Search

Active and relic marine methane‐seep sites are widely distributed globally and are distinguished by distinctive geology, biogeochemistry, and ecosystems. The discovery of methane‐seep sites in the Krishna‐Godavari (K‐G) basin has created exciting new opportunities for methane‐seep research in the Bay of Bengal. In this study, we document the occurrence of authigenic carbonates, including micro‐crystalline aragonite crust (arg‐crusts) admixed with chemosynthetic shells and high‐magnesium carbonate tubular structures (HMC‐tube), from the methane‐seep site SSD‐045/4 in the K‐G basin. The δ13C values of HMC‐tubes (−54.5 to −46.2‰) and arg‐crusts (−57.6 to −34.8‰) indicate biogenic methane as the likely carbon source. Enhanced porewater alkalinity driving carbonate precipitation may be attributed to microbial‐mediated SO₄2−‐AOM processes. Additionally, δ13C values (−35.2 ± 8‰) of the residual organic matter within the carbonates suggest a contribution of methanotrophic bacterial biomass. The δ18Ocarb values of HMC and aragonite indicate methane hydrate degassing and crystallization pathways, respectively. Pelloid‐filled burrows suggest the reworking of shallow HMC deposit by burrowing organisms, whereas the polyphase cementations (aragonite and HMC) within burrows indicate early and burial diagenetic pathways. The wide range in ΣLREE/ΣHREE ratios and Ceanom values in arg‐crusts reflect micro‐spatial variations in redox conditions, likely due to cementation occurring in both open and closed diagenetic systems. In contrast, more constrained Ceanom values and ΣLREE/ΣHREE ratios in HMC tubes suggest persistent sulfidic conditions. Overall, these findings provide insights into the pathways of carbonate formation at the K‐G basin methane‐seep site, highlighting the complex interplay of microbial processes, fluid dynamics, and diagenetic alterations. Plain Language Summary: Methane cold‐seeps are regions on the seabed where methane (CH4) gas oozes out across the sediment‐water interface into the water column. Both active and inactive seepage sites are known across the oceans. Active methane seep sites expel significant quantities of methane into the seawater which influences the oceanic methane budget as well as the carbon cycle. In contrast, the preserved authigenic carbonate deposits and chemosynthetic fauna at the relic seep sites are archives of past seepage activities. The seep ecosystem comprises a variety of chemosynthetic and non‐chemosynthetic organisms, whereas the geological features include mounds, mud volcanoes, carbonate crusts, chimneys, etc. formed due to methane expulsion processes. Here, we investigate the origin of calcium carbonate structures formed in a cold seep region off the east coast of India. The carbonate structures include tubular‐shaped high magnesian carbonates (HMC) and crusts composed of aragonite minerals. These tubes and crusts archive biological and geological processes, including past variations in methane effusion and diffusion through the sediment. Tubular structures are formed by gas flow through the sediments as chimneys and by burrowing activities of benthic organisms. On the other hand, the aragonite crusts are formed where methane flow is high across the seabed. Key Points: Relics of methanogenic high magnesian calcite tubes and aragonite crust recovered from cold seep site K‐G basin east coast of IndiaHMC precipitation is confined to sulfidic conditions in contrast to a wider redox range for aragonite precipitationReworking of unconsolidated HMC produced the pelloid rich tubular structures, whereas aragonite crust formed at high CH4 flow conditions [ABSTRACT FROM AUTHOR]

Cellular senescence is a state of permanent growth arrest. It can be triggered by telomere shortening (replicative senescence) or prematurely induced by stresses such as DNA damage, oncogene overactivation, loss of tumor suppressor genes, oxidative stress, tissue factors, and others. Advances in techniques and experimental designs have provided new evidence about the biology of senescent cells (SnCs) and their importance in human health and disease. This review aims to describe the main aspects of SnCs phenotype focusing on alterations in subcellular compartments like plasma membrane, cytoskeleton, organelles, and nuclei. We also discuss the heterogeneity, dynamics, and plasticity of SnCs' phenotype, including the SASP, and pro‐survival mechanisms. We advance on the multiple layers of phenotypic heterogeneity of SnCs, such as the heterogeneity between inducers, tissues and within a population of SnCs, discussing the relevance of these aspects to human health and disease. We also raise the main challenges as well alternatives to overcome them. Ultimately, we present open questions and perspectives in understanding the phenotype of SnCs from the perspective of basic and applied questions. [ABSTRACT FROM AUTHOR]

Non‐linear microscopy is a powerful imaging tool to examine structural properties and subcellular processes of various biological samples. The competence of Third Harmonic Generation (THG) includes the label free imaging with diffraction‐limited resolution and three‐dimensional visualization with negligible phototoxicity effects. In this study, THG records and quantifies the lipid content of Drosophila haemocytes, upon encountering normal or tumorigenic neural cells, in correlation with their shape or their state. We show that the lipid accumulations of adult haemocytes are similar before and after encountering normal cells. In contrast, adult haemocytes prior to their interaction with cancer cells have a low lipid index, which increases while they are actively engaged in phagocytosis only to decrease again when haemocytes become exhausted. This dynamic change in the lipid accrual of haemocytes upon encountering tumour cells could potentially be a useful tool to assess the phagocytic capacity or activation state of tumour‐associated haemocytes. [ABSTRACT FROM AUTHOR]

Although immunosenescence may result in increased morbidity and mortality, many mammals have evolved effective immune coping strategies to extend their lifespans. Thus, the immune systems of long‐lived mammals present unique models to study healthy longevity. To identify the molecular clues of anti‐immunosenescence, we first built high‐quality reference genome for a long‐lived myotis bat, and then compared three long‐lived mammals (i.e., bat, naked mole rat, and human) versus the short‐lived mammal, mouse, in splenic immune cells at single‐cell resolution. A close relationship between B:T cell ratio and immunosenescence was detected, as B:T cell ratio was much higher in mouse than long‐lived mammals and significantly increased during aging. Importantly, we identified several iron‐related genes that could resist immunosenescence changes, especially the iron chaperon, PCBP1, which was upregulated in long‐lived mammals but dramatically downregulated during aging in all splenic immune cell types. Supportively, immune cells of mouse spleens contained more free iron than those of bat spleens, suggesting higher level of ROS‐induced damage in mouse. PCBP1 downregulation during aging was also detected in hepatic but not pulmonary immune cells, which is consistent with the crucial roles of spleen and liver in organismal iron recycling. Furthermore, PCBP1 perturbation in immune cell lines would result in cellular iron dyshomeostasis and senescence. Finally, we identified two transcription factors that could regulate PCBP1 during aging. Together, our findings highlight the importance of iron homeostasis in splenic anti‐immunosenescence, and provide unique insight for improving human healthspan. [ABSTRACT FROM AUTHOR]

