Molecular Pathology of Rare Bleeding Disorders (RBDs) in India: A Systematic Review

Background

Though rare in occurrence, patients with rare bleeding disorders (RBDs) are highly heterogeneous and may manifest with severe bleeding diathesis. Due to the high rate of consanguinity in many caste groups, these autosomal recessive bleeding disorders which are of rare occurrence in populations across the world, may not be as rare in India.

Objectives

To comprehensively analyze the frequency and nature of mutations in Indian patients with RBDs.

Methods

Pubmed search was used (www.pubmed.com) to explore the published literature from India on RBDs using the key words “rare bleeding disorders”, “mutations”, “India”, “fibrinogen”, “afibrinogenemia”, “factor II deficiency”, “prothrombin” “factor VII deficiency”, “factor V deficiency”, “factor X deficiency”, “factor XI deficiency”, “combined factor V and VIII deficiency”, “factor XIII deficiency”, “Bernard Soulier syndrome” and “Glanzmanns thrombasthenia” in different combinations. A total of 60 relevant articles could be retrieved. The distribution of mutations from India was compared with that of the world literature by referring to the Human Gene Mutation Database (HGMD) (www.hgmd.org).

Results

Taken together, 181 mutations in 270 patients with different RBDs have been reported from India. Though the types of mutations reported from India and their percentage distribution with respect to the world data are largely similar, yet much higher percentage of small deletions, duplication mutations, insertions, indels were observed in this analysis. Besides the identification of novel mutations and polymorphisms, several common mutations have also been reported, which will allow to develop a strategy for mutation screening in Indian patients with RBDs.

Conclusion

There is a need for a consortium of Institutions working on the molecular pathology of RBDs in India. This will facilitate a quicker and cheaper diagnosis of RBDs besides its utility in first trimester prenatal diagnosis of the affected families.     

Gustatory organs of Drosophila melanogaster: fine structure and expression of the putative odorant-binding protein PBPRP2

In Drosophila, as in most insects, gustation is mediated by sensory hairs located on the external and internal parts of the proboscis and on the legs and wings. We describe in detail the organization and ultrastructure of the gustatory sensilla on the labellum and legs and the distribution of PBPRP2, a putative odorant-binding protein, in the gustatory organs of Drosophila. The labellum carries two kinds of sensilla: taste bristles and taste pegs. The former have the typical morphology of gustatory sensilla and can be further subdivided into three morphological subtypes, each with a stereotyped distribution and innervation. Taste pegs have a unique morphology and are innervated by two receptor cells: one mechanoreceptor and the other a putative chemoreceptor cell. PBPRP2 is abundantly expressed in all adult gustatory organs on labellum, legs, and wings and in the internal taste organs on the proboscis. In contrast to olfactory organs, where PBPRP2 is expressed in the epidermis, this protein is absent from the epidermis of labial palps and legs. In the taste bristles of the labellum and legs, PBPRP2 is localized in the crescent-shaped lumen of the sensilla, and not in the lumen where the dendrites of the gustatory neurons are found, making a function in stimulus transport unlikely in these sensilla. In contrast, PBPRP2 in peg sensilla is expressed in the inner sensillum-lymph cavity and is in contact with the dendrites. Thus, PBPRP2 could be involved as a carrier for hydrophobic ligands, e.g., bitter tastants, in these sensilla.     

Possible links between phenotypic variability,habitats and connectivity in the killifish Aphaniops stoliczkanus in Northeast Oman

There is a significant gap in our knowledge of the intraspecific morphological variability in freshwater fish, although such data are crucial for understanding species diversity. Here we use the killifish Aphaniops stoliczkanus (Day, 1872; Aphaniidae: Cyprinodontiformes), which is a widespread but poorly known freshwater species in the Middle East, to investigate variability in morphological traits within and between its populations. As otolith morphology is known to evolve on ecological timescales and can signal the presence of cryptic lineages, a special focus lies on otolith variability. Based on samples from six populations in northern Oman, we found that variation in pigmentation, disparities in body shape and otolith variability can be associated with distinctive environmental conditions. The unique otolith shape of A. stoliczkanus from a hot sulphuric spring (Nakhal) suggests that a cryptic lineage may have emerged there. Our new data can serve as a benchmark for future studies on the diversity of Aphaniops and other Aphaniidae and help to clarify whether cryptic diversity is present in some lineages. Moreover, our data can serve as an actualistic model for studies on fossil fishes, in which morphological characters provide the only accessible data source for taxonomic and phylogenetic interpretations.     

