Miracle-dz/UniFAR-FTUs huggingface dataset:
Super-enhancer landscape reveals leukemia stem cell reliance on X-box binding protein 1 as a therapeutic vulnerability

Description Leukemia stem cells are dependent on the super-enhancer–associated oncogene XBP1, suggesting a potential targeting strategy in relapsed CML. Exploring the epigenetic landscape of leukemia stem cells Leukemia stem cells (LSCs) are often persistent in chronic myelogenous leukemia (CML) and are resistant to tyrosine kinase inhibitor treatment. This leads to relapse in patients, requiring alternative strategies to overcome this disease. Zhou et al. explored the epigenetic regulation of these LSCs and identified that THZ1, a pharmacological CDK7 inhibitor, disrupted super-enhancer–associated gene transcription of XBP1, leading to LSC eradication and improved survival. XBP1 knockdown also reduced survival and self-renewal of human primary CML cells and eradicated LSCs in mice with CML. The identification of LSC reliance on super-enhancer transcription suggests a new opportunity for intervention in CML to improve patient outcomes. Relapse of patients with chronic myelogenous leukemia (CML) may occur at least partially because leukemia stem cells (LSCs) lack sensitivity to tyrosine kinase inhibitors (TKIs) such as imatinib. The precise regulation of LSC stemness is incompletely understood. Given that traits of LSCs are subject to epigenetic regulation, we hypothesized that LSCs might be dependent on continuous active transcription of genes associated with super-enhancers (SEs), which might, in turn, suggest an opportunity for intervention. In this study, we tested this hypothesis and delineated the SE landscape in LSCs from patients with CML. Disruption of the SE-associated gene transcription by THZ1, a covalent cyclin-dependent kinase 7 (CDK7) inhibitor, efficiently eradicated LSCs in retroviral BCR-ABL–driven CML mice while sparing normal hematopoietic stem cells. Furthermore, we found that X-box binding protein 1 (XBP1), a substrate of mRNA-splicing endonuclease IRE1α in the unfolded protein response pathway, was an SE-associated oncogene in LSCs. Knockdown of XBP1 reduced survival and self-renewal capacity in primary CML CD34+ cells and eradicated LSCs in CML mice. Selectively blocking generation of the spliced form of Xbp1 by hematopoietic cell–specific Ire1 conditional knockout suppressed the progression of CML and impaired the leukemogenesis of LSCs in CML mice. Overall, we identified an epigenetic transcriptional program in LSCs, adding to evidence for the theory of “oncogene addiction” and suggesting a potential targeting strategy for CML.
Impact of chronic medications in the perioperative period –anesthetic implications (Part II)

ABSTRACT Background: This review article discusses the pharmacodynamic effects of the most commonly used chronic medications by patients undergoing elective surgical procedures, namely cardiovascular drugs (e.g., beta blockers, alpha-2 agonist, calcium channel blockers, ACE inhibitors, diuretics, etc.), lipid-lowering drugs, gastrointestinal medications (H2-blockers, proton pump inhibitors), pulmonary medications (inhaled β-agonists, anticholinergics,), antibiotics (tetracyclines, clindamycin and macrolide, linezolid.), opioids and non-opioids analgesics (NSAIDs, COX-2 inhibitors, acetaminophen), gabapentanoids, erectile dysfunction (ED) drugs, psychotropic drugs (tricyclic antidepressants [TCAs], monoamine oxidase inhibitors [MAOI], selective serotonin reuptake inhibitors [SSRIs], serotonin norepinephrine reuptake inhibitors [SNRIs], and cannabinol-containing drugs). In addition, the potential adverse drug-interactions between these chronic medications and commonly used anesthetic drugs during the perioperative period will be reviewed. Finally, recommendations regarding the management of chronic medications during the preoperative period will be provided. Materials and Methods: An online search was conducted from January 2000 through February 2021 with the Medline database through PubMed and Google Scholar using the following search terms/keywords: “chronic medications in the perioperative period”, and “chronic medications and anesthetic implications. ” In addition, we searched for anesthetic side effects associated with the major drug groups. Results and Conclusions: An understanding of the pharmacodynamic effects of most used chronic medications is important to avoid untoward outcomes in the perioperative period. These drug interactions may result in altered efficacy and toxicity of the anesthetic medications administered during surgery. These drug-drug interactions can also affect the morbidity, mortality, recovery time of surgical patients and acute relapse of chronic illnesses which could lead to last minute cancellation of surgical procedures. Part II of this two-part review article focuses on the reported interactions between most commonly taken chronic medications by surgical patients and anesthetic and analgesic drugs, as well as recommendations regarding the handling these chronic medications during the perioperative period.
Precipitation of Inorganic Phases through a Photoinduced pH Jump: From Vaterite Spheroids and Shells to ZnO Flakes and Hexagonal Plates