Covalent organic frameworks (COFs) with structural designability and tunability of photophysical properties enable them to be a promising class of organic luminescent materials by incorporating well‐designed fluorescent units directly into the periodic skeletons. The photophysical properties of COFs are mainly affected by the structural features, which determine the conjugation degree, charge delocalization ability, and exciton dynamics of COFs. To understand the relationship between COF structures and their photophysical properties, two COFs with the same pyrene chromophore units but different linkages (imine or vinylene) were designed and synthesized. Interestingly, different linkages endow COFs with huge differences in solid‐state photoluminescence quantum yield (PLQY) for imine‐ and vinylene‐linked pyrene‐based COFs, which possess PLQY values of 0.34 % and 15.43 %, respectively. The femtosecond‐transient absorption spectra and time‐dependent density functional theory reveal the different charge‐transfer pathways in imine‐ and vinylene‐linked COFs, which influence the exciton relaxation way and fluorescence intensity. In addition, an effective white‐light device was obtained by coating the vinylene‐linked COF on a light‐emitting diode strip. [ABSTRACT FROM AUTHOR]

Neurons decline in their functionality over time, and age‐related neuronal alterations are associated with phenotypes of neurodegenerative diseases. In nonneural tissues, an infolded nuclear shape has been proposed as a hallmark of aged cells and neurons with infolded nuclei have also been reported to be associated with neuronal activity. Here, we performed time‐lapse imaging in the visual cortex of Nex‐Cre;SUN1‐GFP mice. Nuclear infolding was observed within 10 min of stimulation in young nuclei, while the aged nuclei were already infolded pre‐stimulation and showed reduced dynamics of the morphology. In young nuclei, the depletion of the stimuli restored the nucleus to a spherical shape and reduced the dynamic behavior, suggesting that nuclear infolding is a reversible process. We also found the aged nucleus to be stiffer than the young one, further relating to the age‐associated loss of nuclear shape dynamics. We reveal temporal changes in the nuclear shape upon external stimulation and observe that these morphological dynamics decrease with age. [ABSTRACT FROM AUTHOR]

The highest risk factor for the development of neurodegenerative diseases like tauopathies is aging. Many physiological decrements underlying aging are linked to cellular senescence. Senescent cells are characterized by an irreversible growth arrest and formation of a senescence‐associated secretory phenotype (SASP), a proinflammatory secretome that modifies the cellular microenvironment and contributes to tissue deterioration. Microglia, the innate immune cells in the brain, can enter a senescent state during aging. In addition, senescent microglia have been identified in the brains of tau‐transgenic mice and patients suffering from tauopathies. While the contribution of senescent microglia to the development of tauopathies and other neurodegenerative diseases is a growing area of research, the effect of tau on microglial senescence remains elusive. Here, we exposed primary microglia to 5 and 15 nanomolar (nM) of monomeric tau for 18 h, followed by a recovery period of 48 h. Using multiple senescence markers, we found that exposure to 15 nM, but not 5 nM of tau increased levels of cell cycle arrest and a DNA damage marker, induced loss of the nuclear envelope protein lamin B1 and the histone marker H3K9me3, impaired tau clearance and migration, altered the cell morphology and resulted in formation of a SASP. Taken together, we show that exposure to tau can lead to microglial senescence. As senescent cells were shown to negatively impact tau pathologies, this suggests the presence of a vicious circle, which should be further investigated in the future. [ABSTRACT FROM AUTHOR]

Artemisinin (ART) and its derivatives have great therapeutical utility as antimalarials and can be repurposed for other indications, such as viral infections, autoimmune diseases, and cancer. This review presents a comprehensive overview of the therapeutic effects of ART‐based drugs, beyond their antimalarial effects. This review also summarizes the information on their repurposing in other pathologies, with the hope that it will guide the future optimization of the use of ART‐based drugs and of the treatment strategies for the listed diseases. By reviewing related literature, ART extraction and structure as well as the synthesis and structure of its derivatives are presented. Subsequently, the traditional roles of ART and its derivatives against malaria are reviewed, including antimalarial mechanism and occurrence of antimalarial resistance. Finally, the potential of ART and its derivatives to be repurposed for the treatment of other diseases are summarized. The great repurposing potential of ART and its derivatives may be useful for the control of emerging diseases with corresponding pathologies, and future research should be directed toward the synthesis of more effective derivatives or better combinations. [ABSTRACT FROM AUTHOR]

Covalent organic frameworks (COFs) with imine linkage are promising solid supports to disperse ultra‐fine metal nanoparticles (NPs), but the modulation of their surface wettability, an important parameter affecting the catalytic performance of metal NPs, is still very challenging. Here, we report the preparation of two imine‐linked COFs with moderate and strong surface hydrophobicity by changing the carbon chain length of side oxyalkyl groups. Ultra‐small Pd NPs with an average size of ∼2.0 nm was successfully loaded on the two COFs, attributed to the strong interactions of Pd NPs and imine linkage as evidenced by the electron donating from imine linkage to Pd NPs by XPS characterizations. The TOF of Pd/COF is much higher than commercial Pd/C (714 h−1 vs 489 h−1) in the hydrogenation of nitrobenzene, which is attributed to the electron rich Pd, the hydrophobic surface and crystalline structure of COFs. Pd NPs on COFs with strong hydrophobicity are more active than those on COFs with moderate hydrophilicity in the hydrogenation of moderate lipophilic nitro compounds such as nitrobenzene, methyl nitrobenzene and nitronaphthalene. Reversed tendency was observed for the hydrogenation of moderate hydrophilic p‐amino‐nitrobenzene. The modulation of the surface wettability of COFs provides an efficient strategy to improve the catalytic performance of supported metal NPs. [ABSTRACT FROM AUTHOR]

Cryo‐electron microscopy (cryo‐EM) is gaining large attention for high‐resolution protein structure determination in solutions. However, a very high percentage of cryo‐EM structures correspond to resolutions of 3–5 Å, making the structures difficult to be used in in silico drug design. In this study, we analyze how useful cryo‐EM protein structures are for in silico drug design by evaluating ligand docking accuracy. From realistic cross‐docking scenarios using medium resolution (3–5 Å) cryo‐EM structures and a popular docking tool Autodock‐Vina, only 20% of docking succeeded, when the success rate doubles in the same kind of cross‐docking but using high‐resolution (<2 Å) crystal structures instead. We decipher the reason for failures by decomposing the contribution from resolution‐dependent and independent factors. The heterogeneity in the protein side‐chain and backbone conformations is identified as the major resolution‐dependent factor causing docking difficulty from our analysis, while intrinsic receptor flexibility mainly comprises the resolution‐independent factor. We demonstrate the flexibility implementation in current ligand docking tools is able to rescue only a portion of failures (10%), and the limited performance was majorly due to potential structural errors than conformational changes. Our work suggests the strong necessity of more robust method developments on ligand docking and EM modeling techniques in order to fully utilize cryo‐EM structures for in silico drug design. [ABSTRACT FROM AUTHOR]

