Miracle-dz/UniFAR-FTUs huggingface dataset:
Structural insights into α-synuclein monomer–fibril interactions

Significance The characteristic feature of Parkinson’s disease is the deposition of α-synuclein into insoluble amyloid fibrils. The so-called secondary nucleation mechanism appears to be key for the aggregation kinetics, because binding of monomers on the fibril surface can autocatalytically induce new amyloid seeds. We show by nuclear magnetic and electron paramagnetic resonance spectroscopy that α-synuclein monomer–fibril binding is primarily mediated by transient electrostatic interactions. These intermolecular contacts result in an unfolding of the loosely packed α-synuclein structures and expose the otherwise protected aggregation-prone non-amyloid-β component of the protein. Our data demonstrate that intramolecular unfolding of α-synuclein is a prerequisite for protein aggregation that leads to rapid multiplication of α-synuclein amyloid fibrils via the secondary nucleation process. Protein aggregation into amyloid fibrils is associated with multiple neurodegenerative diseases, including Parkinson’s disease. Kinetic data and biophysical characterization have shown that the secondary nucleation pathway highly accelerates aggregation via the absorption of monomeric protein on the surface of amyloid fibrils. Here, we used NMR and electron paramagnetic resonance spectroscopy to investigate the interaction of monomeric α-synuclein (α-Syn) with its fibrillar form. We demonstrate that α-Syn monomers interact transiently via their positively charged N terminus with the negatively charged flexible C-terminal ends of the fibrils. These intermolecular interactions reduce intramolecular contacts in monomeric α-Syn, yielding further unfolding of the partially collapsed intrinsically disordered states of α-Syn along with a possible increase in the local concentration of soluble α-Syn and alignment of individual monomers on the fibril surface. Our data indicate that intramolecular unfolding critically contributes to the aggregation kinetics of α-Syn during secondary nucleation.
Adaptive evolution of engineered yeast for squalene production improvement and its genome‐wide analysis

In the present study, the adaptive evolution of a metabolically engineered Saccharomyces cerevisiae strain in the presence of an enzyme inhibitor terbinafine for enhanced squalene accumulation via serial transfer leads to the development of robust strains. After adaptation for nearly 1500 h, a strain with higher squalene production efficiency was identified at a specific growth rate of 0.28 h−1 with a final squalene titer of 193 mg/L, which is 16.5‐fold higher than the BY4741 and 3‐fold higher over the metabolically engineered SK22 strain. Whole‐genome sequencing comparison between the reference strain and the evolved variant SK23 has led to the identification of 462 single‐nucleotide variants (SNVs) between both strains, with 102 SNVs affecting metabolism‐related genes. It was also established that F420I mutation of ERG1 in S. cerevisiae improves squalene synthesis. Further, the effect of increased squalene on lipid droplet and neutral lipid pattern in the evolved mutant strains was investigated by fluorescent techniques proving that the neutral lipid content and clustering of lipid droplets increase with an increase in squalene.
Sum-frequency vibrational spectroscopy of soluble surfactants at the air/water interface

Vibrational spectra of seven surfactants adsorbed at the surface of aqueous solutions have been obtained by IR–VIS sum-frequency generation. From these spectra the degree of conformational disorder and the angle of the terminal methyl group are inferred. In general, the number of gauche conformations increases as the area per chain increases. The angle of the methyl group, which is an indicator of the tilt of the hydrocarbon chains, is not simply related to the area per chain. Comparison of surfactants with the same chain length and area per molecule shows that the structure of the chain region of the monolayer is sensitive to the nature of the head group and not just to the packing density. Quantitative models to explain peak intensities in sum-frequency spectra of surfactants are discussed critically.
Infection Manager System (IMS) as a new hemocytometry-based bacteremia detection tool: A diagnostic accuracy study in a malaria-endemic area of Burkina Faso

