Three-dimensional folding and functional organization principles of the Drosophila genome

Chromosomes are the physical realization of genetic information and thus form the basis for its readout and propagation. Here we present a high-resolution chromosomal contact map derived from a modified genome-wide chromosome conformation capture approach applied to Drosophila embryonic nuclei. The data show that the entire genome is linearly partitioned into well-demarcated physical domains that overlap extensively with active and repressive epigenetic marks. Chromosomal contacts are hierarchically organized between domains. Global modeling of contact density and clustering of domains show that inactive domains are condensed and confined to their chromosomal territories, whereas active domains reach out of the territory to form remote intra- and interchromosomal contacts. Moreover, we systematically identify specific long-range intrachromosomal contacts between Polycomb-repressed domains. Together, these observations allow for quantitative prediction of the Drosophila chromosomal contact map, laying the foundation for detailed studies of chromosome structure and function in a genetically tractable system.     

Competing G protein‐coupled receptor kinases balance G protein and β‐arrestin signaling

Seven‐transmembrane receptors (7TMRs) are involved in nearly all aspects of chemical communications and represent major drug targets. 7TMRs transmit their signals not only via heterotrimeric G proteins but also through β‐arrestins, whose recruitment to the activated receptor is regulated by G protein‐coupled receptor kinases (GRKs). In this paper, we combined experimental approaches with computational modeling to decipher the molecular mechanisms as well as the hidden dynamics governing extracellular signal‐regulated kinase (ERK) activation by the angiotensin II type 1A receptor (AT_1AR) in human embryonic kidney (HEK)293 cells. We built an abstracted ordinary differential equations (ODE)‐based model that captured the available knowledge and experimental data. We inferred the unknown parameters by simultaneously fitting experimental data generated in both control and perturbed conditions. We demonstrate that, in addition to its well‐established function in the desensitization of G‐protein activation, GRK2 exerts a strong negative effect on β‐arrestin‐dependent signaling through its competition with GRK5 and 6 for receptor phosphorylation. Importantly, we experimentally confirmed the validity of this novel GRK2‐dependent mechanism in both primary vascular smooth muscle cells naturally expressing the AT_1AR, and HEK293 cells expressing other 7TMRs.     

Reconstituting Corticostriatal Network on-a-Chip Reveals the Contribution of the Presynaptic Compartment to Huntington’s Disease

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Bias due to methods of parasite detection when estimating prevalence of infection of Triatoma infestans by Trypanosoma cruzi

The study aimed to quantify the bias from parasite detection methods in the estimation of the prevalence of infection of Triatoma infestans by Trypanosoma cruzi, the agent of Chagas disease. Three common protocols that detect T. cruzi in a sample of 640 wild‐caught T. infestans were compared: (1) the microscopic observation of insect fecal droplets, (2) a PCR protocol targeting mini‐exon genes of T. cruzi (MeM‐PCR), and (3) a PCR protocol targeting a satellite repeated unit of the parasite. Agreement among protocols was computed using Krippendorff Kα. The sensitivity (Se) and specificity (Sp) of each protocol was estimated using latent class models. The PCR protocols were more sensitive (Se > 0.97) than microscopy (Se = 0.53) giving a prevalence of infection of 17–18%, twice as high as microscopy. Microscopy may not be as specific as PCR if Trypanosomatid‐like organisms make up a high proportion of the sample. For small T. infestans, microscopy is not efficient, giving a prevalence of 1.5% when PCR techniques gave 10.7%. The PCR techniques were in agreement (Kα = 0.94) but not with microscopy (Kα never significant with both PCR techniques). Among the PCR protocols, the MeM‐PCR was the most efficient (Se=1; Sp=1).     

Design and synthesis of new substrates of HtrA2 protease

HtrA2 belongs to the HtrA (high temperature requirement A) family of ATP-independent serine proteases. The primary function of HtrA2 includes maintaining the mitochondria homeostasis, cell death (by apoptosis, necrosis, or anoikis), and contribution to the cell signaling. Several recent reports have shown involvement of HtrA2 in development of cancer and neurodegenerative disorders. Here, we describe the profiling of HtrA2 protease substrate specificity via the combinatorial chemistry approach that led to the selection of novel intramolecularly quenched substrates. For all synthesized compounds, the highest HtrA2-mediated hydrolysis efficiency and selectivity among tested HtrA family members was observed for ABZ-Ile-Met-Thr-Abu-Tyr-Met-Phe-Tyr(3-NO₂)-NH₂, which displayed a specificity constant k_cat/K_M value of 14,535 M⁻¹ s⁻¹.     

