Oxygen electrocatalytic activities in oxide perovskites are strongly dependent on their conductivity and electron configurations (eg). Herein, we show that an appropriate level of sulfur doping in oxide perovskites (such as LaCoO3, LaNiO3, and LaFeO3) can not only enhance the conductivity but also transform the spin state of Co (Ni, Fe) from low to intermediate spin and, therefore, give rise to much accelerated oxygen electrocatalytic activities. Sulfur-doped LaCoO3 (S-LCO) exhibits significantly enhanced electrocatalytic activities in both oxygen evolution reactions and oxygen reduction reactions, as confirmed by first principle calculations and experimental observation, where the potential rate-determining step is accelerated owing to the introduction of S-dopants and oxygen defects. At the optimized S-doping level, S5.84%-LCO endows a rechargeable Zn–air battery with a high power density (92 mW/cm2 at 144 mA/cm2), excellent stability of charge/recharge, and a large open-circuit voltage of 1.47 V. This study shows that the engineering of the electronic state of oxide perovskite by S-doping is an effective pathway leading to high-performing bifunctional catalysis for energy storage and conversion.

Accumulated unfolded proteins in the endoplasmic reticulum (ER) trigger the unfolded protein response (UPR) to increase ER protein folding capacity. ER proteostasis and UPR signaling need to be regulated in a precise and timely manner. Here, we identify phosphorylation of protein disulfide isomerase (PDI), one of the most abundant and critical folding catalysts in the ER, as an early event during ER stress. The secretory pathway kinase Fam20C phosphorylates Ser357 of PDI and responds rapidly to various ER stressors. Phosphorylation of Ser357 induces an open conformation of PDI and turns it from a "foldase" into a "holdase", which is critical for preventing protein misfolding in the ER. Phosphorylated PDI also binds to the lumenal domain of IRE1a, a major UPR signal transducer, and attenuates excessive IRE1a activity. Importantly, PDI-S359A knock-in mice display enhanced IRE1a activation and liver damage under acute ER stress. We conclude that the Fam20C-PDI axis constitutes a post-translational response to maintain ER proteostasis and plays a vital role in protecting against ER stressinduced cell death.

Cellular and molecular events in osseointegration at the dental implant surface remain largely unknown. We hypothesized that bone marrow stromal cells (BMSCs) participate in this process, and that osterix (Osx) promotes implant osseointegration. To prove this hypothesis, we tracked double-labeled BMSCs in implantation sites created in nude mice transplanted with these cells. We also inserted implants into the femurs of our established transgenic mice after local administration of viruses encoding Osx, to determine the osteogenic effects of Osx. Immunohistochemical results demonstrated that BMSCs can recruit from peripheral circulation and participate in wound healing and osseointegration after implantation. Microcomputed tomography (microCT) analysis revealed an increased bone density at the bone-to-implant interface in the Osx group, and histomorphometric analysis indicated an elevated level of bone-to-implant contact in the Osx group. We concluded that exogenous BMSCs participate in the osseointegration after implantation, and that Osx overexpression accelerates osseointegration.

Family with sequence similarity 20C (Fam20C), the physiological Golgi casein kinase, phosphorylates numerous secreted proteins that are involved in a wide variety of biological processes. However, the role of Fam20C in regulating proteins in the endoplasmic reticulum (ER) lumen is largely unknown. Here, we report that Fam20C interacts with various luminal proteins and that its depletion results in a more reduced ER lumen. We further show that ER oxidoreductin 1α (Ero1α), the pivotal sulfhydryl oxidase that catalyzes disulfide formation in the ER, is phosphorylated by Fam20C in the Golgi apparatus and retrograde-transported to the ER mediated by ERp44. The phosphorylation of Ser145 greatly enhances Ero1α oxidase activity and is critical for maintaining ER redox homeostasis and promoting oxidative protein folding. Notably, phosphorylation of Ero1α is induced under hypoxia, reductive stress, and secretion-demanding conditions such as mammalian lactation. Collectively, our findings open a door to uncover how oxidative protein folding is regulated by phosphorylation in the secretory pathway.

