Localization, Disorder, and Entropy in a Coarse-Grained Model of the Amorphous Solid.

We study the role of disorder in producing the metastable states in which the extent of mass localization is intermediate between that of a liquid and a crystal with long-range order. We estimate the corresponding entropy with the coarse-grained description of a many-particle system used in the classical density functional model. We demonstrate that intermediate localization of the particles results in a change of the entropy from what is obtained from a microscopic approach using for sharply localized vibrational modes following a Debye distribution. An additional contribution is included in the density of vibrational states g(ω) to account for this excess entropy. A corresponding peak in g(ω)/ω2 vs. frequency ω matches the characteristic boson peak seen in amorphous solids. In the present work, we also compare the shear modulus for the inhomogeneous solid having localized density profiles with the corresponding elastic response for the uniform liquid in the limit of high frequencies.

Replication timing is regulated by the number of MCMs loaded at origins.

Replication timing is a crucial aspect of genome regulation that is strongly correlated with chromatin structure, gene expression, DNA repair, and genome evolution. Replication timing is determined by the timing of replication origin firing, which involves activation of MCM helicase complexes loaded at replication origins. Nonetheless, how the timing of such origin firing is regulated remains mysterious. Here, we show that the number of MCMs loaded at origins regulates replication timing. We show for the first time in vivo that multiple MCMs are loaded at origins. Because early origins have more MCMs loaded, they are, on average, more likely to fire early in S phase. Our results provide a mechanistic explanation for the observed heterogeneity in origin firing and help to explain how defined replication timing profiles emerge from stochastic origin firing. These results establish a framework in which further mechanistic studies on replication timing, such as the strong effect of heterochromatin, can be pursued.

How and why multiple MCMs are loaded at origins of DNA replication.

Recent work suggests that DNA replication origins are regulated by the number of multiple mini-chromosome maintenance (MCM) complexes loaded. Origins are defined by the loading of MCM - the replicative helicase which initiates DNA replication and replication kinetics determined by origin's location and firing times. However, activation of MCM is heterogeneous; different origins firing at different times in different cells. Also, more MCMs are loaded in G1 than are used in S phase. These aspects of MCM biology are explained by the observation that multiple MCMs are loaded at origins. Having more MCMs at early origins makes them more likely to fire, effecting differences in origin efficiency that define replication timing. Nonetheless, multiple MCM loading raises new questions, such as how they are loaded, where these MCMs reside at origins, and how their presence affects replication timing. In this review, we address these questions and discuss future avenues of research.

Ott1 (Rbm15) regulates thrombopoietin response in hematopoietic stem cells through alternative splicing of c-Mpl.

Thrombopoietin (Thpo) signaling through the c-Mpl receptor promotes either quiescence or proliferation of hematopoietic stem cells (HSCs) in a concentration-dependent manner; however, in vivo Thpo serum levels are responsive to platelet mass rather than HSC demands, suggesting additional regulation exists. Ott1 (Rbm15), a spliceosomal component originally identified as a fusion partner in t(1;22)-associated acute megakaryocytic leukemia, is also essential for maintaining HSC quiescence under stress. Ott1 controls the alternative splicing of a dominant negative isoform, Mpl-TR, capable of inhibiting HSC engraftment and attenuating Thpo signaling. Ott1, which associates with Hdac3 and the histone methyltransferase, Setd1b, binds to both c-Mpl RNA and chromatin and regulates H4 acetylation and H3K4me3 marks. Histone deacetylase or histone methyltransferase inhibition also increases Mpl-TR levels, suggesting that Ott1 uses an underlying epigenetic mechanism to control alternative splicing of c-Mpl. Manipulation of Ott1-dependent alternative splicing may therefore provide a novel pharmacologic avenue for regulating HSC quiescence and proliferation in response to Thpo.

Linking density functional and mode coupling models for supercooled liquids.

