Integrity of xylan backbone affects plant responses to drought.

Drought is a major factor affecting crops, thus efforts are needed to increase plant resilience to this abiotic stress. The overlapping signaling pathways between drought and cell wall integrity maintenance responses create a possibility of increasing drought resistance by modifying cell walls. Here, using herbaceous and woody plant model species, Arabidopsis and hybrid aspen, respectively, we investigated how the integrity of xylan in secondary walls affects the responses of plants to drought stress. Plants, in which secondary wall xylan integrity was reduced by expressing fungal GH10 and GH11 xylanases or by affecting genes involved in xylan backbone biosynthesis, were subjected to controlled drought while their physiological responses were continuously monitored by RGB, fluorescence, and/or hyperspectral cameras. For Arabidopsis, this was supplemented with survival test after complete water withdrawal and analyses of stomatal function and stem conductivity. All Arabidopsis xylan-impaired lines showed better survival upon complete watering withdrawal, increased stomatal density and delayed growth inhibition by moderate drought, indicating increased resilience to moderate drought associated with modified xylan integrity. Subtle differences were recorded between xylan biosynthesis mutants (irx9, irx10 and irx14) and xylanase-expressing lines. irx14 was the most drought resistant genotype, and the only genotype with increased lignin content and unaltered xylem conductivity despite its irx phenotype. Rosette growth was more affected by drought in GH11- than in GH10-expressing plants. In aspen, mild downregulation of GT43B and C genes did not affect drought responses and the transgenic plants grew better than the wild-type in drought and well-watered conditions. Both GH10 and GH11 xylanases strongly inhibited stem elongation and root growth in well-watered conditions but growth was less inhibited by drought in GH11-expressing plants than in wild-type. Overall, plants with xylan integrity impairment in secondary walls were less affected than wild-type by moderately reduced water availability but their responses also varied among genotypes and species. Thus, modifying the secondary cell wall integrity can be considered as a potential strategy for developing crops better suited to withstand water scarcity, but more research is needed to address the underlying molecular causes of this variability.

Computational Insights into Chromene/pyran Derivatives: Molecular Docking, ADMET Studies, DFT Calculations, and MD Simulations as Promising Candidates for Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative condition characterized by both motor and non-motor symptoms. Although PD is commonly associated with a decline of dopaminergic neurons in the substantia nigra, other diagnostic criteria and biomarkers also exist. In the search for novel therapeutic agents, chromene and pyran derivatives have shown potential due to their diverse pharmacological activities. This study utilizes a comprehensive computational approach to investigate the viability of chromene/pyran compounds as potential treatments for PD. The drug-likeness characteristics of these molecules were analyzed using ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) studies. Molecular docking was performed against PDB ID: 2V5Z. The best three molecules chosen were compound 7, compound 24, and compound 67 have a binding energy of -6.7, -8.6, and -10.9 kcal/mol. Molecules demonstrating positive blood-brain barrier permeability, good solubility, and favorable binding affinity were further evaluated using Density Functional Theory (DFT) calculations and Molecular Dynamics (MD) simulations to assess their electronic structure and stability. DFT calculations indicated that molecule 82 has a dipole moment of 15.70 D. RMSD and RMSF results confirmed the stability of the complexes over a 100 ns simulation, with a maximum of 3 hydrogen bonds formed.

An Updated Review on Functionalized Graphene as Sensitive Materials in Sensing of Pesticides.

