A prebiotically plausible scenario of an RNA-peptide world.

The RNA world concept1 is one of the most fundamental pillars of the origin of life theory2-4. It predicts that life evolved from increasingly complex self-replicating RNA molecules1,2,4. The question of how this RNA world then advanced to the next stage, in which proteins became the catalysts of life and RNA reduced its function predominantly to information storage, is one of the most mysterious chicken-and-egg conundrums in evolution3-5. Here we show that non-canonical RNA bases, which are found today in transfer and ribosomal RNAs6,7, and which are considered to be relics of the RNA world8-12, are able to establish peptide synthesis directly on RNA. The discovered chemistry creates complex peptide-decorated RNA chimeric molecules, which suggests the early existence of an RNA-peptide world13 from which ribosomal peptide synthesis14 may have emerged15,16. The ability to grow peptides on RNA with the help of non-canonical vestige nucleosides offers the possibility of an early co-evolution of covalently connected RNAs and peptides13,17,18, which then could have dissociated at a higher level of sophistication to create the dualistic nucleic acid-protein world that is the hallmark of all life on Earth.

Competing magnetic orders in a bilayer Hubbard model with ultracold atoms.

Fermionic atoms in optical lattices have served as a useful model system in which to study and emulate the physics of strongly correlated matter. Driven by the advances of high-resolution microscopy, the current research focus is on two-dimensional systems1-3, in which several quantum phases-such as antiferromagnetic Mott insulators for repulsive interactions4-7 and charge-density waves for attractive interactions8-have been observed. However, the lattice structure of real materials, such as bilayer graphene, is composed of coupled layers and is therefore not strictly two-dimensional, which must be taken into account in simulations. Here we realize a bilayer Fermi-Hubbard model using ultracold atoms in an optical lattice, and demonstrate that the interlayer coupling controls a crossover between a planar antiferromagnetically ordered Mott insulator and a band insulator of spin-singlets along the bonds between the layers. We probe the competition of the magnetic ordering by measuring spin-spin correlations both within and between the two-dimensional layers. Our work will enable the exploration of further properties of coupled-layer Hubbard models, such as theoretically predicted superconducting pairing mechanisms9,10.

Cardiopulmonary Resuscitation Without Aortic Valve Compression Increases the Chances of Return of Spontaneous Circulation in Out-of-Hospital Cardiac Arrest: A Prospective Observational Cohort Study.

OBJECTIVES: Following current cardiopulmonary resuscitation (CPR) guidelines, which recommend chest compressions at "the center of the chest," ~50% of patients experiencing out-of-hospital cardiac arrest (OHCA) undergo aortic valve (AV) compression, obstructing blood flow. We used resuscitative transesophageal echocardiography (TEE) to elucidate the impact of uncompressed vs. compressed AV on outcomes of adult patients experiencing OHCA. DESIGN: Prospective observational cohort study. SETTING: Single center. PATIENTS: This study included adult OHCA patients undergoing resuscitative TEE in the emergency department. Patients were categorized into AV uncompressed or AV compressed groups based on TEE findings. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was sustained return of spontaneous circulation (ROSC). The secondary outcomes included end-tidal co2 (Etco2) during CPR, any ROSC, survival to ICU and hospital discharge, post-resuscitation withdrawal, and favorable neurologic outcomes at discharge. Additional analyses on intra-arrest arterial blood pressure (ABP) were also conducted. The sample size was pre-estimated at 37 patients/group. From October 2020 to January 2023, 76 patients were enrolled, 39 and 37 in the AV uncompressed and AV compressed groups, respectively. Intergroup baseline characteristics were similar. Compared with the AV compressed group, the AV uncompressed group had a higher probability of sustained ROSC (53.8% vs. 24.3%; adjusted odds ratio [aOR], 4.72; p = 0.010), any ROSC (56.4% vs. 32.4%; aOR, 3.30; p = 0.033), and survival to ICU (33.3% vs. 8.1%; aOR, 6.74; p = 0.010), and recorded higher initial diastolic ABP (33.4 vs. 11.5 mm Hg; p = 0.002) and a larger proportion achieving diastolic ABP greater than 20 mm Hg during CPR (93.8% vs. 33.3%; p < 0.001). The Etco2, post-resuscitation withdrawal, and survival to discharge revealed no significant intergroup differences. No patients were discharged with favorable neurologic outcomes. Uncompressed AV seemed critical for sustained ROSC across all subgroups. CONCLUSIONS: Absence of AV compression during OHCA resuscitation is associated with an increased chance of ROSC and survival to ICU. However, its effect on long-term outcomes remains unclear.

