Baseline cell proliferation rates and response to UV differ in Lymphoblastoid Cell Lines derived from healthy individuals of extreme constitution types

Differences in human phenotypes and susceptibility to complex diseases are an outcome of genetic and environmental interactions. This is evident in diseases that progress through a common set of intermediate patho-endophenotypes. Precision medicine aims to delineate the molecular players for individualized and early interventions. Functional studies in Lymphoblastoid Cell Line (LCL) model of phenotypically well characterized healthy individuals can help deconvolute and validate these molecular mechanisms. We developed LCLs from eight healthy individuals belonging to three extreme constitution types, deep phenotyped on the basis of Ayurveda. LCLs were characterized by karyotyping and immunophenotyping. Growth characteristics and response to UV was studied in these LCLs. We observed significant differences in cell proliferation rates between the contrasting groups such that one type (Kapha) proliferates significantly slower than the other two (Vata, Pitta). In response to UV, one fast growing group (Vata) shows higher cell death but recovers its numbers due to inherent higher rates of proliferation. The baseline differences in cell proliferation are key to understanding the survival of cells in UV stress. Variability in baseline cellular phenotypes not only explains the cellular basis of different constitutions types but can also help set priors during designing an individualized therapy with DNA damaging agents. This is the first study of its kind that shows variability of intermediate patho-phenotypes amongst healthy individuals that have implications in precision medicine.

Analyzing the correlation between stochastic fracture networks geometrical properties and stress variability: a rock and fracture parameters study

In this study, the correlation between geometric properties of the fracture network and stress variability in a fractured rock was studied. Initially, discrete fracture networks were generated using a stochastic approach, then, considering the tensorial nature of stress, the stress field under various tectonic stress conditions was determined using finite-difference method. Ultimately, stress data were analyzed using tensor-based mathematical relations. Subsequently, the effects of four parameters including rock tensile strength, rock cohesion, fracture normal stiffness and fracture dilation angle on the stress perturbation distribution were evaluated. The obtained results indicated that stress perturbation and dispersion are directly related to fracture density, which is expressed as the number of fractures per unit area utilizing the window sampling approach. It was also demonstrated that they are inversely related to power-law length exponent which represents the length of fracture. It was observed that stress distribution, among the evaluated parameters, is more sensitive to the fracture normal stiffness and the effects of rock parameters on stress distribution are negligible. It was concluded that the highest stress distribution is created when the fracture network is dense with fractures having high length and low normal stiffness value.

Increased Burden of Rare Sequence Variants in GnRH-Associated Genes in Women With Hypothalamic Amenorrhea

Context Functional hypothalamic amenorrhea (HA) is a common, acquired form of hypogonadotropic hypogonadism that occurs in the setting of energy deficits and/or stress. Variability in individual susceptibility to these stressors, HA heritability, and previous identification of several rare sequence variants (RSVs) in genes associated with the rare disorder, isolated hypogonadotropic hypogonadism (IHH), in individuals with HA suggest a possible genetic contribution to HA susceptibility. Objective We sought to determine whether the burden of RSVs in IHH-related genes is greater in women with HA than controls. Design We compared patients with HA to control women. Setting The study was conducted at secondary referral centers. Patients and Other Participants Women with HA (n = 106) and control women (ClinSeq study; n = 468). Interventions We performed exome sequencing in all patients and controls. Main Outcome Measure(s) The frequency of RSVs in 53 IHH-associated genes was determined using rare variant burden and association tests. Results RSVs were overrepresented in women with HA compared with controls (P = .007). Seventy-eight heterozygous RSVs in 33 genes were identified in 58 women with HA (36.8% of alleles) compared to 255 RSVs in 41 genes among 200 control women (27.2%). Conclusions Women with HA are enriched for RSVs in genes that cause IHH, suggesting that variation in genes associated with gonadotropin-releasing hormone neuronal ontogeny and function may be a major determinant of individual susceptibility to developing HA in the face of diet, exercise, and/or stress.