Molecular basis for curvature formation in SepF polymerization.

The self-assembly of proteins into curved structures plays an important role in many cellular processes. One good example of this phenomenon is observed in the septum-forming protein (SepF), which forms polymerized structures with uniform curvatures. SepF is essential for regulating the thickness of the septum during bacteria cell division. In Bacillus subtilis, SepF polymerization involves two distinct interfaces, the ß-ß and α-α interfaces, which define the assembly unit and contact interfaces, respectively. However, the mechanism of curvature formation in this step is not yet fully understood. In this study, we employed solid-state NMR (SSNMR) to compare the structures of cyclic wild-type SepF assemblies with linear assemblies resulting from a mutation of G137 on the ß-ß interface. Our results demonstrate that while the sequence differences arise from the internal assembly unit, the dramatic changes in the shape of the assemblies depend on the α-α interface between the units. We further provide atomic-level insights into how the angular variation of the α2 helix on the α-α interface affects the curvature of the assemblies, using a combination of SSNMR, cryo-electron microscopy, and simulation methods. Our findings shed light on the shape control of protein assemblies and emphasize the importance of interhelical contacts in retaining curvature.

Nanopore targeted sequencing-based diagnosis of central nervous system infections in HIV-infected patients.

BACKGROUND: Early and accurate etiological diagnosis is very important for improving the prognosis of central nervous system (CNS) infections in human immunodeficiency virus (HIV)-infected patients. The goal is not easily achieved by conventional microbiological tests. We developed a nanopore targeted sequencing (NTS) platform and evaluated the diagnostic performance for CNS infections in HIV-infected patients, with special focus on cryptococcal meningitis (CM). We compared the CM diagnostic performance of NTS with conventional methods and cryptococcal polymerase chain reaction (PCR). METHODS: This study included 57 hospitalized HIV-infected patients with suspected CNS infections from September 2018 to March 2022. The diagnosis established during hospitalization includes 27 cases of CM, 13 CNS tuberculosis, 5 toxoplasma encephalitis, 2 cytomegalovirus (CMV) encephalitis and 1 Varicella-zoster virus (VZV) encephalitis. The 2 cases of CMV encephalitis also have co-existing CM. Target-specific PCR amplification was used to enrich pathogen sequences before nanopore sequencing. NTS was performed on stored cerebrospinal fluid (CSF) samples and the results were compared with the diagnosis during hospitalization. RESULTS: 53 (93.0%) of the patients were male. The median CD4 cell count was 25.0 (IQR: 14.0-63.0) cells/uL. The sensitivities of CSF culture, India ink staining, cryptococcal PCR and NTS for CM were 70.4% (95%CI: 51.5 - 84.1%), 76.0% (95%CI: 56.6 - 88.5%), 77.8% (59.2 - 89.4%) and 85.2% (95%CI: 67.5 - 94.1%), respectively. All those methods had 100% specificity for CM. Our NTS platform could identify Cryptococcus at species level. Moreover, NTS was also able to identify all the 5 cases of toxoplasma encephalitis, 2 cases of CMV encephalitis and 1 VZV encephalitis. However, only 1 of 13 CNS tuberculosis cases was diagnosed by NTS, and so did Xpert MTB/RIF assay. CONCLUSIONS: NTS has a good diagnostic performance for CM in HIV-infected patients and may have the ability of simultaneously detecting other pathogens, including mixed infections. With continuing improving of the NTS platform, it may be a promising alterative microbiological test for assisting with the diagnosis of CNS infections.

Controlled Construction of Core-Shell Structured Prussian Blue Analogues towards Enhanced Oxygen Reduction.

Metal-organic frameworks-based electrocatalysts have been developed as highly desirable and promising candidates for catalyzing oxygen reduction reaction (ORR), which, however, usually need to be prepared at elevated temperatures and may suffer from the framework collapse in water environments, largely preventing its industrial application. Herein, this work demonstrates a facile low-temperature ion exchange method to synthesize Mn and Fe co-loaded Prussian blue analogues possessing core-shell structured frameworks and favorable water-tolerance. Among the catalysts prepared, the optimal HMPB-2.6Mn shows a high ORR electrocatalytic performance featuring a half-wave potential of 0.86 V and zinc-air battery power density of 119 mW cm-2 , as well as negligible degradation up to 60 h, which are comparable to commercial Pt/C. Such an excellent electrocatalytic performance is attributed to the special core-shell-like structure with Mn concentrated in outer shell, and the synergetic interactions between Mn and Fe, endowing HMPB-Mn with outstanding ORR activity and good stability.

