cIAP1-based degraders induce degradation via branched ubiquitin architectures.

Targeted protein degradation through chemical hijacking of E3 ubiquitin ligases is an emerging concept in precision medicine. The ubiquitin code is a critical determinant of the fate of substrates. Although two E3s, CRL2VHL and CRL4CRBN, frequently assemble with proteolysis-targeting chimeras (PROTACs) to attach lysine-48 (K48)-linked ubiquitin chains, the diversity of the ubiquitin code used for chemically induced degradation is largely unknown. Here we show that the efficacy of cIAP1-targeting degraders depends on the K63-specific E2 enzyme UBE2N. UBE2N promotes degradation of cIAP1 induced by cIAP1 ligands and subsequent cancer cell apoptosis. Mechanistically, UBE2N-catalyzed K63-linked ubiquitin chains facilitate assembly of highly complex K48/K63 and K11/K48 branched ubiquitin chains, thereby recruiting p97/VCP, UCH37 and the proteasome. Degradation of neo-substrates directed by cIAP1-recruiting PROTACs also depends on UBE2N. These results reveal an unexpected role for K63-linked ubiquitin chains and UBE2N in degrader-induced proteasomal degradation and demonstrate the diversity of the ubiquitin code used for chemical hijacking.

Progressive Pattern Interleaver with Multi-Carrier Modulation Schemes and Iterative Multi-User Detection in IoT 6G Environments with Multipath Channels.

Sixth-generation (6G) wireless networks demand a more efficient implementation of non-orthogonal multiple access (NOMA) schemes for severe multipath fading environments to serve multiple users. Using non-orthogonal multiple access (NOMA) schemes in IoT 6G networks is a promising solution to allow multiple users to share the same spectral and temporal resource, increasing spectral efficiency and improving the network's capacity. In this work, we have evaluated the performance of a novel progressive pattern interleaver (PPI) employed to distinguish the users in interleaved division multiple access (IDMA) schemes, suggested by 3GPP guidelines as a NOMA scheme, with two multi-carrier modulation schemes known as single-carrier frequency-division multiple access (SC-FDMA) and orthogonal frequency-division multiplexing (OFDM), resulting in SC-FDMA-IDMA and OFDM-IDMA schemes. Both schemes are multi-carrier schemes with orthogonal sub-carriers to deal against inter-symbol interference (ISI) and orthogonal interleavers for the simultaneous access of multiple users. It has been suggested through simulation outcomes that PPI performance is adequate with SC-FDMA-IDMA and OFDM-IDMA schemes in terms of bit error rate (BER) under multipath channel conditions. Moreover, regarding bandwidth requirement and the implementation complexity of the transmitted interleaver structure, PPI is superior to the conventional random interleaver (RI).

Molecular characterization of 23 Y chromosomal STR markers in the Gurjar population of National Capital Region (NCR), India.

In the present study, DNA samples of 202 unrelated male individuals of Gurjar population were evaluated for the molecular diversity at 23 Y chromosomal Y-STR markers. Out of selected individuals, results showed 143 unique haplotypes. Highest degree of gene diversity (GD), polymorphic information content (PIC), and power of discrimination (PD) was observed as 0.7941, 0.7590, and 0.7902, respectively, for the locus DYS385a/b. Haplotype diversity (HD), gene diversity (GD), polymorphic information content (PIC), and power of discrimination (PD) was found to be 0.7079, 0.999999999989, 0.9999999996, and 0.999999999986, respectively, for the studied 23 Y-STR markers. Allele 11 of locus DYS392 was found to be the most frequent allele with the frequency of 0.762. In inter-population relationship, studied population showed genetic relatedness with the population of Jammu and Kashmir, India, and Ladakh, India. The haplotype data of the present study will not only enrich the existing Indian Y-STR data but will also be useful for forensic DNA application.

Forensic features and phylogenetic analyses of the population of Nayagarh (Odisha), India using 23 Y-STRs.