IL-21, not IL-17A, exacerbates murine primary biliary cholangitis.

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease caused by intrahepatic bile duct injuries, resulting in fibrosis, cirrhosis, and eventually liver failure. T helper (Th) 17 cells are proposed to involve in the pathogenesis of PBC. However, how and which Th17 cell-derived cytokines affect PBC remains unclear. In this study, we investigated the effects of Th17 effector cytokines, including interleukin (IL)-17A, IL-17F, and IL-21 in PBC using a xenobiotic-induced mouse model of autoimmune cholangitis (inducible chemical xenobiotic models of PBC) treated with cytokine-expressing adeno-associated virus. Our results showed that administration of IL-17A, the well-known main cytokine produced by Th17 cells, did not augment liver inflammation or fibrosis. In contrast, we noted IL-17A-treated mice had lower hepatic Th1 cell numbers and higher hepatic CD11b+Ly6G+ polymorphonuclear myeloid-derived suppressor cell numbers. IL-17F did not alter liver inflammation or fibrosis. However, the administration of IL-21 exacerbated liver inflammatory responses and portal cell infiltration. IL-21 markedly increased the numbers of activated CD8+ T cells and liver tissue-resident memory CD8+ T cells. Moreover, IL-21 aggravates liver fibrosis in mice with autoimmune cholangitis. These results emphasized that not IL-17A but IL-21 in Th17 cell-derived cytokines affected the pathogenesis of PBC. IL-21 enhanced liver inflammation and progression to fibrosis by enhancing the numbers and effector activities of CD8+ T cells. Delineation of the effects of different Th17 effector cytokines in PBC offers clues for developing new therapeutic approaches.

Extending the coverage of user-diversified IM-DD PON by FDM: a mathematical model with experimental verification.

Future passive optical networks (PONs) call for more flexibility to support diversified users with various rate demands and link qualities. Using traditional time-division multiplexing (TDM), the concept of a flexible rate PON was proposed to accommodate more users with link diversity by rate adaptation. In this Letter, we reveal the PON coverage can be further extended through frequency-division multiplexing (FDM) in the presence of multiuser diversity, namely, (i) there exist users with frequency-dependent link conditions and (ii) the link conditions exhibit disparity among users. We build a mathematical model and propose an optimization algorithm based on the binary tree search to optimize diversity gain. We experimentally verify its feasibility by studying the diversity gain concerning chromatic dispersion, optical path loss, and signal-to-noise ratio (SNR) variation in a 200G-class intensity-modulation direct-detection (IM-DD) system.

Experimental Ecosystem Eutrophication Causes Offsetting Effects on Emissions of CO2, CH4, and N2O from Agricultural Reservoirs.

Despite decades of research and management efforts, eutrophication remains a persistent threat to inland waters. As nutrient pollution intensifies in the coming decades, the implications for aquatic greenhouse gas (GHG) emissions are poorly defined, particularly the responses of individual GHGs: carbon dioxide (CO2), methane (CH4), and nitrous oxide (N2O). The biogeochemical controls of each gas can differ, making it difficult to predict the overall effect of nutrient pollution on the net radiative forcing of aquatic ecosystems. Here, we induced eutrophication of small nitrogen (N)-limited agricultural reservoirs and measured changes in diffusive GHG emissions within a before-after-control-impact (BACI) study design during June to September 2021. Each gas exhibited a unique response to 300% increases in primary production, with a shift from an overall CO2 source to a sink, a modest increase in N2O flux, and, unexpectedly, no significant change in CH4 emissions. The lack of net directional change in CO2-equivalent GHG emissions in fertilized reservoirs during the summer contrasts findings from empirical studies of eutrophic lakes. Our findings illustrate the difficulty in extrapolating among different sized ecosystems and suggest that forecast 2-fold increases in agricultural N fertilization by 2050 may not result in consistently elevated GHG emissions during summer, at least from small reservoirs in continental grassland regions.

