Independent Evaluation of Green Climate Fund’s Investment Framework

This evaluation of the GCF Investment Framework assesses the overall relevance and effectiveness of the Investment Framework in the context of the GCF’s efforts towards climate change mitigation and adaptation. Overall, the evaluation examines how effective and fit-for-purpose the GCF Investment Framework is in fulfilling strategic goals and mandate. It assesses the coherence and complementarity of the GCF Investment Framework internally with other GCF internal policies, and externally with the country-level climate change strategies and action plans. It also assesses and analyse the efficiency, effectiveness, coherence and complementarity of the GCF Investment Framework with regard to funding proposals, projects and programmes. In addition, it reviews alignment with wider results and risk management frameworks

Multimodal assessment shows misalignment of structural and functional thalamocortical connectivity in children and adolescents born very preterm

Thalamocortical connections are altered following very preterm birth but it is unknown whether structural and functional alterations are linked and how they contribute to neurodevelopmental deficits. We used a multimodal approach in 27 very preterm and 35 term-born children and adolescents aged 10 to 16 years: Structural thalamocortical connectivity was quantified with two measures derived from probabilistic tractography of diffusion tensor data, namely the volume of thalamic segments with cortical connections and mean fractional anisotropy (FA) within the respective segments. High-density sleep EEG was recorded and sleep spindles were identified at each electrode. Sleep spindle density and integrated spindle activity (ISA) were calculated to quantify functional thalamocortical connectivity. In term-born participants, the volume of the global thalamic segment with cortical connections was strongly related to sleep spindles across the entire head (mean r = .53 ± .10; range = .35 to .78). Regionally, the volume of the thalamic segment connecting to frontal brain regions correlated with sleep spindle density in two clusters of electrodes over fronto-temporal brain regions (.42 ± .06; .35 to .51 and .43 ± .08; .35 to .62) and the volume of the thalamic segment connecting to parietal brain regions correlated with sleep spindle density over parietal brain regions (mean r = .43 ± .07; .35 to .61). In very preterm participants, the volume of the thalamic segments was not associated with sleep spindles. In the very preterm group, mean FA within the global thalamic segment was negatively correlated with ISA over a cluster of frontal and temporo-occipital brain regions (mean r = -.53 ± .07; -.41 to -.72). No association between mean FA and ISA was found in the term-born group. With this multimodal study protocol, we identified a potential misalignment between structural and functional thalamocortical connectivity in children and adolescents born very preterm. Eventually, this may shed further light on the neuronal mechanisms underlying neurodevelopmental sequelae of preterm birth

Multimodal assessment shows misalignment of structural and functional thalamocortical connectivity in children and adolescents born very preterm

Thalamocortical connections are altered following very preterm birth but it is unknown whether structural and functional alterations are linked and how they contribute to neurodevelopmental deficits. We used a multimodal approach in 27 very preterm and 35 term-born children and adolescents aged 10–16 years: Structural thalamocortical connectivity was quantified with two measures derived from probabilistic tractography of diffusion tensor data, namely the volume of thalamic segments with cortical connections and mean fractional anisotropy (FA) within the respective segments. High-density sleep EEG was recorded and sleep spindles were identified at each electrode. Sleep spindle density and integrated spindle activity (ISA) were calculated to quantify functional thalamocortical connectivity. In term-born participants, the volume of the global thalamic segment with cortical connections was strongly related to sleep spindles across the entire head (mean r = .53 ± .10; range = 0.35 to 0.78). Regionally, the volume of the thalamic segment connecting to frontal brain regions correlated with sleep spindle density in two clusters of electrodes over fronto-temporal brain regions (.42 ± .06; 0.35 to 0.51 and 0.43 ± .08; 0.35 to 0.62) and the volume of the thalamic segment connecting to parietal brain regions correlated with sleep spindle density over parietal brain regions (mean r = .43 ± .07; 0.35 to 0.61). In very preterm participants, the volume of the thalamic segments was not associated with sleep spindles. In the very preterm group, mean FA within the global thalamic segment was negatively correlated with ISA over a cluster of frontal and temporo-occipital brain regions (mean r = −.53 ± .07; −.41 to −.72). No association between mean FA and ISA was found in the term-born group. With this multimodal study protocol, we identified a potential misalignment between structural and functional thalamocortical connectivity in children and adolescents born very preterm. Eventually, this may shed further light on the neuronal mechanisms underlying neurodevelopmental sequelae of preterm birth.ISSN:1053-8119ISSN:1095-957

Brain maturation in the first 3 months of life, measured by electroencephalogram: A comparison between preterm and term-born infants

OBJECTIVE Preterm infants are at risk for altered brain maturation resulting in neurodevelopmental impairments. Topographical analysis of high-density electroencephalogram during sleep matches underlying brain maturation. Using such an EEG mapping approach could identify preterm infants at risk early in life. METHODS 20 preterm (gestational age  37 weeks) were recorded by 18-channel daytime sleep-EEG at term age (GA 40 weeks for preterm and 2-3 days after birth for term infants) and 3 months (corrected age for preterm infants). RESULTS Preterm infant's power spectrum at term age is immature, leveling off with term infants at 3 months of age. Topographical distribution of maximal power density however, reveals qualitative differences between the groups until 3 months of age. Preterm infants exhibit more temporal than central activation at term age and more occipital than central activation at 3 months of age. Moreover, being less mature at term age predicts being less mature at 3 months of age. CONCLUSION Topographical analysis of sleep EEG reveals changes in brain maturation between term and preterm infants early in life. SIGNIFICANCE In future, automated analysis tools using topographical power distribution could help identify preterm infants at risk early in life

