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The legislative framework against organ trafficking in India has become an imperative issue in recent years due to the increasing incidence of illegal organ trade within the country. This abstract explores the legislative measures adopted by India to combat organ trafficking, focusing on the key laws, regulations, and initiatives introduced to address this grave concern. It examines the legal provisions pertaining to organ transplantation, the prohibition of organ trade, and the protection of vulnerable individuals from exploitation. The analysis also includes an assessment of the effectiveness of the legislative framework, highlighting the challenges and potential areas for improvement. By understanding the existing laws and their implementation, this abstract aims to contribute to the ongoing discourse on organ trafficking and inform policymakers, lawmakers, and stakeholders about the crucial legislative steps required to combat this heinous crime in India. [ABSTRACT FROM AUTHOR]

Sign language is the art of communicating using hand gestures. The communication between an impaired person and the one who doesn't understand sign language could be easy using the computer as a tool. Inconsistent previous works in the field posed a need for more stable and effective model. We take an efficient step in order to tackle the problem of automatic fingerspelling recognition system using the concept that in order to efficiently perceive things, human brain alters some of the information. Moreover, the comparison between previous works and our model is mentioned systematically in this paper. Also, the model is capable to classify the real-time sign without dependency on environment. [ABSTRACT FROM AUTHOR]

Human pathogens need to overcome an elaborate network of host defense mechanisms in order to establish their infection, colonization, proliferation and eventual dissemination. The interaction of pathogens with different effector molecules of the immune system results in their neutralization and elimination from the host. The complement system is one such integral component of innate immunity that is critically involved in the early recognition and elimination of the pathogen. Hence, under this immune pressure, all virulent pathogens capable of inducing active infections have evolved immune evasive strategies that primarily target the complement system, which plays an essential and central role for host defense. Recent reports on several bacterial pathogens have elucidated the molecular mechanisms underlying complement evasion, inhibition of opsonic phagocytosis and cell lysis. This review aims to comprehensively summarize the recent findings on the various strategies adopted by pathogenic bacteria to escape complement-mediated clearance. [ABSTRACT FROM AUTHOR]

KAT6A, and its paralog KAT6B, are histone lysine acetyltransferases (HAT) that acetylate histone H3K23 and exert an oncogenic role in several tumor types including breast cancer where KAT6A is frequently amplified/overexpressed. However, pharmacologic targeting of KAT6A to achieve therapeutic benefit has been a challenge. Here we describe identification of a highly potent, selective, and orally bioavailable KAT6A/KAT6B inhibitor CTx-648 (PF-9363), derived from a benzisoxazole series, which demonstrates anti-tumor activity in correlation with H3K23Ac inhibition in KAT6A over-expressing breast cancer. Transcriptional and epigenetic profiling studies show reduced RNA Pol II binding and downregulation of genes involved in estrogen signaling, cell cycle, Myc and stem cell pathways associated with CTx-648 anti-tumor activity in ER-positive (ER+) breast cancer. CTx-648 treatment leads to potent tumor growth inhibition in ER+ breast cancer in vivo models, including models refractory to endocrine therapy, highlighting the potential for targeting KAT6A in ER+ breast cancer. [Display omitted] • Discovery of CTx-648/PF-9363: a potent, selective, orally bioavailable KAT6A/B inhibitor • CTx-648/PF-9363 inhibits H3K23Ac leading to growth suppression in breast cancer models • CTx-648/PF-9363 anti-tumor activity enriches in ER+/luminal & KAT6A high breast cancer • In ER+ breast cancer, CTx-648/PF-9363 represses ER, cell cycle, Myc and stem cell pathways Sharma et al. describe the discovery and chemical optimization of a potent, selective, orally bioavailable inhibitor of KAT6A/B with anti-tumor activity in ER+ breast cancer. [ABSTRACT FROM AUTHOR]

Iris recognition has become an important tool for human authentication. An efficient and robust iris recognition model based on sparse representation using compressive sensing and k -nearest subspace (segments) has been proposed; k -nearest subspace approach is used for short listing the classes to reduce the time. The shortlisted candidates are divided into sectors and the sparse recognition is applied to each sector. Three classifiers: k -nearest distance classifier, Sector based classifier and Cumulative Sparse Concentration Index (CSCI) based classifiers have been used. An additive function based classifier combination scheme has been adopted in which each classifier is associated with a weight. Genetic algorithm is used to learn the weight of each of the classifier. Results obtained on different databases show that the scheme is highly robust with FAR almost zero. [ABSTRACT FROM AUTHOR]