Strategies enabling solution processing of covalent organic framework (COF) thin films will become increasingly important as these versatile materials are integrated into a wide range of electronic and optical devices. This work highlights an approach to yield thin film synthesis of TAPA‐PDA (TAPA: tris(4‐aminophenyl)amine, PDA: terephthalaldehyde) and TAPB‐PDA (TAPB: 1,3,5‐tris(4‐aminophenyl)benzene) imine COFs using azomethine compounds which can be drop cast onto a variety of substrates. High crystalline COF films are shown to form on various electronically‐relevant substrates. Grazing incidence wide angle X‐ray scattering characterization reveals COF films with a preferred horizontal orientation in the case of TAPA‐PDA COF and a more mixed/vertical orientation in the TAPB‐PDA COF film regardless of the substrate. As this exciting class of crystalline organic materials becomes more relevant for various device applications, solution processing techniques will be vital to take advantage of the properties of thin film COFs. [ABSTRACT FROM AUTHOR]

BODIPY heterochromophores, asymmetrically substituted with perylene and/or iodine at the 2 and 6 positions were prepared and investigated as sensitizers for triplet‐triplet annihilation up conversion (TTA‐UC). Single‐crystal X‐ray crystallographic analyses show that the torsion angle between BODIPY and perylene units lie between 73.54 and 74.51, though they are not orthogonal. Both compounds show intense, charge transfer absorption and emission profiles, confirmed by resonance Raman spectroscopy and consistent with DFT calculations. The emission quantum yield was solvent dependent but the emission profile remained characteristic of CT transition across all solvents explored. Both BODIPY derivatives were found to be effective sensitizers of TTA‐UC with perylene annihilator in dioxane and DMSO. Intense anti‐Stokes emission was observed, and visible by eye from these solvents. Conversely, no TTA‐UC was observed from the other solvents explored, including from non‐polar solvents such as toluene and hexane that yielded brightest fluorescence from the BODIPY derivatives. In dioxane, the power density plots obtained were strongly consistent with TTA‐UC and the power density threshold, the Ith value (the photon flux at which 50 % of ΦTTAUC is achieved), for B2PI was observed to be 2.5x lower than of B2P under optimal conditions, an effect ascribed to the combined influence of spin‐orbit charge transfer intersystem crossing (SOCT‐ISC) and heavy metal on the triplet state formation for B2PI. [ABSTRACT FROM AUTHOR]

BMP6 is an iron-sensing cytokine whose transcription in liver sinusoidal endothelial cells (LSECs) is enhanced by high iron levels, a step that precedes the induction of the iron-regulatory hormone hepcidin. While several reports suggested a cell-autonomous induction of Bmp6 by iron-triggered signals, likely via sensing of oxidative stress by the transcription factor NRF2, other studies proposed the dominant role of a paracrine yet unidentified signal released by iron-loaded hepatocytes. To further explore the mechanisms of Bmp6 transcriptional regulation, we used female mice aged 10-11 months, which are characterized by hepatocytic but not LSEC iron accumulation, and no evidence of systemic iron overload. We found that LSECs of aged mice exhibit increased Bmp6 mRNA levels as compared to young controls, but do not show a transcriptional signature characteristic of activated NFR2-mediated signaling in FACS-sorted LSECs. We further observed that primary murine LSECs derived from both wild-type and NRF2 knock-out mice induce Bmp6 expression in response to iron exposure. By analyzing transcriptomic data of FACS-sorted LSECs from aged versus young mice, as well as early after iron citrate injections, we identified ETS1 as a candidate transcription factor involved in Bmp6 transcriptional regulation. By performing siRNA-mediated knockdown, small-molecule treatments, and chromatin immunoprecipitation in primary LSECs, we show that Bmp6 transcription is regulated by iron via ETS1 and p38/JNK MAP kinase-mediated signaling, at least in part independently of NRF2. Thereby, these findings identify the new components of LSEC iron sensing machinery broadly associated with cellular stress responses., (© 2024 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Fluorescein-tagged proteins are first purified using anti-fluorescein-based immunoprecipitation of the lysate followed by streptavidin coated bead-based pull-down of the first eluate resulting in the enrichment of doubly-labeled proteins, corresponding to their presence in both donor and acceptor compartments. Keywords: new methodology; proximity labeling; TransitID EN new methodology proximity labeling TransitID 546 548 3 10/25/23 20231101 NES 231101 TransitID is a new methodology based on proximity labeling allowing for the study of protein trafficking a the proteome scale. These purified proteins can then be analyzed using tandem mass spectrometry. gl First, the proteome in a donor compartment (localization #1, Figure 1) is biotin-labeled with a compartment-resident TurboID-tagged protein. [Extracted from the article]

Imine‐linked covalent organic frameworks (COFs) have been extensively studied in photocatalysis because of their easy synthesis and excellent crystallinity. The effect of imine‐bond orientation on the photocatalytic properties of COFs, however, is still rarely studied. Herein, we report two novel COFs with different orientations of imine bonds using oligo(phenylenevinylene) moieties. The COFs showed similar structures but great differences in their photoelectric properties. COF‐932 demonstrated a superior hydrogen evolution performance compared to COF‐923 when triethanolamine was used as the sacrificial agent. Interestingly, the use of ascorbic acid led to the protonation of the COFs, further altering the direction of electron transfer. The photocatalytic performances were increased to 23.4 and 0.73 mmol g−1 h−1 for protonated COF‐923 and COF‐932, respectively. This study provides a clear strategy for the design of imine‐linked COF‐based photocatalysts and advances the development of COFs. [ABSTRACT FROM AUTHOR]

Background: In Japan, the vaccination rate against the SARS‐CoV‐2 vaccine for children was low. Therefore, in this study we investigated the factors influencing guardians' decision‐making regarding vaccination of their children. Methods: From November 1, 2022 to March 31, 2023, pediatric clinics, departments, and midwifery clinics in Saitama Prefecture requested guardians of children under the age of 15 to complete an online questionnaire. Results: Responses were obtained from 894 guardians of children aged 6 months to 15 years; 142 had had one of their children vaccinated at least once and 629 had not had any of their children vaccinated. Among guardians who had not had any of their children vaccinated, "the Age of children" was significantly younger (p < 0.001) and "Prevalence" (p < 0.001), "Free vaccination" (p < 0.001), and "Intentions of national and local governments" (p = 0.005) were selected as reasons significantly less frequently in comparison to guardians who had vaccinated their children. "Japanese adverse reactions" (p < 0.001), "Japanese effectiveness" (p < 0.001), "Adverse reactions" (p < 0.001), "History of adverse reactions" (p < 0.001), and "Reputation of friends" (p = 0.006) were selected significantly more frequently by guardians who had not had any of their children vaccinated. Conclusions: Guardians who had had one of their children vaccinated at least once emphasized the importance of prevalence and free vaccination. On the other hand, guardians who had not had any of their children vaccinated placed particular importance on adverse reactions and the Japanese data on effectiveness. To guide the decision‐making of guardians, it is necessary to quickly collect and publish data on adverse reactions and effectiveness, particularly in Japanese individuals, so that citizens can decide whether to vaccinate themselves and their children. [ABSTRACT FROM AUTHOR]