Nanometer-resolution in situ structure of the SARS-CoV-2 postfusion spike protein.

The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mediates membrane fusion to allow entry of the viral genome into host cells. To understand its detailed entry mechanism and develop a specific entry inhibitor, in situ structural information on the SARS-CoV-2 spike protein in different states is urgent. Here, by using cryo-electron tomography, we observed both prefusion and postfusion spikes in ß-propiolactone-inactivated SARS-CoV-2 virions and solved the in situ structure of the postfusion spike at nanometer resolution. Compared to previous reports, the six-helix bundle fusion core, the glycosylation sites, and the location of the transmembrane domain were clearly resolved. We observed oligomerization patterns of the spikes on the viral membrane, likely suggesting a mechanism of fusion pore formation.

Cryo-EM structures of Escherichia coli cytochrome bo3 reveal bound phospholipids and ubiquinone-8 in a dynamic substrate binding site.

Two independent structures of the proton-pumping, respiratory cytochrome bo3 ubiquinol oxidase (cyt bo3 ) have been determined by cryogenic electron microscopy (cryo-EM) in styrene-maleic acid (SMA) copolymer nanodiscs and in membrane scaffold protein (MSP) nanodiscs to 2.55- and 2.19-Å resolution, respectively. The structures include the metal redox centers (heme b, heme o3 , and CuB), the redox-active cross-linked histidine-tyrosine cofactor, and the internal water molecules in the proton-conducting D channel. Each structure also contains one equivalent of ubiquinone-8 (UQ8) in the substrate binding site as well as several phospholipid molecules. The isoprene side chain of UQ8 is clamped within a hydrophobic groove in subunit I by transmembrane helix TM0, which is only present in quinol oxidases and not in the closely related cytochrome c oxidases. Both structures show carbonyl O1 of the UQ8 headgroup hydrogen bonded to D75I and R71I In both structures, residue H98I occupies two conformations. In conformation 1, H98I forms a hydrogen bond with carbonyl O4 of the UQ8 headgroup, but in conformation 2, the imidazole side chain of H98I has flipped to form a hydrogen bond with E14I at the N-terminal end of TM0. We propose that H98I dynamics facilitate proton transfer from ubiquinol to the periplasmic aqueous phase during oxidation of the substrate. Computational studies show that TM0 creates a channel, allowing access of water to the ubiquinol headgroup and to H98I.

Navigating changes: A qualitative study exploring the health-related quality of life of breast cancer survivors during the coronavirus disease 2019 pandemic.

AIMS: To explore the impact of the coronavirus disease 2019 pandemic on the health-related quality of life (HRQoL) of breast cancer survivors. DESIGN: We utilized a qualitative descriptive approach to facilitate interviews among 25 participants, all of whom are survivors of breast cancer and have received treatment in Hong Kong within the preceding 3 years. METHODS: Content analysis was performed to understand how patients' HRQoL views and experiences changed during coronavirus disease 2019 pandemic. RESULTS: The results included six themes delineating the impact of the coronavirus disease 2019 pandemic: (i) survivor sensitivities in pandemic times, (ii) coping and conditioning in pandemic times, (iii) transforming work and home dynamics in pandemic times, (iv) cognitive resilience and adaptation to the COVID-19 protective measures, (v) social resilience in pandemic times and (vi) healthcare adaptation and coping in pandemic times. CONCLUSION: This study provides insights into the experiences and challenges of breast cancer survivors during the coronavirus disease 2019 pandemic. Some survivors had new physical and psychological symptoms, including fear and anxiety, isolation, pain, lymphoedema and burnout, which potentially have long-term impact upon HRQoL. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: This study highlights the unique challenges faced by breast cancer survivors during the coronavirus disease 2019 pandemic, including accessing healthcare services and the impact of social isolation. Healthcare providers should consider the holistic needs of breast cancer survivors in the provision of health care and develop supportive interventions, including telehealth services and online support groups, to address these challenges and improve their HRQoL. IMPACT: Surgery aimed at treating breast cancer or reducing its risk generally influences the appearance of breast areas and donor sites. The continuing effects of these changes on body image and HRQoL are well-reported, although studies have ineffectively examined the initial experiences of women regarding their postoperative appearance, particularly during the pandemic. REPORTING METHOD: The checklist of consolidated criteria for reporting qualitative research (COREQ) was utilized. PATIENT OR PUBLIC CONTRIBUTION: A small selection on breast cancer survivors contributed to the design of this study, in particular the content of the semi-structured interviews.

