Prion-like strain effects in tauopathies.

Tau is a microtubule-associated protein that plays crucial roles in physiology and pathophysiology. In the realm of dementia, tau protein misfolding is associated with a wide spectrum of clinicopathologically diverse neurodegenerative diseases, collectively known as tauopathies. As proposed by the tau strain hypothesis, the intrinsic heterogeneity of tauopathies may be explained by the existence of structurally distinct tau conformers, "strains". Tau strains can differ in their associated clinical features, neuropathological profiles, and biochemical signatures. Although prior research into infectious prion proteins offers valuable lessons for studying how a protein-only pathogen can encompass strain diversity, the underlying mechanism by which tau subtypes are generated remains poorly understood. Here we summarize recent advances in understanding different tau conformers through in vivo and in vitro experimental paradigms, and the implications of heterogeneity of pathological tau species for drug development.

Discovering a New Okadaic Acid Derivative, a Potent HIV Latency Reversing Agent from Prorocentrum lima PL11: Isolation, Structural Modification, and Mechanistic Study.

Marine toxins (MTs) are a group of structurally complex natural products with unique toxicological and pharmacological activities. In the present study, two common shellfish toxins, okadaic acid (OA) (1) and OA methyl ester (2), were isolated from the cultured microalgae strain Prorocentrum lima PL11. OA can significantly activate the latent HIV but has severe toxicity. To obtain more tolerable and potent latency reversing agents (LRAs), we conducted the structural modification of OA by esterification, yielding one known compound (3) and four new derivatives (4-7). Flow cytometry-based HIV latency reversal activity screening showed that compound 7 possessed a stronger activity (EC50 = 46 ± 13.5 nM) but was less cytotoxic than OA. The preliminary structure-activity relationships (SARs) indicated that the carboxyl group in OA was essential for activity, while the esterification of carboxyl or free hydroxyls were beneficial for reducing cytotoxicity. A mechanistic study revealed that compound 7 promotes the dissociation of P-TEFb from the 7SK snRNP complex to reactivate latent HIV-1. Our study provides significant clues for OA-based HIV LRA discovery.

Host-Endosymbiont Genome Integration in a Deep-Sea Chemosymbiotic Clam.

Endosymbiosis with chemosynthetic bacteria has enabled many deep-sea invertebrates to thrive at hydrothermal vents and cold seeps, but most previous studies on this mutualism have focused on the bacteria only. Vesicomyid clams dominate global deep-sea chemosynthesis-based ecosystems. They differ from most deep-sea symbiotic animals in passing their symbionts from parent to offspring, enabling intricate coevolution between the host and the symbiont. Here, we sequenced the genomes of the clam Archivesica marissinica (Bivalvia: Vesicomyidae) and its bacterial symbiont to understand the genomic/metabolic integration behind this symbiosis. At 1.52 Gb, the clam genome encodes 28 genes horizontally transferred from bacteria, a large number of pseudogenes and transposable elements whose massive expansion corresponded to the timing of the rise and subsequent divergence of symbiont-bearing vesicomyids. The genome exhibits gene family expansion in cellular processes that likely facilitate chemoautotrophy, including gas delivery to support energy and carbon production, metabolite exchange with the symbiont, and regulation of the bacteriocyte population. Contraction in cellulase genes is likely adaptive to the shift from phytoplankton-derived to bacteria-based food. It also shows contraction in bacterial recognition gene families, indicative of suppressed immune response to the endosymbiont. The gammaproteobacterium endosymbiont has a reduced genome of 1.03 Mb but retains complete pathways for sulfur oxidation, carbon fixation, and biosynthesis of 20 common amino acids, indicating the host's high dependence on the symbiont for nutrition. Overall, the host-symbiont genomes show not only tight metabolic complementarity but also distinct signatures of coevolution allowing the vesicomyids to thrive in chemosynthesis-based ecosystems.

Genomic Signatures Supporting the Symbiosis and Formation of Chitinous Tube in the Deep-Sea Tubeworm Paraescarpia echinospica.

