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Transverse aortic constriction (TAC) is a well-established model of pressure overload-induced cardiac hypertrophy and failure in mice. The degree of constriction “tightness” dictates the TAC severity and is determined by the gauge (G) of needle used. Though many reports use the TAC model, few studies have directly compared the range of resulting phenotypes. In this study adult male mice were randomized to receive TAC surgery with varying degrees of tightness: mild (25G), moderate (26G) or severe (27G) for 4 weeks, alongside sham-operated controls. Weekly echocardiography and terminal haemodynamic measurements determined cardiac remodelling and function. All TAC models induced significant, severity-dependent left ventricular hypertrophy and diastolic dysfunction compared to sham mice. Mice subjected to 26G TAC additionally exhibited mild systolic dysfunction and cardiac fibrosis, whereas mice in the 27G TAC group had more severe systolic and diastolic dysfunction, severe cardiac fibrosis, and were more likely to display features of heart failure, such as elevated plasma BNP. We also observed renal atrophy in 27G TAC mice, in the absence of renal structural, functional or gene expression changes. 25G, 26G and 27G TAC produced different responses in terms of cardiac structure and function. These distinct phenotypes may be useful in different preclinical settings.

Wound infection by multidrug-resistant (MDR) bacteria is a major disease burden. Systemic administration of broad-spectrum antibiotics colistin methanesulfonate (CMS) and vancomycin are the last lines of defense against deep wound infections by MDR bacteria. However, systemic administration of CMS and vancomycin are linked to life-threatening vital organ damage. Currently there are no effective topical application strategies to deliver these high molecular weight antibiotics across the stratum corneum. To overcome this difficulty, we tested if high molecular weight antibiotics delivered by Droplette micromist technology device (DMTD), a transdermal delivery device that generates a micromist capable of packaging large molecules, could attenuate deep skin tissue infections. Using green fluorescent protein-tagged E. coli and live tissue imaging, we show that (1) the extent of attenuation of deep-skin E. coli infection was similar when treated with topical DMTD- or systemic IP (intraperitoneal)-delivered CMS; (2) DMTD-delivered micromist did not spread the infection deeper; (3) topical DMTD delivery and IP delivery resulted in similar levels of vancomycin in the skin after a 2 h washout period; and (4) IP-delivered vancomycin was about 1000-fold higher in kidney and plasma than DMTD-delivered vancomycin indicating systemic toxicity. Thus, topical DMTD delivery of these antibiotics is a safe treatment for the difficult-to-treat deep skin tissue infections by MDR bacteria.

cGMP-dependent protein kinase 1α (PKG1α) promotes left ventricle (LV) compensation after pressure overload. PKG1-activating drugs improve heart failure (HF) outcomes but are limited by vasodilation-induced hypotension. Signaling molecules that mediate PKG1α cardiac therapeutic effects but do not promote PKG1α-induced hypotension could therefore represent improved therapeutic targets. We investigated roles of mixed lineage kinase 3 (MLK3) in mediating PKG1α effects on LV function after pressure overload and in regulating BP. In a transaortic constriction HF model, PKG activation with sildenafil preserved LV function in MLK3+/+ but not MLK3-/- littermates. MLK3 coimmunoprecipitated with PKG1α. MLK3-PKG1α cointeraction decreased in failing LVs. PKG1α phosphorylated MLK3 on Thr277/Ser281 sites required for kinase activation. MLK3-/- mice displayed hypertension and increased arterial stiffness, though PKG stimulation with sildenafil or the soluble guanylate cyclase (sGC) stimulator BAY41-2272 still reduced BP in MLK3-/- mice. MLK3 kinase inhibition with URMC-099 did not affect BP but induced LV dysfunction in mice. These data reveal MLK3 as a PKG1α substrate mediating PKG1α preservation of LV function but not acute PKG1α BP effects. Mechanistically, MLK3 kinase-dependent effects preserved LV function, whereas MLK3 kinase-independent signaling regulated BP. These findings suggest augmenting MLK3 kinase activity could preserve LV function in HF but avoid hypotension from PKG1α activation.