We compare predictions from two familiar models of the metastable supercooled liquid, respectively, constructed with thermodynamic and dynamic approaches. In the so called density functional theory the free energy F[ρ] of the liquid is a functional of the inhomogeneous density ρ(r). The metastable state is identified as a local minimum of F[ρ]. The sharp density profile characterizing ρ(r) is identified as a single particle oscillator, whose frequency is obtained from the parameters of the optimum density function. On the other hand, a dynamic approach to supercooled liquids is taken in the mode coupling theory (MCT) which predict a sharp ergodicity-non-ergodicity transition at a critical density. The single particle dynamics in the non-ergodic state, treated approximately, represents a propagating mode whose characteristic frequency is computed from the corresponding memory function of the MCT. The mass localization parameters in the above two models (treated in their simplest forms) are obtained, respectively, in terms of the corresponding natural frequencies depicted and are shown to have comparable magnitudes.

Fungal coexistence in the skin mycobiome: a study involving Malassezia, Candida, and Rhodotorula.

Evidence of fungal coexistence in humans points towards fungal adaptation to the host environment, like the skin. The human commensal Malassezia has evolved, especially residing in sebum-rich areas of the mammalian body where it can get the necessary nutrition for its survival. This fungus is primarily responsible for skin diseases like Pityriasis versicolor (PV), characterized by hypo or hyperpigmented skin discoloration and erythematous macules. In this manuscript, we report a 19-year-old healthy female who presented with a one-year history of reddish, hypopigmented, asymptomatic lesions over the chest and a raised erythematous lesion over the face. Upon clinical observation, the patient displayed multiple erythematous macules and erythematous papules over the bilateral malar area of the face, along with multiple hypopigmented scaly macules present on the chest and back. Based on the above clinical findings, a diagnosis of PV and Acne vulgaris (AV) was made. Interestingly, the patient was immunocompetent and didn't have any comorbidities. Upon isolation of skin scrapings and post-culturing, we found the existence of three fungal genera in the same region of the patient's body. We further went on to confirm the identity of the particular species and found it to represent Malassezia, Rhodotorula, and Candida. We report how Malassezia, the predominant microbial resident skin fungus, coexists with other fungal members of the skin mycobiome. This study on an applied aspect of microbiology also shows how important it is to identify the fungal organism associated with skin infections so that appropriate therapeutics can be advised to avoid cases of relapse.

From Skin and Gut to the Brain: The Infectious Journey of the Human Commensal Fungus Malassezia and Its Neurological Consequences.

The human mycobiome encompasses diverse communities of fungal organisms residing within the body and has emerged as a critical player in shaping health and disease. While extensive research has focused on the skin and gut mycobiome, recent investigations have pointed toward the potential role of fungal organisms in neurological disorders. Among those fungal organisms, the presence of the commensal fungus Malassezia in the brain has created curiosity because of its commensal nature and primary association with the human skin and gut. This budding yeast is responsible for several diseases, such as Seborrheic dermatitis, Atopic dermatitis, Pityriasis versicolor, Malassezia folliculitis, dandruff, and others. However recent findings surprisingly show the presence of Malassezia DNA in the brain and have been linked to diseases like Alzheimer's disease, Parkinson's disease, Multiple sclerosis, and Amyotrophic lateral sclerosis. The exact role of Malassezia in these disorders is unknown, but its ability to infect human cells, travel through the bloodstream, cross the blood-brain barrier, and reside along with the lipid-rich neuronal cells are potential mechanisms responsible for pathogenesis. This also includes the induction of pro-inflammatory cytokines, disruption of the blood-brain barrier, gut-microbe interaction, and accumulation of metabolic changes in the brain environment. In this review, we discuss these key findings from studies linking Malassezia to neurological disorders, emphasizing the complex and multifaceted nature of these cases. Furthermore, we discuss potential mechanisms through which Malassezia might contribute to the development of neurological conditions. Future investigations will open up new avenues for our understanding of the fungal gut-brain axis and how it influences human behavior. Collaborative research efforts among microbiologists, neuroscientists, immunologists, and clinicians hold promise for unraveling the enigmatic connections between human commensal Malassezia and neurological disorders.

