Discovery of Selective Small-Molecule Inhibitors for the ENL YEATS Domain.

Eleven-nineteen leukemia (ENL) protein is a histone acetylation reader essential for disease maintenance in acute leukemias, in particular, the mixed-lineage leukemia (MLL)-rearranged leukemia. In this study, we carried out high-throughput screening of a small-molecule library to identify inhibitors for the ENL YEATS domain. Structure-activity relationship studies of the hits and structure-based inhibitor design led to two compounds, 11 and 24, with IC50 values below 100 nM in inhibiting the ENL-acetyl-H3 interaction. Both compounds, and their precursor compound 7, displayed strong selectivity toward the ENL YEATS domain over all other human YEATS domains. Moreover, 7 exhibited on-target inhibition of ENL in cultured cells and a synergistic effect with the bromodomain and extraterminal domain inhibitor JQ1 in killing leukemia cells. Together, we have developed selective chemical probes for the ENL YEATS domain, providing the basis for further medicinal chemistry-based optimization to advance both basic and translational research of ENL.

ATP Synthase c-Subunit Leak Causes Aberrant Cellular Metabolism in Fragile X Syndrome.

Loss of the gene (Fmr1) encoding Fragile X mental retardation protein (FMRP) causes increased mRNA translation and aberrant synaptic development. We find neurons of the Fmr1-/y mouse have a mitochondrial inner membrane leak contributing to a "leak metabolism." In human Fragile X syndrome (FXS) fibroblasts and in Fmr1-/y mouse neurons, closure of the ATP synthase leak channel by mild depletion of its c-subunit or pharmacological inhibition normalizes stimulus-induced and constitutive mRNA translation rate, decreases lactate and key glycolytic and tricarboxylic acid (TCA) cycle enzyme levels, and triggers synapse maturation. FMRP regulates leak closure in wild-type (WT), but not FX synapses, by stimulus-dependent ATP synthase ß subunit translation; this increases the ratio of ATP synthase enzyme to its c-subunit, enhancing ATP production efficiency and synaptic growth. In contrast, in FXS, inability to close developmental c-subunit leak prevents stimulus-dependent synaptic maturation. Therefore, ATP synthase c-subunit leak closure encourages development and attenuates autistic behaviors.

Bioaccumulation of lead, chromium, and nickel by bacteria from three different genera isolated from industrial effluent.

The potential of indigenous bacterial strains to accumulate three metals (Cr, Ni, Pb) was exploited here to remediate the polluted environment. In the present study, metal resistance profiles identified three most potential isolates which could tolerate 700-1000 µg/ml of Ni, 500-1000 µg/ml of Cr, and 1000-1600 µg/ml of Pb. These three bacterial strains were identified as Stenotrophomonas sp. MB339, Klebsiella pneumoniae MB361, and Staphylococcus sp. MB371. UV-Visible and atomic absorption spectrophotometric (AAS) analysis revealed gradual increase in percentage accumulation with increase in time due to increased biomass. Quantitative assessments exhibited maximum removal of Cr (83.51%) by Klebsiella pneumoniae MB361, Pb (85.30%), and Ni (48.78%) by Stenotrophomonas MB339, at neutral pH and 37 °C, whereas Staphylococcus sp. MB371 sorbed 88.33% of Pb at slightly acidic pH. The present study therefore supports the effective utilization of indigenous bacteria for comprehensive treatment of metal-rich industrial effluents.

Sad Fetus Syndrome: Partial Molar Pregnancy with a Live Fetus.

We report a case of partial mole and co-existing live fetus. This condition, uncommonly termed "sad fetus syndrome," is a rare subclass of gestational trophoblastic disease. Our case involves a 25-year-old primigravid woman who presented to the outpatient department at 18 weeks of gestation with lower abdominal pain, vaginal spotting, and severe nausea. Ultrasound revealed a "grape bunch" appearance and a live, coexisting fetus. The patient underwent spontaneous abortion around the twentieth week of gestation. A postoperative ultrasound revealed an empty uterine cavity. She was discharged a few days afterward but was advised to follow up with serial repeat measurements of her beta-human chorionic gonadotropin levels.

Concurrent uptake and metabolism of dyestuffs through bio-assisted phytoremediation: a symbiotic approach.

Manipulation of bio-technological processes in treatment of dyestuffs has attracted considerable attention, because a large proportion of these synthetic dyes enter into natural environment during synthesis and dyeing operations that contaminates different ecosystems. Moreover, these dyestuffs are toxic and difficult to degrade because of their synthetic origin, durability, and complex aromatic molecular structures. Hence, bio-assisted phytoremediation has recently emerged as an innovative cleanup approach in which microorganisms and plants work together to transform xenobiotic dyestuffs into nontoxic or less harmful products. This manuscript will focus on competence and potential of plant-microbe synergistic systems for treatment of dyestuffs, their mixtures and real textile effluents, and effects of symbiotic relationship on plant performances during remediation process and will highlight their metabolic activities during bio-assisted phytodegradation and detoxification.

Knowledge Regarding Basic Facts of Stroke Among Final Year MBBS Students and House Officers: A Cross-Sectional Survey of 708 Respondents from Pakistan.

INTRODUCTION: Stroke is the leading cause of neurological disability in the world. In Pakistan, house officers (HOs) are usually the first contact for a stroke patient in the emergency department. Sometimes they need to make quick decisions regarding diagnosis and management without specialist supervision. Thousands of current final year MBBS (Bachelor of Medicine, Bachelor of Surgery) students will be performing the duties of HOs soon. This study documents the knowledge and confidence levels of final year students and HOs in Pakistan regarding basic facts related to initial diagnosis and management of stroke. MATERIALS AND METHODS: A questionnaire was developed using two standard textbooks of medicine and current stroke guidelines of the American Heart Association. The pre-tested self-administered questionnaire was distributed among 800 final year MBBS students and HOs in 14 medical colleges and hospitals in four different cities. The response rate was 88.5%. Data analysis was done using SPSS V.21. The CMH Lahore Medical College Ethics Review Committee approved this project. RESULTS: Respondents included medical students (n=496) and HOs (N= 212); most were female (n = 452, 63.9%). Of these, 31.4% had managed or assisted in the management of a patient with a stroke and had a higher confidence level in its diagnosis (p< 0.001) and management (p <0.001). Having a family member with stroke was associated with higher confidence in the diagnosis of stroke (p < 0.05) but not with confidence in its management (p = 0.41). Most correctly defined stroke (60.6%), identified the CT scan as the initial diagnostic modality (88.1%), knew the dosage of aspirin (64.9%), knew the time limit for thrombolysis (67.4%), and were familiar with the risk of deep vein thrombosis in immobilized stroke patients (85.4%). Less than half (44.5%) chose tissue plasminogen activator (t-PA) as the preferred initial intervention for acute ischemic stroke. CONCLUSION: This multicenter survey shows that the knowledge and confidence of medical students and HOs in Pakistan regarding initial diagnosis and management of stroke are inadequate in most domains. There is a need to improve the medical training for stroke in emergency departments for optimal outcomes. Public education campaigns about stroke should be conducted to increase the general awareness of the population about the prevention, signs, symptoms, and emergency steps to be taken when encountering a case of stroke.