This report demonstrates a new way to precipitate inorganic phases through pH jumps driven by optical excitation of a photobase. The level of the pH jumps is manipulated by either the wavelength range or illumination time used. The method is demonstrated by precipitation of CaCO3 and ZnO. Vaterite spheroids and shells for CaCO3 as well as flakes and hexagonal plates for ZnO are formed under various controllable conditions. Notably, ZnO films could be formed and patterned directly on quartz substrates using a photomask. The film thickness was easily controlled by illumination time. This method is an important step toward self-organized crystallization with spatiotemporal control fully in the hands of the experimenter.
Association between the socio-economic status of households and a more sustainable diet

Abstract Objective: A sustainable diet is an affordable diet with low environmental impact, high food security and sufficient healthiness. The present study aimed to assess the correlation between the socio-economic status of households and a sustainable diet. Design: The food basket and socio-economic data of Iranian households were evaluated during 2016–2018. The households were classified based on the sustainability of their diet by determining the dietary carbon footprint, dietary water footprint, lower dietary costs of the household than the median and a higher dietary quality index than the median. Logistic regression was used with four models to calculate the OR of a more sustainable diet as the dependent variable regarding the different quartiles of socio-economic status (SES) as the independent variable. Setting: Iran. Participants: Iranian households (n 102 303), nationally representative, were studied. Results: Lower SES was associated with the higher OR of a sustainable diet (OR: 0·90; (95 % CI 0·87, 0·91)). Higher quartiles of SES compared with the lower SES group indicated the higher energy intake and consumption of more dairies, meat, poultry, fish, eggs, legumes, nuts and fruits, as well as the lower intake of bread, cereal, rice and pasta. Conclusion: In countries such as Iran, where nutrition transition occurs rapidly, better economic and social levels in the populations with a higher SES are associated with increased energy intake and higher consumption of animal-based foods, which decreases sustainable diets compared with the groups with a lower SES.
Nature‐Inspired Circular‐Economy Recycling for Proteins: Proof of Concept

The billion tons of synthetic‐polymer‐based materials (i.e. plastics) produced yearly are a great challenge for humanity. Nature produces even more natural polymers, yet they are sustainable. Proteins are sequence‐defined natural polymers that are constantly recycled when living systems feed. Digestion is the protein depolymerization into amino acids (the monomers) followed by their re‐assembly into new proteins of arbitrarily different sequence and function. This breaks a common recycling paradigm where a material is recycled into itself. Organisms feed off of random protein mixtures that are “recycled” into new proteins whose identity depends on the cell's specific needs. In this study, mixtures of several peptides and/or proteins are depolymerized into their amino acid constituents, and these amino acids are used to synthesize new fluorescent, and bioactive proteins extracellularly by using an amino‐acid‐free, cell‐free transcription–translation (TX–TL) system. Specifically, three peptides (magainin II, glucagon, and somatostatin 28) are digested using thermolysin first and then using leucine aminopeptidase. The amino acids so produced are added to a commercial TX–TL system to produce fluorescent proteins. Furthermore, proteins with high relevance in materials engineering (β‐lactoglobulin films, used for water filtration, or silk fibroin solutions) are successfully recycled into biotechnologically relevant proteins (fluorescent proteins, catechol 2,3‐dioxygenase).
Trends in Adjuvant Therapy After Surgery for Oropharyngeal Squamous Cell Carcinoma

