Serum antibodies to Vibrio vulnificus biotype 3 lipopolysaccharide and susceptibility to disease caused by the homologous V. vulnificus biotype

In 1996 an outbreak of severe soft tissue infections caused by Vibrio vulnificus unexpectedly erupted in fish consumers in Israel with relatively little morbidity in fish farmers. To test the hypothesis that recurrent exposure of fishermen to the virulent strain may have provided protection against severe or symptomatic disease, we investigated the association between the immune response to V. vulnificus biotype 3 lipopolysaccharide (BT3 LPS) and disease susceptibility in fish farmers and fish consumers. Serum samples were tested for IgA and IgG of anti-BT3 LPS in fishermen and fish consumers who suffered from V. vulnificus BT3 infections and their matched controls. Pre-existing levels of IgG (IgG0) of anti-BT3 LPS were significantly lower in diseased fishermen who developed disease associated with the homologous biotype, compared to controls. In multivariate analysis, levels of IgG0 anti-BT3 LPS remained the only variable significantly associated with disease occurrence in fishermen. Higher levels of pre-existing IgG anti-BT 3 LPS antibodies may be associated with protection against severe or symptomatic disease with the homologous biotype in fishermen but not in subjects from the general public

Early Miocene Intensification of the North African Hydrological Cycle: Multi-Proxy Evidence From the Shelf Carbonates of Malta

During the Miocene (23.0–5.3 Ma) North Africa experienced both humid and arid intervals, but the underlying cause of these transitions is unknown. Earth's climate was characterized by a unipolar icehouse with a dynamic Antarctic ice sheet, which may have influenced regional hydrology through atmospheric teleconnections. However, the Miocene also witnessed the restriction of the Mesopotamian Seaway, which may have had significant climatic impacts. The Maltese il-Blata section (Central Mediterranean) comprises Late Oligocene to Early Miocene marine deposits previously used to constrain the timing of the Mesopotamian Seaway restriction using the εNd tracer. The location of this section also makes it sensitive to climatic changes in the North African region, and biogeochemical changes in the central Mediterranean. Here, we present lithological and geochemical records of the il-Blata section. We find a marked shift in lithology and an increase in sedimentation rate coeval with the Early Miocene (∼19–20 Ma) restriction of the Mesopotamian Seaway. Concomitant changes in bulk sediment CaCO3, Sr/Ca, K/Al, Ti/Al, Zr/Al, and Si/Ti support a major humid climate transition and associated intensification of river systems over western North Africa. We propose that these changes in North African hydroclimate reflect either a tipping point effect in a gradually warming global climate, or are the result of the initial restriction of the Mesopotamian Seaway, perhaps through consequent changes in Atlantic Meridional Overturning Circulation and the West African Monsoon. We also suggest the restriction of the Mesopotamian Seaway inhibited phosphorite deposition at low latitudes

Cytoskeletal protein kinases: titin and its relations in mechanosensing

Titin, the giant elastic ruler protein of striated muscle sarcomeres, contains a catalytic kinase domain related to a family of intrasterically regulated protein kinases. The most extensively studied member of this branch of the human kinome is the Ca2+–calmodulin (CaM)-regulated myosin light-chain kinases (MLCK). However, not all kinases of the MLCK branch are functional MLCKs, and about half lack a CaM binding site in their C-terminal autoinhibitory tail (AI). A unifying feature is their association with the cytoskeleton, mostly via actin and myosin filaments. Titin kinase, similar to its invertebrate analogue twitchin kinase and likely other “MLCKs”, is not Ca2+–calmodulin-activated. Recently, local protein unfolding of the C-terminal AI has emerged as a common mechanism in the activation of CaM kinases. Single-molecule data suggested that opening of the TK active site could also be achieved by mechanical unfolding of the AI. Mechanical modulation of catalytic activity might thus allow cytoskeletal signalling proteins to act as mechanosensors, creating feedback mechanisms between cytoskeletal tension and tension generation or cellular remodelling. Similar to other MLCK-like kinases like DRAK2 and DAPK1, TK is linked to protein turnover regulation via the autophagy/lysosomal system, suggesting the MLCK-like kinases have common functions beyond contraction regulation