BRCA1 interactors, RAD50 and BRIP1, as prognostic markers for triple-negative breast cancer severity.

Introduction: BRIP1 (BRCA1-interacting protein 1) is one of the major interacting partners of BRCA1, which plays an important role in repair by homologous recombination (HR). This gene is mutated in around 4% of cases of breast cancer; however, its mechanism of action is unclear. In this study, we presented the fundamental role of BRCA1 interactors BRIP1 and RAD50 in the development of differential severity in triple-negative breast cancer (TNBC) among various affected individuals. Methods: We have analyzed the expression of DNA repair-related genes in different BC cells using Real-time PCR and western blotting analysis and assessed changes in stemness property and proliferation through Immunophenotyping. We have performed cell cycle analysis to see the defect in checkpoints and also immunofluorescence assay to confirm the accumulation of gamma-H2AX and BRCA1 foci and subsequent incidence. We have performed a severity analysis using TCGA data sets for comparing the expression in MDA-MB-468 MDA-MB-231 and MCF7 cell line. Results: We showed that in some TNBC cell lines such as MDA-MB-231, the functioning of both BRCA1/TP53 is compromised. Furthermore, the sensing of DNA damage is affected. Due to less damage-sensing capability and low availability of BRCA1 at the damage sites, the repair by HR becomes inefficient, leading to more damage. Accumulation of damage sends a signal for over activation of NHEJ repair pathways. Over expressed NHEJ molecules with compromised HR and checkpoint conditions lead to higher proliferation and error-prone repair, which increases the mutation rate and corresponding tumour severity. The in-silico analysis of the TCGA datasets with gene expression in the deceased population showed a significant correlation of BRCA1 expression with overall survival (OS) in TNBCs (0.0272). The association of BRCA1 with OS became stronger with the addition of BRIP1 expression (0.000876**). Conclusion: The severity phenotypes were more in cells having compromised BRCA1-BRIP1 functioning. Since the OS is directly proportional to the extent of severity, the data analysis hints at the role of BRIP1 in controlling the severity of TNBC.

MCM10 expression is linked to cervical cancer aggressiveness.

Cervical cancer screening is a challenge mainly in developing countries. In developed countries, both incidence and mortality rates have been decreasing due to well organized screening programs. One of the potential biomarkers being exploited are the minichromosome maintenance proteins (MCMs), which show both specificity and sensitivity. MCM2-7 are involved in DNA replication initiation and elongation, and the MCM subunits are highly expressed in malignant tissues. Unlike other MCMs, MCM10, which is not part of the core helicase complex, is a critical determinant of origin activation and its levels are limiting in cancer cells. In this study, we performed bioinformatic analysis on the expression profile of all DNA replication associated MCM proteins in cervical cancer. MCM10 showed a relatively higher expression profile compared to the other MCMs. The mRNA expression levels of the MCMs were significantly increased in tumour tissues compared to normal, and MCM10 showed a fold change of 3.4. In order to understand if MCM10 is associated with the aggressiveness of cervical cancer, we looked into the mRNA expression pattern of MCM10 in three cervical cancer cell lines and one normal cervical cell line. MCM10 expression was significantly higher in the case of the more aggressive cancer cell line HeLa compared to controls. MCM10, therefore, can serve as a prominent biomarker for cancer progression and thus aid in early detection to control the spread of cancer cells. Our results show that MCM10 expression levels in cervical cancer cell lines are associated with cancer aggressiveness, demonstrating its clinical significance.

Time dependent stretching of aging dynamics in a generalized hydrodynamic model for supercooled liquids.

The nonequilibrium dynamics and aging behavior of a supercooled liquid is investigated from an analysis of the correlation of density fluctuations at two different times. The dynamic correlation functions are computed by solving numerically the equations of nonlinear fluctuating hydrodynamics. The aging time dependence follows a modified stretched exponential form with a relaxation time which is dependent on the aging time. This is similar to the behavior seen in the aging data of dielectric response functions of a typical glass forming liquid.