Background New hemocytometric parameters can be used to differentiate causes of acute febrile illness (AFI). We evaluated a software algorithm–Infection Manager System (IMS)—which uses hemocytometric data generated by Sysmex hematology analyzers, for its accuracy to detect bacteremia in AFI patients with and without malaria in Burkina Faso. Secondary aims included comparing the accuracy of IMS with C-reactive protein (CRP) and procalcitonin (PCT). Methods In a prospective observational study, patients of ≥ three-month-old (range 3 months– 90 years) presenting with AFI were enrolled. IMS, blood culture and malaria diagnostics were done upon inclusion and additional diagnostics on clinical indication. CRP, PCT, viral multiplex PCR on nasopharyngeal swabs and bacterial- and malaria PCR were batch-tested retrospectively. Diagnostic classification was done retrospectively using all available data except IMS, CRP and PCT results. Findings A diagnosis was affirmed in 549/914 (60.1%) patients and included malaria (n = 191) bacteremia (n = 69), viral infections (n = 145), and malaria-bacteremia co-infections (n = 47). The overall sensitivity, specificity, and negative predictive value (NPV) of IMS for detection of bacteremia in patients of ≥ 5 years were 97.0% (95% CI: 89.8–99.6), 68.2% (95% CI: 55.6–79.1) and 95.7% (95% CI: 85.5–99.5) respectively, compared to 93.9% (95% CI: 85.2–98.3), 39.4% (95% CI: 27.6–52.2), and 86.7% (95% CI: 69.3–96.2) for CRP at ≥20mg/L. The sensitivity, specificity and NPV of PCT at 0.5 ng/ml were lower at respectively 72.7% (95% CI: 60.4–83.0), 50.0% (95% CI: 37.4–62.6) and 64.7% (95% CI: 50.1–77.6) The diagnostic accuracy of IMS was lower among malaria cases and patients <5 years but remained equal to- or higher than the accuracy of CRP. Interpretation IMS is a new diagnostic tool to differentiate causes of AFI. Its high NPV for bacteremia has the potential to improve antibiotic dispensing practices in healthcare facilities with hematology analyzers. Future studies are needed to evaluate whether IMS, combined with malaria diagnostics, may be used to rationalize antimicrobial prescription in malaria endemic areas. Trial registration ClinicalTrials.gov (NCT02669823) https://clinicaltrials.gov/ct2/show/NCT02669823
A Realist Synthesis of Community-Based Interventions in Vector-Borne Diseases

ABSTRACT Randomized control trials have provided evidence that some community-based interventions (CBIs) work in vector-borne diseases (VBDs). Conversely, there is limited evidence on how well those CBIs succeed in producing specific outcomes in different contexts. To conduct a realist synthesis for knowledge translation on this topic, we examined the extent to which realist concepts (context, mechanisms, and outcomes) and their relationships are present in the existing literature on CBIs for VBDs. Articles on CBIs were identified from prior scoping reviews of health interventions for VBDs. Content of the articles was extracted verbatim if it referred either to realist concepts or CBI features. The number of articles and the average number of words extracted per category per CBI were quantified. Content of the articles was scrutinized to inductively gather qualitative evidence on the interactions between realist concepts. We reviewed 41 articles on 17 CBIs from 12 countries. The average number of words used for mechanisms was much lower than those used for outcomes and context (309,474, and 836, respectively). The average number of words used for mechanisms increased when a CBI was described in three or more articles. There were more extensive accounts on CBI features than on mechanisms. It was difficult to gather evidence on the interactions among realist concepts from the content of the articles. Scarce reporting on mechanisms in published articles limits conducting a realist synthesis of CBIs in VBDs. More transdisciplinary research that goes beyond the biomedical paradigm is needed to boost the development of intervention mechanisms in this field.
Cra and cAMP Receptor Protein Have Opposing Roles in the Regulation of fruB in Vibrio cholerae

Vibrio cholerae is the causative agent of cholera disease. While current treatments of care are accessible, we still lack an understanding of the molecular mechanisms that allow V. cholerae to survive in both aquatic reservoirs and the human small intestine, where pathogenesis occurs. ABSTRACT The Gram-negative bacterium Vibrio cholerae adapts to changes in the environment by selectively producing the necessary machinery to take up and metabolize available carbohydrates. The import of fructose by the fructose-specific phosphoenolpyruvate (PEP) phosphotransferase system (PTS) is of particular interest because of its putative connection to cholera pathogenesis and persistence. Here, we describe the expression and regulation of fruB, which encodes an EIIA-FPr fusion protein as part of the fructose-specific PTS in V. cholerae. Using a series of transcriptional reporter fusions and additional biochemical and genetic assays, we identified Cra (catabolite repressor/activator) and cAMP receptor protein (CRP) as regulators of fruB expression and determined that this regulation is dependent upon the presence or absence of PTS sugars. Cra functions as a repressor, downregulating fruB expression in the absence of fructose when components of PTSFru are not needed. CRP functions as an activator of fruB expression. We also report that Cra and CRP can affect fruB expression independently; however, CRP can modulate cra expression in the presence of fructose and glucose. Evidence from this work provides the foundation for continued investigations into PTSFru and its relationship to the V. cholerae life cycle. IMPORTANCE Vibrio cholerae is the causative agent of cholera disease. While current treatments of care are accessible, we still lack an understanding of the molecular mechanisms that allow V. cholerae to survive in both aquatic reservoirs and the human small intestine, where pathogenesis occurs. Central to V. cholerae’s survival is its ability to use available carbon sources. Here, we investigate the regulation of fruB, which encodes a protein central to the import and metabolism of fructose. We show that fruB expression is controlled by the transcriptional regulators Cra and CRP. This work contributes toward a clearer understanding of how carbon source availability impacts the physiology and, potentially, the persistence of the pathogen.
Measuring the concentration of protein nanoparticles synthesized by desolvation method: comparison of Bradford assay, BCA assay, hydrolysis/UV spectroscopy and gravimetric analysis.

