The onset of grasses in the Amazon drainage basin, evidence from the fossil record

Poaceae (the grass family) originated in the Cretaceous, but first dominate the palynological records of the Amazon drainage basin (ADB) in the Neogene (23 to 2.5 million years ago (Ma)). However, the ecological role of grasses in the landscape during this time remains to be resolved. In this paper, we summarise the global significance of grasses and the relevance of the fossil record, and evaluate the history of the grasses in the ADB. We present a 3-stage model of the changing role of grasses, which we based on a revision of Neogene depositional environments, the palynological record, and modern grass distribution in the Neotropics. Our model comprises the following hypotheses: (H1) assumes that from c. 23 to 9 Ma western Amazonia was dominated by a megawetland (the ‘Pebas system’) that harboured large amounts of (aquatic?) grasses. In (H2) we propose that from c. 9 Ma Andean uplift prompted megafans (extremely large alluvial fans) that extended from the Andes into the lowlands. Meanwhile, the ‘Pebas’ megawetland gradually transformed into a fluvial system. In this scenario, grasses would have had a competitive advantage and were able to colonise the newly formed megafan and fluvial landscapes. Finally, in (H3) we suggest that landscape dynamics and climatic change intensified from c. 3.5 Ma, allowing for a renewed expansion of the grasses. In addition, both the fossil and molecular records suggest that from c. 5 Ma grasses were firmly established in the tropical alpine vegetation (páramo), the tropical lowland floodplains (várzeas), and savannas (cerrado). Although further study will have to confirm the precise nature of the ADB grass history, we anticipate that abiotic processes during the Neogene and Quaternary left a strong imprint in the grass phytogeography of northern South America

Governing wildfires:toward a systematic analytical framework

Despite recent research, a systematic approach to understanding wildfire governance is lacking. This article addresses this deficit by systematically reviewing governance theories and concepts applied so far in the academic literature on wildfires as a step toward achieving their more effective and holistic management. We engage our findings with the wider governance literature to unlock new thinking on wildfires as a process and outcome. This comparative approach enables us to propose a novel framework for analyzing wildfire governance based on four pillars: (1) actor participation in decision-making and decision taking; (2) actor collaboration and coproduction across and within levels, scales, and networks; (3) path dependencies and local place-based dynamics of wildfire incidence and comprehension; and (4) actor adaptation to and anticipation of wildfire risk to fashion effective institutions that address the global wildfire challenge. We show how this framework can help specify a suite of bespoke analytical and policy practitioner approaches to facilitate preemptive and restorative wildfire strategies via new networks between communities, states, and wider society, thus providing the basis for more equitable and sustainable governance of wildfire risks and impacts

Hematological Changes in Women and Infants Exposed to an AZT-Containing Regimen for Prevention of Mother-to-child-transmission of HIV in Tanzania.

Tanzanian guidelines for prevention of mother-to-child-transmission of HIV (PMTCT) recommend an antiretroviral combination regimen involving zidovudine (AZT) during pregnancy, single-dosed nevirapine at labor onset, AZT plus Lamivudine (3TC) during delivery, and AZT/3TC for 1-4 weeks postpartum. As drug toxicities are a relevant concern, we assessed hematological alterations in AZT-exposed women and their infants. A cohort of HIV-positive women, either with AZT intake (n = 82, group 1) or without AZT intake (n = 62, group 2) for PMTCT during pregnancy, was established at Kyela District Hospital, Tanzania. The cohort also included the infants of group 1 with an in-utero AZT exposure ≥4 weeks, receiving AZT for 1 week postpartum (n = 41), and infants of group 2 without in-utero AZT exposure, receiving a prolonged 4-week AZT tail (n = 58). Complete blood counts were evaluated during pregnancy, birth, weeks 4-6 and 12. For women of group 1 with antenatal AZT intake, we found a statistically significant decrease in hemoglobin level, red blood cells, white blood cells, granulocytes, as well as an increase in red cell distribution width and platelet count. At delivery, the median red blood cell count was significantly lower and the median platelet count was significantly higher in women of group 1 compared to group 2. At birth, infants from group 1 showed a lower median hemoglobin level and granulocyte count and a higher frequency of anemia and granulocytopenia. At 4-6 weeks postpartum, the mean neutrophil granulocyte count was significantly lower and neutropenia was significantly more frequent in infants of group 2. AZT exposure during pregnancy as well as after birth resulted in significant hematological alterations for women and their newborns, although these changes were mostly mild and transient in nature. Research involving larger cohorts is needed to further analyze the impact of AZT-containing regimens on maternal and infant health

A global outlook on increasing wildfire risk:current policy situation and future pathways

International audienc

Congenital myasthenic syndrome with mild intellectual disability caused by a recurrent SLC25A1 variant

