Differences in the anatomy and physiology of the human and rat respiratory tracts and impact on toxicological assessments.

Inhalation is a critical route through which substances can exert adverse effects in humans; therefore, it is important to characterize the potential effects that inhaled substances may have on the human respiratory tract by using fit for purpose, reliable, and human relevant testing tools. In regulatory toxicology testing, rats have primarily been used to assess the effects of inhaled substances as they-being mammals-share similarities in structure and function of the respiratory tract with humans. However, questions about inter-species differences impacting the predictability of human effects have surfaced.

Betibeglogene Autotemcel Gene Therapy for Non-β/β Genotype β-Thalassemia.

Background: Betibeglogene autotemcel (beti-cel) gene therapy for transfusion-dependent β-thalassemia contains autologous CD34+ hematopoietic stem cells and progenitor cells transduced with the BB305 lentiviral vector encoding the β-globin (β) gene.

Methods: In this open-label, phase 3 study, we evaluated the efficacy and safety of beti-cel in adult and pediatric patients with transfusion-dependent β-thalassemia and a non-β/β genotype. Patients underwent myeloablation with busulfan (with doses adjusted on the basis of pharmacokinetic analysis) and received beti-cel intravenously.

[Digital eye strain. Symptoms, prevalence, pathophysiology, and management].

The digital revolution, which has been underway since the 1980's, is disrupting our daily routines with an exponential increase in the use of screens, which has not been without consequence to our visual system. Digital eye strain (DES), or computer vision syndrome (CVS), includes all the visual symptoms secondary to the use of digital devices. DES is present in at least 50% of regular users of digital media and is defined by blurred vision, difficulty focusing, ocular irritation or burning, dry eye, visual fatigue, headaches and increased sensitivity to light.

Arrhythmias in Cardiac Sarcoidosis Bench to Bedside: A Case-Based Review.

Cardiac sarcoidosis is a component of an often multiorgan granulomatous disease of still uncertain cause. It is being recognized with increasing frequency, mainly as the result of heightened awareness and new diagnostic tests, specifically cardiac magnetic resonance imaging and F-fluorodeoxyglucose positron emission tomography scans. The purpose of this case-based review is to highlight the potentially life-saving importance of making the early diagnosis of cardiac sarcoidosis using these new tools and to provide a framework for the optimal care of patients with this disease.

The transcription factor EGR2 is the molecular linchpin connecting STAT6 activation to the late, stable epigenomic program of alternative macrophage polarization.

Macrophages polarize into functionally distinct subtypes while responding to microenvironmental cues. The identity of proximal transcription factors (TFs) downstream from the polarization signals are known, but their activity is typically transient, failing to explain the long-term, stable epigenomic programs developed. Here, we mapped the early and late epigenomic changes of interleukin-4 (IL-4)-induced alternative macrophage polarization.

Common functional networks in the mouse brain revealed by multi-centre resting-state fMRI analysis.

Preclinical applications of resting-state functional magnetic resonance imaging (rsfMRI) offer the possibility to non-invasively probe whole-brain network dynamics and to investigate the determinants of altered network signatures observed in human studies. Mouse rsfMRI has been increasingly adopted by numerous laboratories worldwide. Here we describe a multi-centre comparison of 17 mouse rsfMRI datasets via a common image processing and analysis pipeline.

Insights into the molecular architecture and histone H3-H4 deposition mechanism of yeast Chromatin assembly factor 1.

How the very first step in nucleosome assembly, deposition of histone H3-H4 as tetramers or dimers on DNA, is accomplished remains largely unclear. Here, we report that yeast chromatin assembly factor 1 (CAF1), a conserved histone chaperone complex that deposits H3-H4 during DNA replication, binds a single H3-H4 heterodimer in solution. We identify a new DNA-binding domain in the large Cac1 subunit of CAF1, which is required for high-affinity DNA binding by the CAF1 three-subunit complex, and which is distinct from the previously described C-terminal winged-helix domain.

Agonist antibody that induces human malignant cells to kill one another.

An attractive, but as yet generally unrealized, approach to cancer therapy concerns discovering agents that change the state of differentiation of the cancer cells. Recently, we discovered a phenomenon that we call "receptor pleiotropism" in which agonist antibodies against known receptors induce cell fates that are very different from those induced by the natural agonist to the same receptor. Here, we show that one can take advantage of this phenomenon to convert acute myeloblastic leukemic cells into natural killer cells.