Barth Syndrome (BTHS) is an early onset, lethal X-linked disorder caused by a mutation in tafazzin (TAFAZZIN), a mitochondrial acyltransferase that remodels monolysocardiolipin (MLCL) to mature cardiolipin (CL) and is essential for normal mitochondrial, cardiac, and skeletal muscle function. Current gene therapies in preclinical development require high levels of transduction. We tested whether TAFAZZIN gene therapy could be enhanced with the addition of a cell-penetrating peptide, penetratin (Antp). We found that TAFAZZIN-Antp was more effective than TAFAZZIN at preventing the development of pathological cardiac hypertrophy and heart failure. These findings indicate that a cell-penetrating peptide enhances gene therapy for BTHS.

Background: Type-II diabetes (DMII) and metabolic syndrome increase ventricular arrhythmia and sudden cardiac death risk. Objectives: To identify signaling mechanisms through which DMII and metabolic syndrome promote ventricular tachycardia (VT). Methods: We performed ventricular programmed stimulation on leptin receptor mutant (Db/Db) mice with DMII, high fat high sucrose (HFHS)-fed mice with metabolic syndrome, and cGMP-dependent Protein Kinase 1a (PKG1a) leucine zipper mutant (LZM) mice, which do not have DMII or metabolic syndrome but have disrupted PKG1a signaling. Results: During ventricular programmed stimulation, Db/Db and HFHS-fed mice displayed increased VT and T-wave alternans. Cardiomyocytes from these mice displayed early afterdepolarizations. Both models demonstrated decreased heart rate response to parasympathetic inhibition, indicating autonomic dysfunction. cGMP, which mediates cardiac parasympathetic stimulation, was reduced in LVs of Db/Db and HFHS-fed mice. Conversely, cGMP augmentation with soluble guanylate cyclase stimulation (riociguat) or phosphodiesterase 5 inhibition (sildenafil) reduced VT inducibility. PKG1a LZM mice had normal autonomic responsiveness, but excess VT inducibility. Db/Db, HFHS, and LZM mice each demonstrated hyperactivated myocardial glycogen synthase kinase3β (GSK3b). Further, GSK3b inhibition with TWS119 abolished inducible VT in these mice. Diastolic cytosolic Ca2+ reuptake slope decreased in cardiomyocytes from all models, while GSK3β inhibition with TWS119 reversed this effect. Phospholamban (PLB), which inhibits sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a-mediated Ca2+ reuptake, was hyperactivated/hypophosphorylated in HFHS-fed and LZM mice, and this was reversed by TWS119. Conclusions: These findings identify cGMP reduction as driving GSK3β hyperstimulation, calcium dyshomeostasis, and VT in DMII and metabolic syndrome. Pharmacological modulation of these pathways opposes VT pathogenesis.Competing Interest StatementThe authors have declared no competing interest.

Background: Aging-associated left ventricular (LV) dysfunction promotes cardiopulmonary fibrogenic remodeling, Group 2 pulmonary hypertension (PH), and right ventricular failure. At the time of diagnosis, cardiac function has declined, and cardiopulmonary fibrosis has often developed. Here, we sought to develop a molecular positron emission tomography (PET)-magnetic resonance imaging (MRI) protocol to detect both cardiopulmonary fibrosis and fibrotic disease activity in an LV dysfunction model. Methods: LV dysfunction was induced by transverse aortic constriction (TAC) in 6-month-old senescence-accelerated prone (SAMP8) mice, a subset of mice received sham surgery. Three weeks post-surgery, mice underwent simultaneous PET-MR imaging at 4.7 T. Collagen-targeted PET and fibrogenesis MR probes were intravenously administered. PET signal was computed as myocardium- or lung-to-muscle ratio (MMR, LMR). Percent signal increase (%SI) and ΔLMR were computed from the pre-/post-injection MR images. Tissue specimens were analyzed for hydroxyproline (Hyp) and allysine content. Ventricular structure and function were measured by echocardiography and hemodynamic pressure-volume (PV) loop analysis. Results: Allysine in the heart (22±5 (TAC), 13±5 (sham) nmol/g, P=0.02) and lungs (7.5±4 (TAC), 5.8±2 (sham) nmol/lung, P=0.17) of TAC mice corresponded to an increase in myocardial MRI %SI (29±15 (TAC), 6.1±4 (sham), P<0.0001) and ΔLMR (0.3±0.1 (TAC), 0.08±0.1 (sham), P<0.0001). Hyp in the heart (555±90 (TAC), 400±80 (sham) µg/g, P<0.0001) and lungs (189±63 (TAC), 143±31 (sham) µg/lung, P<0.01) were elevated in TAC mice, which corresponded to an increase in PET signal (MMR: 1.8±0.1 (TAC), 1.6±0.2 (sham), P=0.02; LMR: 1.5±0.1 (TAC), 1.2±0.1 (sham), P<0.001). PV loop and echocardiography demonstrated adverse LV remodeling, function, and increased right ventricular systolic pressure in TAC mice. Conclusions: Administration of collagen-targeted PET and allysine-targeted MR probes led to elevated PET-MRI signals in the myocardium and lungs of TAC mice. The study demonstrates the potential to detect fibrosis and fibrogenesis in cardiopulmonary disease through a dual molecular PET-MR imaging protocol.Competing Interest StatementThe authors have declared no competing interest.

