Raymondhodges7933

The main limitation on axon regeneration in the peripheral nervous system (PNS) is the slow rate of regrowth. We recently reported that nerve regeneration can be accelerated by axonal G3BP1 granule disassembly, releasing axonal mRNAs for local translation to support axon growth. Here, we show that G3BP1 phosphorylation by casein kinase 2α (CK2α) triggers G3BP1 granule disassembly in injured axons. CK2α activity is temporally and spatially regulated by local translation of Csnk2a1 mRNA in axons after injury, but this requires local translation of mTor mRNA and buffering of the elevated axonal Ca2+ that occurs after axotomy. CK2α's appearance in axons after PNS nerve injury correlates with disassembly of axonal G3BP1 granules as well as increased phospho-G3BP1 and axon growth, although depletion of Csnk2a1 mRNA from PNS axons decreases regeneration and increases G3BP1 granules. Phosphomimetic G3BP1 shows remarkably decreased RNA binding in dorsal root ganglion (DRG) neurons compared with wild-type and non-phosphorylatable G3BP1; combined with other studies, this suggests that CK2α-dependent G3BP1 phosphorylation on Ser 149 after axotomy releases axonal mRNAs for translation. Translation of axonal mRNAs encoding some injury-associated proteins is known to be increased with Ca2+ elevations, and using a dual fluorescence recovery after photobleaching (FRAP) reporter assay for axonal translation, we see that translational specificity switches from injury-associated protein mRNA translation to CK2α translation with endoplasmic reticulum (ER) Ca2+ release versus cytoplasmic Ca2+ chelation. Our results point to axoplasmic Ca2+ concentrations as a determinant for the temporal specificity of sequential translational activation of different axonal mRNAs as severed axons transition from injury to regenerative growth.The archipelago of Vanuatu has been at the crossroads of human population movements in the Pacific for the past three millennia. To help address several open questions regarding the history of these movements, we generated genome-wide data for 11 ancient individuals from the island of Efate dating from its earliest settlement to the recent past, including five associated with the Chief Roi Mata's Domain World Heritage Area, and analyzed them in conjunction with 34 published ancient individuals from Vanuatu and elsewhere in Oceania, as well as present-day populations. Our results outline three distinct periods of population transformations. First, the four earliest individuals, from the Lapita-period site of Teouma, are concordant with eight previously described Lapita-associated individuals from Vanuatu and Tonga in having almost all of their ancestry from a "First Remote Oceanian" source related to East and Southeast Asians. Second, both the Papuan ancestry predominating in Vanuatu for the past 2,500 years and the smaller component of Papuan ancestry found in Polynesians can be modeled as deriving from a single source most likely originating in New Britain, suggesting that the movement of people carrying this ancestry to Remote Oceania closely followed that of the First Remote Oceanians in time and space. Third, the Chief Roi Mata's Domain individuals descend from a mixture of Vanuatu- and Polynesian-derived ancestry and are related to Polynesian-influenced communities today in central, but not southern, Vanuatu, demonstrating Polynesian genetic input in multiple groups with independent histories.Sensory stimuli with graded intensities often lead to yes-or-no decisions on whether to respond to the stimuli. How this graded-to-binary conversion is implemented in the central nervous system (CNS) remains poorly understood. Here, we show that graded encodings of noxious stimuli are categorized in a decision-associated CNS region in Drosophila larvae, and then decoded by a group of peptidergic neurons for executing binary escape decisions. GABAergic inhibition gates weak nociceptive encodings from being decoded, whereas escalated amplification through the recruitment of second-order neurons boosts nociceptive encodings at intermediate intensities. These two modulations increase the detection accuracy by reducing responses to negligible stimuli whereas enhancing responses to intense stimuli. Selleckchem HDAC inhibitor Our findings thus unravel a circuit mechanism that underlies accurate detection of harmful stimuli.Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases) are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer. They play important roles in acidification of intracellular vesicles, organelles, and the extracellular milieu in eukaryotes. Here, we report cryoelectron microscopy structures of human V-ATPase in three rotational states at up to 2.9-Å resolution. Aided by mass spectrometry, we build all known protein subunits with associated N-linked glycans and identify glycolipids and phospholipids in the Vo complex. We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo subunits and phospholipids in the c-ring. The glycolipids and the glycosylated Vo subunits form a luminal glycan coat critical for V-ATPase folding, localization, and stability. This study identifies mechanisms of V-ATPase assembly and biogenesis that rely on the integrated roles of ATP6AP1, glycans, and lipids.

To study the presenting clinical and demographic features, risk factors, and outcome of infants with late vitamin K deficiency bleeding.

Over a 5-year study period, the presenting clinical features and outcome of all 47 infants observed aged less than 6 months, who were diagnosed with late-onset primary and secondary VKDB by detailed history, physical examination, and laboratory findings were evaluated. Confirmed primary late VKDB was diagnosed when no cause other than breastfeeding could be found, while in the secondary subtype additional risk factors compromising the vitamin K effect were diagnosed.

Secondary late VKDB (83%, 39 patients) was more common than the primary subtype. The mean age of patients was 10.50 ± 5.75 and 9.74 ± 6.04 weeks in primary and secondary VKDB subtypes, respectively, and the age of infants did not have a significant difference (p > 0.05). The male to female ratio was 2.131. The residency, place and mode of delivery, gestational age, and types of feeding of patients did not have a significant difference between VKDB subtypes.