Vestimentiferan tubeworms are iconic animals that present as large habitat-forming chitinized tube bushes in deep-sea chemosynthetic ecosystems. They are gutless and depend entirely on their endosymbiotic sulfide-oxidizing chemoautotrophic bacteria for nutrition. Information on the genomes of several siboglinid endosymbionts has improved our understanding of their nutritional supplies. However, the interactions between tubeworms and their endosymbionts remain largely unclear due to a paucity of host genomes. Here, we report the chromosome-level genome of the vestimentiferan tubeworm Paraescarpia echinospica. We found that the genome has been remodeled to facilitate symbiosis through the expansion of gene families related to substrate transfer and innate immunity, suppression of apoptosis, regulation of lysosomal digestion, and protection against oxidative stress. Furthermore, the genome encodes a programmed cell death pathway that potentially controls the endosymbiont population. Our integrated genomic, transcriptomic, and proteomic analyses uncovered matrix proteins required for the formation of the chitinous tube and revealed gene family expansion and co-option as evolutionary mechanisms driving the acquisition of this unique supporting structure for deep-sea tubeworms. Overall, our study provides novel insights into the host's support system that has enabled tubeworms to establish symbiosis, thrive in deep-sea hot vents and cold seeps, and produce the unique chitinous tubes in the deep sea.

Activity enhancement of a photo-generated carrier in CsPbBr3 nanocrystals improved by Cd element.

Doping Cd element into perovskite materials is an effective strategy to improve the photoelectric property. However, the further discussion for carrier dynamic behavior in perovskites affected by Cd element remains not sufficient. In this research letter, based on steady and transient spectroscopy, it is found that adding Cd element into CsPbBr3 nanocrystals can enhance the activity of photo-generated carriers and accompany with the optimization of crystal structure. The former improves the carrier heating effect, which makes carrier keep high temperature for a long time and accelerate the bimolecular and the Auger recombination simultaneously. The latter can restrict the monomolecular recombination through passivating the defect states. Finally, they together improve the photoluminescence characteristics of the Cd doped CsPbBr3 nanocrystals and make them exhibit a huge potential in the fields of optoelectronics or photo-catalysis.

Homo/Hetero-Dimers of Aromatic Bisabolane Sesquiterpenoids with Neuroprotective Activity from the Fungus Aspergillus versicolor A18 from South China Sea

Chromatographic fractionation of the EtOH extracts of the marine-derived fungus Aspergillus versicolor A18 has led to the isolation of 11 homo/hetero-dimers of aromatic bisabolane sesquiterpenoids including eight diphenyl ether-coupled aromatic bisabolanes (1a/1b and 5−10) and three homodimers (2−4), together with their monomers including three aromatic bisabolanes (11−13) and two diphenyl ethers (14 and 15). Their structures and absolute configurations were elucidated by extensive spectroscopic analysis including HRESIMS, 1D/2D NMR, calculated ECD, and the optical rotatory data. Among the four new compounds, (+/−)-asperbisabol A (1a/1b), asperbisabol B (2), and asperbisabol C (3), the enantiomers 1a and 1b represent an unprecedented skeleton of diphenyl ether-coupled aromatic bisabolane sesquiterpenoids with a spiroketal core moiety. The neuroprotective effects of selected compounds against sodium nitroprusside (SNP)-induced injury were evaluated in PC12 cells by the MTT assay. Five compounds (1a, 6, and 8−10) showed remarkable neuroprotective activities at 10 µM, being more active than the positive control edaravone.

Pathologic tau conformer ensembles induce dynamic, liquid-liquid phase separation events at the nuclear envelope.