Numerous chemical pesticides were employed for a long time to manage pests, but their uncontrolled application harmed the health and the environment. Accurately quantifying pesticide residues is essential for risk evaluation and regulatory purposes. Numerous analytical methods have been developed and utilized to achieve sensitive and specific detection of pesticides in intricate sampl es like water, soil, food, and air. Electrochemical sensors based on amperometry, potentiometry, or impedance spectroscopy offer portable, rapid, and sensitive detection suitable for on-site analysis. This study examines the potential of electrochemical sensors for the accurate evaluation of various effects of pesticides. Emphasizing the use of Graphene (GR), Graphene Oxide (GO), Reduced Graphene Oxide (rGO), and Graphdiyne composites, the study highlights their enhanced performance in pesticide sensing by stating the account of many actual sensors that have been made for specific pesticides. Computational studies provide valuable insights into the adsorption kinetics, binding energies, and electronic properties of pesticide-graphene complexes, guiding the design and optimization of graphene-based sensors with improved performance. Furthermore, the discussion extends to the emerging field of biopesticides. While the GR/GO/rGO based sensors hold immense future prospects, and their existing limitations have also been discussed, which need to be solved with future research.

SHP2 inhibition displays efficacy as a monotherapy and in combination with JAK2 inhibition in preclinical models of myeloproliferative neoplasms.

Myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocytosis, and primary myelofibrosis, are clonal hematopoietic neoplasms driven by mutationally activated signaling by the JAK2 tyrosine kinase. Although JAK2 inhibitors can improve MPN patients' quality of life, they do not induce complete remission as disease-driving cells persistently survive therapy. ERK activation has been highlighted as contributing to JAK2 inhibitor persistent cell survival. As ERK is a component of signaling by activated RAS proteins and by JAK2 activation, we sought to inhibit RAS activation to enhance responses to JAK2 inhibition in preclinical MPN models. We found the SHP2 inhibitor RMC-4550 significantly enhanced growth inhibition of MPN cell lines in combination with the JAK2 inhibitor ruxolitinib, effectively preventing ruxolitinib persistent growth, and the growth and viability of established ruxolitinib persistent cells remained sensitive to SHP2 inhibition. Both SHP2 and JAK2 inhibition diminished cellular RAS-GTP levels, and their concomitant inhibition enhanced ERK inactivation and increased apoptosis. Inhibition of SHP2 inhibited the neoplastic growth of MPN patient hematopoietic progenitor cells and exhibited synergy with ruxolitinib. RMC-4550 antagonized MPN phenotypes and increased survival of an MPN mouse model driven by MPL-W515L. The combination of RMC-4550 and ruxolitinib, which was safe and tolerated in healthy mice, further inhibited disease compared to ruxolitinib monotherapy, including extending survival. Given SHP2 inhibitors are undergoing clinical evaluation in patients with solid tumors, our preclinical findings suggest that SHP2 is a candidate therapeutic target with potential for rapid translation to clinical assessment to improve current targeted therapies for MPN patients.

Divergent evolution of the alcohol-forming pathway of wax biosynthesis among bryophytes.

The plant cuticle is a hydrophobic barrier, which seals the epidermal surface of most aboveground organs. While the cuticle biosynthesis of angiosperms has been intensively studied, knowledge about its existence and composition in nonvascular plants is scarce. Here, we identified and characterized homologs of Arabidopsis thaliana fatty acyl-CoA reductase (FAR) ECERIFERUM 4 (AtCER4) and bifunctional wax ester synthase/acyl-CoA:diacylglycerol acyltransferase 1 (AtWSD1) in the liverwort Marchantia polymorpha (MpFAR2 and MpWSD1) and the moss Physcomitrium patens (PpFAR2A, PpFAR2B, and PpWSD1). Although bryophyte harbor similar compound classes as described for angiosperm cuticles, their biosynthesis may not be fully conserved between the bryophytes M. polymorpha and P. patens or between these bryophytes and angiosperms. While PpFAR2A and PpFAR2B contribute to the production of primary alcohols in P. patens, loss of MpFAR2 function does not affect the wax profile of M. polymorpha. By contrast, MpWSD1 acts as the major wax ester-producing enzyme in M. polymorpha, whereas mutations of PpWSD1 do not affect the wax ester levels of P. patens. Our results suggest that the biosynthetic enzymes involved in primary alcohol and wax ester formation in land plants have either evolved multiple times independently or undergone pronounced radiation followed by the formation of lineage-specific toolkits.

