCas, in combination with robust nuclease editing, opens the door for single-AAV editing of non-liver tissues in vivo, including the use of newer editing modalities such as reverse transcriptase (RT) editing, base editing, and epigenetic editing.

bioengineering↗

Fitting multiple bacterial growth data using continued fraction of straight lines.

The growth of a population is the net result of growth and decline in the number of individuals over time. A population grows when the increase in number of individuals is more than the decrease and declines in the opposite scenario. In other words, the growth rate of a population is influenced by two opposing factors, a growth promoting factor and a growth restricting factor. In this work, we estimate growth rates by applying a biological growth model that is based on the continued fraction of straight lines with two parameters a and m. The parameters a and m represent nonlinear i.e. growth restricting and linear i.e. growth promoting parts of the model, respectively. To fit this model, we use a publicly available dataset that exhibits the growth of three different strains of bacteria depending on the concentration gradient of the antibiotic Tetracycline. We also propose a method to automatically estimate growth rates for large-scale applications. Finally, a growth coordinate system with a and m as the axes is used to interpret the estimations. ImportanceIn this work, multiple bacterial growth data has been fitted with a model based on continued fraction of linear growth. The importance of this work lies in the fitting of both growth and death phase with a single model. Rather than modeling growth with differential equations, this model uses algebraic expressions. Therefore, the growth rates are obtained directly from these expressions after fitting. Several of these models can be superposed, and more flexible fits can be obtained based on requirements. There are two parameters that play key roles in fitting. Their values can be expressed on planar plots which are useful to compare multiple growth data. Thus, this methodology provides simpler, generic, flexible and more interpretable growth models.

microbiology↗

Eusociality evolved at a much higher rate in haplodiploid insects

As a corollary to inclusive fitness theory, W.D. Hamiltons haplodiploid hypothesis proposed that eusociality evolves more readily in haplodiploids because of inflated genetic relatedness between sisters1. For the past sixty years, theoreticians have developed models clarifying how haplodiploidy might favor the evolution of eusociality2-5. Despite this sustained theoretical interest, the predicted relationship between haplodiploidy and eusociality has only very recently been empirically tested6,7. Here, we use two large species-level insect phylogenies with comprehensive sociality and ploidy trait data to test if eusociality evolves more readily in haplodiploids. We find that estimated transition rates to eusociality are higher in haplodiploids, but that this pattern is driven by a much higher transition rate within a single haplodiploid lineage, the aculeate Hymenoptera. Thus, the apparent links between haplodiploidy and eusociality reflect clade-specific dynamics rather than a general effect of haplodiploidy.

evolutionary biology↗

Epithelial to Mesenchymal Transition in the Endometrium Mediated by HOXA10 drives Embryo Implantation

In mammalian reproduction, a significant proportion of embryos fail to implant despite a receptive uterus, suggesting that defects in epithelial remodelling at the embryo-uterine interface contribute to implantation failure. The molecular programs enabling such remodelling remain incompletely understood. Here, we identify a conserved transcriptional circuit involving HOXA10 and TWIST2 that regulates epithelial plasticity in the endometrium via partial epithelial-to-mesenchymal transition (pEMT). HOXA10, a transcription factor essential for uterine receptivity, is specifically downregulated in the luminal epithelium at implantation in mice, hamsters, and monkeys. Integrated CUT&RUN and transcriptomic profiling in human endometrial epithelial cells reveal that HOXA10 directly activates epithelial gene networks and represses mesenchymal programs. HOXA10 loss, both in vitro and in vivo, induces a pEMT state with increased cell motility. Mechanistically, HOXA10 represses TWIST2, a core EMT regulator; its derepression promotes mesenchymal gene expression and epithelial cell displacement. TWIST2 knockdown restores epithelial identity and impairs implantation. These findings establish a mutually antagonistic HOXA10-TWIST2 circuit as a key regulator of pEMT and epithelial remodelling during implantation. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=144 SRC="FIGDIR/small/631632v2_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@1ea7b16org.highwire.dtl.DTLVardef@136f3c5org.highwire.dtl.DTLVardef@be47a8org.highwire.dtl.DTLVardef@5283b2_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

M102, a combined NRF2 and HSF-1 activator for neuroprotection in amyotrophic lateral sclerosis.