Adsorption Site Regulations of [W-O]-Doped CoP Boosting the Hydrazine Oxidation-Coupled Hydrogen Evolution at Elevated Current Density.

Hydrazine oxidation reaction (HzOR) assisted hydrogen evolution reaction (HER) offers a feasible path for low power consumption to hydrogen production. Unfortunately however, the total electrooxidation of hydrazine in anode and the dissociation kinetics of water in cathode are critically depend on the interaction between the reaction intermediates and surface of catalysts, which are still challenging due to the totally different catalytic mechanisms. Herein, the [W-O] group with strong adsorption capacity is introduced into CoP nanoflakes to fabricate bifunctional catalyst, which possesses excellent catalytic performances towards both HER (185.60 mV at 1000 mA cm-2) and HzOR (78.99 mV at 10,00 mA cm-2) with the overall electrolyzer potential of 1.634 V lower than that of the water splitting system at 100 mA cm-2. The introduction of [W-O] groups, working as the adsorption sites for H2O dissociation and N2H4 dehydrogenation, leads to the formation of porous structure on CoP nanoflakes and regulates the electronic structure of Co through the linked O in [W-O] group as well, resultantly boosting the hydrogen production and HzOR. Moreover, a proof-of-concept direct hydrazine fuel cell-powered H2 production system has been assembled, realizing H2 evolution at a rate of 3.53 mmol cm-2 h-1 at room temperature without external electricity supply.

Dual-Site W-O-CoP Catalysts for Active and Selective Nitrate Conversion to Ammonia in a Broad Concentration Window.

Environmentally friendly electrochemical reduction of contaminated nitrate to ammonia (NO3 - RR) is a promising solution for large quantity ammonia (NH3 ) production, which, however, is a complex multi-reaction process involving coordination between different reaction intermediates of nitrate reduction and water decomposition-provided active hydrogen (Hads ) species. Here, a dual-site catalyst of [W-O] group-doped CoP nanosheets (0.6W-O-CoP@NF) has been designed to synergistically catalyze the NO3 - RR and water decomposition, especially the reactions between the intermediates of NO3 - RR and water decomposition-provided Hads species. This catalytic NO3 - RR exhibits an extremely high NH3 yield of 80.92 mg h-1 cm-2 and a Faradaic efficiency (FE) of 95.2% in 1 m KOH containing 0.1 m NO3 - . Significantly, 0.6W-O-CoP@NF presents greatly enhanced NH3 yield and FE in a wide NO3 - concentration ranges of 0.001-0.1 m compared to the reported. The excellent NO3 - RR performance is attributed to a synergistic catalytic effect between [W-O] and CoP active sites, in which the doped [W-O] group promotes the water decomposition to supply abundant Hads , and meanwhile modulates the electronic structure of Co for strengthened adsorption of Hads and the hydrogen (H2 ) release prevention, resultantly facilitating the NO3 - RR. Finally, a Zn-NO3 - battery has been assembled to simultaneously achieve three functions: electricity output, ammonia production, and nitrate treatment in wastewater.

WO3 -Assisted Synergetic Effect Catalyzes Efficient and CO-Tolerant Hydrogen Oxidation for PEMFCs.

Developing anode catalysts with substantially enhanced activity for hydrogen oxidation reaction (HOR) and CO tolerance performance is of great importance for the commercial applications of proton exchange membrane fuel cells (PEMFCs). Herein, an excellent CO-tolerant catalyst (Pd-WO3 /C) has been fabricated by loading Pd nanoparticles on WO3 via an immersion-reduction route. A remarkably high power density of 1.33 W cm-2 at 80 °C is obtained by using the optimized 3Pd-WO3 /C as the anode catalyst of PEMFCs, and the moderately reduced power density (73% remained) in CO/H2 mixed gas can quickly recover after removal of CO-contamination from hydrogen fuel, which is not possible by using Pt/C or Pd/C as anode catalyst. The prominent HOR activity of 3Pd-WO3 /C is attributed to the optimized interfacial electron interaction, in which the activated H* adsorbed on Pd species can be effectively transferred to WO3 species through hydrogen spillover effect and then oxidized through the H species insert/output effect during the formation of Hx WO3 in acid electrolyte. More importantly, a novel synergetic catalytic mechanism about excellent CO tolerance is proposed, in which Pd and WO3 respectively absorbs/activates CO and H2 O, thus achieving the CO electrooxidation and re-exposure of Pd active sites for CO-tolerant HOR.