BACKGROUND: The microtubule-associated protein tau forms aggregates in different neurodegenerative diseases called tauopathies. Prior work has shown that a single P301L mutation in tau gene, MAPT, can promote alternative tau folding pathways that correlate with divergent clinical diagnoses. Using progressive chemical denaturation, some tau preparations from the brain featured complex transitions starting at low concentrations of guanidine hydrochloride (GdnHCl) denaturant, indicating an ensemble of differently folded tau species called conformers. On the other hand, brain samples with abundant, tangle-like pathology had simple GdnHCl unfolding profile resembling the profile of fibrillized recombinant tau and suggesting a unitary conformer composition. In studies here we sought to understand tau conformer progression and potential relationships with condensed liquid states, as well as associated perturbations in cell biological processes. RESULTS: As starting material, we used brain samples from P301L transgenic mice containing tau conformer ensembles that unfolded at low GdnHCl concentrations and with signatures resembling brain material from P301L subjects presenting with language or memory problems. We seeded reporter cells expressing a soluble form of 4 microtubule-binding repeat tau fused to GFP or YFP reporter moieties, resulting in redistribution of dispersed fluorescence signals into focal assemblies that could fuse together and move within processes between adjacent cells. Nuclear envelope fluorescent tau signals and small fluorescent inclusions behaved as a demixed liquid phase, indicative of liquid-liquid phase separation (LLPS); these droplets exhibited spherical morphology, fusion events and could recover from photobleaching. Moreover, juxtanuclear tau assemblies were associated with disrupted nuclear transport and reduced cell viability in a stable cell line. Staining for thioflavin S (ThS) became more prevalent as tau-derived inclusions attained cross-sectional area greater than 3 µm2, indicating (i) a bipartite composition, (ii) in vivo progression of tau conformers, and (iii) that a mass threshold applying to demixed condensates may drive liquid-solid transitions. CONCLUSIONS: Tau conformer ensembles characterized by denaturation at low GdnHCl concentration templated the production of condensed droplets in living cells. These species exhibit dynamic changes and develop in vivo, and the larger ThS-positive assemblies may represent a waystation to arrive at intracellular fibrillar tau inclusions seen in end-stage genetic tauopathies.

Late Presenting Multi-Suture Craniosynostosis.

ABSTRACT: The authors provide the case of a 6-year-old male who presented late with multi-suture craniosynostosis and chronically elevated intracranial pressures (ICPs). He was surgically managed with frontal orbital advancement. This particular case illustrates the significant bleeding and unique bony pathology that can occur in patients with high ICP with concomitant venous collateralization. At 1-month follow-up, he demonstrated significant improvement with maintained expansion and no signs of elevated ICP despite delayed intervention. Frontal orbital advancement serves as an effective method for cranial vault expansion and correction of frontal deformities caused by craniosynostosis.

Two-Stage Treatment of a Large Premaxillary Defect.

ABSTRACT: Bilateral cleft lip and palate (CLP) patients commonly require surgical management to treat maxillary hypoplasia following the primary repair. Rarer is the CLP patient who also presents with a missing premaxillary segment. Here the authors present the case of a 19-year-old female with a history of bilateral CLP who demonstrated significant maxillary hypoplasia in addition to a large premaxillary defect. To correct this deformity, LeFort I advancement with fibular reconstruction of the maxilla and dental implant placement was performed as a single surgical procedure. The authors discuss the advantages of undergoing this single-staged operation. By utilizing virtual surgical planning (VSP) and incorporating a multidisciplinary team within the operating room, the patient was able to successfully undergo maxillary reconstruction and dental implant placement in a single operation.

Pediatric Fronto-Orbital Skull Reconstruction.

Craniofacial surgery in children is a highly challenging discipline that requires extensive knowledge of craniofacial anatomy and pathology. Insults to the fronto-orbital skeleton have the potential to inflict significant morbidity and even mortality in patients due to its proximity to the central nervous system. In addition, significant aesthetic and ophthalmologic disturbances frequently accompany these insults. Craniosynostosis, facial trauma, and craniofacial tumors are all pathologies that frequently affect the fronto-orbital region of the craniofacial skeleton in children. While the mechanisms of these pathologies vary greatly, the underlying principles of reconstruction remain the same. Despite the limited data in certain areas of fronto-orbital reconstruction in children, significant innovations have greatly improved its safety and efficacy. It is imperative that further investigations of fronto-orbital reconstruction are undertaken so that craniofacial surgeons may provide optimal care for these patients.

Diverse, evolving conformer populations drive distinct phenotypes in frontotemporal lobar degeneration caused by the same MAPT-P301L mutation.