Case Report: Lepromatous Leprosy Masquerading as Acute Suppurative Lymphadenitis.

Leprosy is a chronic cutaneous infection. It is usually characterized by thickened nerves and maculo-anesthetic patches. Leprosy often has an unusual presentation, which is a diagnostic challenge. In this case report, we present a case of an elderly male who presented with fever and chronic pus-draining axillary, cervical, and inguinal lymph nodes. He also had a weak left foot for the previous 5 months. During his hospital stay, he developed additional papular lesions over his extremities. We performed fine needle aspiration from the lymph nodes and skin biopsy, which were suggestive of lepromatous leprosy. We initiated him on antileprosy medication. On follow-up, he was responsive to therapy. Although skin and nerve involvement in leprosy is common, this case had an atypical presentation of discharging lymph nodes.

Functional conservation of an AP2/ERF transcription factor in cuticle formation suggests an important role in the terrestrialization of early land plants.

The formation of a hydrophobic cuticle layer on aerial plant parts was a critical innovation for protection from the terrestrial environment during the evolution of land plants. However, little is known about the molecular mechanisms underlying cuticle biogenesis in early terrestrial plants. Here, we report an APETALA2/Ethylene Response Factor (AP2/ERF) transcriptional activator, PpWIN1, involved in cutin and cuticular wax biosynthesis in Physcomitrium patens and Arabidopsis. The transcript levels of PpWIN1 were 2.5-fold higher in gametophores than in the protonema, and increased by approximately 3- to 4.7-fold in the protonema and gametophores under salt and osmotic stresses. PpWIN1 harbouring transcriptional activation activity is localized in the nucleus of tobacco leaf epidermal cells. Δppwin1 knockout mutants displayed a permeable cuticle, increased water loss, and cutin- and wax-deficient phenotypes. In contrast, increased total cutin and wax loads, and decreased water loss rates were observed in PpWIN1-overexpressing Arabidopsis plants. The transcript levels of genes involved in cutin or wax biosynthesis were significantly up-regulated in PpWIN1-overexpressing Arabidopsis lines, indicating that PpWIN1 acts as a transcriptional activator in cuticle biosynthesis. This study suggests that Arabidopsis WIN1/SHN1 orthologs may be functionally conserved from early to vascular land plants.

IL-3 regulates the differentiation of pathogenic Th17 cells.

IL-17-producing Th17 cells play an important role in pathogenesis of rheumatoid arthritis (RA). Aberrant immune activation due to an imbalance between Th17 and regulatory T (Treg) cells is associated with the development of RA and other autoimmune diseases. Targeting pathogenic Th17 cells and their associated molecules is emerging as a promising strategy to treat and reverse RA. Here, we demonstrate that IL-3 inhibits the differentiation of Th17 cells and promotes the development of Treg cells in IL-2-dependent manner. In IL-2 KO mice, we observed that IL-3 has no effect on differentiation of both Th17 and Treg cells. In addition, IL-3 decreases pathogenic IL-17A+ TNF-α+ , IL-17A+ IFN-γ+ and IL-23R+ Th17 cells, secretion of GM-CSF and IFN-γ, and osteoclastogenesis when presented in the culture together with Th17 polarizing cytokines. Mechanistically, IL-3 regulates the development of Th17 cells through the inhibition of STAT3 phosphorylation. IL-3 treatment significantly decreases the pathogenic Th17 cell responses and arthritic scores in the mouse model of RA. Importantly, IL-3 inhibits the differentiation of human Th17 cells. Thus, our results suggest a novel therapeutic role of IL-3 in the regulation of Th17 cell-mediated pathophysiology of RA.

JAK2 inhibitor persistence in MPN: uncovering a central role of ERK activation.