Configurational entropy from a replica approach: A density-functional model.

We study a field-theoretic model for the metastable liquid using a nonlocal free-energy functional with density ρ(x) is the order parameter and three-point correlation effects included in the formulation. We assume fragmentation of the free-energy landscape into distinct basins of local minima and evaluate the partition function for the many-particle system through mapping into a composite system of m identical replicas. Static correlations and configurational entropy S_{c} are calculated in the m=1 limit. The Kauzman packing fraction η_{K} obtained are in agreement with other works.

Functional characterization of the Saccharomyces cerevisiae protein Chl1 reveals the role of sister chromatid cohesion in the maintenance of spindle length during S-phase arrest.

BACKGROUND: Metaphase cells have short spindles for efficient bi-orientation of chromosomes. The cohesin proteins hold sister chromatids together, creating Sister Chromatid Cohesion (SCC) that helps in the maintenance of short spindle lengths in metaphase. The budding yeast protein Chl1p, which has human homologs, is required for DNA damage repair, recombination, transcriptional silencing and aging. This protein is also needed to establish SCC between sister chromatids in S-phase. RESULTS: In the present study we have further characterized Chl1p for its role in the yeast Saccharomyces cerevisiae when cells are under replication stress. We show that when DNA replication is arrested by hydroxyurea (HU), the chl1 mutation causes growth deficiency and a mild loss in cell viability. Although both mutant and wild-type cells remained arrested with undivided nuclei, mutant cells had mitotic spindles, which were about 60-80% longer than wild-type spindles. Spindle extension occurred in S-phase in the presence of an active S-phase checkpoint pathway. Further, the chl1 mutant did not show any kinetochore-related defect that could have caused spindle extension. These cells were affected in the retention of SCC in that they had only about one-fourth of the normal levels of the cohesin subunit Scc1p at centromeres, which was sufficient to bi-orient the chromosomes. The mutant cells showed defects in SCC, both during its establishment in S-phase and in its maintenance in G2. Mutants with partial and pericentromeric cohesion defects also showed spindle elongation when arrested in S-phase by HU. CONCLUSIONS: Our work shows that Chl1p is required for normal growth and cell viability in the presence of the replication block caused by HU. The absence of this protein does not, however, compromize the replication checkpoint pathway. Even though the chl1 mutation gives synthetic lethal interactions with kinetochore mutations, its absence does not affect kinetochore function; kinetochore-microtubule interactions remain unperturbed. Further, chl1 cells were found to lose SCC at centromeres in both S- and G2 phases, showing the requirement of Chl1p for the maintenance of cohesion in G2 phase of these cells. This work documents for the first time that SCC is an important determinant of spindle size in the yeast Saccharomyces cerevisiae when genotoxic agents cause S-phase arrest of cells.

Mental health needs of people living with HIV/AIDS in India: a literature review.

We describe the global conditions associated with the AIDS pandemic and its socioeconomic and psychological impacts. A systematic review was performed to investigate the literature on the mental health needs of people living with HIV/AIDS (PLHA) in India. The focus is on the prevalence, nature, and sociocultural factors of the epidemic in India. A conceptual framework is offered and the findings of this study are presented across three major domains: (a) prevalence of mental health disorders among the HIV-infected population; (b) mental health needs of PLHA; and (c) gaps in policies and programs addressing these issues. Experiences of HIV stigma and discrimination are also noted in this population. We conclude with implications for future research, interventions, and public policy.

The budding yeast protein Chl1p is required for delaying progression through G1/S phase after DNA damage.

