GATA2 mitotic bookmarking is required for definitive haematopoiesis

In mitosis, most transcription factors detach from chromatin, but some are retained and bookmark genomic sites. Mitotic bookmarking has been implicated in lineage inheritance, pluripotency and reprogramming. However, the biological significance of this mechanism in vivo remains unclear. Here, we address mitotic retention of the hemogenic factors GATA2, GFI1B and FOS during haematopoietic specification. We show that GATA2 remains bound to chromatin throughout mitosis, in contrast to GFI1B and FOS, via C-terminal zinc finger-mediated DNA binding. GATA2 bookmarks a subset of its interphase targets that are co-enriched for RUNX1 and other regulators of definitive haematopoiesis. Remarkably, homozygous mice harbouring the cyclin B1 mitosis degradation domain upstream Gata2 partially phenocopy knockout mice. Degradation of GATA2 at mitotic exit abolishes definitive haematopoiesis at aorta-gonad-mesonephros, placenta and foetal liver, but does not impair yolk sac haematopoiesis. Our findings implicate GATA2-mediated mitotic bookmarking as critical for definitive haematopoiesis and highlight a dependency on bookmarkers for lineage commitment

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Identification of Novel Genetic Loci Associated with Thyroid Peroxidase Antibodies and Clinical Thyroid Disease

Peer reviewe

Genomic epidemiology of SARS-CoV-2 in a UK university identifies dynamics of transmission

AbstractUnderstanding SARS-CoV-2 transmission in higher education settings is important to limit spread between students, and into at-risk populations. In this study, we sequenced 482 SARS-CoV-2 isolates from the University of Cambridge from 5 October to 6 December 2020. We perform a detailed phylogenetic comparison with 972 isolates from the surrounding community, complemented with epidemiological and contact tracing data, to determine transmission dynamics. We observe limited viral introductions into the university; the majority of student cases were linked to a single genetic cluster, likely following social gatherings at a venue outside the university. We identify considerable onward transmission associated with student accommodation and courses; this was effectively contained using local infection control measures and following a national lockdown. Transmission clusters were largely segregated within the university or the community. Our study highlights key determinants of SARS-CoV-2 transmission and effective interventions in a higher education setting that will inform public health policy during pandemics.</jats:p

Efectos de luz, temperatura, salinidad y GA3 en la germinación de semillas de Pumamaqui (Oreopanax spp)

Pumamaqui (Oreopanax sp) is a tree species that inhabits the montane forest of the Andes (a threatened ecosystem) and also possesses a low in vivo percentage of germination. In addition to the necessity to protect this threatened species, Pumamaqui is also important to reforest sloped areas. This study tried to assess different parameters that affect Pumamaqui´s seed germination under in vitro conditions. Seeds were inoculated under sterile conditions in the Murishage & Skoog (MS) culture media, under different environmental conditions: two salt concentrations (MS and half its concentration), two temperatures (4°C, 23°C), two light treatments (absence and presence) and two gibberellin concentrations (1.5μM, 3.0μM).El Pumamaqui (Oreopanax sp) crece en el bosque alto andino (ecosistema amenazado por el hombre) y posee un bajo porcentaje de germinación in vivo. Además de la necesidad de proteger a esta especie, el Pumamaqui es importante para la reforestación de laderas. En este estudio se intentaron evaluar distintos parámetros que afectan la germinación de semillas de Pumamaqui mediante técnicas in vitro. Las semillas se sembraron bajo asepsia total en el medio de Murishage y Skoog (MS) con Agar, en diferentes condiciones: dos concentraciones de sales (concentración del medio MS, y la mitad de su concentración), dos temperaturas (4°C, 23°C), dos tratamientos de luz (ausencia y presencia) y dos concentraciones de giberelinas (1.5μM, 3.0μM)

A new andean species of leaf-toed gecko (Phyllodactylidae: Phyllodactylus) from Ecuador

