Plausible Emergence and Self Assembly of a Primitive Phospholipid from Reduced Phosphorus on the Primordial Earth

How life arose on the primitive Earth is one of the biggest questions in science. Biomolecular emergence scenarios have proliferated in the literature but accounting for the ubiquity of oxidized (+?5) phosphate (PO₄^3?) in extant biochemistries has been challenging due to the dearth of phosphate and molecular oxygen on the primordial Earth. A compelling body of work suggests that exogenous schreibersite ((Fe,Ni)₃P) was delivered to Earth via meteorite impacts during the Heavy Bombardment (ca. 4.1–3.8 Gya) and there converted to reduced P oxyanions (e.g., phosphite (HPO₃^2?) and hypophosphite (H₂PO₂^?)) and phosphonates. Inspired by this idea, we review the relevant literature to deduce a plausible reduced phospholipid analog of modern phosphatidylcholines that could have emerged in a primordial hydrothermal setting. A shallow alkaline lacustrine basin underlain by active hydrothermal fissures and meteoritic schreibersite-, clay-, and metal-enriched sediments is envisioned. The water column is laden with known and putative primordial hydrothermal reagents. Small system dimensions and thermal- and UV-driven evaporation further concentrate chemical precursors. We hypothesize that a reduced phospholipid arises from Fischer–Tropsch-type (FTT) production of a C8 alkanoic acid, which condenses with an organophosphinate (derived from schreibersite corrosion to hypophosphite with subsequent methylation/oxidation), to yield a reduced protophospholipid. This then condenses with an α-amino nitrile (derived from Strecker-type reactions) to form the polar head. Preliminary modeling results indicate that reduced phospholipids do not aggregate rapidly; however, single layer micelles are stable up to aggregates with approximately 100 molecules.

     

The border effect in surname structure: an Italian-Slovenian case study

Population surname structure in northeastern Italy municipalities, in which small Slovenian-speaking groups are present, are compared with neighboring populations of both Italian and Slovenian nationality. In the early 20th century those municipalities were part of the Italian territory and underwent a massive Italianization process that led to the mutation of the original Slovenian surnames into a derived Italian form. In order to track surname relationships among the examined communities, two different similarity analyses were performed: the first using the surnames as they are recorded in the Italian and Slovenian official telephone directories, and the second restoring the Italianized Slovenian surnames to their original form and then recalculating the populations' similarity. Both comparisons evidence a separation that depends on nationality, which is less marked after restoring surnames to their original form. Geographical elements, older historical events, and socioeconomic traits allow interpretation of these results.     

Major Challenges in Clinical Management of TB/HIV Coinfected Patients in Eastern Europe Compared with Western Europe and Latin America

Objectives

Rates of TB/HIV coinfection and multi-drug resistant (MDR)-TB are increasing in Eastern Europe (EE). We aimed to study clinical characteristics, factors associated with MDR-TB and predicted activity of empiric anti-TB treatment at time of TB diagnosis among TB/HIV coinfected patients in EE, Western Europe (WE) and Latin America (LA).

Design and Methods

Between January 1, 2011, and December 31, 2013, 1413 TB/HIV patients (62 clinics in 19 countries in EE, WE, Southern Europe (SE), and LA) were enrolled.

Results

Significant differences were observed between EE (N = 844), WE (N = 152), SE (N = 164), and LA (N = 253) in the proportion of patients with a definite TB diagnosis (47%, 71%, 72% and 40%, p<0.0001), MDR-TB (40%, 5%, 3% and 15%, p<0.0001), and use of combination antiretroviral therapy (cART) (17%, 40%, 44% and 35%, p<0.0001). Injecting drug use (adjusted OR (aOR) = 2.03 (95% CI 1.00–4.09), prior anti-TB treatment (3.42 (1.88–6.22)), and living in EE (7.19 (3.28–15.78)) were associated with MDR-TB. Among 585 patients with drug susceptibility test (DST) results, the empiric (i.e. without knowledge of the DST results) anti-TB treatment included ≥3 active drugs in 66% of participants in EE compared with 90–96% in other regions (p<0.0001).

Conclusions

In EE, TB/HIV patients were less likely to receive a definite TB diagnosis, more likely to house MDR-TB and commonly received empiric anti-TB treatment with reduced activity. Improved management of TB/HIV patients in EE requires better access to TB diagnostics including DSTs, empiric anti-TB therapy directed at both susceptible and MDR-TB, and more widespread use of cART.     