Insulin is synthesized by pancreatic β-cells and stored into secretory granules (SGs). SGs fuse with the plasma membrane in response to a stimulus and deliver insulin to the bloodstream. The mechanism of how proinsulin and its processing enzymes are sorted and targeted from the trans-Golgi network (TGN) to SGs remains mysterious. No cargo receptor for proinsulin has been identified. Here, we show that chromogranin (CG) proteins undergo liquid–liquid phase separation (LLPS) at a mildly acidic pH in the lumen of the TGN, and recruit clients like proinsulin to the condensates. Client selectivity is sequence-independent but based on the concentration of the client molecules in the TGN. We propose that the TGN provides the milieu for converting CGs into a “cargo sponge” leading to partitioning of client molecules, thus facilitating receptor-independent client sorting. These findings provide a new receptor-independent sorting model in β-cells and many other cell types and therefore represent an innovation in the field of membrane trafficking.

a b s t r a c t a r t i c l e i n f o Keywords:Tianshui basin Lake deposits Mudflat Calcretes Eolian deposits NeogeneThe Tianshui Basin in central China contains a thick sedimentary sequence (~1400 m) of continental deposits, Aragonian to Villafranchian (Miocene-Pliocene) in age. Intense Himalayan movements around the Paleogene/Miocene boundary triggered the uplift of mountain ranges around the Tianshui Basin, providing the deposition site for continental sediments. The sedimentary infill of the basin consists of four stratigraphic units (I to IV). This paper focuses on Unit II. Most of the accommodation space was occupied by Unit I, so during the sedimentation of Unit II, the morphology of the basin was relatively flat, promoting the development of wide distal fan/mudflat areas and wide shallow lakes. Deposits include: red mudstones, pedogenic and groundwater calcretes, reworked calcrete deposits, sheet-floods, fluvial channels, rippled sandstones/siltstones, ooidal/peloidal packstones, palustrine limestones, bioturbated marls and intraclastic limestones/marls. The characteristics and organization of the deposits indicate the gradual transition from alluvial to lake environments. Within the distal fan/mudflat, the deposition of reworked calcrete clasts as one of the most striking facies of the basin may be attributed to substantial recycling of calcrete levels and red clays. At the lake margins, the presence of ooids and palustrine limestones suggests the possibility of ramplike margins within different energy settings. The origin of some of the deposits of the basin's QA-I section is under discussion, and their consideration as eolian has been recently proposed. However, we believe this possibility is precluded by the characteristics of the deposits. Our proposal has important implications for revising the interpretation of Miocene paleoclimatic conditions in central Asia.

Bone marrow stromal cells (BMSCs) are a rich source of osteogenic progenitor cells. A fundamental question is whether systemically transplanted BMSCs participate in bone regeneration. Luciferase and GFP double-labeled BMSCs were transplanted into irradiated mice. Five weeks after transplantation, artificial bone wounds were created in the mandibles and calvaria of the recipients. Animals were sacrificed at weeks 2, 4, and 6 after surgery and the expressions of luciferase and GFP were determined using Xenogen IVIS Imaging System, immunohistochemical staining and RT-PCR. The results demonstrated that transplanted BMSCs can be detected in wound sites as early as 2 weeks and lasted the whole experimental period. Luciferase expression peaked at 2 weeks after surgery and decreased thereafter, exhibiting a similar expression pattern as that of BSP, while GFP expression was relatively stable during the experimental period. In conclusion, BMSCs can migrate to bone wound sites and participate in bone regeneration in orocraniofacial region.

Defects in the pancreatic β-cell's secretion system are well-described in Type 2 diabetes (T2D) and include impaired proinsulin processing and a deficit in mature insulin-containing secretory granules; however, the cellular mechanisms underlying these defects remain poorly understood. To address this, we used an in situ fluorescent pulse-chase strategy to study proinsulin trafficking. We show that insulin granule formation and the appearance of nascent granules at the plasma membrane are decreased in rodent and cell culture models of pre-diabetes and hyperglycemia. Moreover, we link the defect in insulin granule formation to an early trafficking delay in ER export of proinsulin, which is independent of overt ER stress. Using a ratiometric redox sensor, we show that the ER becomes hyperoxidized in β-cells from a dietary model of rodent pre-diabetes and that addition of reducing equivalents restores ER export of proinsulin and insulin granule formation and partially restores β-cell function. Together, these data identify a critical role for the regulation of ER redox homeostasis in proinsulin trafficking and suggest that alterations in ER redox poise directly contribute to the decline in insulin granule production in T2D.