BACKGROUND: The budding yeast protein Chl1p is a nuclear protein required for sister-chromatid cohesion, transcriptional silencing, rDNA recombination, ageing and plays an instrumental role in chromatin remodeling. This helicase is known to preserve genome integrity and spindle length in S-phase. Here we show additional roles of Chl1p at G1/S phase of the cell cycle following DNA damage. RESULTS: G1 arrested cells when exposed to DNA damage are more sensitive and show bud emergence with faster kinetics in chl1 mutants compared to wild-type cells. Also, more damage to DNA is observed in chl1 cells. The viability falls synergistically in rad24chl1 cells. The regulation of Chl1p on budding kinetics in G1 phase falls in line with Rad9p/Chk1p and shows a synergistic effect with Rad24p/Rad53p. rad9chl1 and chk1chl1 shows similar bud emergence as the single mutants chl1, rad9 and chk1. Whereas rad24chl1 and rad53chl1 shows faster bud emergence compared to the single mutants rad24, rad53 and chl1. In presence of MMS induced damage, synergistic with Rad24p indicates Chl1p's role as a checkpoint at G1/S acting parallel to damage checkpoint pathway. The faster movement of DNA content through G1/S phase and difference in phosphorylation profile of Rad53p in wild type and chl1 cells confirms the checkpoint defect in chl1 mutant cells. Further, we have also confirmed that the checkpoint defect functions in parallel to the damage checkpoint pathway of Rad24p. CONCLUSION: Chl1p shows Rad53p independent bud emergence and Rad53p dependent checkpoint activity in presence of damage. This confirms its requirement in two different pathways to maintain the G1/S arrest when cells are exposed to damaging agents. The bud emergence kinetics and DNA segregation were similar to wild type when given the same damage in nocodazole treated chl1 cells which establishes the absence of any role of Chl1p at the G2/M phase. The novelty of this paper lies in revealing the versatile role of Chl1p in checkpoints as well as repair towards regulating G1/S transition. Chl1p thus regulates the G1/S phase by affecting the G1 replication checkpoint pathway and shows an additive effect with Rad24p for Rad53p activation when damaging agents perturb the DNA. Apart from checkpoint activation, it also regulates the budding kinetics as a repair gene.

The repair gene BACH1 - a potential oncogene.

BACH1 encodes for a protein that belongs to RecQ DEAH helicase family and interacts with the BRCT repeats of BRCA1. The N-terminus of BACH1 functions in DNA metabolism as DNA-dependent ATPase and helicase. The C-terminus consists of BRCT domain, which interacts with BRCA1 and this interaction is one of the major regulator of BACH1 function. BACH1 plays important roles both in phosphorylated as well as dephosphorylated state and functions in coordination with multiple signaling molecules. The active helicase property of BACH1 is maintained by its dephosphorylated state. Imbalance between these two states enhances the development and progression of the diseased condition. Currently BACH1 is known as a tumor suppressor gene based on the presence of its clinically relevant mutations in different cancers. Through this review we have justified it to be named as an oncogene. In this review, we have explained the mechanism of how BACH1 in collaboration with BRCA1 or independently regulates various pathways like cell cycle progression, DNA replication during both normal and stressed situation, recombination and repair of damaged DNA, chromatin remodeling and epigenetic modifications. Mutation and overexpression of BACH1 are significantly found in different cancer types. This review enlists the molecular players which interact with BACH1 to regulate DNA metabolic functions, thereby revealing its potential for cancer therapeutics. We have identified the most mutated functional domain of BACH1, the hot spot for tumorigenesis, justifying it as a target molecule in different cancer types for therapeutics. BACH1 has high potentials of transforming a normal cell into a tumor cell if compromised under certain circumstances. Thus, through this review, we justify BACH1 as an oncogene along with the existing role of being a tumor suppressant.

Genetic Susceptibility to Fungal Infections and Links to Human Ancestry.