M102 is a central nervous system (CNS) penetrant small molecule electrophile which activates in vivo the NFE2-related factor 2 antioxidant response element (NRF2-ARE) pathway, as well as transcription of heat-shock element (HSE) associated genes. In the TDP-43Q331K transgenic mouse model of ALS dosed subcutaneously at 5mg/kg OD or 2.5mg/kg BD with M102, significant improvements in compound muscle action potential (CMAP) amplitude of hind limb muscles and gait parameters were observed at 6 months of age, with associated target engagement. An oral dose response study of M102 in SOD1G93A transgenic mice showed a dose-dependent improvement in the CMAP of hindlimb muscles which correlated with preservation of lumbar spinal motor neurons at the same time point. These data enabled prediction of human efficacious exposures and doses, which were well within the safety margin predicted from Good Laboratory Practice (GLP) toxicology studies. A parallel program of work in vitro showed that M102 rescued motor neuron survival in co-culture with patient-derived astrocytes from sporadic, C9orf72 and SOD1 cases. Markers of oxidative stress, as well as indices of TDP-43 proteinopathy were also reduced by exposure to M102 in these in vitro models. This comprehensive package of preclinical efficacy data across two mouse models as well as patient-derived astrocyte toxicity assays, provides a strong rationale for clinical evaluation of M102 in ALS patients. Combined with the development of target engagement biomarkers and the completed preclinical toxicology package, a clear translational pathway to testing in ALS patients has been developed. One Sentence SummaryM102, a dual NRF2/HSF1 activator, slows disease progression in 2 mouse models and exerts neuroprotection in human cellular models of ALS.

neuroscience↗

Coordinated translational control of multiple immune checkpoints by the integrated stress response pathway in lung cancer

The integrated stress response (ISR) is an adaptive pathway hijacked by cancer cells to survive cellular stresses in the tumor microenvironment. ISR activation potently induces Programmed Death Ligand 1 (PD-L1), leading to suppression of anti-tumor immunity. Here we sought to uncover additional immune checkpoint proteins regulated by the ISR to elucidate mechanisms of tumor immune escape. We show that CD155 and PD-L1 are coordinately induced by the ISR, enhancing translation of both immune checkpoint proteins through bypass of inhibitory upstream open reading frames (uORFs) in their 5' UTRs. Analysis of primary human lung tumors identifies a significant correlation between PD-L1 and CD155 expression. ISR activation accelerates tumorigenesis and inhibits T cell function, effects that can be overcome by combining PD-1 blockade with the ISR inhibitor ISRIB. These studies uncover a novel mechanism by which two immune checkpoint proteins are coordinately regulated and suggest a new therapeutic strategy for lung cancer patients. Statement of SignificanceThis study uncovers a novel mechanism for the coordinated translational regulation of the PD- L1/PD1 and CD155/TIGIT immune checkpoint pathways and highlights the ISR as a therapeutic vulnerability for lung cancer. Inhibition of the ISR pathway bolsters PD-1 blockade, potentially unveiling a new therapeutic strategy for lung cancer patients.

cancer biology↗

Unconventional binding of Calmodulin to CHK2 kinase inhibits catalytic activity

Calmodulin (CaM) serves an essential role in eukaryotic cells as a Ca2+ sensor. Ca2+ binding leads to conformation changes in CaM that enable engagement of a repertoire of enzymes and the regulation of their catalytic activities. Classically, Ca2+-CaM binds to an inhibitory pseudosubstrate sequence C-terminal to the kinase domain in members of the Ca2+-CaM dependent protein kinase (CAMK) family, and relieves inhibition to promote catalytic activity. Here, we report an unexpected mechanism by which CaM can bind CHK2 kinase to inhibit its kinase activity. Using biochemical, biophysical, structural mass spectrometry, and cellular approaches, we identify a direct interaction of Ca2+-CaM with the CHK2 kinase domain that suppresses CHK2 catalytic activity in vitro and is crucial for cell proliferation in human cells following DNA damage. Our findings add direct suppression of kinase activity to the repertoire of CaMs functions, complementing the paradigmatic mechanism of promoting kinase activity through autoinhibitory domain sequestration.

biochemistry↗

Rapamycin increases murine lifespan but does not reduce mineral volume in the Matrix GLA Protein (MGP) knockout mouse model of medial arterial calcification.