Fusarium wilt caused by soil‐borne fungus Fusarium oxysporum f. sp. vasinfectum race 4 (FOV4) is an early season disease causing root rot, and seedling wilt and death. However, it was unknown if cotton (Gossypium spp.) growth stages and root wounding affected genotypic responses to FOV4. The objectives of this study were to investigate the effects of cotton growth stage, cultivar, and root wounding on FOV4‐associated disease development at 7‐, 14‐, 21‐, and 28‐d post inoculation through five replicated tests in controlled environmental conditions with temperatures at 21 to 23 °C. Seedlings inoculated at the cotyledon stage incurred the highest disease incidence (DI), disease severity rating (DSR), and mortality (MR), followed by seedlings inoculated at the 1‐, 3‐, and 5‐true leaf stages in descending order. Root wounding at the cotyledon stage followed by immediate inoculation with FOV4 inoculum made all the tested cultivars and lines highly susceptible. Among the six cultivars tested, FM 2334GLT and Pima DP 359 RF were the most resistant, Pima S‐7 was highly susceptible, and Acala 1517‐08, Acala 1517–18 GLS, and Pima PHY 881 RF were susceptible. The importance of artificial inoculation at a true leaf stage with or without root wounding to identify resistance that may be undetected under field conditions was discussed. Core Ideas: Five replicated, controlled‐environment tests were conducted at 21 to 23 °C temperatures.Cotyledon stage seedlings were most susceptible to FOV4, followed by the 1‐, 3‐, and 5‐true leaf stages.Root wounding disarmed resistant mechanisms provided by the root and made all tested lines susceptible.FM 2334GLT and Pima DP 359 RF were the most resistant among the lines tested.Artificial inoculation at true leaf stages may identify resistance that may be undetected in the field. [ABSTRACT FROM AUTHOR]

Iron is an essential element for all organisms. Iron‐containing proteins play critical roles in cellular functions. The biological importance of iron is largely attributable to its chemical properties as a transitional metal. However, an excess of 'free' reactive iron damages the macromolecular components of cells and cellular DNA through the production of harmful free radicals. On the contrary, most of the body's excess iron is stored in the liver. Not only hereditary haemochromatosis but also some liver diseases with mild‐to‐moderate hepatic iron accumulation, such as chronic hepatitis C, alcoholic liver disease and nonalcoholic steatohepatitis, are associated with a high risk for liver cancer development. These findings have attracted attention to the causative and promotive roles of iron in the development of liver cancer. In the last decade, accumulating evidence regarding molecules regulating iron metabolism or iron‐related cell death programmes such as ferroptosis has shed light on the relationship between hepatic iron accumulation and hepatocarcinogenesis. In this review, we briefly present the current molecular understanding of iron regulation in the liver. Next, we describe the mechanisms underlying dysregulated iron metabolism depending on the aetiology of liver diseases. Finally, we discuss the causative and promotive roles of iron in cancer development. [ABSTRACT FROM AUTHOR]

Lipid droplets (LDs) are important cellular organelles due to their ability to accumulate and store lipids. LD dynamics are associated with various cellular and metabolic processes. Accurate monitoring of LD's size and shape is of prime importance as it indicates the metabolic status of the cells. Unintrusive continuous quantification techniques have a clear advantage in analyzing LDs as they measure and monitor the cells' metabolic function and droplets over time. Here, we present a novel machine‐learning‐based method for LDs analysis by segmentation of phase‐contrast images of differentiated adipocytes (in vitro) and adipose tissue (in vivo). We developed a new workflow based on the ImageJ waikato environment for knowledge analysis segmentation plugin, which provides an accurate, label‐free, live single‐cell, and organelle quantification of LD‐related parameters. By applying the new method on differentiating 3T3‐L1 cells, the size of LDs was analyzed over time in differentiated adipocytes and their correlation with other morphological parameters. Moreover, we analyzed the LDs dynamics during catabolic changes such as lipolysis and lipophagy and demonstrated its ability to identify different cellular subpopulations based on their structural, numerical, and spatial variability. This analysis was also implemented on unstained ex vivo adipose tissues to measure adipocyte size, an important readout of the tissue's metabolism. The presented approach can be applied in different LD‐related metabolic conditions to provide a better understanding of LD biogenesis and function in vivo and in vitro while serving as a new platform that enables rapid and accurate screening of data sets. [ABSTRACT FROM AUTHOR]

An entirely different mechanism and localization were recently proposed for the COPII coat complex, challenging its well‐accepted function to select and concentrate cargo into small COPII‐coated spherical transport vesicles. Instead, the COPII complex is suggested to form a dynamic yet stationary collar that forms a boundary between the ER and the ER export membrane domain. This membrane domain, the ER exit site (ERES), is the site of COPII‐mediated sorting and concentration of transport competent proteins. Subsequently, the ERES is implicated to mature and bud to form a sizeable pleiomorphic transport carrier that translocate on microtubules to fuse with the Golgi apparatus. Despite this drastic mechanistic dogma shift, most of the underlying protein‐protein and protein‐membrane interactions remain unchanged. Here, we attempt to provide a detailed description of the newly proposed model of how ER to Golgi transport works by describing the role of several essential proteins of the transport machinery. [ABSTRACT FROM AUTHOR]

Senescent cells accumulate in tissues over time, favoring the onset and progression of multiple age‐related diseases. Senescent cells present a remarkable increase in lysosomal mass and elevated autophagic activity. Here, we report that two main autophagic pathways macroautophagy (MA) and chaperone‐mediated autophagy (CMA) are constitutively upregulated in senescent cells. Proteomic analyses of the subpopulations of lysosomes preferentially engaged in each of these types of autophagy revealed profound quantitative and qualitative changes in senescent cells, affecting both lysosomal resident proteins and cargo proteins delivered to lysosomes for degradation. These studies have led us to identify resident lysosomal proteins that are highly augmented in senescent cells and can be used as novel markers of senescence, such as arylsulfatase ARSA. The abundant secretome of senescent cells, known as SASP, is considered their main pathological mediator; however, little is known about the mechanisms of SASP secretion. Some secretory cells, including melanocytes, use the small GTPase RAB27A to perform lysosomal secretion. We found that this process is exacerbated in the case of senescent melanoma cells, as revealed by the exposure of lysosomal membrane integral proteins LAMP1 and LAMP2 in their plasma membrane. Interestingly, a subset of SASP components, including cytokines CCL2, CCL3, CXCL12, cathepsin CTSD, or the protease inhibitor SERPINE1, are secreted in a RAB27A‐dependent manner in senescent melanoma cells. Finally, proteins previously identified as plasma biomarkers of aging are highly enriched in the lysosomes of senescent cells, including CTSD. We conclude that the lysosomal proteome of senescent cells is profoundly reconfigured, and that some senescent cells can be highly active in lysosomal exocytosis. [ABSTRACT FROM AUTHOR]