Determinants of Human Immunodeficiency Virus Type 1 Resistance to Membrane-Anchored gp41-Derived Peptides

The expression of a membrane-anchored gp41-derived peptide (M87) has been shown to confer protection from infection through human immunodeficiency virus type 1 (HIV-1) (Hildinger et al., J. Virol. 75:3038-3042, 2001). In an effort to characterize the mechanism of action of this membrane-anchored peptide in comparison to the soluble peptide T-20, we selected resistant variants of HIV-1(NL4-3) and HIV-1(BaL) by serial virus passage using PM1 cells stably expressing peptide M87. Sequence analysis of the resistant isolates showed different patterns of selected point mutations in heptad repeat regions 1 and 2 (HR1 and HR2, respectively) for the two viruses analyzed. For HIV-1(NL4-3) a single amino acid change at position 33 in HR1 (L33S) was selected, whereas for HIV-1(BaL) the majority of the sequences obtained showed two amino acid changes, one in HR1 and one in HR2 (I48V/N126K). In both selections the most important contiguous 3-amino-acid sequence, GIV, within HR1, associated with resistance to soluble T-20, was not changed. Site-directed mutagenesis studies confirmed the importance of the characterized point mutations to confer resistance to M87 as well as to soluble T-20 and T-649. Replication capacity and dual-color competition assays revealed that the double mutation I48V/N126K in HIV-1(BaL) results in a strong reduction of viral fitness, whereas the L33S mutation in HIV-1(NL4-3) did enhance viral fitness compared to the respective parental viruses. However, the selected point mutations did not confer resistance to the more recently described optimized membrane-anchored fusion inhibitor M87o (Egelhofer et al., J. Virol. 78:568-575, 2004), strengthening the importance of this novel antiviral concept for gene therapy approaches

Phosphoproteomic Analysis Reveals Regulatory Mechanisms at the Kidney Filtration Barrier

Diseases of the kidney filtration barrier are a leading cause of ESRD. Most disorders affect the podocytes, polarized cells with a limited capacity for self-renewal that require tightly controlled signaling to maintain their integrity, viability, and function. Here, we provide an atlas of in vivo phosphorylated, glomerulus-expressed proteins, including podocyte-specific gene products, identified in an unbiased tandem mass spectrometry-based approach. We discovered 2449 phosphorylated proteins corresponding to 4079 identified high-confidence phosphorylated residues and performed a systematic bioinformatics analysis of this dataset. We discovered 146 phosphorylation sites on proteins abundantly expressed in podocytes. The prohibitin homology domain of the slit diaphragm protein podocin contained one such site, threonine 234 (T234), located within a phosphorylation motif that is mutated in human genetic forms of proteinuria. The T234 site resides at the interface of podocin dimers. Free energy calculation through molecular dynamic simulations revealed a role for T234 in regulating podocin dimerization. We show that phosphorylation critically regulates formation of high molecular weight complexes and that this may represent a general principle for the assembly of proteins containing prohibitin homology domains

Molecular analysis of circulating tumor cells identifies distinct copy-number profiles in patients with chemosensitive and chemorefractory small-cell lung cancer

In most patients with small-cell lung cancer (SCLC)—a metastatic, aggressive disease—the condition is initially chemosensitive but then relapses with acquired chemoresistance. In a minority of patients, however, relapse occurs within 3 months of initial treatment; in these cases, disease is defined as chemorefractory. The molecular mechanisms that differentiate chemosensitive from chemorefractory disease are currently unknown. To identify genetic features that distinguish chemosensitive from chemorefractory disease, we examined copy-number aberrations (CNAs) in circulating tumor cells (CTCs) from pretreatment SCLC blood samples. After analysis of 88 CTCs isolated from 13 patients (training set), we generated a CNA-based classifier that we validated in 18 additional patients (testing set, 112 CTC samples) and in six SCLC patient-derived CTC explant tumors1. The classifier correctly assigned 83.3% of the cases as chemorefractory or chemosensitive. Furthermore, a significant difference was observed in progression-free survival (PFS) (Kaplan–Meier P value = 0.0166) between patients designated as chemorefractory or chemosensitive by using the baseline CNA classifier. Notably, CTC CNA profiles obtained at relapse from five patients with initially chemosensitive disease did not switch to a chemorefractory CNA profile, which suggests that the genetic basis for initial chemoresistance differs from that underlying acquired chemoresistance

Default network connectivity reflects the level of consciousness in non-communicative brain-damaged patients

The ‘default network’ is defined as a set of areas, encompassing posterior-cingulate/precuneus, anterior cingulate/mesiofrontal cortex and temporo-parietal junctions, that show more activity at rest than during attention-demanding tasks. Recent studies have shown that it is possible to reliably identify this network in the absence of any task, by resting state functional magnetic resonance imaging connectivity analyses in healthy volunteers. However, the functional significance of these spontaneous brain activity fluctuations remains unclear. The aim of this study was to test if the integrity of this resting-state connectivity pattern in the default network would differ in different pathological alterations of consciousness. Fourteen non-communicative brain-damaged patients and 14 healthy controls participated in the study. Connectivity was investigated using probabilistic independent component analysis, and an automated template-matching component selection approach. Connectivity in all default network areas was found to be negatively correlated with the degree of clinical consciousness impairment, ranging from healthy controls and locked-in syndrome to minimally conscious, vegetative then coma patients. Furthermore, precuneus connectivity was found to be significantly stronger in minimally conscious patients as compared with unconscious patients. Locked-in syndrome patient’s default network connectivity was not significantly different from controls. Our results show that default network connectivity is decreased in severely brain-damaged patients, in proportion to their degree of consciousness impairment. Future prospective studies in a larger patient population are needed in order to evaluate the prognostic value of the presented methodology