Foraging behaviour in tadpoles of the bronze frog<Emphasis Type="Italic">Rana temporalis</Emphasis>: Experimental evidence for the ideal free distribution

The ability of bronze frogRana temporalis tadpoles (pure or mixed parental lines) to assess the profitability of food habitats and distribute themselves accordingly was tested experimentally using a rectangular choice tank with a non-continuous input design. Food (boiled spinach) was placed at two opposite ends of the choice tank in a desired ratio (1:1, 1:2 or 1:4) to create habitat A and B. The tadpoles in Gosner stage 28–33, pre-starved for 24 h, were introduced in an open ended mesh cylinder placed in the center of the choice tank, held for 4 min (for acclimation) and then released to allow free movement and habitat selection. The number of tadpoles foraging at each habitat was recorded at 10, 15, 20, 25 and 30 min time intervals. The actual suitability,S _i (the food available in a habitat after colonization of tadpoles) of each habitat was obtained from the equationS _i =B _i−f _i (d _i) whereB _i is basic suitability (amount of food provided at each habitat before release of tadpoles),f _i is the rate of depletion of food (lowering effect) with introduction of each tadpole, andd _i is the density of tadpoles in habitati. The expected number of tadpoles at each habitat was derived from the actual suitability. With no food in the choice tank, movement of the tadpoles in the test arena was random indicating no bias towards any end of the choice tank or the procedure. In tests with a 1:1 food ratio, the observed ratio of tadpoles (11.71: 12.28) was comparable with the expected 12:12 ratio. The observed number of tadpoles in the habitats with a 1:2 food ratio was 8.71:15.29 and 7.87:16.13 for pure and mixed parental lines respectively. In both cases, the observed ratios were close to the expected values (7:17). Likewise, in experiments with a 1:4 food ratio, the observed number of tadpoles in the two habitats (10.78:37.22) did not differ significantly from the expected ratio of 7:41. In all tests, the number ofR. temporalis tadpoles matched ideally with habitat profitability (undermatching indexK ≜ 1. The study shows that tadpoles of the bronze frog exhibit an ideal free distribution while foraging regardless of whether they are siblings or non-siblings in a group, which correlates well with their group living strategy in nature.     

Phenylphenalenones protect banana plants from infection by Mycosphaerella fijiensis and are deactivated by metabolic conversion

Phenylphenalenones, polycyclic aromatic natural products from some monocotyledonous plants, are known as phytoalexins in banana (Musa spp.). In this study, ¹H nuclear magnetic resonance (NMR)‐based metabolomics along with liquid chromatography and mass spectrometry were used to explore the chemical responses of the susceptible ‘Williams’ and the resistant ‘Khai Thong Ruang’ Musa varieties to the ascomycete fungus Mycosphaerella fijiensis, the agent of the black leaf Sigatoka disease. Principal component analysis discriminated strongly between infected and non‐infected plant tissue, mainly because of specialized metabolism induced in response to the fungus. Phenylphenalenones are among the major induced compounds, and the resistance level of the plants was correlated with the progress of the disease. However, a virulent strain of M. fijiensis was able to overcome plant resistance by converting phenylphenalenones to sulfate conjugates. Here, we report the first metabolic detoxification of fungitoxic phenylphenalenones to evade the chemical defence of Musa plants.     

The temperature dependence of the binding of 5 alpha-dihydrotestosterone, testosterone and estradiol to the sex hormone globulin (SHBG) of human plasma

The binding of 5 alpha-dihydrotestosterone (DHT), testosterone and estradiol to the sex hormone binding globulin (SHBG) and albumin in human plasma has been studied at 4, 20 and 37 degrees C using the method of equilibrium partition in an aqueous two-phase system based on dextran, poly(ethylene glycol) and water. The intrinsic association constants for the binding to SHBG and the apparent association constant for the binding to albumin have been determined from Scatchard-type binding plots. The affinity of SHBG for DHT is 1.2-1.3 times higher than that for testosterone and 4 times higher than that for estradiol. The affinity of SHBG for the steroids decreases with increasing temperature. The mean values of the free energy of binding, delta G degree, in the temperature range used are -52.3, -51.7 and -48.9 kJ X mol-1 for the binding of DHT, testosterone and estradiol, respectively, to SHBG. The corresponding values of the enthalpy change, delta H degree, are 73.7, 70.0 and 99.0 J X mol-1 X K-1. These values are discussed in terms of the difference in the structure of the steroids. The affinity of albumin for testosterone and estradiol is almost equal and is lower than that for DHT. The delta G degree for the binding to albumin is about 55% lower than that for the binding to SHBG.     

