Stress Induces Dynamic, Cytotoxicity-Antagonizing TDP-43 Nuclear Bodies via Paraspeckle LncRNA NEAT1-Mediated Liquid-Liquid Phase Separation.

Despite the prominent role of TDP-43 in neurodegeneration, its physiological and pathological functions are not fully understood. Here, we report an unexpected role of TDP-43 in the formation of dynamic, reversible, liquid droplet-like nuclear bodies (NBs) in response to stress. Formation of NBs alleviates TDP-43-mediated cytotoxicity in mammalian cells and fly neurons. Super-resolution microscopy reveals distinct functions of the two RRMs in TDP-43 NB formation. TDP-43 NBs are partially colocalized with nuclear paraspeckles, whose scaffolding lncRNA NEAT1 is dramatically upregulated in stressed neurons. Moreover, increase of NEAT1 promotes TDP-43 liquid-liquid phase separation (LLPS) in vitro. Finally, we discover that the ALS-associated mutation D169G impairs the NEAT1-mediated TDP-43 LLPS and NB assembly, causing excessive cytoplasmic translocation of TDP-43 to form stress granules, which become phosphorylated TDP-43 cytoplasmic foci upon prolonged stress. Together, our findings suggest a stress-mitigating role and mechanism of TDP-43 NBs, whose dysfunction may be involved in ALS pathogenesis.

Evidence supporting the MICU1 occlusion mechanism and against the potentiation model in the mitochondrial calcium uniporter complex.

The mitochondrial calcium uniporter is a Ca2+ channel that imports cytoplasmic Ca2+ into the mitochondrial matrix to regulate cell bioenergetics, intracellular Ca2+ signaling, and apoptosis. The uniporter contains the pore-forming MCU subunit, an auxiliary EMRE protein, and the regulatory MICU1/MICU2 subunits. Structural and biochemical studies have suggested that MICU1 gates MCU by blocking/unblocking the pore. However, mitoplast patch-clamp experiments argue that MICU1 does not block, but instead potentiates MCU via allosteric mechanisms. Here, we address this direct clash of the proposed MICU1 function. Supporting the MICU1-occlusion mechanism, patch-clamp demonstrates that purified MICU1 strongly suppresses MCU Ca2+ currents, and this inhibition is abolished by mutating the MCU-interacting K126 residue. Moreover, a membrane-depolarization assay shows that MICU1 prevents MCU-mediated Na+ flux into intact mitochondria under Ca2+-free conditions. Examining the observations underlying the potentiation model, we found that MICU1 occlusion was not detected in mitoplasts not because MICU1 cannot block, but because MICU1 dissociates from the uniporter complex. Furthermore, MICU1 depletion reduces uniporter transport not because MICU1 can potentiate MCU, but because EMRE is down-regulated. These results firmly establish the molecular mechanisms underlying the physiologically crucial process of uniporter regulation by MICU1.

A family of unusual immunoglobulin superfamily genes in an invertebrate histocompatibility complex.

Most colonial marine invertebrates are capable of allorecognition, the ability to distinguish between themselves and conspecifics. One long-standing question is whether invertebrate allorecognition genes are homologous to vertebrate histocompatibility genes. In the cnidarian Hydractinia symbiolongicarpus, allorecognition is controlled by at least two genes, Allorecognition 1 (Alr1) and Allorecognition 2 (Alr2), which encode highly polymorphic cell-surface proteins that serve as markers of self. Here, we show that Alr1 and Alr2 are part of a family of 41 Alr genes, all of which reside in a single genomic interval called the Allorecognition Complex (ARC). Using sensitive homology searches and highly accurate structural predictions, we demonstrate that the Alr proteins are members of the immunoglobulin superfamily (IgSF) with V-set and I-set Ig domains unlike any previously identified in animals. Specifically, their primary amino acid sequences lack many of the motifs considered diagnostic for V-set and I-set domains, yet they adopt secondary and tertiary structures nearly identical to canonical Ig domains. Thus, the V-set domain, which played a central role in the evolution of vertebrate adaptive immunity, was present in the last common ancestor of cnidarians and bilaterians. Unexpectedly, several Alr proteins also have immunoreceptor tyrosine-based activation motifs and immunoreceptor tyrosine-based inhibitory motifs in their cytoplasmic tails, suggesting they could participate in pathways homologous to those that regulate immunity in humans and flies. This work expands our definition of the IgSF with the addition of a family of unusual members, several of which play a role in invertebrate histocompatibility.