JAK inhibitors and the risk of malignancy: a meta-analysis across disease indications.

OBJECTIVES: To estimate the association of Janus kinase inhibitors (JAKi) with the incidence of malignancy, compared with placebo, tumour necrosis factor (TNF)-α inhibitors (TNFi) and methotrexate. METHODS: Systematic searches of databases were performed, to December 2022, to identify phase II/III/IV randomised clinical trials (RCTs) and long-term extension (LTE) studies of JAKi (tofacitinib, baricitinib, upadacitinib, filgotinib, peficitinib) compared with placebo, TNFi or methotrexate, in adults with rheumatoid arthritis, psoriatic arthritis, psoriasis, axial spondyloarthritis, inflammatory bowel disease or atopic dermatitis. Network and pairwise meta-analyses were performed to estimate incidence rate ratios (IRRs) for malignancy between JAKi and comparators. Bias was assessed using the Cochrane Risk of Bias-2 tool. RESULTS: In 62 eligible RCTs and 16 LTE studies, there were 82 366 person-years of exposure to JAKi, 2924 to placebo, 7909 to TNFi and 1074 to methotrexate. The overall malignancy incidence rate was 1.15 per 100 person-years in RCTs, and 1.26 per 100 person-years across combined RCT and LTE data. In network meta-analyses, the incidence of all malignancies including non-melanomatous skin cancers (NMSCs) was not significantly different between JAKi and placebo (IRR 0.71; 95% CI 0.44 to 1.15) or between JAKi and methotrexate (IRR 0.77; 95% CI 0.35 to 1.68). Compared with TNFi, however, JAKi were associated with an increased incidence of malignancy (IRR 1.50; 95% CI 1.16 to 1.94). Findings were consistent when analysing NMSC only and when analysing combined RCT/LTE data. CONCLUSIONS: JAKi were associated with a higher incidence of malignancy compared with TNFi but not placebo or methotrexate. Cancers were rare events in all comparisons. PROSPERO REGISTRATION NUMBER: CRD42022362630.

Transition Metal-Catalyzed Regioselective Direct C-H Amidation: Interplay between Inner- and Outer-Sphere Pathways for Nitrene Cross-Coupling Reactions.

