Paramagnetic artifact and safety criteria for human brain mapping

Biological effects of magnetic field and their safety criteria, especially effects of gradient magnetic field on the cerebral and pulmonary circulation during functional brain mapping are still unclear. Here we estimated that magnetically induced artifacts for the blood oxygenation level- and flow- based functional magnetic resonance imaging are less than 0.1%, and disturbance in the pulmonary circulation is less than 1.3% even if the field strength of magnetic resonance system is risen up to 10 tesla. These paramagnetic effects are considered to be small and harmless during human brain mapping

A General Chemical Method to Regulate Protein Stability in the Mammalian Central Nervous System

SummaryThe ability to make specific perturbations to biological molecules in a cell or organism is a central experimental strategy in modern research biology. We have developed a general technique in which the stability of a specific protein is regulated by a cell-permeable small molecule. Mutants of the Escherichia coli dihydrofolate reductase (ecDHFR) were engineered to be degraded, and, when this destabilizing domain is fused to a protein of interest, its instability is conferred to the fused protein resulting in rapid degradation of the entire fusion protein. A small-molecule ligand trimethoprim (TMP) stabilizes the destabilizing domain in a rapid, reversible, and dose-dependent manner, and protein levels in the absence of TMP are barely detectable. The ability of TMP to cross the blood-brain barrier enables the tunable regulation of proteins expressed in the mammalian central nervous system

High SDF-1 Expression in HIV-1 Carriers Does Not Correlate with CD8+T-Cell-Mediated Suppression of Viral Replication

AbstractStromal cell-derived factor 1 (SDF-1) inhibits T-cell tropic (T-tropic) HIV-1 infectionin vitro. In this study, we examined the regulatory role of SDF-1 on HIV-1 replication in peripheral blood mononuclear cells (PBMC) of HIV-infected individuals. We found that the amount of SDF-1 mRNA in freshly isolated PBMC of HIV-1 carriers was higher than in healthy donors. Moreover, PBMC from some asymptomatic carriers (ACs) exhibited high levels of SDF-1 mRNA expression. The level of SDF-1 expression in PBMC did not correlate with the magnitude of CD8+T cell-mediated suppression of HIV-1 among ACs. SDF-1 inhibited HIV-1 replication at the viral entry step, whereas a single-cycle HIV-1 infection system showed that the major part of the CD8+T-cell-mediated suppression occurs after intracellular penetration of the virus. Our results suggest that SDF-1 acts as a suppressor of virus replication in a CD8+T-cell-independent mechanism in HIV-infected individuals

Multiple transcripts of Ca 2ϩ channel ␣ 1 -subunits and a novel spliced variant of the ␣ 1C -subunit in rat ductus arteriosus

3 H]thymidine incorporation, suggesting that L-and T-type Ca 2ϩ channels are involved in smooth muscle cell proliferation in the DA. Third, we found that a novel alternatively spliced variant of the ␣ 1C-isoform was highly expressed in the neointimal cushion of the DA, where proliferating and migrating smooth muscle cells are abundant. The basic channel properties of the spliced variant did not differ from those of the conventional ␣1C-subunit. We conclude that multiple VDCC subunits were identified in the DA, and, in particular, ␣ 1C-and ␣1G-subunits were predominant in the DA. A novel spliced variant of the ␣1C-subunit gene may play a distinct role in neointimal cushion formation in the DA. alternative spliced; development; gene expression; fetal circulation THE DUCTUS ARTERIOSUS (DA) is a fetal arterial connection between the pulmonary artery and the descending aorta. After birth, the DA closes immediately, in accordance with its smooth muscle contraction. An increase in oxygen tension and a dramatic decline in circulating prostaglandins are the most important triggers of DA contraction (5). Generally, vascular smooth muscle contraction is induced by Ca 2ϩ / calmodulin-dependent phosphorylation of the regulatory myosin light chain, which is mediated by an increase in intracellular Ca 2ϩ . Ca 2ϩ influx through voltage-dependent Ca 2ϩ channels (VDCCs) and Ca 2ϩ release from intracellular stores are major sources of this increase (8, 26). Thus VDCCs must play an important role in vascular myogenic reactivity and tone of the DA. VDCCs are classified, according to their distinct electrophysiological and pharmacological properties, into low (Ttype) and high (L-, N-, P-, Q-, and R-type) VDCCs (20, In addition to their role in determining contractile state, a growing body of evidence has demonstrated that VDCCs play an important role in regulating differentiation and remodeling of vascular smooth muscle cells (SMCs) (14, In the present study, we identified multiple VDCC subunits in the DA by semiquantitative and quantitative RT-PCR and immunodetection. In particular, ␣ 1C -and ␣ 1G -subunits were predominant in the DA. Furthermore, we will demonstrate the identification of a novel spliced variant of the ␣ 1C -subunit gene that may play a role in neointimal cushion formation of the DA

Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy

Checkpoint blockade immunotherapies can be extraordinarily effective, but might benefit only the minority of patients whose tumors are pre-infiltrated by T cells. Here, using lung adenocarcinoma mouse models, including genetic models, we show that autochthonous tumors that lacked T cell infiltration and resisted current treatment options could be successfully sensitized to host antitumor T cell immunity when appropriately selected immunogenic drugs (e.g., oxaliplatin combined with cyclophosphamide for treatment against tumors expressing oncogenic Kras and lacking Trp53) were used. The antitumor response was triggered by direct drug actions on tumor cells, relied on innate immune sensing through toll-like receptor 4 signaling, and ultimately depended on CD8 + T cell antitumor immunity. Furthermore, instigating tumor infiltration by T cells sensitized tumors to checkpoint inhibition and controlled cancer durably. These findings indicate that the proportion of cancers responding to checkpoint therapy can be feasibly and substantially expanded by combining checkpoint blockade with immunogenic drugs

Data Descriptor : Collocated observations of cloud condensation nuclei, particle size distributions, and chemical composition

Cloud condensation nuclei (CCN) number concentrations alongside with submicrometer particle number size distributions and particle chemical composition have been measured at atmospheric observatories of the Aerosols, Clouds, and Trace gases Research InfraStructure (ACTRIS) as well as other international sites over multiple years. Here, harmonized data records from 11 observatories are summarized, spanning 98,677 instrument hours for CCN data, 157,880 for particle number size distributions, and 70,817 for chemical composition data. The observatories represent nine different environments, e.g., Arctic, Atlantic, Pacific and Mediterranean maritime, boreal forest, or high alpine atmospheric conditions. This is a unique collection of aerosol particle properties most relevant for studying aerosol-cloud interactions which constitute the largest uncertainty in anthropogenic radiative forcing of the climate. The dataset is appropriate for comprehensive aerosol characterization (e.g., closure studies of CCN), model-measurement intercomparison and satellite retrieval method evaluation, among others. Data have been acquired and processed following international recommendations for quality assurance and have undergone multiple stages of quality assessment.Peer reviewe

Absolute lymphocyte count and neutrophil-to-lymphocyte ratio as predictors of CDK 4/6 inhibitor efficacy in advanced breast cancer

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) are the standard agents for treating patients with estrogen receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer (ER + HER2 - ABC). However, markers predicting the outcomes of CDK4/6i treatment have yet to be identified. This study was a single-center retrospective cohort study. We retrospectively evaluated 101 patients with ER + HER2 - ABC receiving CDK4/6i in combination with endocrine therapy at Fukuyama City Hospital between November 2017 and July 2021. We investigated the clinical outcomes and the safety of CDK4/6i treatment, and the absolute lymphocyte count (ALC) and neutrophil-to-lymphocyte ratio (NLR) as predictive markers for CDK4/6i. We defined the cut-off values as 1000/mu L for ALC and 3 for NLR, and divided into "low" and "high" groups, respectively. We evaluated 43 and 58 patients who received abemaciclib and palbociclib, respectively. Patients with high ALC and low NLR had significantly longer overall survival than those with low ALC and high NLR (high vs. low; ALC: HR 0.29; 95% CI 0.12-0.70; NLR: HR 2.94; 95% CI 1.21-7.13). There was no significant difference in efficacy between abemaciclib and palbociclib and both had good safety profiles. We demonstrated that ALC and NLR might predict the outcomes of CDK4/6i treatment in patients with ER + HER2 - ABC