Negative corona discharge strategy for efficient quantum dot light-emitting diodes.

In colloid quantum dot light-emitting diodes (QLEDs), the control of interface states between ZnO and quantum dots (QDs) plays a vital role. We present a straightforward and efficient method using a negative corona discharge to modify the QD film, creating a dipole moment at the interface of QDs and magnesium-doped ZnO (ZnMgO) for balanced charge carrier distribution within the QDs. This process boosts external quantum efficiencies in red, green, and blue QLEDs to 17.71%, 14.53%, and 9.04% respectively. Notably, optimized devices exhibit significant enhancements, especially at lower brightness levels (1000 to 10,000 cd·m-2), vital for applications in mobile displays, TV screens, and indoor lighting.

Modulating the voltage sensor of a cardiac potassium channel shows antiarrhythmic effects.

Cardiac arrhythmias are the most common cause of sudden cardiac death worldwide. Lengthening the ventricular action potential duration (APD), either congenitally or via pathologic or pharmacologic means, predisposes to a life-threatening ventricular arrhythmia, Torsade de Pointes. IKs (KCNQ1+KCNE1), a slowly activating K+ current, plays a role in action potential repolarization. In this study, we screened a chemical library in silico by docking compounds to the voltage-sensing domain (VSD) of the IKs channel. Here, we show that C28 specifically shifted IKs VSD activation in ventricle to more negative voltages and reversed the drug-induced lengthening of APD. At the same dosage, C28 did not cause significant changes of the normal APD in either ventricle or atrium. This study provides evidence in support of a computational prediction of IKs VSD activation as a potential therapeutic approach for all forms of APD prolongation. This outcome could expand the therapeutic efficacy of a myriad of currently approved drugs that may trigger arrhythmias.

XY sex determination in a cnidarian.

BACKGROUND: Sex determination occurs across animal species, but most of our knowledge about its mechanisms comes from only a handful of bilaterian taxa. This limits our ability to infer the evolutionary history of sex determination within animals. RESULTS: In this study, we generated a linkage map of the genome of the colonial cnidarian Hydractinia symbiolongicarpus and used it to demonstrate that this species has an XX/XY sex determination system. We demonstrate that the X and Y chromosomes have pseudoautosomal and non-recombining regions. We then use the linkage map and a method based on the depth of sequencing coverage to identify genes encoded in the non-recombining region and show that many of them have male gonad-specific expression. In addition, we demonstrate that recombination rates are enhanced in the female genome and that the haploid chromosome number in Hydractinia is n = 15. CONCLUSIONS: These findings establish Hydractinia as a tractable non-bilaterian model system for the study of sex determination and the evolution of sex chromosomes.

Pressure-Modulated Interface Engineering toward Realizing Core@Shell Configuration Transition.

The strained interface of core@shell nanocrystals (NCs) can effectively modulate the energy level alignment, thereby significantly affecting the optical properties. Herein, the unique photoluminescence (PL) response of doped Mn ions is introduced as a robust probe to detect the targeted pressure-strain relation of CdS@ZnS NCs. Results show that the core experiences actually less pressure than the applied external pressure, attributed to the pressure-induced optimized interface that reduces the compressive strain on core. The pressure difference between core and shell increases the conduction band and valence band offsets and further achieves the core@shell configuration transition from quasi type II to type I. Accordingly, the PL intensity of CdS@ZnS NCs slightly increases, along with a faster blue-shift rate of PL peak under low pressure. This study elucidates the interplay between external physical pressure and interfacial chemical stress for core@shell NCs, leading to precise construction of interface engineering for practical applications.

Tailoring Near-Infrared-IIb Fluorescence of Thulium(III) by Nanocrystal Structure Engineering.