Over the ages, fungi have associated with different parts of the human body and established symbiotic associations with their host. They are mostly commensal unless there are certain not so well-defined factors that trigger the conversion to a pathogenic state. Some of the factors that induce such transition can be dependent on the fungal species, environment, immunological status of the individual, and most importantly host genetics. In this review, we discuss the different aspects of how host genetics play a role in fungal infection since mutations in several genes make hosts susceptible to such infections. We evaluate how mutations modulate the key recognition between the pathogen associated molecular patterns (PAMP) and the host pattern recognition receptor (PRR) molecules. We discuss the polymorphisms in the genes of the immune system, the way it contributes toward some common fungal infections, and highlight how the immunological status of the host determines fungal recognition and cross-reactivity of some fungal antigens against human proteins that mimic them. We highlight the importance of single nucleotide polymorphisms (SNPs) that are associated with several of the receptor coding genes and discuss how it affects the signaling cascade post-infection, immune evasion, and autoimmune disorders. As part of personalized medicine, we need the application of next-generation techniques as a feasible option to incorporate an individual's susceptibility toward invasive fungal infections based on predisposing factors. Finally, we discuss the importance of studying genomic ancestry and reveal how genetic differences between the human race are linked to variation in fungal disease susceptibility.

Over-expression of Brassica napus phosphatidylinositol-phospholipase C2 in canola induces significant changes in gene expression and phytohormone distribution patterns, enhances drought tolerance and promotes early flowering and maturation.

Phosphatidylinositol-specific phospholipase C (PtdIns-PLC2) plays a central role in the phosphatidylinositol-specific signal transduction pathway. It catalyses the hydrolysis of membrane-bound phosphatidylinositol 4,5-bisphosphate to produce two second messengers, sn-1,2-diacylglycerol and inositol 1,4,5-trisphosphate. The former is a membrane activator of protein kinase C in mammalian systems, and the latter is a Ca(2+) modulator which induces distinctive oscillating bursts of cytosolic Ca(2+), resulting in regulation of gene expression and activation of proteins. Sustained over-expression of BnPtdIns-PLC2 in transgenic Brassica napus lines brought about an early shift from vegetative to reproductive phases, and shorter maturation periods, accompanied by notable alterations in hormonal distribution patterns in various tissues. The photosynthetic rate increased, while stomata were partly closed. Numerous gene expression changes that included induction of stress-related genes such as glutathione S-transferase, hormone-regulated and regulatory genes, in addition to a number of kinases, calcium-regulated factors and transcription factors, were observed. Other changes included increased phytic acid levels and phytohormone organization patterns. These results suggest the importance of PtdIns-PLC2 as an elicitor of a battery of events that systematically control hormone regulation, and plant growth and development in what may be a preprogrammed mode.

Potential role of N-myristoyltransferase in cancer.

Colorectal cancer is the second leading cause of malignant death, and better preventive strategies are needed. The treatment of colonic cancer remains difficult because of the lack of effective chemotherapeutic agents; therefore it is important to continue to search for cellular functions that can be disrupted by chemotherapeutic drugs resulting in the inhibition of the development and progression of cancer. The current knowledge of the modification of proteins by myristoylation involving myristoyl-CoA: protein N-myristoyltransferase (NMT) is in its infancy. This process is involved in the pathogenesis of cancer. We have reported for the first time that NMT activity and protein expression were higher in human colorectal cancer, gallbladder carcinoma and brain tumors. In addition, an increase in NMT activity appeared at an early stage in colonic carcinogenesis. It is conceivable therefore that NMT can be used as a potential marker for the early detection of cancer. These observations lead to the possibility of developing NMT specific inhibitors, which may be therapeutically useful. We proposed that HSC70 and/or enolase could be used as an anticancer therapeutic target. This review summarized the status of NMT in cancer which has been carried in our laboratory.

Fluctuating nonlinear hydrodynamics does not support an ergodic-nonergodic transition.

Despite its appeal, real and simulated glass forming systems do not undergo an ergodic-nonergodic (ENE) transition. We reconsider whether the fluctuating nonlinear hydrodynamics (FNH) model for this system, introduced by us in 1986, supports an ENE transition. Using nonperturbative arguments, with no reference to the hydrodynamic regime, we show that the FNH model does not support an ENE transition. Our results support the findings in the original paper. Assertions in the literature questioning the validity of the original work are shown to be in error.