Precision oncology benefits from effective early phase drug discovery decisions. Recently, drugging inactive protein conformations has shown impressive successes, raising the cardinal questions of which targets can profit and what are the principles of the active/inactive protein pharmacology. Cancer driver mutations have been established to mimic the protein activation mechanism. We suggest that the decision whether to target an inactive (or active) conformation should largely rest on the protein mechanism of activation. We next discuss the recent identification of double (multiple) same‐allele driver mutations and their impact on cell proliferation and suggest that like single driver mutations, double drivers also mimic the mechanism of activation. We further suggest that the structural perturbations of double (multiple) in cis mutations may reveal new surfaces/pockets for drug design. Finally, we underscore the preeminent role of the cellular network which is deregulated in cancer. Our structure‐based review and outlook updates the traditional Mechanism of Action, informs decisions, and calls attention to the intrinsic activation mechanism of the target protein and the rewired tumor‐specific network, ushering innovative considerations in precision medicine. [ABSTRACT FROM AUTHOR]

The rapid development of nanoscience and nanoengineering provides new perspectives on the composition of food materials, and has great potential for food biology research and applications. The use of nanoparticle additives and the discovery of endogenous nanoparticles in food make it important to elucidate in vivo safety of nanomaterials. Nanoparticles will spontaneously adsorb proteins during transporting in blood and a protein corona can be formed on the nanoparticle surface inside the human body. Protein corona affects the physicochemical properties of nanoparticles and the structure and function of proteins, which in turn affects a series of biological reactions. This article reviewed basic information about protein corona of food‐related nanoparticles, elucidated the influence of protein corona on nanoparticles properties and protein structure and function, and discussed the effect of protein corona on nanoparticles in vivo. The effects of protein corona on nanoparticles transport, cellular uptake, cytotoxicity, and immune response were reviewed, and the reasons for these effects were also discussed. Finally, future research perspectives for food protein corona were proposed. Protein corona gives food nanoparticles a new identity, which makes proteins bound to nanoparticles undergo structural transformations that affect their recognition by receptors in vivo. It can have positive or negative impacts on cellular uptake and toxicity of nanoparticles and even trigger immune responses. Understanding the effects of protein corona have potential in evaluating the fate of the food‐related nanoparticles, providing physicochemical and biological information about the interaction between proteins and foodborne nanoparticles. The review article will help to evaluate the safety of protein coronas formed on nanoparticles in food, and may provide fundamental information for understanding and controlling nanotoxicity. [ABSTRACT FROM AUTHOR]

Gas hydrate saturation and porosity are the two essential parameters for characterizing a gas hydrate reservoir. Generally, porosities determined at the well locations are interpolated and extrapolated over the seismic volume, which is not so appropriate to get an estimate of gas hydrate saturation. Here, we propose a method to predict both porosity and gas hydrate saturation directly by inverting seismic data using a global optimization technique known as Very Fast Simulated Annealing. Acoustic impedance, as a function of water saturation and porosity, is defined by a second‐degree polynomial equation used as a forward problem. These are used as the primary model parameters. Acoustic impedance derived from these values is then used to compute synthetic seismograms that are compared against observed traces. We demonstrate our approach on a 23.5 km two‐dimensional seismic line crossing four wells in the Krishna Godavari Basin, eastern Indian offshore. First, the proposed method is tested on well log data and then applied on post‐stack seismic data. The posterior probability density function and the correlation matrix between the model parameters (gas hydrate saturation and porosity) are calculated to measure the associated uncertainty in prediction. Inversion results illustrate that the approach can be efficiently used for the prediction of porosity and gas hydrate saturation directly from the seismic data. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most prevalent form of dementia, with complex pathophysiology that is not fully understood. While β‐amyloid plaque and neurofibrillary tangles define the pathology of the disease, the mechanism of neurodegeneration is uncertain. Ferroptosis is an iron‐mediated programmed cell death mechanism characterised by phospholipid peroxidation that has been observed in clinical AD samples. This review will outline the growing molecular and clinical evidence implicating ferroptosis in the pathogenesis of AD, with implications for disease‐modifying therapies. [ABSTRACT FROM AUTHOR]

The exploration of memtransistors as a combination of a memristor and a transistor has recently attracted intensive attention because it offers a promising candidate for next‐generation multilevel nonvolatile memories and synaptic devices. However, the present state‐of‐the‐art memtransistors, which are based on a single material, such as MoS2 or perovskite, exhibit a relatively low switching ratio, require extremely high electric fields to modulate bistable resistance states and do not perform multifunctional operations. Here, the realization of an electrically and optically controllable p–n junction memtransistor using an Al2O3 encapsulated 2D Te/ReS2 van der Waals heterostructure is reported. The hybrid memtransistor shows a reversible bipolar resistance switching behavior between a low resistance state and a high resistance state with a high switching ratio up to 106 at a low operating voltage (<10 V), high cycling endurance, and long retention time. Moreover, multiple resistance states are achieved by applying different bias voltages, gate voltages, or light powers. In addition, logical operations, including the inverter and AND/OR gates, and synaptic activities are performed by controlling the optical and electrical inputs. The work offers a novel strategy for the reliable fabrication of p–n junction memtransistors for multifunctional devices and neuromorphic applications. [ABSTRACT FROM AUTHOR]

Volume‐dependent magnetic susceptibility (κ) is commonly used for paleoenvironmental reconstructions in both terrestrial and marine sedimentary environments where it reflects a mixed signal between primary deposition and secondary diagenesis. In the marine environment, κ is strongly influenced by the abundance of ferrimagnetic minerals regulated by sediment transport processes. Post‐depositional alteration by H2S, however, can dissolve titanomagnetite, releasing reactive Fe that promotes pyritization and subsequently decreases κ. Here, we provide a new approach for isolating the detrital signal in κ and identifying intervals of diagenetic alteration of κ driven by organoclastic sulfate reduction (OSR) and the anaerobic oxidation of methane (AOM) in methane‐bearing marine sediments offshore India. Using the correlation of a heavy mineral proxy from X‐ray fluorescence data (Zr/Rb) and κ in unaltered sediments, we predict the primary detrital κ signal and identify intervals of decreased κ, which correspond to increased total sulfur content. Our approach is a rapid, high‐resolution method that can identify overprinted κ resulting from pyritization of titanomagnetite due to H2S production in marine sediments. In addition, total organic carbon, total sulfur, and authigenic carbonate δ13C measurements indicate that both OSR and AOM can drive the observed κ loss, but AOM drives the greatest decreases in κ. Overall, our approach can enhance paleoenvironmental reconstructions and provide insight into paleo‐positions of the sulfate‐methane transition zone, past enhancements of OSR or paleo‐methane seepage, and the role of detrital iron oxide minerals on the marine sediment sulfur sink, with consequences influencing the development of chemosynthetic biological communities at methane seeps. Plain Language Summary: In continental margin environments, variation in the magnetic susceptibility (κ) of marine sediments is influenced primarily by the delivery of detrital magnetic minerals from continental erosion and secondarily by diagenetically driven dissolution and/or growth of new magnetic minerals within the sediments. Bulk sediment measurements of κ often record a mixed signal from these processes, making it difficult to distinguish the original depositional detrital signal from in situ diagenetic effects. Here, we provide a new approach for isolating the detrital signal in κ and identifying intervals of diagenetic alteration in methane‐bearing marine sediments in the offshore Krishna‐Godavari basin, eastern peninsular India. We utilize measurements of κ, magnetic properties, a heavy mineral proxy (Zr/Rb from X‐ray fluorescence), total organic carbon (TOC) and total sulfur (TS), and authigenic carbonate carbon isotopes to determine which portions of the records reflect primary deposition and which reflect diagenesis associated with abundant TOC or abundant methane. Overall, by decoupling the mixed signal of κ, our approach can allow for improved interpretation of marine sediment sequences globally and has implications for reconstructing the role of detrital magnetic minerals on the marine sediment sulfur cycle and the development of chemosynthetic biological communities at methane seeps. Key Points: Zr/Rb as a heavy mineral proxy tracks well with magnetic susceptibility (κ) in stratigraphy unaltered by diagenesisPyritization driven by both organoclastic sulfate reduction and the anaerobic oxidation of methane results in a relative loss of (κ)At methane seeps pyritization is regulated by detrital Fe‐oxides, limiting or enhancing the role of pyrite as a global sulfur sink [ABSTRACT FROM AUTHOR]