Currently, mainstream lanthanide probes with fluorescence located in the second near-infrared subwindow of 1500-1700 nm (NIR-IIb) are predominantly Er(III)-based nanoparticles (NPs). Here we report a newly developed NIR-IIb fluorescent nanoprobe, α-Tm NP (cubic-phase NaYF4@NaYF4:Tm@NaYF4), with an emission at 1630 nm. We activate the 1630 nm emission of Tm(III) in α-Tm NP through the large spread of the Stark split sublevels induced by the crystal-field effect of the α-NaYF4 host. Further, we systematically investigated the effect of crystalline structure of the host NaYF4 NP (cubic phase (α) or hexagonal phase (ß)), the type and concentrations of dopants (Yb(III), Tm(III), and Ca(II) ions) in the α-phase host, and the thicknesses of the interlayer and inert shell on the NIR-IIb fluorescence of Tm(III). The ultimate nanostructure presents a significant enhancement factor of the NIR-IIb photoluminescence intensity of Tm(III) up to ∼315. With this bright NIR-IIb fluorescent nanoprobe, we demonstrate high-spatial-resolution time-coursing imaging of breast cancer bone metastasis.

Sustainable energy solutions: Well retrofit analysis and emission reduction for a net-zero future in the Intermountain West, United States of America.

To achieve net-zero emissions by 2050, we need economic means of sequestering carbon dioxide (CO2) and reducing greenhouse gas emissions (GHG). We analyze the sequestration potential of the Intermountain West (I-West) region, US, as a primary energy transition hub through analysis of wellbore retrofit potential and emission reduction in both fugitive gas abatement and flare gas. We selected the I-West region due to its abundant energy sources and oil and gas production legacy. Preliminary analysis hints that well retrofits can breathe new life into a well at a fraction of the cost of a new drill. With millions of potential candidates in the US, even a modest fraction (1% or less) suitable for retrofit could accelerate the shift to large-scale CO2 sequestration. Fugitive gas, the unintentional release of wellbore gases such as methane, is a significant emissions source. Through conservative analysis, it is estimated that wellhead leakage alone may account for 5 million tonnes of carbon dioxide equivalent (CO2e) emissions. We conclude by assessing the CO2 emissions from flaring, which is the burning of associated gas during well operations, conservative analysis indicates flaring contributes another 2 million tonnes of CO2 emissions to the region. We find that with targeted retrofit and better controls on emissions sources, the I-West region can make a significant impact in the nation's push to become net-zero. This study outlines economic feasibility and actionable items to achieve the critical reductions in emissions and increases in sequestration necessary to attain net zero.

Considerable Piezochromism in All-Inorganic Zero-Dimensional Perovskite Nanocrystals via Pressure-Modulated Self-Trapped Exciton Emission.

Piezochromic materials refer to a class of matters that alter their photoluminescence (PL) colors in response to the external stimuli, which exhibit promising smart applications in anti-counterfeiting, optoelectronic memory and pressure-sensing. However, so far, most reported piezochromic materials have been confined to organic materials or hybrid materials containing organic moieties with limited piezochromic range of less than 100 nm in visible region. Here, we achieved an intriguing piezochromism in all-inorganic zero-dimensional (0D) Cs3Cu2Cl5 nanocrystals (NCs) with a considerable piezochromic range of 232 nm because of their unique inorganic rigid structure. The PL energy shifted from the lowest-energy red fluorescence (1.85 eV) to the highest-energy blue fluorescence (2.83 eV), covering almost the entire visible wavelength range. Pressure-modulated self-trapped exciton emission between different energy levels of self-trapped states within Cs3Cu2Cl5 NCs was the main reason for this piezochromism property. Note that the quenched emission, which is over five times more intense than that in the initial state, is retained under ambient conditions upon decompression. This work provides a promising pressure indicating material, particularly used in pressure stability monitoring for equipment working at extreme environments.

Interface-Mediation-Enabled High-Performance Near-Infrared AgAuSe Quantum Dot Light-Emitting Diodes.