AIM: The present study was designed to explore the STR diversity and genomic history of the inhabitants of Nayagarh district of Odisha, India. We also tested the proficiency of the most recent, new generation PowerPlexR Y23 multiplex system for forensic characterisation and to decipher the phylogenetic affinities. SUBJECTS AND METHODS: The genetic diversity and polymorphism among 236 healthy unrelated male volunteers from Nayagarh district of Odisha, India was investigated. This investigation was carried out via 23 Y-chromosomal STRs using capillary electrophoresis. RESULT: A total 223 unique haplotypes were reported. Discrimination capacity (DC), gene diversity (GD) and power of discrimination (PD) were observed as 0.945, 0.999999999998333, and 0.99999999999794, respectively. Polymorphic information content (PIC) and matching probability (PM) were reported as 0.999999999925535 and 2.06 × 10-12, respectively. Simultaneously, the haplogroup analysis characterised with C2, E1b1a, E1b1b, G2a, H1, I2a, J2a, J2b, L, O, O1, O2, Q, R1a, R2, and T haplogroups, disclosing the possible geographical relatedness of the studied population to different areas of the world. CONCLUSION: Phylogenetic analysis with previously reported Indian and Asian populations showed the genetic closeness of the studied population to different Indian populations and the Bangladeshi population of Dhaka, whereas the Bhotra population of Odisha and Han population of China showed much less genetic affinity.

Haplogroup diversity in the Indian population using 23 Y-STRs.

BACKGROUND: A Y-STR polymorphism study is a convenient tool in molecular anthropology and forensic DNA analysis. AIM: Through standard ethical procedures, the proposed study explored the genetic scenario in male lineage in Madhya Pradesh, a central Indian state, by Y-STR genotyping and haplogroup studies. SUBJECTS AND METHODS: Five hundred and eleven unrelated male blood samples were directly amplified, and fragment separation was done using capillary electrophoresis to generate a Y-STR profile for 23 forensic relevant markers through PowerPlex® Y 23 multiplex system. The different statistical methods were applied for studying the forensic and genetics parameters. Subsequently, population comparison was performed by AMOVA, PCoA, and MDS plot, and Haplogroups were predicted with Whit Athey's haplogroup predictor tool. CONCLUSION: These data represented the potential value of the PowerPlex® Y-23 multiplex system for the forensic and human genetics application in the population of Madhya Pradesh, India. Simultaneously the Haplogroup analysis revealed information about the multi-geographic origin as well as multi-ethnic genetic affinities of the Madhya Pradesh population.

An evaluation of inter and intra population structure of Uttar Pradesh, inferred from 24 autosomal STRs.

AIM: The present study was designed to explore the STR diversity and genomic history of the inhabitants of the most populous subdivision of the country. A set of 24 hypervariable autosomal STRs was used to estimate the genetic diversity within the studied population. A panel of 15 autosomal STRs, which is most common in the previously reported data sets, was used to estimate the genetic diversity between the studied population, and obtained unique relations were reported here. METHOD: The genetic diversity and polymorphism among 636 individuals of different ethnic groups, residing in Bareilly, Pilibhit, Shahjahanpur, Gorakhpur, Jhansi, and Varanasi regions of Uttar Pradesh, India, was investigated. This investigation was carried out via 24 autosomal STRs. RESULT: The 24 loci studied showed the highest value of combined power of discrimination (CPD = 1), combined power of exclusion (CPE = 0.99999999985), combined paternity index (CPI = 6.10 × 109) and lowest combined matching probability (CPM = 7.90 × 10-31). CONCLUSION: The studied population showed genetic closeness with the population of Uttarakhand, the Jats of Delhi,the Jat Sikh (Punjab), and the population of Rajasthan. Among the tested loci, SE33 and Penta E were found to be most useful in terms of the highest discrimination power, lowest matching probability, the highest power of exclusion, and highest polymorphism information content for the Uttar Pradesh population .

Forensic characterization and genetic evaluation in the Central Indian population using 27 Y-STRs.

INTRODUCTION: Forensic characterization and genetic evaluation study in the 539 randomly selected unrelated adult healthy individuals belonging to the Central Indian population was undertaken. METHODS: The study was performed using a multiplex of 27 Y-STRs incoporated in Yfiler™ Plus multiplex kit. RESULTS: Out of 539 samples, 6 samples were observed for large deletion and tri-allelic patterns, which were removed from the analysis, and out of 533 samples, a total of 507 haplotypes were found, and out of these haplotypes, 482 unique haplotypes were found in this piece of work. The forensically important parameters, i.e., gene diversity (GD) and discrimination capacity (DC), were found to be 0.669 and 0.951, respectively, for the tested Y STR loci. The genetic data of this study will enrich the Y STR data bank and being used as a potential tool for forensic DNA and various genetic studies.

Genetic variation of 20 autosomal STRs in Jats belonging to Delhi, India.

