To Ub or not to Ub: The epic dilemma of histones that regulate gene expression and epigenetic cross-talk.

A dynamic array of histone post-translational modifications (PTMs) regulate diverse cellular processes in the eukaryotic chromatin. Among them, histone ubiquitination is particularly complex as it alters nucleosome surface area fostering intricate cross-talk with other chromatin modifications. Ubiquitin signaling profoundly impacts DNA replication, repair, and transcription. Histones can undergo varied extent of ubiquitination such as mono, multi-mono, and polyubiquitination, which brings about distinct cellular fates. Mechanistic studies of the ubiquitin landscape in chromatin have unveiled a fascinating tapestry of events that orchestrate gene regulation. In this review, we summarize the key contributors involved in mediating different histone ubiquitination and deubiquitination events, and discuss their mechanism which impacts cell transcriptional identity and DNA damage response. We also focus on the proteins bearing epigenetic reader modules critical in discerning site-specific histone ubiquitination, pivotal for establishing complex epigenetic crosstalk. Moreover, we highlight the role of histone ubiquitination in different human diseases including neurodevelopmental disorders and cancer. Overall the review elucidates the intricate orchestration of histone ubiquitination impacting diverse cellular functions and disease pathogenesis, and provides insights into the current challenges of targeting them for therapeutic interventions.

Human testis-specific Y-encoded protein-like protein 5 is a histone H3/H4-specific chaperone that facilitates histone deposition in vitro.

DNA and core histones are hierarchically packaged into a complex organization called chromatin. The nucleosome assembly protein (NAP) family of histone chaperones is involved in the deposition of histone complexes H2A/H2B and H3/H4 onto DNA and prevents nonspecific aggregation of histones. Testis-specific Y-encoded protein (TSPY)-like protein 5 (TSPYL5) is a member of the TSPY-like protein family, which has been previously reported to interact with ubiquitin-specific protease USP7 and regulate cell proliferation and is thus implicated in various cancers, but its interaction with chromatin has not been investigated. In this study, we characterized the chromatin association of TSPYL5 and found that it preferentially binds histone H3/H4 via its C-terminal NAP-like domain both in vitro and ex vivo. We identified the critical residues involved in the TSPYL5-H3/H4 interaction and further quantified the binding affinity of TSPYL5 toward H3/H4 using biolayer interferometry. We then determined the binding stoichiometry of the TSPYL5-H3/H4 complex in vitro using a chemical cross-linking assay and size-exclusion chromatography coupled with multiangle laser light scattering. Our results indicate that a TSPYL5 dimer binds to either two histone H3/H4 dimers or a single tetramer. We further demonstrated that TSPYL5 has a specific affinity toward longer DNA fragments and that the same histone-binding residues are also critically involved in its DNA binding. Finally, employing histone deposition and supercoiling assays, we confirmed that TSPYL5 is a histone chaperone responsible for histone H3/H4 deposition and nucleosome assembly. We conclude that TSPYL5 is likely a new member of the NAP histone chaperone family.

Molecular characterization of substrate-induced ubiquitin transfer by UBR7-PHD finger, a newly identified histone H2BK120 ubiquitin ligase.

Monoubiquitination of histone H2B at lysine 120 plays a vital role in active transcription and DNA damage response pathways. Ubiquitin protein ligase E3 component N-recognin 7 (UBR7) has been recently identified as an H2BK120 monoubiquitin ligase. However, the molecular details of its ubiquitin transfer mechanism are not well understood. Here, we report that the plant homeodomain (PHD) finger of UBR7 is essential for its association with E2 UbcH6 and consequent ubiquitin transfer to its substrate histone H2B. We also identified the critical region of UbcH6 involved in this function and shown that the residues stretching from 114 to 125 of histone H2B C-terminal tail are sufficient for UBR7/UbcH6-mediated ubiquitin transfer. We also employed antibody-independent mass spectrometry to confirm UBR7-mediated ubiquitination of the H2B C-terminal tail. We demonstrated that the PHD finger of UBR7 forms a dimer and this dimerization is essential for ubiquitination of histone H2B. We mapped the critical residues involved in the dimerization and mutation of these residues that abrogate E3 ligase activity and are associated with cancer. Furthermore, we compared the mode of ubiquitin discharge from UbcH6 mediated by UBR7 and RING finger protein 20 (RNF20) through a thioester hydrolysis assay. Interestingly, binding of substrate H2B to UBR7 induces a conformational change in the PHD finger, which triggers ubiquitin transfer from UbcH6. However, the RNF20 RING finger alone is sufficient to promote the release of ubiquitin from UbcH6. Overall, the mechanism of ubiquitin transfer by the newly identified E3 ubiquitin ligase UBR7 is markedly different from that of RNF20.

Scalable Estimation of Epidemic Thresholds via Node Sampling.