OdoriFy: A conglomerate of artificial intelligence–driven prediction engines for olfactory decoding

The molecular mechanisms of olfaction, or the sense of smell, are relatively underexplored compared with other sensory systems, primarily because of its underlying molecular complexity and the limited availability of dedicated predictive computational tools. Odorant receptors (ORs) allow the detection and discrimination of a myriad of odorant molecules and therefore mediate the first step of the olfactory signaling cascade. To date, odorant (or agonist) information for the majority of these receptors is still unknown, limiting our understanding of their functional relevance in odor-induced behavioral responses. In this study, we introduce OdoriFy, a Web server featuring powerful deep neural network–based prediction engines. OdoriFy enables (1) identification of odorant molecules for wildtype or mutant human ORs (Odor Finder); (2) classification of user-provided chemicals as odorants/nonodorants (Odorant Predictor); (3) identification of responsive ORs for a query odorant (OR Finder); and (4) interaction validation using Odorant–OR Pair Analysis. In addition, OdoriFy provides the rationale behind every prediction it makes by leveraging explainable artificial intelligence. This module highlights the basis of the prediction of odorants/nonodorants at atomic resolution and for the ORs at amino acid levels. A key distinguishing feature of OdoriFy is that it is built on a comprehensive repertoire of manually curated information of human ORs with their known agonists and nonagonists, making it a highly interactive and resource-enriched Web server. Moreover, comparative analysis of OdoriFy predictions with an alternative structure-based ligand interaction method revealed comparable results. OdoriFy is available freely as a web service at https://odorify.ahujalab.iiitd.edu.in/olfy/.     

The language of lizards: interpreting the function of visual displays of the Indian rock lizard, Psammophilus dorsalis (Agamidae)

The first step in understanding any communication system is to document signal diversity relative to the context of signalling (e.g. sex of the signaller and audience). Observation of 30 free-ranging rock lizards (Psammophilus dorsalis) on rock outcrops in southern India over a period of 18 months revealed that these lizards produce a complex array of ritualized signals involving push-ups (head-bobbing), dorsal flattening, extension of the legs or gular region, and tail-raising. Push-ups were performed by both sexes, usually after moving from one location to another. Push-ups were rarely accompanied by other postural modifications, and seem to function as non-directed signals. Dorsal flattening was elicited by birds flying overhead, and seems to make the lizard less conspicuous to predators. There was, nonetheless, a strong sex difference in the frequency of this behaviour, because the habitats used by males (open rocks) exposed them to more birds. Males displayed to females by extending their gular folds and arching their backs; other animals (e.g. squirrels, monkeys) also elicited the latter posture from both sexes. Leg extension was observed for both males and females, but in different contexts—males in response to conspecifics, females in response to other animals. Females raised their tails in response to encountering a male. Thus, these lizards have a complex repertoire of postures for predator evasion, for interaction with other species and with conspecifics, and for communicating sex-specific social information about gender (tail-raise) or dominance status (gular extension, leg extension).     

Solution Structure and Peptide Binding of the PTB Domain from the AIDA1 Postsynaptic Signaling Scaffolding Protein

AIDA1 links persistent chemical signaling events occurring at the neuronal synapse with global changes in gene expression. Consistent with its role as a scaffolding protein, AIDA1 is composed of several protein-protein interaction domains. Here we report the NMR structure of the carboxy terminally located phosphotyrosine binding domain (PTB) that is common to all AIDA1 splice variants. A comprehensive survey of peptides identified a consensus sequence around an NxxY motif that is shared by a number of related neuronal signaling proteins. Using peptide arrays and fluorescence based assays, we determined that the AIDA1 PTB domain binds amyloid protein precursor (APP) in a similar manner to the X11/Mint PTB domain, albeit at reduced affinity (∼10 µM) that may allow AIDA1 to effectively sample APP, as well as other protein partners in a variety of cellular contexts.