The Philadelphia chromosome negative myeloproliferative neoplasms, including polycythemia vera, essential thrombocytosis, and myelofibrosis, are driven by hyper activation of the JAK2 tyrosine kinase, the result of mutations in three MPN driving genes: JAK2, MPL, and CALR. While the anti-inflammatory effects of JAK2 inhibitors can provide improved quality of life for many MPN patients, the upfront and persistent survival of disease-driving cells in MPN patients undergoing JAK2 inhibitor therapy thwarts potential for remission. Early studies indicated JAK2 inhibitor therapy induces heterodimeric complex formation of JAK2 with other JAK family members leading to sustained JAK2-dependent signaling. Recent work has described novel cell intrinsic details as well as cell extrinsic mechanisms that may contribute to why JAK2 inhibition may be ineffective at targeting MPN driving cells. Diverse experimental strategies aimed at uncovering mechanistic details that contribute to JAK2 inhibitor persistence have each highlighted the role of MEK/ERK activation. These approaches include, among others, phosphoproteomic analyses of JAK2 signaling as well as detailed assessment of JAK2 inhibition in mouse models of MPN. In this focused review, we highlight these and other studies that collectively suggest targeting MEK/ERK in combination with JAK2 inhibition has the potential to improve the efficacy of JAK2 inhibitors in MPN patients. As MPN patients patiently wait for improved therapies, such studies should further strengthen optimism that pre-clinical research is continuing to uncover mechanistic insights regarding the ineffectiveness of JAK2 inhibitors, which may lead to development of improved therapeutic strategies.

A Study on Prevalence of Trigger Factors and Associated Disorders in Tension-type Headache.

OBJECTIVE: To study the prevalence of trigger factors and associated disorders in tension-type headache (TTH). Trigger factors have been widely studied in the context of migraine, but very few studies have investigated trigger factors in the context of TTH. MATERIALS AND METHODS: A total of 400 patients above the age of 15 years fulfilling the third edition of the International Classification of Headache Disorders (ICHD 3) criteria of frequent episodic tension-type headache (FETTH) and chronic tension-type headache (CTTH) were enrolled and evaluated using a questionnaire. Details regarding demographics, headache characteristics, triggers, and associated symptoms were obtained. Associated psychiatric disorders were also recorded. Data were analyzed using Microsoft Excel and statistical analysis was done using SPSS 22 trial version. Chi-square test and Fischer's exact test were used for statistical analysis and subgroup comparison. RESULTS: Out of 400 patients, 360 (90%) were found to have triggers. The mean headache intensity on visual analog scale (VAS) was 6.7. The most common trigger factor was emotional stress among both males and females. There was a statistically significant difference in the frequency of trigger factors between men and women for emotional stress, sunlight, sleep deprivation/insomnia, noise, weather change, studying, fried food, and hypersomnia. Psychiatric comorbidity was found in 29% of individuals, with sleep disorder being the most common. CONCLUSIONS: TTH has been an underrated diagnosis despite being an extremely common disorder. The trigger factors are less studied and their interactions are lesser known. The diagnostic criteria as per ICHD 3 make TTH a diagnosis of exclusion, rather than a positive diagnosis of inclusion. The trigger factors must be included in the diagnostic criteria in future versions of ICHD and associated psychiatric disorders should be sought for and treated simultaneously for better management and quality of life.

Block-chain application Based Economic impact of Coronavirus pandemic on Medicine industry inventory System for Deteriorating objects with two-warehouse and wastewater treatment using PSO.