We describe a new species of Phyllodactylus from a xerophytic forest in the Andes of southern Ecuador. The new species differs from other mainland species of Phyllodactylus from South America by the combination of the following characters: preanal scales similar in size to other ventral scales, well-defined longitudinal rows of tubercles dorsally, a medial longitudinal row of enlarged caudal scales ventrally, tubercles on dorsal surface of tibia present, enlarged postanal scale absent, tubercles on dorsal surface of forearm absent, interorbital scales homogeneous in size, enlarged scales on proximal one-fourth of tail absent, gular scales granular, and maximum snout-vent length of 55 mm. Even though morphological similarity suggests a close relationship between the new species and Phyllodactylus reissii, phylogenetic analyses of 10 nuclear and mitochondrial genes contradict this hypothesis. We also report the first records of Phyllodactylus kofordi for Ecuador. © 2013 Society for the Study of Amphibians and Reptiles

Solving the microwave heating uniformity conundrum for scalable high-temperature processes via a toroidal fluidised-bed reactor

Challenges exist to implementing high-temperature microwave processes with changing dielectric properties that achieve uniform processing. This paper presents a new high-temperature hybrid microwave processing system which overcomes these challenges in a robust, scalable way, integrating a slotted waveguide ring microwave feed into a toroidal fluidised bed reactor and maintaining its fluidisation behaviour. The prototype operates at a frequency of 2450 MHz with a maximum power of 10 kW and within a temperature range of 50-300°C, though it is scalable to industrial levels. Electromagnetic simulations of the system were experimentally validated using a range of agri-crop feedstocks. Hydrodynamic and thermodynamic reactor characterisation was performed, and treatment performance was quantified regarding surface bed temperature variation. Excellent treatment uniformities were found under microwave and hybrid regimes, with a temperature coefficient of variation (CoV) across the bed's surface below 2 %, an order of magnitude better than existing microwave processes, generally regarded as highly uniform with CoV of approximately 20 %. The integration of microwaves and toroidal fluidised beds, without exposed moving parts, potentially unlocks a range of applications previously inaccessible to microwave technology or fluidised bed technologies on their own. Future work involves process development, techno-economic studies, and large-scale pilot trials

Safety and efficacy of pegunigalsidase alfa in patients with Fabry disease who were previously treated with agalsidase alfa: results from BRIDGE, a phase 3 open-label study

Background Pegunigalsidase alfa is a novel, PEGylated α-galactosidase-A enzyme-replacement therapy approved in the EU and US to treat patients with Fabry disease (FD). Objective/methods BRIDGE is a phase 3 open-label, switch-over study designed to assess safety and efficacy of 12 months of pegunigalsidase alfa (1 mg/kg every 2 weeks) treatment in adults with FD who had been previously treated with agalsidase alfa (0.2 mg/kg every 2 weeks) for ≥ 2 years. Results Twenty-seven patients were screened; 22 met eligibility criteria; and 20 (13 men, 7 women) completed the study. Pegunigalsidase alfa was well-tolerated, with 97% of treatment-emergent adverse events (TEAEs) being of mild or moderate severity. The incidence of treatment-related TEAEs was low, with 2 (9%) discontinuations due to TEAEs. Five patients (23%) reported infusion-related reactions. Overall mean (SD; n = 22) baseline estimated glomerular filtration rate (eGFR) was 82.5 (23.4) mL/min/1.73 m2 and plasma lyso-Gb3 level was 38.3 (41.2) nmol/L (men: 49.7 [45.8] nmol/L; women: 13.8 [6.1] nmol/L). Before switching to pegunigalsidase alfa, mean (standard error [SE]) annualized eGFR slope was − 5.90 (1.34) mL/min/1.73 m2/year; 12 months post-switch, the mean eGFR slope was − 1.19 (1.77) mL/min/1.73 m2/year; and mean plasma lyso-Gb3 reduced by 31%. Seven (35%) out of 20 patients were positive for pegunigalsidase alfa antidrug antibodies (ADAs) at ≥ 1 study timepoint, two of whom had pre-existing ADAs at baseline. Mean (SE) changes in eGFR slope for ADA-positive and ADA-negative patients were + 5.47 (3.03) and + 4.29 (3.15) mL/min/1.73 m2/year, respectively, suggesting no negative impact of anti-pegunigalsidase alfa ADAs on eGFR slope. Conclusion Pegunigalsidase alfa may offer a safe and effective treatment option for patients with FD, including those previously treated with agalsidase alfa. TRN: NCT03018730. Date of registration: January 2017.publishedVersio