Peripheral artery disease (PAD) is the narrowing of the arteries that carry blood to the lower extremities. PAD has been traditionally associated with atherosclerosis. However, recent studies have found that thrombotic events triggered by medial arterial calcification (MAC) is the primary cause of chronic limb ischemia below the knee. MAC is localized around the elastic fibers surrounding smooth muscle cells (SMCs) in arteries. Matrix GLA protein (MGP) binds circulating calcium and prevents hydroxyapatite mineral deposition, while also modulating proosteogenic signaling by attenuating BMP-2-mediated activation of Runx2 gene expression. Mgp-/- mice develop severe MAC and die around 8 weeks after birth due to aortic rupture or heart failure. We previously discovered a rare genetic disease Arterial Calcification due to Deficiency of CD73 (ACDC), in which patients present with extensive MAC in their lower extremity arteries. Using a patient-specific induced pluripotent stem cell model, we found that rapamycin inhibited calcification. Here we investigated whether rapamycin could reduce MAC in vivo using the Mgp-/- murine model. Mgp+/+ and Mgp-/- mice received 5mg/kg rapamycin or vehicle. Calcification content was assessed via microCT, and vascular morphology and extracellular matrix content were assessed histologically. Immunostaining and western blot analysis were used to examine SMC phenotype and extracellular matrix content. Rapamycin prolonged Mgp-/- mice lifespan, decreased mineral density in the arteries, maintained SMC contractile phenotype, and improved vessel structure, however, calcification volume was unchanged. Mgp-/- mice with SMC-specific deletion of Raptor or Rictor did not recapitulate treatment with rapamycin. These findings suggest rapamycin promotes beneficial vascular remodeling in vessels with MAC. NEWS AND NOTEWORTHYPeripheral artery disease (PAD) is associated with medial arterial calcification (MAC), which involves calcification of arterial elastic fibers and smooth muscle cells (SMCs). Matrix GLA protein (MGP) inhibits vascular calcification, and Mgp-/- mice develop severe MAC. Using this model, we found rapamycin prolonged lifespan, reduced arterial mineral density, maintained SMC contractile phenotype, and improved vessel structure, though calcification volume remained unchanged. Findings highlight rapamycins potential for vascular remodeling in MAC.

physiology↗

Molecular basis for plasma membrane recruitment of PI4KA by EFR3

The lipid kinase phosphatidylinositol 4 kinase III alpha (PI4KIII/PI4KA) is a master regulator of the lipid composition and asymmetry of the plasma membrane. PI4KA exists primarily in a heterotrimeric complex with its regulatory proteins TTC7 and FAM126. Fundamental to PI4KA activity is its targeted recruitment to the plasma membrane by the lipidated proteins EFR3A and EFR3B. Here, we report a cryo-EM structure of the C-terminus of EFR3A bound to the PI4KA-TTC7B-FAM126A complex, with extensive validation using both hydrogen deuterium exchange mass spectrometry (HDX-MS), and mutational analysis. The EFR3A C-terminus undergoes a disorder-order transition upon binding to the PI4KA complex, with an unexpected direct interaction with both TTC7B and FAM126A. Complex disrupting mutations in TTC7B, FAM126A, and EFR3 decrease PI4KA recruitment to the plasma membrane. Multiple post-translational modifications and disease linked mutations map to this site, providing insight into how PI4KA membrane recruitment can be regulated and disrupted in human disease. One sentence summaryThe cryo-EM structure of the C-terminus of EFR3A bound to the PI4KA complex reveals the molecular mechanism underlying PI4KA membrane localisation, and provides novel insight into PI4KA regulation and its involvement in human disease.

biochemistry↗

Structure of Calcineurin bound to PI4KA reveals dual interface in both PI4KA and FAM126A

Phosphatidylinositol 4-kinase alpha (PI4KA) maintains the PI4P and phosphatidylserine pools of the plasma membrane. A key regulator of PI4KA is its association into a complex with TTC7 and FAM126 proteins. This complex can be regulated by the CNA{beta}1 isoform of the phosphatase Calcineurin. We previously identified that CNA{beta}1 directly binds to FAM126A. Here, we report a cryo-EM structure of a truncated PI4KA complex bound to Calcineurin, revealing a direct Calcineurin interaction with PI4KA. Additional HDX-MS and computational analysis show that Calcineurin forms a complex with an evolutionarily conserved IKISVT sequence in PI4KAs horn domain. We also characterised conserved LTLT and PSISIT Calcineurin binding sequences in the C-terminus of FAM126A. These sites are in close proximity to phosphorylation sites in the PI4KA complex, suggesting key roles of Calcineurin-regulated phosphosites in PI4KA regulation. This work reveals novel insight into how Calcineurin can regulate PI4KA activity.

biochemistry↗

Emergent Collective Behavior Evolves More Rapidly Than Individual Behavior Among Ant Species