Near-infrared (NIR) quantum dot (QD) light-emitting diodes (LEDs) (NIR-QLEDs) for recognition and tracking applications underpin the future of night-vision technology. However, the performance of environmentally benign materials and devices has lagged far behind that of their Pb-containing counterparts. In this study, we demonstrate the superior performance of NIR-QLEDs based on efficient AgAuSe QDs with contact interface mediation. Consequently, we reveal that using cysteamine-treated QD film contact heterointerfaces can effectively eliminate contact defects in devices and preserve their excellent emissive properties. Additionally, the dipole moment orientation of the coordinated additives is inverse of the heterojunction potential difference, simultaneously blocking electrons and enhancing hole injection in operando, optimizing the LED charge injection balance. These devices exhibit a high external quantum efficiency (EQE) and a power conversion efficiency (PCE) of 15.8 and 12.7% at 1046 nm, respectively, a sub-band gap turn-on voltage of 0.9 V, and a low current density (over 10% of the EQE from 0.0017 to 0.31 mA cm-2). These are the highest EQE and PCE values ever reported for environmentally benign NIR-QLEDs. The results of this study can provide a general strategy for the practical application of QDs in electroluminescent devices.

Pressure Regulating Self-Trapped States toward Remarkable Emission Enhancement of Zero-Dimensional Lead-Free Halides Nanocrystals.

Copper(I)-based halides have recently attracted increasing attention as a substitute for lead halides, owing to their nontoxicity, abundance, unique structure, and optoelectric properties. However, exploring an effective strategy to further improve their optical activities and revealing structure-optical property relationships still remain a great concern. Here, by using high pressure technique, a remarkable enhancement of self-trapped exciton (STE) emission associated with the energy exchange between multiple self-trapped states in zero-dimensional lead-free halide Cs3 Cu2 I5 NCs is successfully achieved. Furthermore, high-pressure processing endows the piezochromism of Cs3 Cu2 I5 NCs by experiencing a white light and a strong purple light emission, which is able to be stabilized at near-ambient pressure. The distortion of [Cu2 I5 ] clusters composing of tetrahedral [CuI4 ] and trigonal planar [CuI3 ] and the decreased Cu-Cu distance between the adjacent Cu-I tetrahedron and triangle are responsible for the significant STEs emission enhancement under high pressure. The experiments combined with first-principles calculations not only shed light on the structure-optical property relationships of [Cu2 I5 ] clusters halide, but also provide guidance for improving emission intensity that is highly desirable in solid-state lighting applications.

Biodegradation of asphaltenes by an indigenous bioemulsifier-producing Pseudomonas stutzeri YWX-1 from shale oil in the Ordos Basin: Biochemical characterization and complete genome analysis.

Crude oil pollution is environmentally ubiquitous and has become a global public concern about its impact on human health. Asphaltenes are the key components of heavy crude oil (HCO) that are underutilized due to their high viscosity and density, and yet, the associated information about biodegradation is extremely limited in the literature. In the present study, an indigenous bacterium with effective asphaltene-degrading activity was isolated from oil shale and identified as Pseudomonas stutzeri by a polyphasic taxonomic approach, named YWX-1. Supplemented with 75 g L-1 heavy crude oil as the sole carbon source for growth in basic mineral salts liquid medium (MSM), strain YWX-1 was able to remove 49% of asphaletene fractions within 14 days, when it was cultivated with an initial inoculation size of 1%. During the degradation process, the bioemulsifier produced by strain YWX-1 could emulsify HCO obviously into particles, as well as it had the ability to solubilize asphaletenes. The bioemulsifier was identified to be a mixture of polysaccharide and protein through Fourier transform infrared spectroscopy (FT-IR). The genome of strain YWX-1 contains one circular chromosome of 4488441 bp with 63.98% GC content and 4145 protein coding genes without any plasmid. Further genome annotation indicated that strain YWX-1 possesses a serial of genes involved in bio-emulsification and asphaltenes biodegradation. This work suggested that P. stutzeri YWX-1 could be a promising species for bioremediation of HCO and its genome analysis provided insight into the molecular basis of asphaltene biodegradation and bioemulsifier production.