Tau protein accumulation is a common denominator of major dementias, but this process is inhomogeneous, even when triggered by the same germline mutation. We considered stochastic misfolding of human tau conformers followed by templated conversion of native monomers as an underlying mechanism and derived sensitive conformational assays to test this concept. Assessments of brains from aged TgTauP301L transgenic mice revealed a prodromal state and three distinct signatures for misfolded tau. Frontotemporal lobar degeneration (FTLD)-MAPT-P301L patients with different clinical phenotypes also displayed three signatures, two resembling those found in TgTauP301L mice. As physicochemical and cell bioassays confirmed diverse tau strains in the mouse and human brain series, we conclude that evolution of diverse tau conformers is intrinsic to the pathogenesis of this uni-allelic form of tauopathy. In turn, effective therapeutic interventions in FTLD will need to address evolving repertoires of misfolded tau species rather than singular, static molecular targets.

Antimicrobial and Antioxidant Polyketides from a Deep-Sea-Derived Fungus Aspergillus versicolor SH0105.

Fifteen polyketides, including four new compounds, isoversiol F (1), decumbenone D (2), palitantin B (7), and 1,3-di-O-methyl-norsolorinic acid (8), along with 11 known compounds (3-6 and 9-15), were isolated from the deep-sea-derived fungus Aspergillus versicolor SH0105. Their structures and absolute configurations were determined by comprehensive spectroscopic data, including 1D and 2D NMR, HRESIMS, and ECD calculations, and it is the first time to determine the absolute configuration of known decumbenone A (6). All of these compounds were evaluated for their antimicrobial activities against four human pathogenic microbes and five fouling bacterial strains. The results indicated that 3,7-dihydroxy-1,9-dimethyldibenzofuran (14) displayed obvious inhibitory activity against Staphylococcus aureus (ATCC 27154) with the MIC value of 13.7 µM. In addition, the antioxidant assays of the isolated compounds revealed that aspermutarubrol/violaceol-I (15) exhibited significant 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity with the IC50 value of 34.1 µM, and displayed strong reduction of Fe3+ with the ferric reducing antioxidant power (FRAP) value of 9.0 mM under the concentration of 3.1 µg/mL, which were more potent than ascorbic acid.

Solvent-dependent ultrafast optical response of conjugated push-pull chromophores.

Two new difluoroboron ß-carbonyl cyclic ketonate complexes C2B and DC2B were investigated using several spectroscopic methods. Relative to the absorption spectra, the fluorescence spectra were more affected by the polarity of the solvent. Also, compound C2B showed a more pronounced Stokes' shift after solvent polarity increased. Transient absorption measurements then demonstrated the relaxation behaviour of the excited state compound molecule. The kinetic results showed that the excited state C2B in tetrahydrofuran (THF) can return from the intramolecular charge-transfer (ICT) state and the initial excited state to the ground state. The kinetic relaxation pathway after THF was replaced by dimethyl sulfoxide became single. When the carbazole unit was introduced, DC2B also exhibited an ICT state but there was no significant difference in the excited state relaxation path after solvent polarity was changed. The results indicated that C2B is more susceptible to solvent polarity regulation. The global fit results revealed that an increase in the solvent polarity prolonged the lifetime of the ICT state of compound C2B and had the opposite effect on compound DC2B. These results provide guidance for understanding the relationship between solvent polarity and the designing and synthesizing advanced compound materials.

Periodic and Spatial Spreading of Alkanes and Alcanivorax Bacteria in Deep Waters of the Mariana Trench.