Interplay Between Side Chain Pattern,Polymer Aggregation,and Charge Carrier Dynamics in PBDTTPD:PCBM Bulk‐Heterojunction Solar Cells

Poly(benzo[1,2‐b:4,5‐b′]dithiophene–alt–thieno[3,4‐c]pyrrole‐4,6‐dione) (PBDTTPD) polymer donors with linear side‐chains yield bulk‐heterojunction (BHJ) solar cell power conversion efficiencies (PCEs) of about 4% with phenyl‐C₇₁‐butyric acid methyl ester (PC₇₁BM) as the acceptor, while a PBDTTPD polymer with a combination of branched and linear substituents yields a doubling of the PCE to 8%. Using transient optical spectroscopy it is shown that while the exciton dissociation and ultrafast charge generation steps are not strongly affected by the side chain modifications, the polymer with branched side chains exhibits a decreased rate of nongeminate recombination and a lower fraction of sub‐nanosecond geminate recombination. In turn the yield of long‐lived charge carriers increases, resulting in a 33% increase in short circuit current (J _sc). In parallel, the two polymers show distinct grazing incidence X‐ray scattering spectra indicative of the presence of stacks with different orientation patterns in optimized thin‐film BHJ devices. Independent of the packing pattern the spectroscopic data also reveals the existence of polymer aggregates in the pristine polymer films as well as in both blends which trap excitons and hinder their dissociation.     

On the causes of trends in the seasonal amplitude of atmospheric CO2

No consensus has yet been reached on the major factors driving the observed increase in the seasonal amplitude of atmospheric CO₂ in the northern latitudes. In this study, we used atmospheric CO₂ records from 26 northern hemisphere stations with a temporal coverage longer than 15 years, and an atmospheric transport model prescribed with net biome productivity (NBP) from an ensemble of nine terrestrial ecosystem models, to attribute change in the seasonal amplitude of atmospheric CO₂. We found significant (p < .05) increases in seasonal peak‐to‐trough CO₂ amplitude (AMP_P‐T) at nine stations, and in trough‐to‐peak amplitude (AMP_T‐P) at eight stations over the last three decades. Most of the stations that recorded increasing amplitudes are in Arctic and boreal regions (>50°N), consistent with previous observations that the amplitude increased faster at Barrow (Arctic) than at Mauna Loa (subtropics). The multi‐model ensemble mean (MMEM) shows that the response of ecosystem carbon cycling to rising CO₂ concentration (eCO₂) and climate change are dominant drivers of the increase in AMP_P‐T and AMP_T‐P in the high latitudes. At the Barrow station, the observed increase of AMP_P‐T and AMP_T‐P over the last 33 years is explained by eCO₂ (39% and 42%) almost equally than by climate change (32% and 35%). The increased carbon losses during the months with a net carbon release in response to eCO₂ are associated with higher ecosystem respiration due to the increase in carbon storage caused by eCO₂ during carbon uptake period. Air‐sea CO₂ fluxes (10% for AMP_P‐T and 11% for AMP_T‐P) and the impacts of land‐use change (marginally significant 3% for AMP_P‐T and 4% for AMP_T‐P) also contributed to the CO₂ measured at Barrow, highlighting the role of these factors in regulating seasonal changes in the global carbon cycle.     

High‐Throughput DNA sequencing of ancient wood

Reconstructing the colonization and demographic dynamics that gave rise to extant forests is essential to forecasts of forest responses to environmental changes. Classical approaches to map how population of trees changed through space and time largely rely on pollen distribution patterns, with only a limited number of studies exploiting DNA molecules preserved in wooden tree archaeological and subfossil remains. Here, we advance such analyses by applying high‐throughput (HTS) DNA sequencing to wood archaeological and subfossil material for the first time, using a comprehensive sample of 167 European white oak waterlogged remains spanning a large temporal (from 550 to 9,800 years) and geographical range across Europe. The successful characterization of the endogenous DNA and exogenous microbial DNA of 140 (~83%) samples helped the identification of environmental conditions favouring long‐term DNA preservation in wood remains, and started to unveil the first trends in the DNA decay process in wood material. Additionally, the maternally inherited chloroplast haplotypes of 21 samples from three periods of forest human‐induced use (Neolithic, Bronze Age and Middle Ages) were found to be consistent with those of modern populations growing in the same geographic areas. Our work paves the way for further studies aiming at using ancient DNA preserved in wood to reconstruct the micro‐evolutionary response of trees to climate change and human forest management.