Infectious or contagious diseases can be transmitted from one person to another through social contact networks. In today's interconnected global society, such contagion processes can cause global public health hazards, as exemplified by the ongoing Covid-19 pandemic. It is therefore of great practical relevance to investigate the network transmission of contagious diseases from the perspective of statistical inference. An important and widely studied boundary condition for contagion processes over networks is the so-called epidemic threshold. The epidemic threshold plays a key role in determining whether a pathogen introduced into a social contact network will cause an epidemic or die out. In this paper, we investigate epidemic thresholds from the perspective of statistical network inference. We identify two major challenges that are caused by high computational and sampling complexity of the epidemic threshold. We develop two statistically accurate and computationally efficient approximation techniques to address these issues under the Chung-Lu modeling framework. The second approximation, which is based on random walk sampling, further enjoys the advantage of requiring data on a vanishingly small fraction of nodes. We establish theoretical guarantees for both methods and demonstrate their empirical superiority.

A New Multi-resolution Analysis Method for Electrooculography Signals.

Electrooculography (EOG) signals indicate the degree and direction of eye movements. Hence, EOG signals have been useful in eye movement controlled rehabilitation systems. Denoising and accurate identification of the type of eye movement in EOG signals are the major challenges in their analysis. The state-of-the-art techniques for EOG signal analysis concerning denoising and eye movement extraction are based on multi-resolution analysis using wavelet bases, such as Haar or Daubechies. However, these wavelets are designed for general purpose signal processing applications and hence are not optimized for the EOG signal structures. In this paper, we propose a new multi-resolution basis specific to the analysis of EOG signals. The scaling and wavelet functions for the basis are derived from the signatures of blinks and saccades respectively, and hence we name them as blinklets and saclets accordingly, thereby forming a new multi-resolution basis. These descriptors are found to be more effective than standard wavelets for EOG signals, signal denoising, and for identifying the different eye movement signatures such as saccades, blinks, smooth pursuits, and fixations, as tested on the Physiosig and Centre for Biomedical Cybernetics Eye Movement (CBC-EM) EOG Databases.

Atypical plant homeodomain of UBR7 functions as an H2BK120Ub ligase and breast tumor suppressor.

The roles of Plant Homeodomain (PHD) fingers in catalysis of histone modifications are unknown. We demonstrated that the PHD finger of Ubiquitin Protein Ligase E3 Component N-Recognin7 (UBR7) harbors E3 ubiquitin ligase activity toward monoubiquitination of histone H2B at lysine120 (H2BK120Ub). Purified PHD finger or full-length UBR7 monoubiquitinated H2BK120 in vitro, and loss of UBR7 drastically reduced H2BK120Ub genome-wide binding sites in MCF10A cells. Low UBR7 expression was correlated with occurrence of triple-negative breast cancer and metastatic tumors. Consistently, UBR7 knockdown enhanced the invasiveness, induced epithelial-to-mesenchymal transition and promoted metastasis. Conversely, ectopic expression of UBR7 restored these cellular phenotypes and reduced tumor growth. Mechanistically, UBR7 loss reduced H2BK120Ub levels on cell adhesion genes, including CDH4, and upregulated the Wnt/ß-Catenin signaling pathway. CDH4 overexpression could partially revert UBR7-dependent cellular phenotypes. Collectively, our results established UBR7 as a histone H2B monoubiquitin ligase that suppresses tumorigenesis and metastasis of triple-negative breast cancer.

An evaluation of multi-probe locality sensitive hashing for computing similarities over web-scale query logs.

Many modern applications of AI such as web search, mobile browsing, image processing, and natural language processing rely on finding similar items from a large database of complex objects. Due to the very large scale of data involved (e.g., users' queries from commercial search engines), computing such near or nearest neighbors is a non-trivial task, as the computational cost grows significantly with the number of items. To address this challenge, we adopt Locality Sensitive Hashing (a.k.a, LSH) methods and evaluate four variants in a distributed computing environment (specifically, Hadoop). We identify several optimizations which improve performance, suitable for deployment in very large scale settings. The experimental results demonstrate our variants of LSH achieve the robust performance with better recall compared with "vanilla" LSH, even when using the same amount of space.

A Multimodal System for Assessing Alertness Levels Due to Cognitive Loading.

This paper proposes a scheme for assessing the alertness levels of an individual using simultaneous acquisition of multimodal physiological signals and fusing the information into a single metric for quantification of alertness. The system takes electroencephalogram, high-speed image sequence, and speech data as inputs. Certain parameters are computed from each of these measures as indicators of alertness and a metric is proposed using a fusion of the parameters for indicating alertness level of an individual at an instant. The scheme has been validated experimentally using standard neuropsychological tests, such as the Visual Response Test (VRT), Auditory Response Test (ART), a Letter Counting (LC) task, and the Stroop Test. The tests are used both as cognitive tasks to induce mental fatigue as well as tools to gauge the present degree of alertness of the subject. Correlation between the measures has been studied and the experimental variables have been statistically analyzed using measures such as multivariate linear regression and analysis of variance. Correspondence of trends obtained from biomarkers and neuropsychological measures validate the usability of the proposed metric.

Evolutionary perspective on the origin of Haitian cholera outbreak strain.