Emergence is a fundamental concept in biology and other disciplines, but whether emergent phenotypes evolve similarly to non-emergent phenotypes is unclear. The hypothesized process of emergent evolution posits that evolutionary change in collective behavior is irreducible to evolutionary change in the intrinsic behaviors of isolated individuals. As a result, collective behavior might evolve more rapidly and diversify more between populations compared to individual behavior. To test if collective behavior evolves emergently, we conducted a large comparative study using 22 ant species and gathered over 1,500 behavioral rhythm time series from hundreds of colonies and isolated individuals, totaling over 1.5 years of behavioral data. We show that analogous traits measured at individual and collective levels exhibit distinct evolutionary patterns. The estimated rates of phenotypic evolution for the rhythmicity of activity in ant colonies were faster than the evolutionary rates of the same behavior measured in isolated individual ants, and total variation across species in collective behavior was higher than variation in individual behavior. We hypothesize that more rapid evolution and higher variation is a general feature of emergent phenotypes relative to lower-level phenotypes across complex biological systems.

evolutionary biology↗

Anti-dengue viral activity of Glycyrrhiza glabra roots in Vero cells

Dengue is a global public health problem but no antiviral agent exists for dengue. Plants have been the source of many pharmaceutical agents. Therefore, we explored the antiviral potential of the aqueous extracts of Glycyrrhiza glabra (GG) roots on dengue viruses. Cell cytotoxicity assay with 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2H-tetrazolium bromide solution was used for estimating the maximum nontoxic dose (MNTD) and 50% cytotoxic concentration (CC50). Plaque reduction antiviral assay on Vero cells infected with dengue virus serotypes 1,2,3 and 4 were treated with dilutions of the MNTD of GG extract to calculate the half maximal inhibitory concentration (IC50). Selectivity index (SI) was calculated as CC50/IC50 ratio. Following bioactivity guided fractionation, MNTD, CC50, IC50 and SI values for fractions E and F were similarly obtained. Inhibition of NS1 antigen levels produced by dengue serotype-1 infected monocytes was studied in the presence and absence of GG extract after 48 hours. GG MNTD and CC50 were 166.7 {micro}g/mL and 651.9 {micro}g/mL. GG extract showed 98-100% inhibition of all four dengue serotypes at the MNTD and the IC50 values of the four serotypes ranged from 10-50 {micro}g/mL indicating moderate pan-serotype inhibitory activity. Cytotoxicity of GG against Vero cells was low (CC50 >500 {micro}g/mL). SI of GG extract for all four dengue serotypes were >10, indicating it had good potential as an antiviral agent. Fraction E and F had low to moderate inhibitory activity for all four serotypes and showed good potential as an antiviral agent only for dengue 4. This is the first report of significant anti-dengue viral activity of GG extract on all four dengue serotypes. Author SummaryDengue is a global public health problem but no antiviral agent exists for dengue. This study explores the antiviral potential of the aqueous extract of Glycyrrhiza glabra (GG) roots on dengue viruses. Virus inhibition in Vero cell lines infected with dengue virus serotypes 1-4 and treated with GG extract was demonstrated. GG extract was 98-100% inhibitory to all four serotypes and had moderate pan-serotype inhibitory activity. It had good potential as an antiviral agent with low cytotoxicity. This is the first report of significant anti-dengue viral activity of GG extract on all four dengue serotypes.

microbiology↗

The LH receptor regulates hippocampal spatial memory and restores dendritic spine density in ovariectomized APP/PS1 AD mice

Activation of the luteinizing hormone receptor (LHCGR) rescues spatial memory function and spine density losses associated with gonadectomy and high circulating gonadotropin levels in females. However, whether this extends to the AD brain or the mechanisms that underlie these benefits remain unknown. To address this question, we delivered the LHCGR agonist human chorionic gonadotropin (hCG) intracerebroventricularly (ICV), under reproductively intact and ovariectomized conditions to mimic the post-menopausal state in the APP/PS1mouse brain. Cognitive function was tested using the Morris water maze task, and hippocampal dendritic spine density, A{beta} pathology, and signaling changes associated with these endpoints were determined to address mechanisms. Here we show that central LHCGR activation restored function in ovariectomized APP/PS1 female mice to wild-type levels without altering A{beta} pathology. LHCGR activation increased hippocampal dendritic spine density regardless of reproductive status, and this was mediated by BDNF-dependent and independent signaling. We also show that ovariectomy in the APP/PS1 brain elicits an increase in peripherally derived pro-inflammatory genes which are inhibited by LHCGR activation. This may mediate reproductive status specific effects of LHCGR agonism on cognitive function and BDNF expression. Together, this work highlights the relevance of the LHCGR on cognition and its therapeutic potential in the "menopausal" AD brain.