Active site recovery and N-N bond breakage during hydrazine oxidation boosting the electrochemical hydrogen production.

Substituting hydrazine oxidation reaction for oxygen evolution reaction can result in greatly reduced energy consumption for hydrogen production, however, the mechanism and the electrochemical utilization rate of hydrazine oxidation reaction remain ambiguous. Herein, a bimetallic and hetero-structured phosphide catalyst has been fabricated to catalyze both hydrazine oxidation and hydrogen evolution reactions, and a new reaction path of nitrogen-nitrogen single bond breakage has been proposed and confirmed in hydrazine oxidation reaction. The high electro-catalytic performance is attributed to the instantaneous recovery of metal phosphide active site by hydrazine and the lowered energy barrier, which enable the constructed electrolyzer using bimetallic phosphide catalyst at both sides to reach 500 mA cm-2 for hydrogen production at 0.498 V, and offer an enhanced hydrazine electrochemical utilization rate of 93%. Such an electrolyzer can be powered by a bimetallic phosphide anode-equipped direct hydrazine fuel cell, achieving self-powered hydrogen production at a rate of 19.6 mol h-1 m-2.

High Cytomegalovirus Viral Load Is Associated With 182-Day All-Cause Mortality in Hospitalized People With Human Immunodeficiency Virus.

BACKGROUND: Cytomegalovirus (CMV) infection is associated with increased mortality in persons with HIV (PWH). It is less clear whether CMV infection is still associated with mortality when routinely screened and adequately treated. METHODS: This retrospective cohort study recruited 1003 hospitalized adults with HIV with CD4 cell counts <200 cells/µL from May 2017 to June 2021. Blood CMV DNA was routinely measured and CMV DNAemia was treated if end-organ disease occurred. CMV viral load was categorized into below the limit of quantification (BLQ; <500 IU/mL), low viral load (LVL; 500-10 000 IU/mL), and high viral load (HVL; ≥10 000 IU/mL) groups. We compared the 182-day all-cause mortality among different groups. RESULTS: The median (IQR) CD4 cell count of patients was 33 (13-84) cells/µL. The prevalence of CMV DNAemia was 39.8% (95% CI: 36.7-42.9%) and was significantly associated with CD4 cell count. The 182-day all-cause mortality was 9.9% (95% CI: 8.0-11.7%). Univariable analysis showed that, compared with BLQ, LVL and HVL were associated with 1.73-fold and 3.81-fold increased risks of mortality, respectively (P = .032 and P < .001). After adjustment for predefined confounding factors, HVL but not LVL was still associated with increased risk of mortality (adjusted hazard ratio: 2.63; 95% CI: 1.61-4.29; P < .001). However, for patients on effective antiretroviral therapy, the impact of HVL on 182-day mortality was not significant (P = .713). CONCLUSIONS: High CMV viral load in hospitalized PWH was associated with higher mortality, even when identified early by screening. Optimalization of the management for those patients needs to be explored in future studies.

The co-effect of copper and lipid vesicles on Aß aggregation.

Both metal ions and lipid membranes have a wide distribution in amyloid plaques and play significant roles in AD pathogenesis. Although influences of different metal ions or lipid vesicles on the aggregation of Aß peptides have been extensively studied, their combined effects are less understood. In this study, we reported a unique effect of copper ion on Aß aggregation in the presence of lipid vesicles, different from other divalent metal ions. Cu2+ in a super stoichiometric amount leads to the rapid formation of ß-sheet rich structure, containing abundant low molecular weight (LMW) oligomers. We demonstrated that oligomerization of Aß40 induced by Cu2+ binding was an essential prerequisite for the rapid conformation transition. Overall, the finding provided a new view on the complex triple system of Aß, copper ion and lipid vesicles, which might help understanding of Aß pathologies.

CoW Bimetallic Carbide Nanocatalysts: Computational Exploration, Confined Disassembly-Assembly Synthesis and Alkaline/Seawater Hydrogen Evolution.

