Genetic and phenotypic landscape of pediatric-onset epilepsy in 142 Indian families: Counseling and therapeutic implications.

The application of genomic technologies has led to unraveling of the complex genetic landscape of disorders of epilepsy, gaining insights into their underlying disease mechanisms, aiding precision medicine, and providing informed genetic counseling. We herein present the phenotypic and genotypic insights from 142 Indian families with epilepsy with or without comorbidities. Based on the electroclinical findings, epilepsy syndrome diagnosis could be made in 44% (63/142) of the families adopting the latest proposal for the classification by the ILAE task force (2022). Of these, 95% (60/63) of the families exhibited syndromes with developmental epileptic encephalopathy or progressive neurological deterioration. A definitive molecular diagnosis was achieved in 74 of 142 (52%) families. Infantile-onset epilepsy was noted in 81% of these families (61/74). Fifty-five monogenic, four chromosomal, and one imprinting disorder were identified in 74 families. The genetic variants included 65 (96%) single-nucleotide variants/small insertion-deletions, 1 (2%) copy-number variant, and 1 (2%) triplet-repeat expansion in 53 epilepsy-associated genes causing monogenic disorders. Of these, 35 (52%) variants were novel. Therapeutic implications were noted in 51% of families (38/74) with definitive diagnosis. Forty-one out of 66 families with monogenic disorders exhibited autosomal recessive and inherited autosomal dominant disorders with high risk of recurrence.

Homozygous loss-of-function variants in FILIP1 cause autosomal recessive arthrogryposis multiplex congenita with microcephaly.

Arthrogryposis multiplex congenita forms a broad group of clinically and etiologically heterogeneous disorders characterized by congenital joint contractures that involve at least two different parts of the body. Neurological and muscular disorders are commonly underlying arthrogryposis. Here, we report five affected individuals from three independent families sharing an overlapping phenotype with congenital contractures affecting shoulder, elbow, hand, hip, knee and foot as well as scoliosis, reduced palmar and plantar skin folds, microcephaly and facial dysmorphism. Using exome sequencing, we identified homozygous truncating variants in FILIP1 in all patients. FILIP1 is a regulator of filamin homeostasis required for the initiation of cortical cell migration in the developing neocortex and essential for the differentiation process of cross-striated muscle cells during myogenesis. In summary, our data indicate that bi-allelic truncating variants in FILIP1 are causative of a novel autosomal recessive disorder and expand the spectrum of genetic factors causative of arthrogryposis multiplex congenita.

Covalently bonded interface in polymer/boron nitride nanosheet composite toward enhanced mechanical and thermal behaviour.

This experimental study aimed to enhance the mechanical and thermal properties of BN (hexagonal boron nitride) nanosheet-reinforced high-density polyethylene by functionalizing its interface. The challenges associated with this nanocomposites are its poor dispersion and weak interface. Accordingly, to improve the load transfer at the interface, BN nanosheets were chemically modified with silane functional groups ((3-aminopropyl)tri-ethoxy silane), making it possible to form covalent bonds between the maleic anhydride-grafted polyethylene and nanosheet. Consequently, three different types of nanocomposite samples were fabricated based on the covalently bonded or non-bonded interface. Two nanocomposite configurations featured a non-bonded interface between the nanofiller and PE matrix (p-BN/PE and (silane functionalized) s-BN/PE). In contrast, the third configuration had a covalently bonded interface (silane-functionalized h-BN + maleic anhydride-grafted PE, i.e., PE-g-BN). According to the zeta potential analysis, the silane-functionalized BN nanosheets were stable suspensions and uniformly dispersed in the polymer matrix. The tensile and flexure strength of the nanocomposites showed over 100% improvement due to the covalently bonded interface. The lamellae structure of PE in the bonded interface samples was responsible for achieving higher mechanical strength in the nanocomposites. Furthermore, the thermal conductivity of the nanocomposites was significantly affected by the type of interfacial bonding, BN wt%, and operating temperature.