Cholera epidemic has not been reported in Haiti for at least 100 years, although cholera has been present in Latin America since 1991. Surprisingly, the recent cholera epidemic in Haiti (October 2010) recorded more than 250,000 cases and 4000 deaths in the first 6 months and became one of the most explosive and deadly cholera outbreak in recent history. In the present study, we conducted genomic analyses of pathogenicity islands of three Haitian Vibrio cholerae strains and compared them with nine different V. cholerae O1 El Tor genomes. Although CIRS101 is evolutionarily most similar to the Haitian strains, our study also provides some important differences in the genetic organization of pathogenicity islands of Haitian strains with CIRS101. Evolutionary analysis suggests that unusual functional constraints have been imposed on the Haitian strains and we hypothesize that amino acid substitution is more deleterious in Haitian strains than in nonHaitian strains.

Persistently elevated laboratory markers of thrombosis and fibrinolysis after clinical recovery in malaria points to residual and smouldering cellular damage.

Screening coagulation tests and assays for thrombosis and fibrinolysis were performed in 80 cases of malaria at presentation and during the course of the disease. Close correlation between the degree of thrombocytopenia (observed in >97% cases) and the presence hemorrhagic manifestations at presentation, and improvement in the platelet count in parallel with clinical recovery emphasised the role of platelets in the pathogenesis of coagulopathy in malaria. A potential selection bias resulting from inclusion of only patients admitted at a tertiary care hospital could explain the higher incidence (27.5%) of clinical bleeding observed in this study compared to that reported in the literature. Although a significant correlation between overt bleeding and abnormal PT/INR and APTT (observed in 20-37% cases) could not be demonstrated, a good correlation existed between normal screening coagulation tests and the absence of bleeding complications. Elevated D-Dimer and FDP levels in almost all cases (90%) of both types of malaria confirmed the high prevalence of disseminated intravascular coagulation and fibrinolysis. A correlation between rising D-Dimer levels and the incidence of bleeding was observed. Follow up studies in six cases with complications showed normalization of platelet counts and of screening coagulation assays with clinical recovery. D-Dimer and FDP levels however, remained elevated in most of these cases indicating the continuation of a smouldering coagulopathy even after full clinical recovery possibly due to the persistence of residual damage to the cells caused by the parasitic infection. Knowledge of this fact is important for avoiding unnecessary investigations and longer hospital stay in patients admitted with malaria.

Agrofuels capitalism: a view from political economy.

This article considers the global expansion of agrofuels feedstock production from a political economy perspective. It considers and dismisses the environmental and pro-poor developmental justifications attached to agrofuels. To local populations and direct producers, the specific destination of the crop as fuel, food, cosmetics or other final uses in faraway places is probably of less interest than the forms of (direct or indirect) appropriation of their land and the forms of their insertion or exclusion as producers in global commodity chains. Global demand for both agrofuels and food is stimulating new forms (or the resurgence of old forms) of corporate land grabbing and expropriation, and of incorporation of smallholders in contracted production. Drawing both on recent studies on agrofuels expansion and on the political economy literature on agrarian transition and capitalism in agriculture, this article raises the question whether "agrofuels capitalism" is in any way essentially different from other forms of capitalist agrarian monocrop production, and in turn whether the agrarian transitions involved require new tools of analysis.

A prospective and randomized study of radiotherapy, sequential chemotherapy radiotherapy and concomitant chemotherapy-radiotherapy in unresectable non small cell carcinoma of the lung.

PURPOSE: Treatment of advanced Non small cell lung cancer (NSCLC) often produces dismal results. Combination of available treatment modalities has reportedly improved the outcome. A prospectively randomized trial was conducted, comparing combined treatment modalities versus radiotherapy alone, in treatment of unresectable NSCLC. MATERIALS AND METHODS: A total of 103 patients were randomized to three groups. In group 'A', 32 patients received radiotherapy alone (6500 cGy/30 fraction). In group 'B', 35 patients received neoadjuvant chemotherapy (Cisplatin 80 mg/m2 on day 1 and Etoposide 100 mg/m day 1-3 intravenously q3 weeks for 3 cycles), followed by radiotherapy (6000 cGy/30 fractions) and 3 more cycles of Chemotherapy, with the same regimen. In group 'C', 36 patients received radiotherapy (5000 cGy/25 fractions) with concurrent chemotherapy (cisplatin 20 mg/m2 + Etoposide 75 mg/m2 intravenously on day 1-5 and day 22-26), followed by 2 more cycles of chemotherapy, q3 weeks with the same regimen. RESULTS: Initial treatment responses were significantly higher in group 'B' (P < 0.05) and 'C' (P < 0.03), compared to group 'A'. Follow-up observations showed, that addition of chemotherapy brought down distant metastasis's from 62.5% (group 'A') to 48.6% (group 'B') and 44.4% (group 'C'). The median time to tumour progression also improved from 16 months (Group 'A') to 21 months (Group 'B' and 'C'). But 2 year follow up did not show any survival benefit. Acute toxicities were more frequent in group 'B' and 'C', but were manageable. CONCLUSION: Addition of chemotherapy with radiation in unresectable NSCLC improves response rates, time to tumour progression and disease free survival, though the same effect is not translated in overall survival.