A two million year record of low-latitude aridity linked to continental weathering from the Maldives

Indian-Asian monsoon has oscillated between warm/wet interglacial periods and cool/dry glacial periods with periodicities closely linked to variations in Earth’s orbital parameters. However, processes that control wet versus dry, i.e. aridity cyclical periods on the orbital time-scale in the low latitudes of the Indian-Asian continent remain poorly understood because records over millions of years are scarce. The sedimentary record from International Ocean Discovery Program (IODP) Expedition 359 provides a well-preserved, high-resolution, continuous archive of lithogenic input from the Maldives reflecting on low-latitude aridity cycles. Variability within the lithogenic component of sedimentary deposits of the Maldives results from changes in monsoon-controlled sedimentary sources. Here, we present X-ray fluorescence (XRF) core-scanning results from IODP Site U1467 for the past two million years, allowing full investigation of orbital periodicities. We specifically use the Fe/K as a terrestrial climate proxy reflecting on wet versus dry conditions in the source areas of the Indian-Asian landmass, or from further afield. The Fe/K record shows orbitally forced cycles reflecting on changes in the relative importance of aeolian (stronger winter monsoon) during glacial periods versus fluvial supply (stronger summer monsoon) during interglacial periods. For our chronology, we tuned the Fe/K cycles to precessional insolation changes, linking Fe/K maxima/minima to insolation minima/maxima with zero phase lag. Wavelet and spectral analyses of the Fe/K record show increased dominance of the 100 kyr cycles after the Mid Pleistocene Transition (MPT) at 1.25 Ma in tandem with the global ice volume benthic δ 18 O data (LR04 record). In contrast to the LR04 record, the Fe/K profile resolves 100-kyr-like cycles around the 130 kyr frequency band in the interval from 1.25 to 2 million years. These 100-kyr-like cycles likely form by bundling of two or three obliquity cycles, indicating that low-latitude Indian-Asian climate variability reflects on increased tilt sensitivity to regional eccentricity insolation changes (pacing tilt cycles) prior to the MPT. The implication of appearance of the 100 kyr cycles in the LR04 and the Fe/K records since the MPT suggests strengthening of a climate link between the low and high latitudes during this period of climate transition. The Correction to this article has been published in Progress in Earth and Planetary Science 2019 6:21 - https://doi.org/10.1186/s40645-019-0259-

Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer

A common key regulator of oncogenic signaling pathways in multiple tumor types is the unique isomerase Pin1. However, available Pin1 inhibitors lack the required specificity and potency. Using mechanism-based screening, here we find that all-trans retinoic acid (ATRA)--a therapy for acute promyelocytic leukemia (APL) that is considered the first example of targeted therapy in cancer, but its drug target remains elusive--inhibits and degrades active Pin1 selectively in cancer cells by directly binding to the substrate phosphate- and proline-binding pockets in the Pin1 active site. ATRA-induced Pin1 ablation degrades the fusion oncogene PML-RARα and treats APL in cell and animal models and human patients. ATRA-induced Pin1 ablation also inhibits triple negative breast cancer cell growth in human cells and in animal models by acting on many Pin1 substrate oncogenes and tumor suppressors. Thus, ATRA simultaneously blocks multiple Pin1-regulated cancer-driving pathways, an attractive property for treating aggressive and drug-resistant tumors

Dynamics of biomolecules: assignment of local motions by fluorescence anisotropy decay.