CD19-specific CAR T cells were produced centrally for a global study in young people with relapsed B-cell ALL. The overall remission rate was 81%, and patients with a response were negative for minimal residual disease. High-grade toxic effects were frequent but treatable.

Many species of microalgae produce greatly enhanced amounts of triacylglycerides (TAGs), the key product for biodiesel production, in response to specific environmental stresses. Improvement of TAG production by microalgae through optimization of growth regimes is of great interest. This relies on understanding microalgal lipid metabolism in relation to stress response in particular the deprivation of nutrients that can induce enhanced TAG synthesis. In this study, a detailed investigation of changes in lipid composition in Chlorella sp. and Nannochloropsis sp. in response to nitrogen deprivation (N-deprivation) was performed to provide novel mechanistic insights into the lipidome during stress. As expected, an increase in TAGs and an overall decrease in polar lipids were observed. However, while most membrane lipid classes (phosphoglycerolipids and glycolipids) were found to decrease, the non-nitrogen containing phosphatidylglycerol levels increased considerably in both algae from initially low levels. Of particular significance, it was observed that the acyl composition of TAGs in Nannochloropsis sp. remain relatively constant, whereas Chlorella sp. showed greater variability following N-deprivation. In both algae the overall fatty acid profiles of the polar lipid classes were largely unaffected by N-deprivation, suggesting a specific FA profile for each compartment is maintained to enable continued function despite considerable reductions in the amount of these lipids. The changes observed in the overall fatty acid profile were due primarily to the decrease in proportion of polar lipids to TAGs. This study provides the most detailed lipidomic information on two different microalgae with utility in biodiesel production and nutraceutical industries and proposes the mechanisms for this rearrangement. This research also highlights the usefulness of the latest MS-based approaches for microalgae lipid research.

Observationally, kilonovae are astrophysical transients powered by the radioactive decay of nuclei heavier than iron, thought to be synthesized in the merger of two compact objects 1 – 4 . Over the first few days, the kilonova evolution is dominated by a large number of radioactive isotopes contributing to the heating rate 2 , 5 . On timescales of weeks to months, its behaviour is predicted to differ depending on the ejecta composition and the merger remnant 6 – 8 . Previous work has shown that the kilonova associated with gamma-ray burst 230307A is similar to kilonova AT2017gfo (ref. 9 ), and mid-infrared spectra revealed an emission line at 2.15 micrometres that was attributed to tellurium. Here we report a multi-wavelength analysis, including publicly available James Webb Space Telescope data 9 and our own Hubble Space Telescope data, for the same gamma-ray burst. We model its evolution up to two months after the burst and show that, at these late times, the recession of the photospheric radius and the rapidly decaying bolometric luminosity ( L bol  ∝  t −2.7±0.4 , where t is time) support the recombination of lanthanide-rich ejecta as they cool. A modelling analysis shows that an unusually long gamma-ray burst gave rise to a lanthanide-rich kilonova following the merger of a neutron star–neutron star or of a neutron star–black hole.