We consider the problem of learning preferences over trajectories for mobile manipulators such as personal robots and assembly line robots. The preferences we learn are more intricate than simple geometric constraints on trajectories; they are rather governed by the surrounding context of various objects and human interactions in the environment. We propose a coactive online learning framework for teaching preferences in contextually rich environments. The key novelty of our approach lies in the type of feedback expected from the user: the human user does not need to demonstrate optimal trajectories as training data, but merely needs to iteratively provide trajectories that slightly improve over the trajectory currently proposed by the system. We argue that this coactive preference feedback can be more easily elicited than demonstrations of optimal trajectories. Nevertheless, theoretical regret bounds of our algorithm match the asymptotic rates of optimal trajectory algorithms. We implement our algorithm on two high-degree-of-freedom robots, PR2 and Baxter, and present three intuitive mechanisms for providing such incremental feedback. In our experimental evaluation we consider two context rich settings, household chores and grocery store checkout, and show that users are able to train the robot with just a few feedbacks (taking only a few minutes). [ABSTRACT FROM AUTHOR]

Summary: Cancer cells typically exhibit aberrant DNA methylation patterns that can drive malignant transformation. Whether cancer cells are dependent on these abnormal epigenetic modifications remains elusive. We used experimental and bioinformatic approaches to unveil genomic regions that require DNA methylation for survival of cancer cells. First, we surveyed the residual DNA methylation profiles in cancer cells with highly impaired DNA methyltransferases. Then, we clustered these profiles according to their DNA methylation status in primary normal and tumor tissues. Finally, we used gene expression meta-analysis to identify regions that are dependent on DNA methylation-mediated gene silencing. We further showed experimentally that these genes must be silenced by DNA methylation for cancer cell survival, suggesting these are key epigenetic events associated with tumorigenesis. [ABSTRACT FROM AUTHOR]

Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Global changes in the epigenetic landscape are a hallmark of cancer. The initiation and progression of cancer, traditionally seen as a genetic disease, is now realized to involve epigenetic abnormalities along with genetic alterations. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer including DNA methylation, histone modifications, nucleosome positioning and non-coding RNAs, specifically microRNA expression. The reversible nature of epigenetic aberrations has led to the emergence of the promising field of epigenetic therapy, which is already making progress with the recent FDA approval of three epigenetic drugs for cancer treatment. In this review, we discuss the current understanding of alterations in the epigenetic landscape that occur in cancer compared with normal cells, the roles of these changes in cancer initiation and progression, including the cancer stem cell model, and the potential use of this knowledge in designing more effective treatment strategies. [ABSTRACT FROM PUBLISHER]

Due to their important function in cancer, lysine acetyltransferases (KATs) are an emerging class of drug targets. Small-molecule KAT inhibitors have been discovered targeting bromodomains and acetyl-CoA catalytic domains. CREB binding protein (CREBBP)/EP300 bromodomain and KAT6A/B catalytic inhibitors are in early clinical development. New approaches to degrade KATs or redirect their activity to unique promoters offer new targeting strategies and the potential to specifically target KAT activity in cancer tissues. Lysine acetyltransferases (KATs) are a family of epigenetic enzymes involved in the regulation of gene expression; they represent a promising class of emerging drug targets. The frequent molecular dysregulation of these enzymes, as well as their mechanistic links to biological functions that are crucial to cancer, have led to exploration around the development of small-molecule inhibitors against KATs. Despite early challenges, recent advances have led to the development of potent and selective enzymatic and bromodomain (BRD) KAT inhibitors. In this review we discuss the discovery and development of new KAT inhibitors and their application as oncology therapeutics. Additionally, new chemically induced proximity approaches are presented, offering opportunities for unique target selectivity profiles and tissue-specific targeting of KATs. Emerging clinical data for CREB binding protein (CREBBP)/EP300 BRD inhibitors and KAT6 catalytic inhibitors indicate the promise of this target class in cancer therapeutics. [ABSTRACT FROM AUTHOR]