We aim to 1) evaluate trends in adjuvant treatment of human papilloma virus (HPV)‐related oropharyngeal cancer; 2) assess change in complications and functional outcomes over time; and 3) assess change in overall and disease‐free survival (DFS) over time.
Coordinated IgG2 and IgE responses as a marker of allergen immunotherapy efficacy

IgG2 responses are associated with repeated antigen exposure and display highly mutated variable domains. A recent study highlighted a role of IgG2+ memory B cells and allergen‐specific IgG2 levels after a 3rd consecutive pre‐seasonal sublingual allergen immunotherapy (AIT) with grass pollen tablet. Herein, we aim to explore changes in allergen‐specific IgG2 in individuals undergoing house dust mite immunotherapy (HDM‐AIT) and explore whether the interrelationship with other humoral responses (i.e., IgG4 and IgE) may discriminate between high and low responders.
Varied effects of doxorubicin (DOX) on the corpus luteum of C57BL/6 mice during early pregnancy

Abstract Certain chemotherapeutic drugs are toxic to ovarian follicles. The corpus luteum (CL) is normally developed from an ovulated follicle for producing progesterone (P4) to support early pregnancy. To fill in the knowledge gap about effects of chemotherapy on the CL, we tested the hypothesis that chemotherapy may target endothelial cells and/or luteal cells in the CL to impair CL function in P4 steroidogenesis using doxorubicin (DOX) as a representative chemotherapeutic drug in mice. In both mixed background mice and C57BL/6 mice, a single intraperitoneal injection of DOX (10 mg/kg) on 0.5-day postcoitum (D0.5, postovulation) led to ∼58% D3.5 mice with serum P4 levels lower than the serum P4 range in the phosphate buffer saline-treated control mice. Further studies in the C57BL/6 ovaries revealed that CLs from DOX-treated mice with low P4 levels had less defined luteal cords and disrupted collagen IV expression pattern, indicating disrupted capillary, accompanied with less differentiated luteal cells that had smaller cytoplasm and reduced StAR expression. DOX-treated ovaries had increased granulosa cell death in the growing follicles, reduced proliferating cell nuclear antigen-positive endothelial cells in the CLs, enlarged lipid droplets, and disrupted F-actin in the luteal cells. These novel data suggest that the proliferating endothelial cells in the developing CL may be the primary target of DOX to impair the vascular support for luteal cell differentiation and subsequently P4 steroidogenesis. This study fills in the knowledge gap about the toxic effects of chemotherapy on the CL and provides critical information for risk assessment of chemotherapy in premenopausal patients. Summary sentence Our finding that doxorubicin may target proliferating endothelial cells in the developing corpus luteum to impair the vascular support for luteal cell differentiation and subsequent progesterone synthesis fills in the knowledge gap about toxic effects of chemotherapy on the corpus luteum.
Evaluation of different vagus nerve stimulation anatomical targets in the ear by vagus evoked potential responses

Electrical auricular vagus nerve stimulation (taVNS) is an emerging therapy. Stimuli are transported to brainstem nuclei, whereby its multiple projections reach to many subcortical and cortical areas, thus allowing the neuromodulation of several systemic physiological processes. We aim to define the best auricular target for taVNS through vagus somatosensory evoked potential (VSEP) elicited stimulating different auricular areas with different electrode sizes.
Fusion of cellobiose phosphorylase and potato alpha-glucan phosphorylase facilitates substrate channeling for enzymatic conversion of cellobiose to starch

Abstract We previously reported an in vitro enzymatic pathway for conversion of nonfood cellulose to starch (PNAS,110 (18): 7182–7187, 2013), in which the two sequential enzymes cellobiose phosphorylase (CBP) from Clostridium thermocellum and potato alpha-glucan phosphorylase (PGP) from Solanum tuberosum were the two key enzymes responsible for the whole conversion rate. In this work CBP and PGP were fused to form a large enzyme and it turned out that the fusion protein could exhibit a good bifunctionality when PGP moiety was put at the N-terminus and CBP moiety at the C-terminus (designated as PGP-CBP). Although the coupled reaction rate of PGP-CBP was decreased by 23.0% compared with the free enzymes, substrate channeling between the two active sites in PGP-CBP was formed, demonstrated by the introduction of the competing enzyme of PGP to the reaction system. The potential of PGP-CBP fusion enzyme being applied to the conversion of cellulose to amylose was discussed. Graphical Abstract
Clinically significant findings of high-risk mutations in human SLC29A4 gene associated with diabetes mellitus type 2 in Pakistani population