The present study based on 20 autosomal STR polymorphism reveals the genetic diversity of the Jat population of Delhi, India (n = 120). A total of 240 alleles were observed for this study. The allele frequency ranged from 0.004 to 0.508. The studied loci followed the Hardy-Weinberg equilibrium (HWE), and the heterozygosity ranged from 0.658 to 0.908. The locus Penta-E was found the most polymorphic and discriminating in the studied population with the value 0.910 and 0.981, respectively, whereas the locus TPOX was found least polymorphic and discriminating with the value 0.612 and 0.833, respectively. The combined paternity index (CPI) was 1.46 × 109, and the probability of match (CPm) was 2.68 × 10-25 for all 20 autosomal STR loci. The generated data adds to the Indian population database. It will be used for forensic purposes and in other population-based genetic studies.

Genetic diversity and forensic characterization of 15 autosomal microsatellite markers in the North-east Indian Tripuri population.

This study was conducted to explore the genomic diversity and forensic characterization of 15 autosomal microsatellite markers in the East Indian Tripuri population. In the studied population, we observed 158 different alleles with the average 10.53 alleles per locus. The locus D2S1338 (PIC= 0.862) was found to be the most polymorphic wheres locus TPOX (PIC= 0.647) as the least polymorphic, among all the studied loci. The locus FGA was found with the highest number of effective alleles (Nall=19) whereas locus TH01 showed least number of effective alleles (Nall=6). The cumulative values for matching probability (CPm), power of discrimination (CPD), power of exclusion CPE), and paternity index (CPI) were found as 1.94×10-18, 1, 0.999998, and 4.8×105 respectively. The studied population showed genetic closeness with the Gorkha population. In neighbor-joining tree, Tripura population pooled with the population of Nepal and Tibet. The genetic data obtained from the present study will not only enrich the existing autosomal STR database but will also be useful for forensic DNA application and genealogical studies.

Genomic insight into Y-STR diversity in the population of Odisha, India.

This study evaluated the haplotype diversity of 17 Y chromosomal genetic markers among 202 unrelated males who were randomly selected in the population of Odisha, India. Out of total 196 haplotypes observed in this study, 190 were unique haplotypes. Forensic relevant parameters, viz., gene diversity (GD) and discrimination capacity (DC), were calculated as 0.999999998 and 0.970 respectively, for the studied population. The highest genetic diversity was observed at the locus DYS385a/b (0.9541) and lowest at the locus DYS437 (0.3326) among all the studied Y chromosomal loci. The polymorphic information content (PIC), power of discrimination (PD), and matching probability (PM) was found to be 0.999999965, 0.999999998, and 1.6×10-9 for the tested Y STR loci. The genetic data observed in this study would enrich the existing Y STR data of the Indian population and would also be useful for forensic application.

Forensic characterization and genomic diversity of Assam population viewed from 23 autosomal STRs.

In order to find out the genetic structure and characterize the forensic features of 23 autosomal STRs in the population of Assam, PowerPlex® Fusion 6C amplification kit was employed to genotype 292 unrelated individuals from Assam, India. A total of 79 different alleles were observed across 23 autosomal STRs with the corresponding frequency of alleles, which ranges from 0.002 to 0.406. Selected 23 loci were observed useful together with the highest value of combined discrimination power (CPD = 1), combined exclusion power (CPE = 0.999999999914), combined paternity index (CPI = 3.04 × 109), and all studied loci combined showing the lowest matching probability which is (CPM = 1.29 × 10-29). Additionally, in comparison with neighboring population, Assam population showed genetic closeness with Indian population. The genetic data of the present study will enrich the existing Indian autosomal DNA database and be useful for forensic and genealogical applications.

Genomic polymorphism in tribal population of Tripura: Signifying their closer affinity with the Nepalese and Tibetan populations.

BACKGROUND: India is the second most populous country in the world, which is aligned into various community segments. AIM: To evaluate the genetic diversity of the tribal population of Tripura, we carried out this study. SUBJECTS AND METHODS: 15 autosomal STR markers were used for investigation of genomic diversity, inter- and intra- population relationships among the studied population, and other reported neighbouring tribal and caste populations. RESULTS: Results indicated that the tribals of Tripura share their closer genetic affinity with the Trans-Himalayan (Nepalese, Bhutanese and Tibetan) populations. Locus D18S51 was found as the most discriminatory among all the studied loci with uppermost discrimination power (PD = 0.964) and lowest matching probability (Pm = 0.036) in the study. All the evaluated loci herein are useful, having the maximum value of combined power of discrimination (CPD = 1), combined power of exclusion (CPE = 0.99999746), combined paternity index (CPI = 3 × 105) and combined matching probability (CPm = 2.12 × 1 0 -7). CONCLUSION: Population genetic analysis showed that the studied population has genetic relatedness with the compared Nepalese and Tibetan populations i.e., Kathmandu, Tibet, Newar, and Gorkhas, followed by eastern and central Indian populations.