In the quest for greater autonomy, there is an increasing need for solutions that would enable a large set of robots to coalesce and perform complicated multi-robot tasks. This problem, also known as the multi-robot coalition formation problem has been traditionally approached as a single objective optimization problem. However, robots in the real world have to optimize multiple conflicting criteria such as battery life, number of completed tasks, and distance traveled. Researchers have only recently addressed the robot coalition formation problem as a multi-objective optimization problem, however the proposed solutions have computational bottlenecks that make them unsuitable for real time robotic applications. In this paper we address the issue of scalability by proposing parallelized algorithms in the CUDA programming framework. NSGA-II and PAES algorithm have been parallelized due to their suitability to the coalition formation domain as outlined in our previous work. The parallelized versions of these algorithms have been applied to both the additive and non-additive coalition formation environments. Simulations have been performed in the player/stage environment to validate the applicability of our approach to real robot situations. Results establish that the multi-point PAES parallel variant yields significant performance gains in terms of running time and solution quality when the problem is scaled to deal with large inputs. This suggests that the algorithm may be viable for real time robotic applications. Experiments demonstrate significant speedup when the proposed parallel algorithms were compared with the serial solutions proposed earlier. [ABSTRACT FROM AUTHOR]

Inhibitors of dihydroorotate dehydrogenase (DHODH), a key enzyme for de novo synthesis of pyrimidine nucleotides, have failed in clinical trials for various cancers despite robust efficacy in preclinical animal models. To probe for druggable mediators of DHODH inhibitor resistance, we performed a combination screen with a small molecule library against pancreatic cancer cell lines that are highly resistant to the DHODH inhibitor brequinar (BQ). The screen revealed that CNX-774, a preclinical Bruton tyrosine kinase (BTK) inhibitor, sensitizes resistant cell lines to BQ. Mechanistic studies showed that this effect is independent of BTK and instead results from inhibition of equilibrative nucleoside transporter 1 (ENT1) by CNX-774. We show that ENT1 mediates BQ resistance by taking up extracellular uridine, which is salvaged to generate pyrimidine nucleotides in a DHODH-independent manner. In BQ-resistant cell lines, BQ monotherapy slowed proliferation and caused modest pyrimidine nucleotide depletion, whereas combination treatment with BQ and CNX-774 led to profound cell viability loss and pyrimidine starvation. We also identify N-acetylneuraminic acid accumulation as a potential marker of the therapeutic efficacy of DHODH inhibitors. In an aggressive, immunocompetent pancreatic cancer mouse model, combined targeting of DHODH and ENT1 dramatically suppressed tumor growth and prolonged mouse survival. Overall, our study defines CNX-774 as a previously uncharacterized ENT1 inhibitor and provides strong proof of concept support for dual targeting of DHODH and ENT1 in pancreatic cancer. [ABSTRACT FROM AUTHOR]

Proper DNA methylation patterns are essential for mammalian development and differentiation. DNA methyltransferases (DNMTs) primarily establish and maintain global DNA methylation patterns; however, the molecular mechanisms for the generation and inheritance of methylation patterns are still poorly understood. We used sucrose density gradients of nucleosomes prepared by partial and maximum micrococcal nuclease digestion, coupled with Western blot analysis to probe for the interactions between DNMTs and native nucleosomes. This method allows for analysis of the in vivo interactions between the chromatin modification enzymes and their actual nucleosomal substrates in the native state. We show that little free DNA methyltransferase 3A and 3B (DNMT3A/3B) exist in the nucleus and that almost all of the cellular contents of DNMT3A/3B, but not DNMT1, are strongly anchored to a subset of nucleosomes. This binding of DNMT3A/3B does not require the presence of other well-known chromatin-modifying enzymes or proteins, such as proliferating cell nuclear antigen, heterochromatin protein 1, methyl-CpG binding protein 2, Enhancer of Zeste homolog 2, histone deacetylase 1, and UHRF1, but it does require an intact nucleosomal structure. We also show that nucleosomes containing methylated SINE and LINE elements and CpG islands are the main sites of DNMT3A/3B binding. These data suggest that inheritance of DNA methylation requires cues from the chromatin component in addition to hemimethylation. [ABSTRACT FROM AUTHOR]

It was recently shown that a large portion of the human transcriptome can originate from within repetitive elements, leading to ectopic expression of protein-coding genes. However the mechanism of transcriptional activation of repetitive elements has not been definitively elucidated. For the first time, we directly demonstrate that hypomethylation of retrotransposons can cause altered gene expression in humans. We also reveal that active LINE-1s switch from a tetranucleosome to dinucleosome structure, acquiring H2A.Z- and nucleosome-free regions upstream of TSSs, previously shown only at active single-copy genes. Hypomethylation of a specific LINE-1 promoter was also found to induce an alternate transcript of the MET oncogene in bladder tumors and across the entire urothelium of tumor-bearing bladders. These data show that, in addition to contributing to chromosomal instability, hypomethylation of LINE-1s can alter the functional transcriptome and plays a role not only in human disease but also in disease predisposition. [ABSTRACT FROM AUTHOR]