The desolvation technique is one of the most popular methods for preparing protein nanoparticles for medicine, biotechnology, and food applications. We fabricated 11 batches of BSA nanoparticles and 2 batches of gelatin nanoparticles by desolvation method. BSA nanoparticles from 2 batches were cross-linked by heating at +70 °C for 2 h; other nanoparticles were stabilized by glutaraldehyde. We compared several analytical approaches to measuring their concentration: gravimetric analysis, bicinchoninic acid assay, Bradford assay, and alkaline hydrolysis combined with UV spectroscopy. We revealed that the cross-linking degree and method of cross-linking affect both Bradford and BCA assay. Direct measurement of protein concentration in the suspension of purified nanoparticles by dye-binding assays can lead to significant (up to 50-60%) underestimation of nanoparticle concentration. Quantification of non-desolvated protein (indirect method) is affected by the presence of small nanoparticles in supernatants and can be inaccurate when the yield of desolvation is low. The reaction of cross-linker with protein changes UV absorbance of the latter. Therefore pure protein solution is an inappropriate calibrator when applying UV spectroscopy for the determination of nanoparticle concentration. Our recommendation is to determine the concentration of protein nanoparticles by at least two different methods, including gravimetric analysis.
Bacterial contamination of neglected hospital surfaces and equipment in an Algerian hospital: an important source of potential infection

ABSTRACT Hospital surfaces are heavily contaminated with bacteria, which are a potential source of nosocomial infections. This study was undertaken to identify bacterial communities isolated from neglected hospital surfaces after cleaning routine in a Algerian public hospital. Screening of bacterial contamination in patient bed (PB), reception land-line phones (TF), door handles (DH) and medical equipment (ME) during five months generated 108 inocula. Isolates obtained were identiﬁed based on biochemical characteristics and confirmed by analysis of 16S rRNA sequences. Statistical analysis was performed to reveal possible relationship between bacterial diversity and swabbed surfaces. Our findings showed a high prevalence of bacteria in various hospital surfaces, reaching (65.25%), where a highest contaminated surface was the PB (47.22%) and a lowest contaminated was TF (5.55%). Gram negative bacteria were the dominant group (62.03%) mainly represented by Entrobacteriaceae (42.59%), whereas Staphylococcus aureus belonging to Gram positive was the main expanded pathogen with (15.74%).
Genome wide association study of HTLV-1–associated myelopathy/tropical spastic paraparesis in the Japanese population