PEDF deficiency increases the susceptibility of rd10 mice to retinal degeneration.

The SERPINF1 gene encodes pigment epithelium-derived factor (PEDF), a member of the serpin superfamily with neurotrophic and antiangiogenic properties in the retina. We hypothesized that absence of PEDF would lead to increased stress-associated retinal degeneration in Serpinf1 null mice. Accordingly, using a Serpinf1 null mouse model, we investigated the impact of PEDF absence on retinal morphology, and susceptibility to induced and inherited retinal degeneration. We studied the pattern of Serpinf1 expression in the mouse retina layers. PEDF protein was detected by western blotting. Transmission electron microscopy was performed on mouse retina. Serpinf1 null mice and wild type littermates were injected with NaIO3 (30 mg/kg body weight) intraperitonially. At post-injection day 1, 3, 4, 6 and 8 mice were euthanized, and eyes were enucleated. Serpinf1 null and rd10 double mutant mice were generated and their eyes enucleated at different time points from post-natal day 15 to post-natal day 28. Enucleated eyes were processed for hematoxylin and eosin staining and histopathological evaluations. We found that Serpinf1 was expressed in the retinal pigment epithelium, in the inner nuclear layer and in the ganglion cell layer, but undetectable in the outer nuclear layer of wild type mice. Plasma PEDF protein levels were undetectable in Serpinf1 null animals. RPE atrophy and retinal thinning were observed in NaIO3-treated wild type mice that progressed with time post-injection. NaIO3-treated Serpinf1 null mice showed comparatively better retinal morphology than wild type mice at day 4 post-injection. However, the absence of PEDF in Serpinf1 null x rd10 mice increased the susceptibility to retinal degeneration relative to that of rd10 mice. We concluded that histopathological evaluation of retinas lacking PEDF showed that removal of the Serpinf1 gene may activate PEDF-independent compensatory mechanisms to protect the retina against oxidative stress, while it increases the susceptibility to degenerate the retina in inherited retinal degeneration models.

Estimating genetic polymorphism in Bhuiyan population of eastern India using 20 autosomal STR loci.

We conducted a study of 182 unrelated adult individuals belonging to Bhuiyan population resident of Eastern India in order to estimate genetic polymorphism by using 20 autosomal STR loci. The results obtained from this study were compared with the published data of Indian and neighbouring countries' populations. This research study is expected to contribute significantly to forensic investigations for human identification and parentage testing.

Allelic frequency database of 15 polymorphic autosomal STRs in the Malayalam-speaking population of Kerala, India.

In this study, we assessed and established an allelic frequency database of Malayalam-speaking population of south western Indian state Kerala, using 15 polymorphic short tandem repeats (STRs) genetic markers. For this study, 464 unrelated healthy individuals were randomly selected following the ethical standards. The most polymorphic and most discriminating locus was D2S1338, with a value of 0.860 and 0.968, respectively. The range of heterozygosity extended from a minimum of 0.668 (TH01) to a maximum of 0.847 (D2S1338). The combined discrimination power (CPD) and combined exclusion power (CPE) were 1 and 0.999997861, respectively, for all 15 autosomal STR loci under study. The combined probability of match (CPM) and combined paternity index (CPI) for all 15 autosomal STR loci were found to be 9.85 × 10-19 and 4.18 × 105, respectively.

Forensic effectiveness and genetic distribution of 23 autosomal STRs included in Verifiler PlusTM multiplex in a population sample from Madhya Pradesh, India.

We report here the first ever global study on genetic polymorphism using a Verifiler PlusTM autosomal STR multiplex system. The study evaluated genetic characteristics of 23 autosomal STRs in 200 unrelated residents of Guna district of Madhya Pradesh, India. Allele frequencies and forensic parameters are reported. Population comparison analysis was also performed using NJ tree and PCA plot. Penta E marker showed highest power of discrimination (0.938) among all 23 studied markers. The study also presents the first ever global forensic assessment in Indian population on D6S1043 marker (PD 0.937). The results demonstrated that all the 23 markers were highly polymorphic and the Verifiler PlusTM kit is suitable for forensic purposes in Indian population.

Genomic blueprint of population of Rajasthan based on autosomal STR markers.