Earth-abundant tungsten carbide exhibits potential hydrogen evolution reaction (HER) catalytic activity owing to its Pt-like d-band electronic structure, which, unfortunately, suffers from the relatively strong tungsten-hydrogen binding, deteriorating its HER performance. Herein, a catalyst design concept of incorporating late transition metal into early transition metal carbide is proposed for regulating the metal-H bonding strength and largely enhancing the HER performance, which is employed to synthesize CoW bi-metallic carbide Co6 W6 C by a "disassembly-assembly" approach in a confined environment. Such synthesized Co6 W6 C nanocatalyst features the optimal Gibbs free energy of *H intermediate and dissociation barrier energy of H2 O molecules as well by taking advantage of the electron complementary effect between Co and W species, which endows the electrocatalyst with excellent HER performance in both alkaline and seawater/alkaline electrolytes featuring especially low overpotentials, elevated current densities, and much-enhanced operation durability in comparison to commercial Pt/C catalyst. Moreover, a proof-of-concept Mg/seawater battery equipped with Co6 W6 C-2-600 as cathode offers a peak power density of 9.1 mW cm-2 and an open-circuit voltage of ≈1.71 V, concurrently realizing hydrogen production and electricity output.

Chromosome 1q21 gain is an adverse prognostic factor for newly diagnosed multiple myeloma patients treated with bortezomib-based regimens.

Chromosome 1q21 aberration is one of the most common cytogenetic abnormalities in multiple myeloma, and is considered an important prognostic factor. The present study analyzed the clinical relevance and prognostic impact of 1q21 gain in 194 patients with newly diagnosed multiple myeloma treated with bortezomib-based regimens. 1q21 gain was detected in 45.9% (89/194) of patients, and those with 1q21 gain had a worse prognosis. Strikingly, our results showed that excluding the effects of other coinciding genetic anomalies, patients carrying at least four copies of 1q21 had worse survival outcome. Moreover, del(13q) strongly correlates with 1q21 gain, and the coexistence of del(13q) and 1q21 gain plays an important role in reducing PFS and OS times. Therefore, 1q21 gain should be considered a high-risk feature in multiple myeloma patients treated with a bortezomib-based regimen.

Structural Insights into the Interaction between Bacillus subtilis SepF Assembly and FtsZ by Solid-State NMR Spectroscopy.

In many species of Gram-positive bacteria, SepF participated in the membrane tethering of FtsZ Z-ring during bacteria division. However, atomic-level details of interaction between SepF and FtsZ in an assembled state are lacking. Here, by combining solid-state NMR (SSNMR) with biochemical analyses, the interaction of Bacillus subtilis SepF and the C-terminal domain (CTD) of FtsZ was investigated. We obtained near complete chemical shift assignments of SepF and determined the structural model of the SepF monomer. Interaction with FtsZ-CTD caused further packing of SepF rings, and SSNMR experiments revealed the affected residues locating at α1, α2, ß3, and ß4 of SepF. Solution NMR experiments of dimeric SepF constructed by point mutation strategy proved a prerequisite role of α-α interface formation in SepF for FtsZ binding. Overall, our results provide structural insights into the mechanisms of SepF-FtsZ interaction for better understanding the function of SepF in bacteria.

Fe2+ /Fe3+ Cycling for Coupling Self-Powered Hydrogen Evolution and Preparation of Electrode Catalysts.

A novel Zn-Fe flow battery featuring an Fe3+ reduction reaction (Fe3+ RR)-coupled zinc oxidation, and an Fe2+ oxidation reaction (Fe2+ OR)-coupled hydrogen evolution reaction (HER) system as well, was established. This battery is capable of driving two Fe2+ OR-coupled HER systems in series based on the above Fe2+ /Fe3+ cycling, for efficient self-powered hydrogen evolution. Meanwhile, this Fe2+ /Fe3+ cycling enables the preparation of a multifunctional catalyst, Pt-3@SXNS (siloxene nanosheet), by the Fe2+ OR-promoted dispersion of Pt nanoparticles on SXNS; alternatively, this support could be obtained by Fe3+ RR-assisted exfoliation using Fe3+ from the anolyte of Fe2+ OR-coupled HER. The Pt-3@SXNS catalyst exhibits excellent catalytic activities toward Fe3+ RR in the Zn-Fe flow battery, HER, and Fe2+ OR in the electrolyzer, which is attributed to the strong electronic interaction between Pt and Si. This work offers a new strategy for energy storage and low-cost hydrogen production from acidic wastewater.

N-Doped Carbon Electrocatalyst: Marked ORR Activity in Acidic Media without the Contribution from Metal Sites?