In subduction zones, serpentinization and biological processes may release alkanes to the deep waters, which would probably result in the rapid spread of Alcanivorax However, the timing and area of the alkane distribution and associated enrichment of alkane-degrading microbes in the dark world of the deep ocean have not been explored. In this study, we report the richness (up to 17.8%) of alkane-degrading bacteria, represented by Alcanivorax jadensis, in deep water samples obtained at 3,000 to 6,000 m in the Mariana Trench in two cruises. The relative abundance of A. jadensis correlated with copy numbers of functional almA and alkB genes, which are involved in alkane degradation. In these water samples, we detected a high flux of alkanes, which probably resulted in the prevalence of A. jadensis in the deep waters. Contigs of A. jadensis were binned from the metagenomes for examination of alkane degradation pathways and deep sea-specific pathways, which revealed a lack of nitrate and nitrite dissimilatory reduction in our A. jadensis strains. Comparing the results for the two cruises conducted close to each other, we suggest periodic release of alkanes that may spread widely but periodically in the trench. Distribution of alkane-degrading bacteria in the world's oceans suggests the periodic and remarkable contributions of Alcanivorax to the deep sea organic carbon and nitrogen sources.IMPORTANCE In the oligotrophic environment of the Mariana Trench, alkanes as carbohydrates are important for the ecosystem, but their spatial and periodic spreading in deep waters has never been reported. Alkane-degrading bacteria such as Alcanivorax spp. are biological signals of the alkane distribution. In the present study, Alcanivorax was abundant in some waters, at depths of up to 6,000 m, in the Mariana Trench. Genomic, transcriptomic, and chemical analyses provide evidence for the presence and activities of Alcanivorax jadensis in deep sea zones. The periodic spreading of alkanes, probably from the subductive plates, might have fundamentally modified the local microbial communities, as well as perhaps the deep sea microenvironment.

(+)-Isobicyclogermacrenal and spathulenol from Aristolochia yunnanensis alleviate cardiac fibrosis by inhibiting transforming growth factor ß/small mother against decapentaplegic signaling pathway.

Cardiac fibrosis contributes to both systolic and diastolic dysfunction in many cardiac pathophysiologic conditions. Antifibrotic therapies are likely to be a crucial strategy in curbing many fibrosis-related cardiac diseases. In our previous study, an ethyl acetate extract of a traditional Chinese medicine Aristolochia yunnanensis Franch. was found to have a therapeutic effect on myocardial fibrosis in vitro and in vivo. However, the exact chemicals and their mechanisms responsible for the activity of the crude extract have not been illustrated yet. In the current study, 10 sesquiterpenoids (1-10) were isolated from the active extract, and their antifibrotic effects were systematically evaluated in transforming growth factor ß 1 (TGFß1)-stimulated cardiac fibroblasts and NIH3T3 fibrosis models. (+)-Isobicyclogermacrenal (1) and spathulenol (2) were identified as the main active components, being more potent than the well-known natural antifibrotic agent oxymatrine. Compounds 1 and 2 could inhibit the TGFß1-induced cardiac fibroblasts proliferation and suppress the expression of the fibrosis biomarkers fibronectin and α-smooth muscle actin via down-regulation of their mRNA levels. The mechanism study revealed that 1 and 2 could inhibit the phosphorylation of TGFß type I receptor, leading to the decrease of the phosphorylation levels of downstream Smad2/3, then consequently blocking the nuclear translocation of Smad2/3 in the TGFß/Smad signaling pathway. These findings suggest that 1 and 2 may serve as promising natural leads for the development of anticardiac fibrosis drugs.

Hyperhidrotic Macrodactylism Caused by Osteoid Osteoma: A Case Report and Review of the Literature.

Macrodactylism or macrodactyly is referred to as congenital deformity of fingers or toes, and the corresponding incidence rate is relatively low. In this article, we describe a young male with macrodactylism of the second toe of his right foot. He was suffering from persistent pain, overgrowth, and hyperhidrosis ofthe involved toe. Radiographic examination of the right foot showed a small translucent area surrounded by hyperplasia and sclerotic bone in the second distal phalanx, in addition to increased soft tissue density and volume. Surgical resection of the bone lesion and reduction of the soft tissue bulk were performed. Pathological findings showed osteoblast hyperplasia, which was diagnosed as osteoid osteoma, and noabnormal findings were seen in the skin. Symptoms of pain and hyperhidrosis disappeared postsurgery and did not recur over the subsequent 2-year follow-up. As far as we know, this was a rare case of osteoid osteoma occurring in the toe that resulted in macrodactylism, which was also associated with localized hyperhidrosis.