Competitive Delocalized Charge Transfer Boosted by Solvent Induction Strategy for Survivable Colorimetric Detection of ng-Level Urea.

Achieving sensitive and robust colorimetry is of great significance for on-site chemical detection, but has always been a dilemma or at the expense of practicality. Here, from the perspective of solvent, which is commonly the indispensable medium for chemical sensing, the solvent induction strategy concerning the hydrophobic shielding and hydrophilic bonding solvent cage was proposed considering the configuration branching ratio in the reagent and the prevention of the autoxidation channel. Due to the competitive delocalized charge transfer in the probe and the effective viscous drag in the reagent, remarkable sensing signal concentrating and moisture retention capability were achieved. We expect the present strategy would facilitate the active but robust chemical reaction design and provide a universal methodology for the exploration of high-performance chemical sensors.

Outlier detection in multimodal MRI identifies rare individual phenotypes among more than 15,000 brains.

Outliers in neuroimaging represent spurious data or the data of unusual phenotypes that deserve special attention such as clinical follow-up. Outliers have usually been detected in a supervised or semi-supervised manner for labeled neuroimaging cohorts. There has been much less work using unsupervised outlier detection on large unlabeled cohorts like the UK Biobank brain imaging dataset. Given its large sample size, rare imaging phenotypes within this unique cohort are of interest, as they are often clinically relevant and could be informative for discovering new processes. Here, we developed a two-level outlier detection and screening methodology to characterize individual outliers from the multimodal MRI dataset of more than 15,000 UK Biobank subjects. In primary screening, using brain ventricles, white matter, cortical thickness, and functional connectivity-based imaging phenotypes, every subject was parameterized with an outlier score per imaging phenotype. Outlier scores of these imaging phenotypes had good-to-excellent test-retest reliability, with the exception of resting-state functional connectivity (RSFC). Due to the low reliability of RSFC outlier scores, RSFC outliers were excluded from further individual-level outlier screening. In secondary screening, the extreme outliers (1,026 subjects) were examined individually, and those arising from data collection/processing errors were eliminated. A representative subgroup of 120 subjects from the remaining non-artifactual outliers were radiologically reviewed, and radiological findings were identified in 97.5% of them. This study establishes an unsupervised framework for investigating rare individual imaging phenotypes within a large neuroimaging cohort.

TRIC-A Channel Maintains Store Calcium Handling by Interacting With Type 2 Ryanodine Receptor in Cardiac Muscle.

RATIONALE: Trimeric intracellular cation (TRIC)-A and B are distributed to endoplasmic reticulum/sarcoplasmic reticulum intracellular Ca2+ stores. The crystal structure of TRIC has been determined, confirming the homotrimeric structure of a potassium channel. While the pore architectures of TRIC-A and TRIC-B are conserved, the carboxyl-terminal tail (CTT) domains of TRIC-A and TRIC-B are different from each other. Aside from its recognized role as a counterion channel that participates in excitation-contraction coupling of striated muscles, the physiological function of TRIC-A in heart physiology and disease has remained largely unexplored. OBJECTIVE: In cardiomyocytes, spontaneous Ca2+ waves, triggered by store overload-induced Ca2+ release mediated by the RyR2 (type 2 ryanodine receptor), develop extrasystolic contractions often associated with arrhythmic events. Here, we test the hypothesis that TRIC-A is a physiological component of RyR2-mediated Ca2+ release machinery that directly modulates store overload-induced Ca2+ release activity via CTT. METHODS AND RESULTS: We show that cardiomyocytes derived from the TRIC-A-/- (TRIC-A knockout) mice display dysregulated Ca2+ movement across sarcoplasmic reticulum. Biochemical studies demonstrate a direct interaction between CTT-A and RyR2. Modeling and docking studies reveal potential sites on RyR2 that show differential interactions with CTT-A and CTT-B. In HEK293 (human embryonic kidney) cells with stable expression of RyR2, transient expression of TRIC-A, but not TRIC-B, leads to apparent suppression of spontaneous Ca2+ oscillations. Ca2+ measurements using the cytosolic indicator Fura-2 and the endoplasmic reticulum luminal store indicator D1ER suggest that TRIC-A enhances Ca2+ leak across the endoplasmic reticulum by directly targeting RyR2 to modulate store overload-induced Ca2+ release. Moreover, synthetic CTT-A peptide facilitates RyR2 activity in lipid bilayer reconstitution system, enhances Ca2+ sparks in permeabilized TRIC-A-/- cardiomyocytes, and induces intracellular Ca2+ release after microinjection into isolated cardiomyocytes, whereas such effects were not observed with the CTT-B peptide. In response to isoproterenol stimulation, the TRIC-A-/- mice display irregular ECG and develop more fibrosis than the WT (wild type) littermates. CONCLUSIONS: In addition to the ion-conducting function, TRIC-A functions as an accessory protein of RyR2 to modulate sarcoplasmic reticulum Ca2+ handling in cardiac muscle.