In this paper, the determined economic impact of the Medicine industry of the Coronavirus pandemic for aggravating items with a ramp-type demand with inflation effects in two-warehouse storage devices and wastewater treatment cost using PSO is developed. The owned warehouse has a fixed capacity of W units; rented warehouse has unlimited capacity. Here, we hypothesized that the Block chain Economic Impact of the Coronavirus Pandemic Medicine Industry in Inventory Cost of Inventory in RW is greater than that in OW using PSO. The shortcomings of the economic impact of the Coronavirus pandemic Medicine industry are allowed and partially lagged behind, and it is assumed that Block chain's economic impact of the Coronavirus medicine pandemic industry decreases over time with a variable deterioration rate and wastewater treatment cost using PSO. The effect of inflation was also considered due to the different costs associated with Blockchain applying the Economic Impact of the Coronavirus Medicine Industry Inventory System and wastewater treatment cost using PSO. The numerical sample is also used to study the behavior of the model using particle size optimization. The cost minimization technique is used to obtain expressions for total costs and other parameters.

Organofluorine Hydrazone Derivatives as Multifunctional Anti-Alzheimer's Agents with CK2 Inhibitory and Antioxidant Features.

A set of novel hydrazone derivatives were synthesized and analyzed for their biological activities. The compounds were tested for their inhibitory effect on the phosphorylating activity of the protein kinase CK2, and their antioxidant activity was also determined in three commonly used assays. The hydrazones were evaluated for their radical scavenging against the DPPH, ABTS and peroxyl radicals. Several compounds have been identified as good antioxidants as well as potent protein kinase CK2 inhibitors. Most hydrazones containing a 4-N(CH3 )2 residue or perfluorinated phenyl rings showed high activity in the radical-scavenging assays and possess nanomolar IC50 values in the kinase assays.

A micellar mediated novel method for the determination of selenium in environmental samples using a chromogenic reagent.

A novel, simple, sensitive and rapid spectrophotometric method for the determination of selenium(iv) in an acidic medium using rhodamine B hydrazide (RBH) has been developed. The method is based on the micellar mediated oxidation of RBH by Se(iv) in an acidic medium to produce a pinkish violet color of rhodamine B, which was monitored spectrophotometrically at λmax 585 nm. The sensitivity of the method was found to increase when the reaction was performed in a micellar medium. Beer's law was obeyed in the concentration range of 0.002-0.032 µg mL-1. The reaction variables such as time, temperature, reagent concentration, and acidity have been optimized for the reaction. Sandell's sensitivity and molar absorptivity for the reaction system were found to be 0.00004 µg cm-2 and 42.52 × 106 L mol-1 cm-1, respectively. The developed method was successfully applied for the determination of Se(iv) in several real samples with quantitative results.

Finding a Jill for JAK: Assessing Past, Present, and Future JAK Inhibitor Combination Approaches in Myelofibrosis.

Myelofibrosis (MF) is a myeloproliferative neoplasm hallmarked by the upregulation of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway with associated extramedullary hematopoiesis and a high burden of disease-related symptoms. While JAK inhibitor therapy is central to the management of MF, it is not without limitations. In an effort to improve treatment for MF patients, there have been significant efforts to identify combination strategies that build upon the substantial benefits of JAK inhibition. Early efforts to combine agents with additive therapeutic profiles have given way to rationally designed combinations hoping to demonstrate clinical synergism and modify the underlying disease. In this article, we review the preclinical basis and existing clinical data for JAK inhibitor combination strategies while highlighting emerging strategies of particular interest.

Female genital tract melanoma: Analysis from a regional cancer institute.