Aim: Genetic diversity and forensic efficacy of 20 autosomal STR genetic markers were investigated in a highly diverse population of Rajasthan, a state in north-western India.Subjects and methods: In this study, 317 blood samples from unrelated healthy individuals were directly amplified using the PowerPlex® 21 multiplex system (Promega). Amplified products were separated by capillary electrophoresis using a Genetic Analyser -3500 XL (Thermo Fisher Scientific). The data thus obtained was statistically analysed using population genetic software.Results: The studied population showed genetic affinity with the geographically close populations. The locus Penta-E was found to be the most polymorphic with a value of 0.90 in the studied population. The combined discrimination power (CPD) and combined power of exclusion (CPE) were observed as >0.999999999 and 0.999999997, respectively, for all the studied 20 autosomal STR loci. The combined probability of match (CPm) was 1.39 × 10-25 and combined paternity index (CPI) was 3.66 × 108 for all the studied loci.Conclusion: The results conclusively support the hypothesis that the studied autosomal STR loci are polymorphic in nature and, besides being useful in forensic applications they can also be applied in anthropological and other population genetic studies. This study supports the 'isolation-by-distance' model. Genetic data obtained from this study will enrich the population data bank.

Paclitaxel-Loaded Colloidal Silica and TPGS-Based Solid Self-Emulsifying System Interferes Akt/mTOR Pathway in MDA-MB-231 and Demonstrates Anti-tumor Effect in Syngeneic Mammary Tumors.

A solid self-emulsifying drug delivery system (SEDDS) of paclitaxel (PTX) was developed that could enhance its oral bioavailability and neutralize other niggles associated with conventional delivery systems of PTX. TPGS-centered SEDDS containing PTX was optimized by Box-Behnken experimental design and then formulated as fumed colloidal silica-based solid SEDDS microparticles (Si-PTX-S-SEDDS). AFM analysis exhibited round-shaped microparticles of approximately 2-3 µM diameter, whereas after reconstitution, particle size measurement showed nanoemulsion droplets of 30.00 ± 2.00 nm with a zeta potential of 17.38 ± 2.88 mV. Si-PTX-S-SEDDS displayed improved efficacy proven by reduced IC50 of 0.19 ± 0.03 µM against MDA-MB-231 cells and a 45.83-fold higher cellular uptake in comparison to free PTX. Molecular mechanistic studies showed mitochondria-mediated intrinsic pathway of apoptosis following Akt/mTOR pathway, which is accompanied by survivin downregulation. Rhodamine 123 assay and chylomicron flow blocking studies revealed P-gp inhibition potential and lymphatic uptake of Si-PTX-S-SEDDS, responsible for over 4-fold increment in oral bioavailability compared to PTX administered as Taxol. In vivo anti-tumor studies in syngeneic mammary tumor model in SD rats revealed higher efficacy of Si-PTX-S-SEDDS as evident from significant reduction in tumor burden. In total, the developed Si-PTX-S-SEDDS formulation was found as an appropriate option for oral delivery of PTX.

Forensic genetic analysis of population of Madhya Pradesh with PowerPlex Fusion 6C™ Multiplex System.

Performance of PowerPlex Fusion 6C kit (PP F6C) was assessed in 374 unrelated individuals belonging to Madhya Pradesh, an Indian state. The study evaluated the forensic parameters for the loci included in PP F6C Multiplex System. The combined discrimination power (CPD) and combined exclusion power (CPE) were 1 and 0.999999995, respectively, for all 23 autosomal STR loci. SE33 showed the greatest power of discrimination (0.990) in the studied population, whereas TPOX showed the lowest (0.843). The availability of three Y-STR loci in the Multiplex System is suitable for assessing male contribution and amelogenin deletion in a single Multiplex PCR simultaneously. The study also presents the first global report on polymorphism in the Indian population on SE 33 autosomal STR loci and PP Fusion 6C Multiplex System. The results revealed that the studied STR Multiplex System is highly polymorphic and suitable for forensic purposes.

Genetic data for PowerPlex 21™ autosomal and PowerPlex 23 Y-STR™ loci from population of the state of Uttar Pradesh, India.

In the present study, the statistical forensic parameters were evaluated for the loci present in PowerPlex 21 autosomal and PowerPlex 23 Y-STR multiplex systems in 168 unrelated individuals living in the state of Uttar Pradesh, India. The combined discrimination power (CPD) and combined exclusion power (CPE) was 1 and 0.999999 respectively for all 20 autosomal STR loci. Penta E showed the greatest (0.980) and CSF1PO showed the lowest (0.855) power of discrimination in the studied population. The haplotype diversity for 23 Y-STR loci was observed to be 0.999. The study also presents the first global report on polymorphism on D1S1656, D6S1043 and D12S391 autosomal STR loci in the Indian population. The resulting data revealed that these STR multiplex systems are highly polymorphic and can be used for forensic purposes.