Abstract This study conducted an in-depth analysis combining computational and experimental verifications of the deleterious missense mutations associated with the SLC29A4 protein. The functional annotation of the non-synonymous single nucleotide polymorphism (nsSNPs), followed by structure-function analysis, revealed 13 single nucleotide polymorphisms (SNP) as the most damaging. Among these, six mutants P429T/S, L144S, M108V, N86H, and V79E, were predicted as structurally and functionally damaging by protein stability analysis. Also, these variants are located at evolutionary conserved regions, either buried, contributing to the structural damage, or exposed, causing functional changes in the protein. These mutants were further taken for molecular docking studies. When verified via experimental analysis, the SNPs M108V (rs149798710), N86H (rs151039853), and V79E (rs17854505) showed an association with type 2 diabetes mellitus (T2DM). Minor allele frequency for rs149798710 (A > G) was 0.23 in controls, 0.29 in metformin responders, 0.37 in metformin non-responder, for rs151039853 (A > C) was 0.21 in controls, 0.28 in metformin responders, 0.36 in metformin non-responder and for rs17854505 (T > A) was 0.20 in controls, 0.25 in metformin responders, 0.37 in metformin non-responder. Hence, this study concludes that SLC29A4 M108V (rs149798710), N86H (rs151039853), and V79E (rs17854505) polymorphisms were associated with the increased risk of T2DM as well as with the increased risk towards the failure of metformin therapeutic response in T2DM patients of Pakistan. Communicated by Ramaswamy H. Sarma
Use of risk scores for predicting new atrial fibrillation after ischemic stroke or transient ischemic attack—A systematic review

Background Newly detected atrial fibrillation (NDAF) following an ischemic stroke or transient ischemic attack is often paroxysmal in nature. While challenging to detect, extended electrocardiographic (ECG) monitoring is often used to identify NDAF which has resource implications. Prognostic risk scores have been derived which may stratify the risk of NDAF and inform patient selection for ECG monitoring approaches after ischemic stroke/transient ischemic attack. Aim The overall aim was to identify risk scores that were derived and/or validated to predict NDAF after ischemic stroke/transient ischemic attack and evaluate their performance. Summary of review A systematic literature review was undertaken in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, with application of the Quality Assessment of Diagnostic Accuracy-2 tool. Published studies, which derived and validated clinical risk scores in patients with ischemic stroke/transient ischemic attack, or externally validated an existing score to predict NDAF after ischemic stroke/transient ischemic attack, were considered and independently screened by two reviewers. Twenty-one studies involving 23 separate cohorts were analyzed from which 17 integer-based risk scores were identified. The overall frequency of NDAF was 9.7% (95% confidence intervals 8%–11.5%; I2 = 98%). The performance of the scores varied widely among derivation and validation cohorts (area under the receiver operating characteristic curve (AUC) 0.54–0.94); scores derived from stroke cohorts (12 scores) appeared to perform better (AUC 0.7–0.94) than those derived from non-stroke cohorts (five scores; AUC 0.53–0.79). The scores also varied considerably in their complexity, ascertainment, component variables, participant characteristics, outcome definition, and ease of application limiting their generalizability and utility. Conclusion Overall, the risk scores identified performed variably in their discriminative ability and the utility of these scores to predict NDAF in clinical practice remains uncertain. Further studies are required using larger prospective cohorts and randomized control trials to evaluate the usefulness of such scores for clinical decision making and preventative intervention.
tiRNA signaling via stress-regulated vesicle transfer in the hematopoietic niche