Retinal degeneration, characterised by the progressive death of retinal neurons, is the most common cause of visual impairment. Oxysterols are the cholesterol derivatives produced via enzymatic and/or free radical oxidation that regulate cholesterol homeostasis in the retina. Preclinical and clinical studies have suggested a connection between oxysterols and retinal degeneration. Here, we summarise early and recent work related to retina oxysterol‐producing enzymes and the distribution of oxysterols in the retina. We examine the impact of loss of oxysterol‐producing enzymes on retinal pathology and explore the molecular mechanisms associated with the toxic or protective roles of individual oxysterols in different types of retinal degeneration. We conclude that increased efforts to better understand the oxysterol‐associated pathophysiology will help in the development of effective retinal degeneration therapies. LINKED ARTICLES: This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc [ABSTRACT FROM AUTHOR]

Background and Purpose: 2‐Hydroxypropyl‐β‐cyclodextrin (HPCD) is an FDA approved vehicle for drug delivery and an efficient cholesterol‐lowering agent. HPCD was proposed to lower tissue cholesterol via multiple mechanisms including those mediated by oxysterols. CYP27A1 and CYP46A1 are the major oxysterol‐producing enzymes in the retina that convert cholesterol to 27‐ and 24‐hydroxycholesterol, respectively. We investigated whether HPCD treatments affected the retina of wild‐type and Cyp27a1−/−Cyp46a1−/− mice that do not produce the major retinal oxysterols. Experimental Approach HPCD administration was either by i.p., p.o. or s.c. Delivery to the retina was confirmed by angiography using the fluorescently labelled HPCD. Effects on the levels of retinal sterols, mRNA and proteins were evaluated by GC–MS, qRT‐PCR and label‐free approach, respectively. Key Results: In both wild‐type and Cyp27a1−/−Cyp46a1−/− mice, HPCD crossed the blood–retinal barrier when delivered i.p. and lowered the retinal cholesterol content when administered p.o. and s.c. In both genotypes, oral HPCD treatment affected the expression of cholesterol‐related genes as well as the proteins involved in endocytosis, lysosomal function and lipid homeostasis. Mechanistically, liver X receptors and the altered expression of Lipe (hormone‐sensitive lipase), Nceh1 (neutral cholesterol ester hydrolase 1) and NLTP (non‐specific lipid‐transfer protein) could mediate some of the HPCD effects. Conclusions and Implications: HPCD treatment altered retinal cholesterol homeostasis and is a potential therapeutic approach for the reduction of drusen and subretinal drusenoid deposits, cholesterol‐rich lesions and hallmarks of age‐related macular degeneration. LINKED ARTICLES: This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc [ABSTRACT FROM AUTHOR]

New heteroleptic indium complexes, i. e. [MeIn(mdpa)(tmhd)]2 (2), [MeIn(mdpa)(acac)]2 (3), [MeIn(edpa)(tmhd)]2 (4), and [MeIn(edpa)(acac)]2 (5), with three different ligands, bearing N‐alkoxy carboxamide and β‐diketonate were designed and synthesized as indium precursors for indium oxide thin films by atomic layer deposition (ALD) using [Me2In(edpa)]2 and [Me2In(mdpa)]2 (1) as starting materials. The resulting complexes were characterized by NMR and FT‐IR spectroscopy, elemental analysis (EA), thermogravimetric analysis (TGA), and single crystal X‐ray diffraction. TGA curves of all the complexes showed clear single‐step weight losses, with low residual masses of 7–13 %. Among them, complex 5 was volatile and thermally stable, and thus, it can be used as potential indium precursor for indium oxide‐based thin films. [ABSTRACT FROM AUTHOR]

Injectable sensors can significantly improve the volume of critical biomedical information emerging from the human body in response to injury or disease. Optical oxygen sensors with rapid response times can be achieved by incorporating oxygen‐sensitive luminescent molecules within polymeric matrices with suitably high surface area to volume ratios. In this work, electrospraying utilizes these advances to produce conveniently injectable, oxygen sensing particles made up of a core‐shell polysulfone‐polysulfone structure containing a phosphorescent oxygen‐sensitive palladium porphyrin species within the core. Particle morphology is highly dependent on solvent identity and electrospraying parameters; DMF offers the best potential for the creation of uniform, sub‐micron particles. Total internal reflection fluorescence microscopy confirms the existence of both core‐shell structure and oxygen sensitivity. The dissolved oxygen response time is rapid (<0.30 s), ideal for continuous real‐time monitoring of oxygen concentration. The incorporation of Pluronic F‐127 surfactant enables efficient dispersion; selection of an appropriate electrospraying solvent (DMF) yields particles readily injected even through a < 100 μm diameter needle. [ABSTRACT FROM AUTHOR]

This Supplement on Getting to the heart of stigma across the HIV continuum of care aims to draw attention to HIV-related and intersecting stigma and discrimination across the HIV prevention and care continuum. Keywords: community leadership; HIV; intersectionality; measurement; methods; Stigma EN community leadership HIV intersectionality measurement methods Stigma 1 3 3 07/14/22 20220702 NES 220702 More than 40 years into the global HIV pandemic, we are still grappling with HIV-related stigma and its intersections with other marginalized identities, health conditions and social practices. They argue that segregating people into HIV prevention and HIV treatment research disrupts the organic and close kinship structures, and conclude by calling on funders to develop mechanisms that support the development and testing of HIV status-neutral interventions. HIV-related stigma, conceptualized as the devaluing, mistreatment and constrained access to power and opportunities experienced by people living with and associated with HIV, remains a critical concern inhibiting the HIV response [1]. [Extracted from the article]