The flexibility of two tropomyosin mutants, D175N and E180G, that cause hypertrophic cardiomyopathy

Point mutations targeting muscle thin filament proteins are the cause of a number of cardiomyopathies. In many cases, biological effects of the mutations are well-documented, whereas their structural and mechanical impact on filament assembly and regulatory function is lacking. In order to elucidate molecular defects leading to cardiac dysfunction, we have examined the structural mechanics of two tropomyosin mutants, E180G and D175N, which are associated with hypertrophic cardiomyopathy (HCM). Tropomyosin is an α-helical coiled-coil dimer which polymerizes end-to-end to create an elongated superhelix that wraps around F-actin filaments of muscle and non-muscle cells, thus modulating the binding of other actin-binding proteins. Here, we study how flexibility changes in the E180G and D175N mutants might affect tropomyosin binding and regulatory motion on F-actin. Electron microscopy and Molecular Dynamics simulations show that E180G and D175N mutations cause an increase in bending flexibility of tropomyosin both locally and globally. This excess flexibility is likely to increase accessibility of the myosin-binding sites on F-actin, thus destabilizing the low-Ca(2+) relaxed-state of cardiac muscle. The resulting imbalance in the on-off switching mechanism of the mutants will shift the regulatory equilibrium towards Ca(2+)-activation of cardiac muscle, as is observed in affected muscle, accompanied by enhanced systolic activity, diastolic dysfunction, and cardiac compensations associated with HCM and heart failure.     

Exosome-associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early Alzheimer disease

Recent demonstrations that the secretion, uptake, and interneuronal transfer of tau can be modulated by disease-associated tau modifications suggest that secretion may be an important element in tau-induced neurodegeneration. Here, we show that much of the tau secreted by M1C cells occurs via exosomal release, a widely characterized mechanism that mediates unconventional secretion of other aggregation-prone proteins (α-synuclein, prion protein, and β-amyloid) in neurodegenerative disease. Exosome-associated tau is also present in human CSF samples and is phosphorylated at Thr-181 (AT270), an established phosphotau biomarker for Alzheimer disease (AD), in both M1C cells and in CSF samples from patients with mild (Braak stage 3) AD. A preliminary analysis of proteins co-purified with tau in secreted exosomes identified several that are known to be involved in disease-associated tau misprocessing. Our results suggest that exosome-mediated secretion of phosphorylated tau may play a significant role in the abnormal processing of tau and in the genesis of elevated CSF tau in early AD.     

Transgenic mouse proteomics identifies new 14-3-3-associated proteins involved in cytoskeletal rearrangements and cell signaling

Identification of protein-protein interactions is crucial for unraveling cellular processes and biochemical mechanisms of signal transduction. Here we describe, for the first time, the application of the tandem affinity purification (TAP) and LC-MS method to the characterization of protein complexes from transgenic mice. The TAP strategy developed in transgenic mice allows the emplacement of complexes in their physiological environment in contact with proteins that might only be specifically expressed in certain tissues while simultaneously ensuring the right stoichiometry of the TAP protein versus their binding partners and represents a novelty in proteomics approaches used so far. Mouse lines expressing TAP-tagged 14-3-3zeta protein were generated, and protein interactions were determined. 14-3-3 proteins are general regulators of cell signaling and represent up to 1% of the total brain protein. This study allowed the identification of almost 40 novel 14-3-3zeta-binding proteins. Biochemical and functional characterization of some of these interactions revealed new mechanisms of action of 14-3-3zeta in several signaling pathways, such as glutamate receptor signaling via binding to homer homolog 3 (Homer 3) and in cytoskeletal rearrangements and spine morphogenesis by binding and regulating the activity of the signaling complex formed by G protein-coupled receptor kinase-interactor 1 (GIT1) and p21-activated kinase-interacting exchange factor beta (betaPIX).     

Distribution of surnames and linguistic-cultural identities of the Slovenian and German minorities of northeastern Italy

In this study we have compared the structure of surnames of Slovenian and German (Carinthian) minorities of northeastern Italy with other municipalities of the neighbourhood. The analysis has been carried out by using estimates of the similarities between populations and the topological representation obtained by them, as well as the spatial autocorrelation. On the whole, this research shows some distinctions which depend on the territorial geography, especially in the mountainous area. Moreover, movements of individuals in the limited zones of the plain are evident, probably due to socioeconomic conditions, the moving of the people and their change of dwelling. Finally, it is probable that different Slovenian dialects generated characteristic structures of surnames which were well preserved in the most peripherical municipalities of the territory.