Catalytic C-N bond cross-coupling reactions have been a subject of fundamental importance in synthetic organic and medicinal chemistry because amides and amines are ubiquitous motifs in natural products, functional materials, and pharmaceuticals. Since the pioneering works of Breslow and Mansuy on the metalloporphyrin-catalyzed direct hydrocarbon amidation using sulfonyliminoiodinane reagents, substantial development has been achieved toward practical and selective amination protocols. Notably, Du Bois's group developed the dirhodium(II,II) carboxylate catalytic system for direct C(sp3)-H amidations via Rh-sulfonyl nitrene intermediates. Yet, this protocol suffers from competitive alkene aziridination and is limited to electron-rich tertiary and ethereal C-H bonds; analogous direct amidation of arenes remained ineffective.This Account discusses our early effort to explore cyclopalladated complexes for ortho-selective C(aryl)-H amidations. While Buchwald-Hartwig amination cannot be directly applied to arenes, effective amidation of the 2-arylpyridines occurred when an external oxidant such as K2S2O8 was employed. Preliminary studies suggested that the amidation may proceed through reactive Pd-nitrene intermediates. Aiming to develop more diversified amidation protocols, we employed nosyloxycarbamates as nitrene precursors for the Pd-catalyzed ortho-amidation of N-pivalanilides. Likewise, we developed the ortho-selective amidation of benzoic acids to produce anthranilic acids, which are versatile precursors for many medicinally valuable heterocycles. In an attempt to expand the C(aryl)-N coupling reactions to amines, we studied the d6 piano-stool Cp*Rh(III) systems [Cp* = pentamethylcyclopentadienyl]. Our work established a sound reaction platform based on the electrophilic aminating reagents including N-chloroamines, hydroxyamides, and N-carboxyhydrazides for effective C(aryl)-N bond formation in aryl-metal complexes.Building upon the metal-nitrene reaction platform, we moved forward to examine γ-lactam synthesis by intramolecular carbonyl nitrene C(sp3)-H insertion. Noted that carbonyl nitrenes are prone to undergo Curtius-type rearrangement to form isocyanate; we found that the π-basic Ru(II) center effectively decomposes dioxazolones to afford the carbonyl nitrene for regioselective γ-C(sp3)-H insertion. With chiral diphenylethylenediamines (dpen) as ligands bearing electron-withdrawing arylsulfonyl substituents, the [(p-cymene)Ru(dpen)] complex catalyzed the decomposition of the dioxazolones to afford chiral γ-lactams by formal carbonyl nitrene C(sp3)-H insertion. Enantioselective nitrene insertion to allylic and propargylic C(sp3)-H bonds was also achieved with remarkable tolerance to the C═C and C≡C bonds. Notably, the selectivity of the [(p-cymene)Ru] system switched to C(aryl)-H bonds to give dihydroquinolinones when l-proline was employed as ligand. Recently, we aimed to address the regiocontrolled amidation of unactivated methylene C-H bonds using NiH catalyst. While tertiary and benzyl C-H bonds can be differentiated by their bond dissociation energies and steric properties, methylene groups making up the hydrocarbon skeleton display similar electronic and steric properties. In this context, we exploited the five-membered nickelacycle formation to terminate the NiH-mediated chain-walk isomerization, and the nickelacycle reacted with dioxazolones to furnish the C(sp3)-N bond at the γ-methylene position.This Account summarizes our contribution to the development of C-N bond cross-coupling reactions via C-H activation. By exploiting the inner-sphere and outer-sphere reaction pathways, we successfully developed regioselective protocols that target C(sp3)-H and C(aryl)-H bonds. The mechanistic underpinning of the selectivity of different C-H bonds and related studies on the affiliated catalytic systems will be discussed.

Peak-tracking BOTDA with dynamic ternary search.

We propose a peak-tracking BOTDA (PT-BOTDA) equipped with an efficient dynamic Brillouin frequency shift (BFS) searching scheme based on ternary search. The proposed scheme establishes a feedback loop between the selected frequency and the corresponding Brillouin gain to reduce the required number of scanning frequencies in one measurement. We also demonstrate the performance evaluation of the proposed scheme under scenarios with different searching granularities and dynamic sensing ranges. Experimental results indicate that in all situations, the proposed PT-BOTDA can achieve at least 85% and 97% reduction in the number of scanning frequencies for 1-MHz and 0.1-MHz frequency steps, respectively, with a 3-meter spatial resolution, while maintaining a convincing BFS searching accuracy under sufficient SNR condition using a smaller searching interval.

Nonlinear distortion mitigation of DML-based OFDM optical systems with non-orthogonal DFT-precoding.