"On-the-Fly" Fabrication of Highly-Ordered Interconnected Cylindrical and Spherical Porous Microparticles via Dual Polymerization Zone Microfluidics.

A microfluidic platform with dual photopolymerization zones has been developed for production of novel uniform interconnected porous particles with shapes imposed either by the geometry of the external capillary or by the thermodynamic minimization of interfacial area. Double w/o/w (water/oil/water) drops with well-defined internal droplet size and number were produced and then exposed to online photopolymerization to create the porous particles. Cylindrical interconnected porous particles were produced in a segmented flow where the drops took the shape of the capillary. The microfluidic setup included an extension capillary where the drops relaxed and conformed to their thermodynamically favored morphology. Window opening of the particles occurred "on-the-fly" during UV polymerization without using any offline auxiliary methods. A distinction was made between critically and highly packed arrangements in double drops. The window opening occurred consistently for highly packed spherical drops, but only for critically packed drops containing more than six internal cores at internal phase ratios as low as 0.35. The size and number of cores and shape and structure of double drops could be precisely tuned by the flow rate and by packing structure of the inner droplets.

Flexible Asymmetric Encapsulation for Dehydration-Responsive Hybrid Microfibers.

A new class of smart alginate microfibers with asymmetric oil encapsulates is introduced. These fibers are produced by injecting an aqueous alginate solution into an outer aqueous calcium chloride solution to form alginate fibers, which are asymmetrically loaded with oil entities through eccentrically aligned inner capillaries. The fiber morphology and its degree of asymmetry can be tuned via altering the size, location, and frequency of the oil encapsulates. These asymmetric fibers reveal significant potential for applications where conventional symmetric fibers fail to perform. It is shown how asymmetric oil-encapsulated fibers can become dehydration-sensitive, and trigger the release of encapsulates if their hydration level drops below a critical value. It is also shown how the triggered response could be switched off on demand by stabilizing the oil encapsulates. The capability of asymmetric fibers to carry and release multiple cargos in parallel is demonstrated. The fibers loaded with equal-sized spheres are more asymmetric than those containing unequal drops, have a higher tensile strength, and show better potential for a triggered response.

Large ultrathin shelled drops produced via non-confined microfluidics.

We present a facile approach for producing large and monodisperse core-shell drops with ultrathin shells using a single-step process. A biphasic compound jet is introduced into a quiescent third (outer) phase that ruptures to form core-shell drops. Ultrathin shelled drops could only be produced within a certain range of surfactant concentrations and flow rates, highlighting the effect of interfacial tension in engulfing the core in a thin shell. An increase in surfactant concentrations initially resulted in drops with thinner shells. However, the drops with thinnest shells were obtained at an optimum surfactant concentration, and a further increase in the surfactant concentrations increased the shell thickness. Highly monodisperse (coefficient of variation smaller than 3 %) core-shell drops with diameter of ∼200 µm-2 mm with shell thickness as small as ∼2 µm were produced. The resulting drops were stable enough to undergo polymerisation and produce ultrathin shelled capsules.

De novo variants underlying monogenic syndromes with intellectual disability in a neurodevelopmental cohort from India.