Fe-N-C electrocatalysts have been demonstrated to be the most promising substitutes for benchmark Pt/C catalysts for the oxygen reduction reaction (ORR). Herein, we report that N-doped carbon materials with trace amounts of iron (0-0.08 wt. %) show excellent ORR activity and durability comparable and even superior to those of Pt/C in both alkaline and acidic media without significant contribution by the metal sites. Such an N-doped carbon (denoted as N-HPCs) features a hollow and hierarchically porous architecture, and more importantly, a noncovalently bonded N-deficient/N-rich heterostructure providing the active sites for oxygen adsorption and activation owing to the efficient electron transfer between the layers. The primary Zn-air battery using N-HPCs as the cathode delivers a much higher power density of 158 mW cm-2 , and the maximum power density in the H2 -O2 fuel cell reaches 486 mW cm-2 , which is comparable to and even better than those using conventional Fe-N-C catalysts at cathodes.

Construction of CoP2-Mo4P3/NF Heterogeneous Interfacial Electrocatalyst for Boosting Water Splitting.

Developing highly efficient, cost effective and durable bifunctional electrocatalyst remains a key challenge for overall water splitting. Herein, a bifunctional catalyst CoP2-Mo4P3/NF with rich heterointerfaces was successfully prepared by a two-step hydrothermal-phosphorylation method. The synergistic interaction between CoP2 and Mo4P3 heterogeneous interfaces can optimize the electronic structure of active sites, leading to the weak adsorption of H on the Mo sites and the increased redox activity of the Co site, resultantly improving the HER/OER bifunctional catalytic activity. The synthesized CoP2-Mo4P3/NF catalyst exhibits excellent electrocatalytic activity in 1.0 M KOH with low overpotentials of 77.6 and 300.3 at 100 mA cm-2 for HER and OER, respectively. Additionally, the assembled CoP2-Mo4P3/NF||CoP2-Mo4P3/NF electrolyzer delivers a current density of 100 mA cm-2 at a cell voltage of 1.59 V and remains stable for at least 370 h at 110 mA cm-2, indicating the potential application prospective in water splitting.

Risk factors and prognosis analysis of acute myeloid leukemia in children.

PURPOSE: To explore the efficacy and related prognostic factors of acute myeloid leukemia (AML) in children except acute promyelocytic leukemia (APL). METHODS: The clinical data of 89 non-APL children with AML treated in our hospital were retrospectively analyzed. The remission status was analyzed after chemotherapy, the long-term survival was evaluated using the Kaplan-Meier method, and the influencing factors for the prognosis were detected using univariate and multivariate Cox regression analyses. RESULTS: Complete remission (CR) was realized in 71 cases (79.8%) after the first course of treatment, 13 cases (14.6%) after the second course of treatment, and 5 cases (5.6%) after the third course of treatment. The 5-year event-free survival (EFS) rate and overall survival (OS) rate were 53.9% and 66.3%, respectively. The children were divided into low-risk group (n=31), middle-risk group (n=36) and high-risk group (n=22). In the three groups, the 5-year OS rate was 74.2%, 72.2% and 45.5%, respectively, while the 5-year EFS rate was 67.7%, 55.6% and 31.8%, respectively. Extramedullary infiltration at the time of initial diagnosis [HR=3.313 (95% CI: 1.748-13.664)], CD56+ [HR=1.592 (95% CI: 1.172-2.255)] and recurrence time <1 year [HR=3.040 (95% CI: 1.087-5.508)] were independent risk factors affecting the prognosis, and CR achieved after the first course [HR=0.786 (95% CI: 0.228-0.803)] was an independent factor improving the prognosis of patients. CONCLUSIONS: The prognosis is poor in non-APL children with AML who have extramedullary infiltration at the time of initial diagnosis, CD56+ and recurrence time <1 year, and CR achieved after the first course is an independent factor improving the prognosis of patients. The long-term EFS rate is significantly lower in high-risk group than that in low- and middle-risk groups. Intensive chemotherapy or early hematopoietic stem cell transplantation should be performed for high-risk patients.

Exploring interactions between lipids and amyloid-forming proteins: A review on applying fluorescence and NMR techniques.

A hallmark of Alzheimer's, Parkinson's, and other amyloid diseases is the assembly of amyloid proteins into amyloid aggregates or fibrils. In many cases, the formation and cytotoxicity of amyloid assemblies are associated with their interaction with cell membranes. Despite studied for many years, the characterization of the interaction is challenged for reasons on the multiple aggregation states of amyloid-forming proteins, transient and weak interactions in the complex system. Although several strategies such as computation biology, spectroscopy, and imaging methods have been performed, there is an urgent need to detail the molecular mechanism in different time scales and high resolutions. This review highlighted the recent applications of fluorescence, solution and solid-state NMR in exploring the interactions between amyloid protein and membranes attributing to their advantages of high sensitivity and atomic resolution.