The metal–semiconductor–metal (MSM) structure is widely applied in photodetectors (PDs) owing to its simple preparation method and a more effective light collecting area. However, the realization of weak light detection remains a daunting challenge, attributed to the low external quantum efficiency (EQE) in MSM‐based PDs. Herein, sandwich structure PD (SSPD), a new structure of PD based on MSM structure, is presented to solve the problem of low gain in MSM PDs. Herein, the high‐EQE MgZnO/Au/ZnO SSPD with avalanche effect is reported for the first time. The avalanche effect is realized by changing the position of electronic transmission through energy band engineering between MgZnO and ZnO in the sandwich structure. The SSPD exhibits high EQE when photogenerated carriers get transported at the interface of ZnO and MgZnO. Under 275 nm illumination, the MgZnO/Au/ZnO SSPD achieves avalanche multiplication at 63 V and shows EQE of up to 502780% at 90 V. These results reveal that a high EQE originates from the special sandwich structure existing in MgZnO/Au/ZnO SSPD. This study presents possible guidance for high‐performance ZnO‐based avalanche PD for applications in telecommunications, sensing, and single‐photon detection. [ABSTRACT FROM AUTHOR]

Evaluation of the kinetics of systemic distribution of IV injected monoclonal antibodies modi... B A.M. Carias SP 1 sp , J. Schneider SP 2 sp , M. McRaven SP 1 sp , S. Xiao SP 1 sp , K. Rogers SP 3 sp , M. Araínga SP 3 sp , R. Veazey SP 4 sp , F. Villinger SP 3 sp , T.J Hope SP 1 sp b SP 1 sp Northwestern University, Cell and Developmental Biology, Evanston, United States, SP 2 sp Rush University, United States, SP 3 sp New Iberia Research Center, United States, SP 4 sp Tulane National Primate Research Center, United States B Background: b Antibody-mediated protection against HIV/SHIV transmission has been illustrated in non-human primates (NHP) with IV injection of broadly neutralizing monoclonal antibodies (bNAbs). Understanding the mechanisms behind why IgA inhibits Fc responses could lead to improved future HIV vaccine design and educate passive transfer monoclonal antibody therapies. B Results: b 18,172 surveyed adults were categorized into one of six HIV risk types, each showing a unique pattern of five risk factors that conveyed HIV transmission and/or acquisition risk propensity. [Extracted from the article]

During the middle Miocene, Earth's climate changed from a global warm period (Miocene Climatic Optimum) into a colder one with the expansion of the Antarctic ice sheet. This prominent climate transition was also a period of drastic changes in global atmospheric circulation. The development of the South Asian monsoon is not well understood and mainly derived from proxy records of wind strength. Data for middle Miocene changes in rainfall are virtually non‐existent for India and the Arabian Sea prior to 11 Ma. This study presents planktic foraminiferal trace element (Mg/Ca and Ba/Ca) and stable oxygen isotope records from NGHP‐01 Site 01A off the coast of West India in the Eastern Arabian Sea (EAS) to reconstruct the regional surface hydrography and hydroclimate in the South Asian monsoon (SAM) region during the middle Miocene. The Ba/Ca and local seawater δ18O (δ18Osw) changes reveal a notable gradual increase in SAM rainfall intensity during the middle Miocene. Additionally to this long‐term increase in precipitation, the seawater δ18O is punctuated by a prominent decrease, i.e. freshening, at ~14 Ma contemporary with Antarctic glaciation. This suggests that Southern Ocean Intermediate Waters (SOIW) transmitted Antarctic salinity changes into the Arabian Sea via an "oceanic tunnel" mechanism. The middle Miocene increase in SAM rainfall is consistent with climate model simulations of an overall strengthening Asian monsoon from the Eocene to the middle/late Miocene with a further acceleration after the middle Miocene climate transition. Key Points: We present the first South Asian monsoon (SAM) rainfall record for the Eastern Arabian Sea region for the middle to late MioceneWe find an intensification of SAM rainfall from ~15 to 11 MaIntensification of the SAM is consistent with climate models of an overall strengthening Asian monsoon from the Eocene to late Miocene [ABSTRACT FROM AUTHOR]

The nucleolar structure is highly dynamic and strictly regulated in response to internal cues, such as metabolic rates, and to external cues, such as mechanical forces applied to cells. Although the multilayered nucleolar structure is largely determined by the liquid‐like properties of RNA and proteins, the mechanisms regulating the morphology and number of nucleoli remain elusive. The linker of the nucleoskeleton and cytoskeleton (LINC) complex comprises inner nuclear membrane Sad1/UNC‐84 (SUN) proteins and outer nuclear membrane‐localized nesprins. We previously showed that the depletion of SUN1 proteins affects nucleolar morphologies. This study focuses on the function of SUN1 splicing variants in determining nucleolar morphology. An RNA interference strategy showed that the predominantly expressed variants, SUN1_888 and SUN1_916, were crucial for nucleolar morphology but functionally distinct. In addition, the depletion of either SUN1_888 or SUN1_916 altered the chromatin structure and affected the distribution of histone modifications. Based on these results, we propose a model in which the LINC complex plays a role in modulating nucleolar morphology and numbers via chromatin. [ABSTRACT FROM AUTHOR]

Fonio grains are a type of small‐seeded cereals native to Western Africa and are important cereal crops for food security. The two species are white fonio (Digitaria exilis) (commonly called acha) and black fonio (Digitaria iburua) (commonly called iburu). As a novel food, fonio has attracted attention from other parts of the world due to their attractive nutritional properties (e.g., in whole grain form and being gluten free) and potential food applications. The information regarding the functional properties and applications of fonio is rather scattered. This review summarizes the chemical composition, physicochemical and nutritional properties, and diverse food applications of fonio. The nutritional composition and processing properties of fonio are similar to other cereals. Fonio has potential to be complementary to major cereals for diverse food uses. There are research opportunities to better explore fonio grains for value‐added applications. [ABSTRACT FROM AUTHOR]

Gas hydrate is an ice‐like form of water and low molecular weight gas stable at temperatures of roughly −10°C to 25°C and pressures of ~3 to 30 MPa in geologic systems. Natural gas hydrates sequester an estimated one sixth of Earth's methane and are found primarily in deepwater marine sediments on continental margins, but also in permafrost areas and under continental ice sheets. When gas hydrate is removed from its stability field, its breakdown has implications for the global carbon cycle, ocean chemistry, marine geohazards, and interactions between the geosphere and the ocean‐atmosphere system. Gas hydrate breakdown can also be artificially driven as a component of studies assessing the resource potential of these deposits. Furthermore, geologic processes and perturbations to the ocean‐atmosphere system (e.g., warming temperatures) can cause not only dissociation, but also more widespread dissolution of hydrate or even formation of new hydrate in reservoirs. Linkages between gas hydrate and disparate aspects of Earth's near‐surface physical, chemical, and biological systems render an assessment of the rates and processes affecting the persistence of gas hydrate an appropriate Centennial Grand Challenge. This paper reviews the thermodynamic controls on methane hydrate stability and then describes the relative importance of kinetic, mass transfer, and heat transfer processes in the formation and breakdown (dissociation and dissolution) of gas hydrate. Results from numerical modeling, laboratory, and some field studies are used to summarize the rates of hydrate formation and breakdown, followed by an extensive treatment of hydrate dynamics in marine and cryospheric gas hydrate systems. Key Points: Gas hydrates are widespread, store large amounts of carbon, and are susceptible to degradation under warming ocean‐atmosphere conditionsGas hydrate formation and breakdown rates are generally limited by mass transport and heat transport processes, respectivelyHydrate dissolution, not dissociation, is the more common breakdown process; sufficient dissolved gas in adjacent fluids is necessary for hydrate to persist [ABSTRACT FROM AUTHOR]