Many biological systems have multiple fluorophores that experience multiple depolarizing motions, requiring multiple lifetimes and correlation times to define the fluorescence intensity and anisotropy decays, respectively. To simplify analyses, an assumption often made is that all fluorophores experience all depolarizing motions. However, this assumption usually is invalid, because each lifetime is not necessarily associated with each correlation time. To help establish the correct associations and recover accurate kinetic parameters, a general kinetic scheme that can examine all possible associations is presented. Using synthetic data sets, the ability of the scheme to discriminate among all nine association models possible for two lifetimes and two correlation times has been evaluated. Correct determination of the association model, and accurate recovery of the decay parameters, required the global analysis of related data sets. This general kinetic scheme was then used for global analyses of liver alcohol dehydrogenase anisotropy data sets. The results indicate that only one of the two tryptophan residues in each subunit is depolarized by process(es) independent of the enzyme's rotations. By applying the proper kinetic scheme and appropriate analysis procedures to time-resolved fluorescence anisotropy data, it is therefore possible to examine the dynamics of specific portions of a macromolecule in solution

Myocyte apoptosis during acute myocardial infarction in the mouse localizes to hypoxic regions but occurs independently of p53.

Significant numbers of myocytes die by apoptosis during myocardial infarction. The molecular mechanism of this process, however, remains largely unexplored. To facilitate a molecular genetic analysis, we have developed a model of ischemia-induced cardiac myocyte apoptosis in the mouse. Surgical occlusion of the left coronary artery results in apoptosis, as indicated by the presence of nucleosome ladders and in situ DNA strand breaks. Apoptosis occurs mainly in cardiac myocytes, and is shown for the first time to be limited to hypoxic regions during acute infarction. Since hypoxia-induced apoptosis in other cell types is dependent on p53, and p53 is induced by hypoxia in cardiac myocytes, we investigated the necessity of p53 for myocyte apoptosis during myocardial infarction. Myocyte apoptosis occurs as readily, however, in the hearts of mice nullizygous for p53 as in wild-type littermates. These data demonstrate the existence of a p53-independent pathway that mediates myocyte apoptosis during myocardial infarction

Early Miocene Intensification of the North African Hydrological Cycle: Multi‐Proxy Evidence From the Shelf Carbonates of Malta

During the Miocene (23.0 to 5.3 Ma) North Africa experienced both humid and arid intervals, but the underlying cause of these transitions is unknown. Earth’s climate was characterised by a unipolar icehouse with a dynamic Antarctic ice sheet, which may have influenced regional hydrology through atmospheric teleconnections. However, the Miocene also witnessed the restriction of the Mesopotamian Seaway, which may have had significant climatic impacts. The Maltese il-Blata section (Central Mediterranean) comprises Late Oligocene to Early Miocene marine deposits previously used to constrain the timing of the Mesopotamian Seaway restriction using the εNd tracer. The location of this section also makes it sensitive to climatic changes in the North African region, and biogeochemical changes in the central Mediterranean. Here, we present lithological and geochemical records of the il-Blata section. We find a marked shift in lithology and an increase in sedimentation rate coeval with the Early Miocene (∼19 to 20 Ma) restriction of the Mesopotamian Seaway. Concomitant changes in bulk sediment CaCO3, Sr/Ca, K/Al, Ti/Al, Zr/Al, and Si/Ti support a major humid climate transition and associated intensification of river systems over western North Africa. We propose that these changes in North African hydroclimate reflect either a tipping point effect in a gradually warming global climate, or are the result of the initial restriction of the Mesopotamian Seaway, perhaps through consequent changes in Atlantic Meridional Overturning Circulation and the West African Monsoon. We also suggest the restriction of the Mesopotamian Seaway inhibited phosphorite deposition at low latitudes. Key Points - The climate over the central Mediterranean shifted from a cool-arid to a humid regime during the Early Miocene around 19.0 Ma - The transition to more humid conditions may have been a consequence of the first Miocene restriction of the Mesopotamian Seaway (MSR-1) - Circulation changes in the proto-Mediterranean coupled with changes in the sedimentation may have terminated regional phosphorite episode