Nonsurgical Secondary Prophylaxis of Esophageal Variceal Bleeding in Cirrhotic Patients: A Systematic Review and Network Meta-analysis.

INTRODUCTION: The aim of this study was to evaluate the effectiveness of nonsurgical secondary prophylaxis interventions for esophageal varices (EV) rebleeding in cirrhotic patients using network meta-analysis. MATERIALS AND METHODS: Secondary prophylaxis of EV rebleeding in cirrhosis is searched on PubMed, Embase, and the Cochrane Library databases. The quality of literatures was extracted by 2 independent investigators according to the requirements of Cochrane Handbook for Systematic Reviews of Interventions, Version 5.0.0. Meta-analysis was performed on Review Manager 5.3 software for the incidence of cirrhosis EV rebleeding, rebleeding-related mortality, and overall mortality; and STATA 15.1 software was used for network meta-analysis. RESULTS: In all, 57 randomized controlled trials were reviewed. Endoscopic band ligation (EBL)+argon plasma coagulation has not been recommended by guidelines, and it is rarely used; the number of existing studies and the sample size are small. Considering poor stability of the combined results, these studies were excluded; 55 literatures were included. In terms of reducing the incidence of rebleeding, transjugular intrahepatic portosystemic shunt (TIPS) surface under the cumulative ranking curve (SUCRA) (94.3%) was superior to EBL+endoscopic injection sclerotherapy (EIS) (84.4%), EIS+ß-blockers (77.9%), EBL (59.8%), EBL+ß-blockers+isosorbide-5-mononitrate (52.7%), EBL+ß-blockers (51.4%), EIS (34.2%), ß-blockers+isosorbide-5-mononitrate (23.7%), ß-blockers (20.8%), and placebo (0.8%). In reducing rebleeding-related mortality, TIPS SUCRA (87.2%) was more efficacious than EBL+EIS (83.5%), EIS (47.9%), EBL+ß-blockers (47.4%), ß-blockers (41.8%), EBL (34.5%), and placebo (7.6%). In reducing overall mortality, TIPS SUCRA (81.1%) was superior to EBL+EIS (68.9%), EIS+ß-blockers (59.2%), EBL+ß-blockers (55.4%), EIS (48.8%), EBL (48.7%), ß-blockers (34.2%), placebo (3.6%). CONCLUSIONS: TIPS was more effective in reducing the incidence of cirrhosis EV rebleeding, rebleeding-related mortality, and overall mortality in cirrhosis. Combined with the above results, TIPS is more likely to be recommended as a secondary prophylaxis intervention for EV in cirrhosis.

Amyloid-like aggregation and fibril core determination of TDP-43 C-terminal domain.

Cytoplasmic inclusion of TAR DNA-binding protein 43 (TDP-43) is a hallmark of most ALS (amyotrophic lateral sclerosis) and FTLD (Frontotemporal dementia), yet the aggregation of TDP-43 remains unclear. In this study, we proved the existence of amyloid-like structures of C-terminal domain of TDP-43 (TDP-C) in bacterial inclusion bodies (IBs), and obtained a homogenous fibril sample by seeding from the components of aggregated TDP-C in Escherichiacoli IBs. The results from solid-state NMR spectroscopy suggest that the homogenous fibrils were seeded from a tiny amount of aggregated TDP-C compositions in IBs; the structure characteristics of the rigid fibril core are identified of ß-rich structures, and show subtle relativity with the hydrophobicity of residues. Our study here provides a further understanding of TDP-43 protein aggregation and fibrillation.

Structural Mechanism of Barriers to Interspecies Seeding Transmissibility of Full-Length Prion Protein Amyloid.

A puzzling feature of prion diseases is the cross-species barriers. The detailed molecular mechanisms underlying these interspecies barriers remain poorly understood because of a lack of high-resolution structural information on the scrapie isoform of the prion protein (PrPSc ). In this study we identified the critical role of the residues 165/167 in the barrier to seeding mouse PrP (mPrP) fibril seeds to human cellular prion protein (PrPC ). Solid-state NMR revealed a C-terminal ß-sheet core spanning residues 165-230 and the packing arrangement of mPrP fibrils. Residues 165/167 are located on one end of the fibril core. Molecular dynamics simulations demonstrated that the stabilities of the seeding-induced ß-strand structures are significantly impacted by hydrogen bonds involving the side chain of residue 167 and steric resistance involving residue 165. These findings suggest that the α2-ß2 loop containing residues 165/167 could be the initial site of seed-template conformational conversion.