Local anesthetics can cause severe toxicity when absorbed systemically. Rapid intravenous administration of lipid emulsion (LE) is the standard of care for severe local anesthetic systemic toxicity which can cause cardiovascular and central nervous system (CNS) injury. The biological mechanism by which LE alleviates CNS toxicity remains unknown and understudied. Previous research has suggested that local anesthetics cause an imbalance of excitatory and inhibitory transmission in the brain. Therefore, this study aimed to observe the effect of LE on glutamate‐ and GABA‐induced currents in CA1 pyramidal neurons after bupivacaine‐induced CNS toxicity. We further characterized post‐synaptic modifications in these cells to try to elucidate the mechanism by which LE mediates bupivacaine‐induced CNS toxicity. Sprague–Dawley rats received intravenous bupivacaine (1 mg kg−1 min−1) in either normal saline or LE (or LE without bupivacaine) for 5 min. An acute brain slice preparation and a combination of whole‐cell patch clamp techniques and whole‐cell recordings were used to characterize action potential properties, miniature excitatory, and inhibitory post‐synaptic currents, and post‐synaptic modifications of excitatory and inhibitory transmission in CA1 hippocampal pyramidal neurons. The expression level of GABAA receptors were assessed with western blotting, whereas H&E and TUNEL staining were used to assess cytoarchitecture and apoptosis levels respectively. Bupivacaine treatment significantly increased the number of observed action potentials, whereas significantly decreasing rheobase, the first interspike interval (ISI), and hyperpolarization‐activated cation currents (Ih) in CA1 pyramidal neurons. LE treatment significantly reduced the frequency of miniature inhibitory post‐synaptic currents and enhanced GABA‐induced paired pulse ratio with 50 ms interval stimulation in bupivacaine‐treated rats. Regulation of GABAA levels is a promising mechanism by which LE may ameliorate CNS toxicity after systemic absorption of bupivacaine. [ABSTRACT FROM AUTHOR]

Two quantum mechanical (QM)‐cluster models are built for studying the acylation and deacylation mechanism and kinetics of Streptomyces R61 DD‐peptidase with the penicillin G at atomic level detail. DD‐peptidases are bacterial enzymes involved in the cross‐linking of peptidoglycan to form the cell wall, necessary for bacterial survival. The cross‐linking can be inhibited by antibiotic beta‐lactam derivatives through acylation, preventing the acyl‐enzyme complex from undergoing further deacylation. The deacylation step was predicted to be rate‐limiting. Transition state and intermediate structures are found using density functional theory in this study, and thermodynamic and kinetic properties of the proposed mechanism are evaluated. The acyl‐enzyme complex is found lying in a deep thermodynamic sink, and deacylation is indeed the severely rate‐limiting step, leading to suicide inhibition of the peptidoglycan cross‐linking. The usage of QM‐cluster models is a promising technique to understand, improve, and design antibiotics to disrupt function of the Streptomyces R61 DD‐peptidase. [ABSTRACT FROM AUTHOR]

Niemann–Pick type C disease (NPCD) was first described in 1914 and affects approximately 1 in 150 000 live births. It is characterized clinically by diverse symptoms affecting liver, spleen, motor control, and brain; premature death invariably results. Its molecular origins were traced, as late as 1997, to a protein of late endosomes and lysosomes which was named NPC1. Mutation or absence of this protein leads to accumulation of cholesterol in these organelles. In this review, we focus on the intracellular events that drive the pathology of this disease. We first introduce endocytosis, a much‐studied area of dysfunction in NPCD cells, and survey the various ways in which this process malfunctions. We briefly consider autophagy before attempting to map the more complex pathways by which lysosomal cholesterol storage leads to protein misregulation, mitochondrial dysfunction, and cell death. We then briefly introduce the metabolic pathways of sphingolipids (as these emerge as key species for treatment) and critically examine the various treatment approaches that have been attempted to date. [ABSTRACT FROM AUTHOR]

Warburg Micro syndrome and Martsolf syndrome are phenotypically overlapping autosomal recessive conditions characterized by multiple organ abnormalities involving the ocular, nervous, and endocrine systems. Warburg Micro syndrome, the more severe of the two conditions, is caused by loss of function mutations in RAB3GAP1, RAB3GAP2, RAB18, and TBC1D20 genes, whereas Martsolf syndrome has been attributed to less damaging mutations in RAB3GAP1 and RAB3GAP2 genes. We report the clinical description and molecular characterization of a consanguineous Iranian family with two siblings, a male and a female, with dysmorphic features, bilateral congenital cataracts, optic nerve atrophy, congenital glaucoma, mild to moderate intellectual disability, seizures, hypogonadism, and mild osteoporosis. Spastic quadriplegia with contractures was observed in the male patient, while the female patient showed only mild hyperreflexia. Magnetic resonance imaging scans performed in the male patient showed a normal brain structure. Both siblings had neither microcephaly nor postnatal growth retardation. Whole exome sequencing identified a novel homozygous nonsense mutation [c.1060C>T; p.(Arg354Ter)] in the TBC1D20 gene in both siblings and confirmed the heterozygous carrier status of both parents. This report describes a novel mutation in the TBC1D20 gene in two Iranian patients with Martsolf syndrome, further extending the allelic heterogeneity and phenotypic spectrum of this rare condition. The genotype and phenotype of the patients are compared with those of Martsolf syndrome and Warburg Micro syndrome patients reported in the literature. [ABSTRACT FROM AUTHOR]

Summary: The anti‐tumor immune response is considered to be due to the T‐cell receptor (TCR) binding to tumor antigens, which can be either wild‐type, early stem cell proteins, presumably foreign to a developed immune system; or mutant peptides, foreign to the immune system because of a mutant amino acid (aa) or otherwise somatically altered aa sequence. Recently, very large numbers of TCR complementarity‐determining region‐3 (CDR3) aa sequences obtained from tumor specimens have become available. We developed a novel algorithm for assessing the complementarity of tumor mutant peptides and TCR CDR3s, based on the retrieval of TCR CDR3 aa sequences from both tumor specimen and patient blood exomes and by using an automated process of assessing CDR3 and mutant aa electrical charges. Results indicated many instances where high electrostatic complementarity was associated with a higher survival rate. In particular, our approach led to the identification of specific genes contributing significantly to the complementary, TCR CDR3‐mutant aa. These results suggest a novel approach to tumor immunoscoring and may lead to the identification of high‐priority neo‐antigen, peptide vaccines; or to the identification of ex vivo stimulants of tumor‐infiltrating lymphocytes. [ABSTRACT FROM AUTHOR]