A novel isosteviol-based bifunctional squaramide organocatalyst for enantioselective Michael addition of acetylacetone to nitroolefins.

Chiral amine-squaramide is a kind of effective hydrogen bond donor bifunctional catalyst to promote many asymmetric transformations. In this paper, novel chiral tertiary amine-squaramide derived from the natural product of the stevioside was developed and applied into the asymmetric Michael addition of acetylacetone to nitroolefins. This asymmetric reaction performed well, and a series of enantiomerically enriched compounds were obtained in high yields (up to 96%) with excellent enantioselectivities (up to 99% ee).

Enantioselective synthesis of coumarins catalyzed by an isosteviol-derived tertiary amine-squaramide catalyst.

A newly tertiary amine-squaramide organocatalyst has been successfully developed and applied into the asymmetric Michael addition of 4-hydroxycoumarin to ß,γ-unsaturated α-ketoesters. The catalyst system performed well with a low catalyst loading of 1 mol% under mild reaction conditions. A series of coumarin derivatives were obtained in good to high yields (up to 97%) with high enantioselectivities (up to 96% ee).

Interhemispheric plasticity is mediated by maximal potentiation of callosal inputs.

Central or peripheral injury causes reorganization of the brain's connections and functions. A striking change observed after unilateral stroke or amputation is a recruitment of bilateral cortical responses to sensation or movement of the unaffected peripheral area. The mechanisms underlying this phenomenon are described in a mouse model of unilateral whisker deprivation. Stimulation of intact whiskers yields a bilateral blood-oxygen-level-dependent fMRI response in somatosensory barrel cortex. Whole-cell electrophysiology demonstrated that the intact barrel cortex selectively strengthens callosal synapses to layer 5 neurons in the deprived cortex. These synapses have larger AMPA receptor- and NMDA receptor-mediated events. These factors contribute to a maximally potentiated callosal synapse. This potentiation occludes long-term potentiation, which could be rescued, to some extent, with prior long-term depression induction. Excitability and excitation/inhibition balance were altered in a manner consistent with cell-specific callosal changes and support a shift in the overall state of the cortex. This is a demonstration of a cell-specific, synaptic mechanism underlying interhemispheric cortical reorganization.

A Bietti Crystalline Dystrophy Mouse Model Shows Increased Sensitivity to Light-Induced Injury.

Bietti crystalline corneo-retinal dystrophy (BCD) is an autosomal recessive inherited retinal dystrophy characterized by multiple shimmering yellow-white deposits in the posterior pole of the retina in association with atrophy of the retinal pigment epithelium (RPE), pigment clumps, and choroidal atrophy and sclerosis. Blindness and severe visual damage are common in late-stage BCD patients. We generated a Cyp4v3 knockout mouse model to investigate the pathogenesis of BCD. This model exhibits decreased RPE numbers and signs of inflammation response in the retina. Rod photoreceptors were vulnerable to light-induced injury, showing increased deposits through fundoscopy, a decrease in thickness and a loss of cells in the ONL, and the degeneration of rod photoreceptors. These results suggest that an inflammatory response might be an integral part of the pathophysiology of BCD, suggesting that it might be reasonable for BCD patients to avoid strong light, and the results provide a useful model for evaluating the effects of therapeutic approaches.