We propose a non-orthogonal discrete Fourier transform (DFT) matrix precoding scheme for the mitigation of nonlinear distortion induced by the interaction between laser chirp and fiber dispersion in a directly modulated laser (DML)-based orthogonal frequency division multiplexing (OFDM) transmission system. Compared with conventional OFDM, the proposed method can decrease the peak-to-average power ratio (PAPR) and significantly reduce the nonlinear distortion without sacrificing spectral efficiency (SE). The cascaded binary-phase-shift-keying iterative detection (CBID) algorithm is used to eliminate the inter-carrier interference (ICI) that is purposely induced by the non-orthogonal precoding. The performance of the proposed scheme is experimentally evaluated, achieving ∼0.4-dB sensitivity improvement at the KP4-forward error correction (FEC) threshold over the T/2-spaced third-order Volterra nonlinear equalizer (VNLE). Meanwhile, compared to the VNLE, the reduction in computational complexity of one OFDM frame is 90% for multiplication and 88.32% for addition in this work.

AGA induces sub-G1 cell cycle arrest and apoptosis in human colon cancer cells through p53-independent/p53-dependent pathway.

BACKGROUND: Despite the advancement in chemotherapeutic drugs for colon cancer treatment, it is still a life-threatening disease worldwide due to drug resistance. Therefore, an urgently needed to develop novel drugs for colon cancer therapies. AGA is a combination of traditional Chinese medicine Antler's extract (A), Ganoderma lucidum (G), and Antrodia camphorata (A); it contains a lot of biomolecules like polysaccharides, fatty acids, and triterpenoids that are known to exerting anti-oxidative, anti-inflammatory, anti-microbial and anti-tumor activities in oral cancer. In this study, we investigate AGA anti-proliferative, anti-metastatic and apoptotic activity to explore its anti-cancer activity against colon cancer cells and its underlying mechanism. METHOD: Here, in-vitro studies were performed to determine the antiproliferative activity of AGA through MTT and colony formation assays. Wound healing and transwell migration assay were used to evaluate the metastasis. Flow cytometry and protein expression were used to investigate the involved molecular mechanism by evaluating the cell cycle and apoptosis. The in-vivo anti-cancerous activity of AGA was assessed by xenograft mice model of colon cancer cells. RESULTS: We found that AGA significantly inhibited the proliferative capacity and metastasis of colon cancer cells in-vitro. In addition, AGA induced cell cycle arrest in the sub-G1 phase through upregulating p21 and downregulating CDK2, CDK6 in SW620, and CDK4 in SW480 and HT29, respectively. Annexin-v assay indicated that colon cancer cells had entered early and late apoptosis after treatment with AGA. Furthermore, a mechanistic protein expressions study revealed that AGA in p53-dependent and independent regulated the apoptosis of colon cancer by downregulating the p53 protein expression in SW620 and SW480 cells but upregulating in a dose-dependent manner in HT29 cells and increasing the expression of Bax and caspase-9 to inhibit the colon cancer cells. In vivo study, we found that AGA significantly reduced the xenograft tumor growth in NOD/SCID mice with no adverse effect on the kidney and liver. CONCLUSION: Collectively, AGA has the potential to inhibit colon cancer through inhibiting proliferation, migration, and cell cycle kinase by upregulating p21 protein expression and promoting the apoptotic protein in a p53-dependent and independent manner.

Platelet-derived biomaterial with hyaluronic acid alleviates temporal-mandibular joint osteoarthritis: clinical trial from dish to human.