neuroscience↗

Cross-talk between tissues is critical for intergenerational acclimation to environmental change

An organisms reaction to environmental changes is mediated by coordinated responses of multiple tissues. Additionally, parental priming may increase offsprings acclimation potential to changing environmental conditions. As the effects of human-induced climate change, such as ocean acidification (OA), continue to intensify it is critical to assess the acclimation potential of species at the whole organismal scale. For this we need to understand the cross-talk between tissues in regulating and responding to pH changes. Here by using a multi-tissue approach we determine the influence of 1) variation in parental behavioural tolerance and 2) parental environment, on molecular responses of their offspring in a coral reef fish. The gills and liver showed the highest transcriptional response to OA conditions in juvenile fish regardless of the parental environment, while the brain and liver showed the greatest signal of intergenerational acclimation. Key functional pathways that were altered in the brain upon within-generational CO2 exposure were restored to control levels when parents were exposed to OA conditions. Furthermore, the expression of a new complement of genes involved in key functions was altered in the offspring only when parents were previously exposed to OA conditions. Therefore, previous parental conditioning to OA can reprogram tissue transcriptomic profiles of the offspring enabling them to better cope in an environment with elevated CO2 levels. Overall, our results reveal tissue-specific transcriptional changes underlying intergenerational plastic responses to elevated CO2 exposure and highlight the integration of these changes in promoting organismal acclimation to OA.

ecology↗

Epigenetic regulation of p63 blocks squamous-to-neuroendocrine transdifferentiation in esophageal development and malignancy

While cell fate determination and maintenance are important in establishing and preserving tissue identity and function during development, aberrant cell fate transition leads to cancer cell heterogeneity and resistance to treatment. Here, we report an unexpected role for the transcription factor p63 (Trp63/TP63) in the fate choice of squamous versus neuroendocrine lineage in esophageal development and malignancy. Deletion of p63 results in extensive neuroendocrine differentiation in the developing mouse esophagus and esophageal progenitors derived from human embryonic stem cells. In human esophageal neuroendocrine carcinoma (eNEC) cells, p63 is transcriptionally silenced by EZH2-mediated H3K27 trimethylation (H3K27me3). Upregulation of the major p63 isoform {Delta}Np63, through either ectopic expression or EZH2 inhibition, promotes squamous transdifferentiation of eNEC cells. Together these findings uncover p63 as a rheostat in coordinating the transition between squamous and neuroendocrine cell fates during esophageal development and tumor progression.

cell biology↗

Zoledronic acid improves bone quality and muscle function in a high bone turnover state

SUMMARYZoledronic acid (ZA) prevents muscle weakness in mice with bone metastases; however, its role in muscle weakness in non-tumor-associated metabolic bone diseases and as an effective treatment modality for the prevention of muscle weakness associated with bone disorders, is unknown. We demonstrate the role of ZA-treatment on bone and muscle using a mouse model of accelerated bone remodeling, which represents the clinical manifestation of non-tumor associated metabolic bone disease. ZA increased bone mass and strength and rescued osteocyte lacunocanalicular organization. Short-term ZA treatment increased muscle mass, whereas prolonged, preventive treatment improved muscle mass and function. In these mice, muscle fiber-type shifted from oxidative to glycolytic and ZA restored normal muscle fiber distribution. By blocking TGF{beta} release from bone, ZA improved muscle function, promoted myoblast differentiation and stabilized Ryanodine Receptor-1 calcium channel. These data demonstrate the beneficial effects of ZA in maintaining bone health and preserving muscle mass and function in a model of metabolic bone disease. Context and significanceTGF{beta} is a bone regulatory molecule which is stored in bone matrix, released during bone remodeling, and must be maintained at an optimal level for the good health of the bone. Excess TGF{beta} causes several bone disorders and skeletal muscle weakness. Reducing excess TGF{beta} release from bone using zoledronic acid in mice not only improved bone volume and strength but also increased muscle mass, and muscle function. Progressive muscle weakness coexists with bone disorders, decreasing quality of life and increasing morbidity and mortality. Currently, there is a critical need for treatments improving muscle mass and function in patients with debilitating weakness. Zoledronic acids benefit extends beyond bone and could also be useful in treating muscle weakness associated with bone disorders.

cancer biology↗