Abstract: Congenital myasthenic syndromes (CMS) are a clinically and genetically heterogeneous group of disorders caused by mutations which lead to impaired neuromuscular transmission. SLC25A1 encodes a mitochondrial citrate carrier, associated mainly with the severe neurometabolic disease combined D-2- and L-2-hydroxyglutaric aciduria (D/L-2-HGA). We previously reported a single family with a homozygous missense variant in SLC25A1 with a phenotype restricted to relatively mild CMS with intellectual disability, but to date no additional cases of this CMS subtype had been reported. Here, we performed whole exome sequencing (WES) in three additional and unrelated families presenting with CMS and mild intellectual disability to identify the underlying causative gene. The WES analysis revealed the presence of a homozygous c.740G>A; p.(Arg247Gln) missense SLC25A1 variant, the same SLC25A1 variant as identified in the original family with this phenotype. Electron microscopy of muscle from two cases revealed enlarged and accumulated mitochondria. Haplotype analysis performed in two unrelated families suggested that this variant is a result of recurrent mutation and not a founder effect. This suggests that p.(Arg247Gln) is associated with a relatively mild CMS phenotype with subtle mitochondrial abnormalities, while other variants in this gene cause more severe neurometabolic disease. In conclusion, the p.(Arg247Gln) SLC25A1 variant should be considered in patients presenting with a presynaptic CMS phenotype, particularly with accompanying intellectual disability

Preponderance of the oncogenic V599E and V599K mutations in B-raf kinase domain is enhanced in melanoma cutaneous/subcutaneous metastases

BACKGROUND: Downstream of Ras, the serine/threonine kinase B-raf has been reported to be mutated, among other carcinomas, in a substantial subset of primary melanomas with a preponderance of mutations within the kinase domain including the activating V599E and V599K transitions. METHODS: We here investigated a representative series of 60 resection specimens of cutaneous and subcutaneous melanoma metastases for the presence of mutations within the activation segment (exon 15) of the B-raf kinase domain by polymerase chain reaction (PCR) and single-strand conformation polymorphism (SSCP) gel electrophoresis. RESULTS: Sequencing of cloned PCR-SSCP amplicons resulted in 24 (40%) samples harbouring somatic mutations which is not exceeding the mutation frequency in recently investigated primary melanomas. The activating mutation T1796A was present in 24/60 (40%) resection specimens, followed in frequency by the oncogenic g1795A mutation in 8/60 (13%) cases. As to the B-raf protein sequence, the acidic amino acid transitions V599E and V599K were predicted in 19/60 (32%) and 6/60 (10%) cases, resepectively, but were not associated with enhanced risk for subsequent metastasis in patients' follow up. In comparison to the primary melanomas that we recently investigated, the spectrum of predicted B-raf protein mutations narrowed significantly in the cutaneous/subcutaneous metastases. Unexpectedly, V599 and V599E mutations were absent in cutaneous/subcutaneous metastases derived from acrolentiginous melanomas as preceding primary tumours. CONCLUSION: During transition from primary melanomas towards cutaneous/subcutaneous metastases, the spectrum of predicted B-raf mutations narrows significantly. Focusing on the V599E and V599K, these oncogenic mutations are likely to affect melanocyte-specific pathways controlling proliferation and differentiation

Unequal allelic expression of wild-type and mutated β-myosin in familial hypertrophic cardiomyopathy

Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disease, which in about 30% of the patients is caused by missense mutations in one allele of the β-myosin heavy chain (β-MHC) gene (MYH7). To address potential molecular mechanisms underlying the family-specific prognosis, we determined the relative expression of mutant versus wild-type MYH7-mRNA. We found a hitherto unknown mutation-dependent unequal expression of mutant to wild-type MYH7-mRNA, which is paralleled by similar unequal expression of β-MHC at the protein level. Relative abundance of mutated versus wild-type MYH7-mRNA was determined by a specific restriction digest approach and by real-time PCR (RT-qPCR). Fourteen samples from M. soleus and myocardium of 12 genotyped and clinically well-characterized FHC patients were analyzed. The fraction of mutated MYH7-mRNA in five patients with mutation R723G averaged to 66 and 68% of total MYH7-mRNA in soleus and myocardium, respectively. For mutations I736T, R719W and V606M, fractions of mutated MYH7-mRNA in M. soleus were 39, 57 and 29%, respectively. For all mutations, unequal abundance was similar at the protein level. Importantly, fractions of mutated transcripts were comparable among siblings, in younger relatives and unrelated carriers of the same mutation. Hence, the extent of unequal expression of mutated versus wild-type transcript and protein is characteristic for each mutation, implying cis-acting regulatory mechanisms. Bioinformatics suggest mRNA stability or splicing effectors to be affected by certain mutations. Intriguingly, we observed a correlation between disease expression and fraction of mutated mRNA and protein. This strongly suggests that mutation-specific allelic imbalance represents a new pathogenic factor for FHC

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Large-scale sequencing identifies multiple genes and rare variants associated with Crohn’s disease susceptibility

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