BACKGROUND: Bioactive materials have now raised considerable attention for the treatment of osteoarthritis (OA), such as knee OA, rheumatoid OA, and temporomandibular joint (TMJ) OA. TMJ-OA is a common disease associated with an imbalance of cartilage regeneration, tissue inflammation, and disability in mouth movement. Recently, biological materials or molecules have been developed for TMJ-OA therapy; however, ideal treatment is still lacking. In this study, we used the combination of a human platelet rich plasma with hyaluronic acid (hPRP/HA) for TMJ-OA therapy to perform a clinical trial in dish to humans. METHOD: Herein, hPRP was prepared, and the hPRP/HA combined concentration was optimized by MTT assay. For the clinical trial in dish, pro-inflammatory-induced in-vitro and in-vivo mimic 3D TMJ-OA models were created, and proliferation, gene expression, alcian blue staining, and IHC were used to evaluate chondrocyte regeneration. For the animal studies, complete Freund's adjuvant (CFA) was used to induce the TMJ-OA rat model, and condyle and disc regeneration were investigated through MRI. For the clinical trial in humans, 12 patients with TMJ-OA who had disc displacement and pain were enrolled. The disc displacement and pain at baseline and six months were measured by MRI, and clinical assessment, respectively. RESULTS: Combined hPRP/HA treatment ameliorated the proinflammatory-induced TMJ-OA model and promoted chondrocyte proliferation by activating SOX9, collagen type I/II, and aggrecan. TMJ-OA pathology-related inflammatory factors were efficiently downregulated with hPRP/HA treatment. Moreover, condylar cartilage was regenerated by hPRP/HA treatment in a proinflammatory-induced 3D neocartilage TMJ-OA-like model. During the animal studies, hPRP/HA treatment strongly repaired the condyle and disc in a CFA-induced TMJ-OA rat model. Furthermore, we performed a clinical trial in humans, and the MRI data demonstrated that after 6 months of treatment, hPRP/HA regenerated the condylar cartilage, reduced disc displacement, alleviated pain, and increased the maximum mouth opening (MMO). Overall, clinical trials in dish to human results revealed that hPRP/HA promoted cartilage regeneration, inhibited inflammation, reduced pain, and increased joint function in TMJ-OA. CONCLUSION: Conclusively, this study highlighted the therapeutic potential of the hPRP and HA combination for TMJ-OA therapy, with detailed evidence from bench to bedside. Trial registration Taipei Medical University Hospital (TMU-JIRB No. N201711041). Registered 24 November 2017. https://tmujcrc.tmu.edu.tw/inquiry_general.php .

Lineage tracing and single-cell analysis reveal proliferative Prom1+ tumour-propagating cells and their dynamic cellular transition during liver cancer progression.

OBJECTIVE: Hepatocellular carcinoma (HCC) has high intratumoral heterogeneity, which contributes to therapeutic resistance and tumour recurrence. We previously identified Prominin-1 (PROM1)/CD133 as an important liver cancer stem cell (CSC) marker in human HCC. The aim of this study was to investigate the heterogeneity and properties of Prom1+ cells in HCC in intact mouse models. DESIGN: We established two mouse models representing chronic fibrotic HCC and rapid steatosis-related HCC. We performed lineage tracing post-HCC induction using Prom1C-L/+; Rosa26tdTomato/+ mice, and targeted depletion using Prom1C-L/+; Rosa26DTA/+ mice. Single-cell RNA sequencing (scRNA-seq) was carried out to analyse the transcriptomic profile of traced Prom1+ cells. RESULTS: Prom1 in HCC tumours marks proliferative tumour-propagating cells with CSC-like properties. Lineage tracing demonstrated that these cells display clonal expansion in situ in primary tumours. Labelled Prom1+ cells exhibit increasing tumourigenicity in 3D culture and allotransplantation, as well as potential to form cancers of differential lineages on transplantation. Depletion of Prom1+ cells impedes tumour growth and reduces malignant cancer hallmarks in both HCC models. scRNA-seq analysis highlighted the heterogeneity of Prom1+ HCC cells, which follow a trajectory to the dedifferentiated status with high proliferation and stem cells traits. Conserved gene signature of Prom1 linage predicts poor prognosis in human HCC. The activated oxidant detoxification underlies the protective mechanism of dedifferentiated transition and lineage propagation. CONCLUSION: Our study combines in vivo lineage tracing and scRNA-seq to reveal the heterogeneity and dynamics of Prom1+ HCC cells, providing insights into the mechanistic role of malignant CSC-like cells in HCC progression.

Anionic Lipids Confine Cytochrome c2 to the Surface of Bioenergetic Membranes without Compromising Its Interaction with Redox Partners.