The contribution of de novo variants as a cause of intellectual disability (ID) is well established in several cohorts reported from the developed world. However, the genetic landscape as well as the appropriate testing strategies for identification of de novo variants of these disorders remain largely unknown in low-and middle-income countries like India. In this study, we delineate the clinical and genotypic spectrum of 54 families (55 individuals) with syndromic ID harboring rare de novo variants. We also emphasize on the effectiveness of singleton exome sequencing as a valuable tool for diagnosing these disorders in resource limited settings. Overall, 46 distinct disorders were identified encompassing 46 genes with 51 single-nucleotide variants and/or indels and two copy-number variants. Pathogenic variants were identified in CREBBP, TSC2, KMT2D, MECP2, IDS, NIPBL, NSD1, RIT1, SOX10, BRWD3, FOXG1, BCL11A, KDM6B, KDM5C, SETD5, QRICH1, DCX, SMARCD1, ASXL1, ASXL3, AKT3, FBN2, TCF12, WASF1, BRAF, SMARCA4, SMARCA2, TUBG1, KMT2A, CTNNB1, DLG4, MEIS2, GATAD2B, FBXW7, ANKRD11, ARID1B, DYNC1H1, HIVEP2, NEXMIF, ZBTB18, SETD1B, DYRK1A, SRCAP, CASK, L1CAM, and KRAS. Twenty-four of these monogenic disorders have not been previously reported in the Indian population. Notably, 39 out of 53 (74%) disease-causing variants are novel. These variants were identified in the genes mainly encoding transcriptional and chromatin regulators, serine threonine kinases, lysosomal enzymes, molecular motors, synaptic proteins, neuronal migration machinery, adhesion molecules, structural proteins and signaling molecules.

Deciphering functional biomolecule potential of marine diatoms through complex network approach.

Marine diatoms are unique reservoirs of bioactive compounds having enormous applications in therapeutics. But high-throughput screening methods are needed to elucidate the interaction between numerous biomolecules and their targets, facilitating rapid screening for novel drug molecules. So, in the present study chemical constituents were extracted from five marine diatoms using un-targeted metabolite profiling and in-silico virtual screening bioinformatics was employed to predict their bioactivity and molecular targets. A total of 17 chemical constituents out of 51 showed interactions with 76 protein targets associated with 213 pathways. Ingredient-target-pathway network revealed oleic acid, linoleic acid and cholest-5-en-3-ol as major active constituents. Core subnetwork and protein association network showed involvement of these compounds in key metabolic pathways related to cell signaling, cell growth and metabolism of xenobiotics. Thus, the present study for the first time revealed the main active ingredients and their associated pathways from marine diatoms using complex network approach.

Transformable bubble-filled alginate microfibers via vertical microfluidics.

A novel buoyancy-assisted vertical microfluidic setup has been developed to fabricate a new class of transformable bubble-filled hydrogel microfibers. A co-axial flow of an aqueous sodium-alginate solution enveloping an air phase was injected into a quiescent aqueous CaCl2 solution, through a vertically-oriented co-axial glass-capillary setup. This induced instantaneous gelation and produced bubble-filled calcium-alginate fibers. The surface-morphology of the resulting fibers was controlled from smooth to wavy by slowing down the gelation kinetics. The advantage of the buoyancy force acting on the fibers by the trapped air bubbles was taken not only to shape the fibers, but to transform them into several other novel hydrogel structures, such as water-filled segmented fibers, beaded microfibers, and threaded capsules. The ultimate transformability was demonstrated by the fibers being allowed to elongate and then undergo controlled destruction to produce uniform anisotropic micro-particles with a wide range of sizes and shapes from frustums to barrel and cylindrical types.

Net2Align: An Algorithm For Pairwise Global Alignment of Biological Networks.

The amount of data on molecular interactions is growing at an enormous pace, whereas the progress of methods for analysing this data is still lacking behind. Particularly, in the area of comparative analysis of biological networks, where one wishes to explore the similarity between two biological networks, this holds a potential problem. In consideration that the functionality primarily runs at the network level, it advocates the need for robust comparison methods. In this paper, we describe Net2Align, an algorithm for pairwise global alignment that can perform node-to-node correspondences as well as edge-to-edge correspondences into consideration. The uniqueness of our algorithm is in the fact that it is also able to detect the type of interaction, which is essential in case of directed graphs. The existing algorithm is only able to identify the common nodes but not the common edges. Another striking feature of the algorithm is that it is able to remove duplicate entries in case of variable datasets being aligned. This is achieved through creation of a local database which helps exclude duplicate links. In a pervasive computational study on gene regulatory network, we establish that our algorithm surpasses its counterparts in its results. Net2Align has been implemented in Java 7 and the source code is available as supplementary files.