Tumor expression, plasma levels and genetic polymorphisms of the coagulation inhibitor TFPI are associated with clinicopathological parameters and survival in breast cancer, in contrast to the coagulation initiator TF.

Introduction: Hypercoagulability in malignancy increases the risk of thrombosis, but is also involved in cancer progression. Experimental studies suggest that tissue factor (TF) and tissue factor pathway inhibitor (TFPI) are involved in cancer biology as a tumor- promoter and suppressor, respectively, but the clinical significance is less clear. Here, we aimed to investigate the clinical relevance of TF and TFPI genetic and phenotypic diversity in breast cancer.

An HD-domain phosphodiesterase mediates cooperative hydrolysis of c-di-AMP to affect bacterial growth and virulence.

The nucleotide cyclic di-3',5'- adenosine monophosphate (c-di-AMP) was recently identified as an essential and widespread second messenger in bacterial signaling. Among c-di-AMP-producing bacteria, altered nucleotide levels result in several physiological defects and attenuated virulence. Thus, a detailed molecular understanding of c-di-AMP metabolism is of both fundamental and practical interest.

Selective pharmacologic inhibition of a PASTA kinase increases Listeria monocytogenes susceptibility to β-lactam antibiotics.

While β-lactam antibiotics are a critical part of the antimicrobial arsenal, they are frequently compromised by various resistance mechanisms, including changes in penicillin binding proteins of the bacterial cell wall. Genetic deletion of the penicillin binding protein and serine/threonine kinase-associated protein (PASTA) kinase in methicillin-resistant Staphylococcus aureus (MRSA) has been shown to restore β-lactam susceptibility. However, the mechanism remains unclear, and whether pharmacologic inhibition would have the same effect is unknown.

Aerobic exercise increases peripheral and hepatic insulin sensitivity in sedentary adolescents.

Context: Data are limited on the effects of controlled aerobic exercise programs (without weight loss) on insulin sensitivity and glucose metabolism in children and adolescents.

Objective: To determine whether a controlled aerobic exercise program (without weight loss) improves peripheral and hepatic insulin sensitivity and affects glucose production (GPR), gluconeogenesis and glycogenolysis in sedentary lean and obese Hispanic adolescents.

Patients And Design: Twenty-nine post-pubertal adolescents (14 lean: 15.

Noncontact laser microdissection and pressure catapulting: sample preparation for genomic, transcriptomic, and proteomic analysis.

The understanding of the molecular mechanisms of cellular metabolism and proliferation necessitates accurate identification, isolation, and finally characterization of a specific cell or a population of cells and subsequently their subsets of biomolecules. For the simultaneous analysis of thousands of molecular parameters within a single experiment, as realized by DNA, RNA, and protein microarray technologies, a defined number of homogeneous cells derived from a distinct morphological origin is required. Sample preparation is therefore a very crucial step for high-resolution downstream applications.

High quality RNA retrieved from samples obtained by using LMPC (laser microdissection and pressure catapulting) technology.

Isolation of intact RNA in high quality is the first and often the most critical step in performing many fundamental molecular biology experiments, and is essential for many techniques used in gene expression analysis. As many factors influence nucleic acid preservation, RNA isolation should include some important steps before and after the actual RNA extraction. We tested the influence of fixation and staining protocols regarding RNA integrity and concentration.

[A simple dose-effect model for the optimization of IMRT].

Optimization of percutaneous photon beams with intensity modulation was investigated in terms of the influence of different dose-effect functions for lung tissue on the resulting dose distributions. The fluence profiles were optimized for a cylindrical phantom with a L-shaped target, the spinal cord and lung presenting the critical organs. Concurrent criteria were a minimum dose constraint for the target and a maximum dose constraint for the spinal cord.

[Studies on the E rosette test (author's transl)].

The number of T lymphocytes in the peripheral blood of normal subjects and patients with bronchial carcinoma was determined by using the E rosette test. In a comparative study we counted the "total" rosette forming cells and the "active" rosette forming cells using a lymphocytes-sheep red cells-ratio (Ly-SRBC-R) of 1:8 and 1:40. The numbers or rosettes in the two test systems are in correlation with the Ly-SRBC-R despite other differences in the techniques.