OBJECTIVE: Malignant melanoma of the genital tract comprises 3% of all melanomas afflicting females. They are characterized by poor prognosis with 5-year survival of 0-25% and high incidence for distant metastasis. This study was performed to assess various clinical features, treatment options, and thre management of genital melanomas. MATERIALS AND METHODS: This was a retrospective analysis where records of patients with genital melanomas between 2005 to 2018 were reviewed to obtain demographic and clinical information, including age of diagnosis, presenting symptoms, performance status, pathology reports, treatment, follow-up, and survival. RESULTS: Between 2005 and 2018, 31 women were analyzed. The median age was 53.5 (range: 28.5-85) years. Vaginal bleeding was the most common presenting symptom (80.6%), followed by discharge (29%), mass in the vagina/perineum (19.3%), pain (16.1%), and difficulty in micturition (9.6%). The most common site of origin was the vagina (67.7%), followed by that vulva (19.3%) and cervix (12.9%). Tumor diameter was more than 3 cm in 74.2% (23/31). Out of 31 patients, only 16 opted for treatment. Four patients underwent surgery, 10 received primary chemotherapy, and two needed palliative radiotherapy for heavy bleeding. The median survival in the treatment group was 5 (range: 2.5-28) months, almost similar to patients not receiving any treatment (5 months, range: 2-11). CONCLUSION: Genital melanoma are rare but aggressive tumors. Diagnosis is usually made with biopsy. No effective treatment strategy is yet available. However, surgery is the preferred first- line treatment, radiotherapy and chemotherapy have been used in adjuvant settings.

Occurrence of land-plant-specific glycerol-3-phosphate acyltransferases is essential for cuticle formation and gametophore development in Physcomitrella patens.

During the evolution of land plants from aquatic to terrestrial environments, their aerial surfaces were surrounded by cuticle composed of cutin and cuticular waxes to protect them from environmental stresses. Glycerol-3-phosphate acyltransferase (GPAT) harboring bifunctional sn-2 acyltransferase/phosphatase activity produces 2-monoacylglycerol, a precursor for cutin synthesis. Here, we report that bifunctional sn-2 GPATs play roles in cuticle biosynthesis and gametophore development of Physcomitrella patens. Land plant-type cuticle was observed in gametophores but not in protonema. The expression of endoplasmic reticulum-localized PpGPATs was significantly upregulated in gametophores compared with protonema. Floral organ fusion and permeable cuticle phenotypes of Arabidopsis gpat6-2 petals were rescued to the wild type (WT) by the expression of PpGPAT2 or PpGPAT4. Disruption of PpGPAT2 and PpGPAT4 caused a significant reduction of total cutin loads, and a prominent decrease in the levels of palmitic and 10,16-dihydroxydecanoic acids, which are major cutin monomers in gametophores. Δppgpat2 mutants displayed growth retardation, delayed gametophore development, increased cuticular permeability, and reduced tolerance to drought, osmotic and salt stresses compared to the WT. Genome-wide analysis of genes encoding acyltransferase or phosphatase domains suggested that the occurrence of sn-2 GPATs with both domains may be a key event in cuticle biogenesis of land plants.

The pan-PIM inhibitor INCB053914 displays potent synergy in combination with ruxolitinib in models of MPN.

Aberrant JAK2 tyrosine kinase signaling drives the development of Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis. However, JAK2 kinase inhibitors have failed to significantly reduce allele burden in MPN patients, underscoring the need for improved therapeutic strategies. Members of the PIM family of serine/threonine kinases promote cellular proliferation by regulating a variety of cellular processes, including protein synthesis and the balance of signaling that regulates apoptosis. Overexpression of PIM family members is oncogenic, exemplified by their ability to induce lymphomas in collaboration with c-Myc. Thus, PIM kinases are potential therapeutic targets for several malignancies such as solid tumors and blood cancers. We and others have shown that PIM inhibitors augment the efficacy of JAK2 inhibitors by using in vitro models of MPNs. Here we report that the recently developed pan-PIM inhibitor INCB053914 augments the efficacy of the US Food and Drug Administration-approved JAK1/2 inhibitor ruxolitinib in both in vitro and in vivo MPN models. INCB053914 synergizes with ruxolitinib to inhibit cell growth in JAK2-driven MPN models and induce apoptosis. Significantly, low nanomolar INCB053914 enhances the efficacy of ruxolitinib to inhibit the neoplastic growth of primary MPN patient cells, and INCB053914 antagonizes ruxolitinib persistent myeloproliferation in vivo. These findings support the notion that INCB053914, which is currently in clinical trials in patients with advanced hematologic malignancies, in combination with ruxolitinib may be effective in MPN patients, and they support the clinical testing of this combination in MPN patients.