Anti-inflammatory Ingenane Diterpenoids from the Roots of Euphorbia kansui.

Bioassay-guided fractionation of the ethanolic extract of the roots of Euphorbia kansui led to the isolation of two new ingenane diterpenoids, euphorkans A (1: ) and B (2: ), together with 16 known analogues (3:  - 18: ). Their structures were determined by combined spectral and chemical methods. All the isolates were evaluated for their inhibitory effects on lipopolysaccharide-induced nitric oxide production in RAW264.7 macrophage cells. Compounds 1:  - 6: and 10:  - 13: exhibited pronounced inhibitory activity with IC50 values in the range of 2.78 - 10.6 µM, and were more potent than the positive control, quercetin (IC50 = 15.8 µM). Compounds 1: and 5: were selected for further assays toward the key inflammation mediators TNF-α and IL-6, and showed a significant inhibition in a dose-dependent manner. The preliminary mechanistic study revealed that 1: and 5: inhibited NF-κB activity, which may exert a role in their anti-inflammatory activity.

Molecular Characterization of a Novel N-Acetylneuraminate Lyase from a Deep-Sea Symbiotic Mycoplasma.

N-acetylneuraminic acid (Neu5Ac) based novel pharmaceutical agents and diagnostic reagents are highly required in medical fields. However, N-acetylneuraminate lyase（NAL）for Neu5Ac synthesis is not applicable for industry due to its low catalytic efficiency. In this study, we biochemically characterized a deep-sea NAL enzyme (abbreviated form: MyNal) from a symbiotic Mycoplasma inhabiting the stomach of a deep-sea isopod, Bathynomus jamesi. Enzyme kinetic studies of MyNal showed that it exhibited a very low Km for both cleavage and synthesis activities compared to previously described NALs. Though it favors the cleavage process, MyNal out-competes the known NALs with respect to the efficiency of Neu5Ac synthesis and exhibits the highest kcat/Km values. High expression levels of recombinant MyNal could be achieved (9.56 mol L-1 culture) with a stable activity in a wide pH (5.0-9.0) and temperature (40-60 °C) range. All these features indicated that the deep-sea NAL has potential in the industrial production of Neu5Ac. Furthermore, we found that the amino acid 189 of MyNal (equivalent to Phe190 in Escherichia coli NAL), located in the sugar-binding domain, GX189DE, was also involved in conferring its enzymatic features. Therefore, the results of this study improved our understanding of the NALs from different environments and provided a model for protein engineering of NAL for biosynthesis of Neu5Ac.

A new selaginellin derivative and a new triarylbenzophenone analog from the whole plant of Selaginella pulvinata.

Five selaginellin derivatives (1 and 3-6) including a new one, selaginellin T (1), and a new triarylbenzophenone analog, selagibenzophenone A (2), were isolated from the whole plants of Selaginella pulvinata. Their structures were determined by 1D- and 2D-NMR and HR-ESI-MS data. Selagibenzophenone A (2) is the first example of naturally occurring triarylbenzophenone. The results of the phosphodiesterase-4 (PDE4) inhibitory screening assays showed that compounds 1-6 exhibited potent activities with the IC50 values in the range of 1.04-9.35 µM.

Thielavins W-Z7, New Antifouling Thielavins from the Marine-Derived Fungus Thielavia sp. UST030930-004.

Eleven new depsides-thielavins W-Z (1-4) and thielavins Z1-Z7 (5-11)-and also four known thielavins-A, H, J, and K (12-15)-were isolated from the ethyl acetate extract of a marine-derived fungal strain Thielavia sp UST030930-004. All of these compounds were evaluated for antifouling activity against cyprids of the barnacle Balanus (=Amphibalanus) amphitrite. The results showed that compounds 1-3 and 6-13 were active, with EC50 values ranging from 2.95 ± 0.59 to 69.19 ± 9.51 µM, respectively. The inhibitive effect of compounds 1-3 and 7 was reversible. This is the first description of the antifouling activity of thielavins against barnacle cyprids.