Cytochrome c2 (cyt. c2) is a major element in electron transfer between redox proteins in bioenergetic membranes. While the interaction between cyt. c2 and anionic lipids abundant in bioenergetic membranes has been reported, their effect on the shuttling activity of cyt. c2 remains elusive. Here, the effect of anionic lipids on the interaction and binding of cyt. c2 to the cytochrome bc1 complex (bc1) is investigated using a combination of molecular dynamics (MD) and Brownian dynamics (BD) simulations. MD is used to generate thermally accessible conformations of cyt. c2 and membrane-embedded bc1, which were subsequently used in multireplica BD simulations of diffusion of cyt. c2 from solution to bc1, in the presence of various lipids. We show that, counterintuitively, anionic lipids facilitate association of cyt. c2 with bc1 by localizing its diffusion to the membrane surface. The observed lipid-mediated bc1 association is further enhanced by the oxidized state of cyt. c2, in line with its physiological function. This lipid-mediated enhancement is salinity-dependent, and anionic lipids can disrupt cyt. c2-bc1 interaction at nonphysiological salt levels. Our data highlight the importance of the redox state of cyt. c2, the lipid composition of the chromatophore membrane, and the salinity of the chromatophore in regulating the efficiency of the electron shuttling process mediated by cyt. c2. The conclusions can be extrapolated to mitochondrial systems and processes, or any bioenergetic membrane, given the structural similarity between cyt. c2 and bc1 and their mitochondrial counterparts.

Dynamic polarization-insensitive BOTDA in direct-detection OFDM with CNN-based BFS extraction.

We propose a dynamic polarization-insensitive Brillouin optical time domain analyzer (D/PI-BOTDA) with orthogonal frequency division multiplexing (OFDM) based on intensity-modulated direct-detection (IM-DD). A polarization-division-multiplexed (PDM) pump signal enables polarization diversity of the stimulated Brillouin scattering while a multi-frequency OFDM probe signal realizes dynamic sensing with single-shot transmission. We experimentally demonstrated distributed temperature sensing along a total 940-meter fiber with a temperature sensing coefficient of 1.2°C/MHz. The experimental results indicated a remarkable suppression of Brillouin gain fluctuation up to 4.38 times compared to the case without polarization diversity. To facilitate the Brillouin frequency shift (BFS) extraction process, we also implement a CNN-based BFS extraction method with SE-Res2Net block. The adopted algorithm achieves a higher accuracy than conventional curve fitting method, with a 10-time enhancement in the time efficiency.

Synergistic activation of inflammatory cytokine genes by interferon-γ-induced chromatin remodeling and toll-like receptor signaling.

Synergistic activation of inflammatory cytokine genes by interferon-γ (IFN-γ) and Toll-like receptor (TLR) signaling is important for innate immunity and inflammatory disease pathogenesis. Enhancement of TLR signaling, a previously proposed mechanism, is insufficient to explain strong synergistic activation of cytokine production in human macrophages. Rather, we found that IFN-γ induced sustained occupancy of transcription factors STAT1, IRF-1, and associated histone acetylation at promoters and enhancers at the TNF, IL6, and IL12B loci. This priming of chromatin did not activate transcription but greatly increased and prolonged recruitment of TLR4-induced transcription factors and RNA polymerase II to gene promoters and enhancers. Priming sensitized cytokine transcription to suppression by Jak inhibitors. Genome-wide analysis revealed pervasive priming of regulatory elements by IFN-γ and linked coordinate priming of promoters and enhancers with synergistic induction of transcription. Our results provide a synergy mechanism whereby IFN-γ creates a primed chromatin environment to augment TLR-induced gene transcription.

The Limited Palette for Photonic Block-Copolymer Materials: A Historical Problem or a Practical Limitation?

Block-copolymer self-assembly has proven to be an effective route for the fabrication of photonic films and, more recently, photonic pigments. However, despite extensive research on this topic over the past two decades, the palette of monomers and polymers employed to produce such structurally colored materials has remained surprisingly limited. In this Scientific Perspective, the commonly used block-copolymer systems reported in the literature are summarized (considering both linear and brush architectures) and their use is rationalized from the point of view of both their historical development and physicochemical constraints. Finally, the current challenges facing the field are discussed and promising new areas of research are highlighted to inspire the community to pursue new directions.