Prognostic and therapeutic relevance of cathepsin B in pediatric acute myeloid leukemia.

AML, the second most common childhood leukemia is also one of the deadliest cancers. High mortality rate in AML is due to high incidence of relapse after complete remission with chemotherapy and inadequate prognostic assessment of patients. Moreover, there is dearth of therapeutic targets for treatment of this malignancy. Previous pilot study (n = 24) by our group revealed strong association between cathepsin B (CTSB) overexpression in peripheral blood mononuclear cells (PBMCs) and poor survival outcome in pediatric AML patients. To further explore the clinical utility and role of this protease in pediatric AML, we measured its enzymatic activity and mRNA expression in PBMCs as well as bone marrow mononuclear cells (BMMCs) of patients (n = 101) and PBMCs of healthy controls. Our results revealed elevated CTSB activity (P < 0.01) and overexpression of its mRNA (P < 0.01) in AML patients. Interestingly CTSB in BMMCs of patients emerged as an independent prognostic marker when compared with other known risk factors. Moreover, chemical inhibition of CTSB activity compromised survival, and induced apoptosis in an AML cell line THP-1. We further demonstrate the inhibition of CTSB activity by chemotherapeutic agent doxorubicin in these cells. Docking and simulation studies suggested the binding of doxorubicin to CTSB with higher affinity than its known specific inhibitor CA-074 Me, thereby indicating that cell death induced by this drug may at least partly be mediated by CTSB inhibition. CTSB, therefore, may serve as a prognostic marker and an attractive chemotherapeutic target in pediatric AML.

Prognostic significance of cathepsin L expression in pediatric acute myeloid leukemia.

Overexpression of cathepsin L (CTSL), an endolysosomal cysteine protease, is associated with inferior survival of patients with various human malignancies. We evaluated the expression/activity of CTSL in peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells (BMMCs) of 103 pediatric acute myeloid leukemia (AML) patients to assess its prognostic significance in this malignancy. Thirty-five healthy siblings of patients served as controls. Our results revealed significantly higher CTSL activity (p < .0001), protein (p < .05), and mRNA levels (p < .01) in both PBMCs and BMMCs of patients as compared with controls. BMMCs displayed higher activity of CTSL than PBMCs (p < .01). A dramatic reduction in CTSL activity was recorded after chemotherapy in a significant proportion (74%) of patients (p < .0001). By multivariate analysis, CTSL in BMMCs emerged as a strong independent prognostic marker for overall survival (OS) (p = .004). Thus, our results suggest the potential utility of CTSL in predicting the outcome of pediatric AML.

Epigenetics and Epigenomics of Plants.

The genetic material DNA in association with histone proteins forms the complex structure called chromatin, which is prone to undergo modification through certain epigenetic mechanisms including cytosine DNA methylation, histone modifications, and small RNA-mediated methylation. Alterations in chromatin structure lead to inaccessibility of genomic DNA to various regulatory proteins such as transcription factors, which eventually modulates gene expression. Advancements in high-throughput sequencing technologies have provided the opportunity to study the epigenetic mechanisms at genome-wide levels. Epigenomic studies using high-throughput technologies will widen the understanding of mechanisms as well as functions of regulatory pathways in plant genomes, which will further help in manipulating these pathways using genetic and biochemical approaches. This technology could be a potential research tool for displaying the systematic associations of genetic and epigenetic variations, especially in terms of cytosine methylation onto the genomic region in a specific cell or tissue. A comprehensive study of plant populations to correlate genotype to epigenotype and to phenotype, and also the study of methyl quantitative trait loci (QTL) or epiGWAS, is possible by using high-throughput sequencing methods, which will further accelerate molecular breeding programs for crop improvement. Graphical Abstract.