Extracellular vesicles transfer complex biologic material between cells, whose role in in-vivo organismal physiology is poorly defined. Here, we demonstrate that osteoblastic cells in the bone marrow elaborate extracellular vesicles that are taken up by hematopoietic progenitor cells in vivo. Genotoxic or infectious stress rapidly increased stromal-derived extracellular vesicle transfer to granulocyte-monocyte progenitors. Stimulating osteoblastic cells with parathyroid hormone or activating its receptor enhanced extracellular vesicle transfer, myeloid recovery post radiation and improved animal survival from Candida sepsis. The extracellular vesicles contained tiRNAs known to modulate protein translation. 5’-ti-Pro-CGG-1 was preferentially abundant in osteoblast-derived extracellular vesicles and when transferred to granulocyte macrophage progenitors, increased protein translation, cell proliferation and myeloid differentiation. Therefore, EV-mediated tiRNA transfer provides a stress modulated signaling axis distinct from conventional cytokine-driven stress responses. One sentence summary Stress regulated tiRNA transfer alters hematopoiesis
Venous stenting for idiopathic intracranial hypertension: lessons learned from a high-volume practice

INTRODUCTION In recent years, venous sinus stenting (VSS) has emerged as an effective surgical treatment for idiopathic intracranial hypertension (IIH) with concomitant venous sinus stenosis. Metaanalyses of small series of VSS have demonstrated an excellent safety profile with improvement in headaches, pulsatile tinnitus, papilledema, and visual symptoms in the majority of patients. This has led to a rapid growth of VSS being performed with few practitioners having substantial experience. This fact is concerning for several reasons. First, little is known about the pathophysiology of the stenosis or why it might recur following stenting, other than untested theories. 3 Second, more realistic series suggest that as many as 60% of patients with IIH have symptoms that persist or recur after VSS. Third, major complications, including death, occur in about 2% of treated patients. These complications are largely avoidable and can potentially be minimized by thoughtful patient selection and safe procedural techniques. Yet recommendations for the selection of patients and performance of VSS are quite limited, with little published advice or educational resources available for surgeons interested in performing these procedures. The purpose of this manuscript is to present lessons learned from a highvolume VSS practice to aid neurointerventionalists in caring for patients with IIH. My personal experience includes over 150 VSS stent procedures and over 400 cerebral venogram procedures over a 5year period (roughly 30 and 80 procedures annually, respectively). Admittedly, there is little scientific evidence supporting most of the principles presented, but for those learning points where some data exist, references are included. In many instances, alternative strategies not discussed in this paper may be equally (or more) effective; there are many ways to take good care of patients. As such, the views expressed in this commentary are strictly my own and should not be considered ‘evidencebased,’ but instead represent ‘pearls’ from an experienced practitioner to aid physicians with limited experience with this procedure.
Three Distinct Proteases Are Responsible for Overall Cell Surface Proteolysis in Streptococcus thermophilus

Streptococcus thermophilus is a lactic acid bacterium used widely as a starter in the dairy industry. Due to its “generally recognized as safe” status and its weak cell surface proteolytic activity, it is also considered a potential bacterial vector for heterologous protein production. ABSTRACT The lactic acid bacterium Streptococcus thermophilus was believed to display only two distinct proteases at the cell surface, namely, the cell envelope protease PrtS and the housekeeping protease HtrA. Using peptidomics, we demonstrate here the existence of an additional active cell surface protease, which shares significant homology with the SepM protease of Streptococcus mutans. Although all three proteases—PrtS, HtrA, and SepM—are involved in the turnover of surface proteins, they demonstrate distinct substrate specificities. In particular, SepM cleaves proteins involved in cell wall metabolism and cell elongation, and its inactivation has consequences for cell morphology. When all three proteases are inactivated, the residual cell-surface proteolysis of S. thermophilus is approximately 5% of that of the wild-type strain. IMPORTANCE Streptococcus thermophilus is a lactic acid bacterium used widely as a starter in the dairy industry. Due to its “generally recognized as safe” status and its weak cell surface proteolytic activity, it is also considered a potential bacterial vector for heterologous protein production. Our identification of a new cell surface protease made it possible to construct a mutant strain with a 95% reduction in surface proteolysis, which could be useful in numerous biotechnological applications.