Significance Human T cell leukemia virus type 1 (HTLV-1) proviral load is associated with the risk of developing HTLV-1–associated myelopathy/tropical spastic paraparesis (HAM/TSP) and several small-scale candidate gene approaches have also identified associations of particular HLA alleles with HAM/TSP risk. However, no large-scale genome-wide association (GWA) studies have been performed to date. By a large-scale GWA study and comprehensive genotyping of classical HLA genes, we found that HLA-DRB1 alleles carrying leucine at the antigen presentation groove domain (DRB1-GB-7-Leu) increased the susceptibility to HAM/TSP. Individuals who were homozygous for DRB1-GB-7-Leu had a ninefold increased odds of developing HAM/TSP. This effect of DRB1-GB-7-Leu was independent of proviral load. These findings identify DRB1-GB-7-Leu as a genetic risk marker of HAM/TSP development. HTLV-1–associated myelopathy (HAM/TSP) is a chronic and progressive inflammatory disease of the central nervous system. The aim of our study was to identify genetic determinants related to the onset of HAM/TSP in the Japanese population. We conducted a genome-wide association study comprising 753 HAM/TSP patients and 899 asymptomatic HTLV-1 carriers. We also performed comprehensive genotyping of HLA-A, -B, -C, -DPB1, -DQB1, and -DRB1 genes using next-generation sequencing technology for 651 HAM/TSP patients and 804 carriers. A strong association was observed in HLA class I (P = 1.54 × 10−9) and class II (P = 1.21 × 10−8) loci with HAM/TSP. Association analysis using HLA genotyping results showed that HLA-C*07:02 (P = 2.61 × 10−5), HLA-B*07:02 (P = 4.97 × 10−10), HLA-DRB1*01:01 (P = 1.15 × 10−9) and HLA-DQB1*05:01 (P = 2.30 × 10−9) were associated with disease risk, while HLA-B*40:06 (P = 3.03 × 10−5), HLA-DRB1*15:01 (P = 1.06 × 10−5) and HLA-DQB1*06:02 (P = 1.78 × 10−6) worked protectively. Logistic regression analysis identified amino acid position 7 in the G-BETA domain of HLA-DRB1 as strongly associated with HAM/TSP (P = 9.52 × 10−10); individuals homozygous for leucine had an associated increased risk of HAM/TSP (odds ratio, 9.57), and proline was protective (odds ratio, 0.65). Both associations were independent of the known risk associated with proviral load. DRB1-GB-7-Leu was not significantly associated with proviral load. We have identified DRB1-GB-7-Leu as a genetic risk factor for HAM/TSP development independent of proviral load. This suggests that the amino acid residue may serve as a specific marker to identify the risk of HAM/TSP even without knowledge of proviral load. In light of its allele frequency worldwide, this biomarker will likely prove useful in HTLV-1 endemic areas across the globe.
Structural determinants of suicide during the global financial crisis in Spain: Integrating explanations to understand a complex public health problem

Introduction Suicide is a complex public health problem in contemporary societies. Macroeconomic downturns derived from the economic crisis have been found to be associated with growing suicide mortality in the United States and in Europe. The present work is aimed to assess the association between the recent economic downturns and suicide patterns using interrupted time series analysis and, particularly, adjusting this relationship by indicators of social cohesion and community values that might provide additional insights on the complex explanation of suicidal trends. Methods We combined suicide, social and economic data extracted from the National Statistics Institute (INE), the Eurostat database, and the World Values Survey to assess the association between the socio-economic factors and trends in suicide rates. To study the association between the financial crisis and changes in suicide rates in Spain, we used interrupted time series analysis (ITSA). Results Our findings confirm that suicides increased after the 2011 recession, but remained moderately constant after the 2008 economic downturn. Suicides particularly increased after the 2011 recession in the 10–14, and 45–64 years old intervals between males and females, and apparently in older groups. However, during the 2008–2011 time period suicide rates decreased during working years (specifically among 40–44, 45–49, and 55–59 years old groups). Our results highlight the importance of social protection against unemployment and, to a lesser extent, social protection in disability and family, in reducing suicides, as well as the economic prosperity of the country. Conclusion This result corroborates that the economic crisis has possibly impacted the growing suicide rates of the most vulnerable groups, but exclusively during the period characterised by economic cuts after the 2011 recession. This study highlights the need to implement tailored policies that protect these collectives against suicide.
Homonuclear J-Coupling Spectroscopy at Low Magnetic Fields using Spin-Lock Induced Crossing.

Nuclear magnetic resonance (NMR) spectroscopy usually requires high magnetic fields to create spectral resolution among different proton species. Although proton signals can also be detected at low fields, if J-coupling is stronger than chemical shift dispersion, the spectrum instead exhibits just a single line. In this work, we demonstrate that spectra can nevertheless be acquired in this strong-coupling regime using a novel pulse sequence called spin-lock induced crossing (SLIC). This probes energy level crossings induced by a weak spin-locking pulse and produces a unique J-coupling spectrum for most organic molecules. Unlike other forms of low-field J-coupling spectroscopy, our technique does not require the presence of heteronuclei and can be used for most compounds in their native state. We performed SLIC spectroscopy on a number of small molecules at 276 kHz and 20.8 MHZ, and we show that SLIC spectra can be simulated in good agreement with measurements.
Multi-Party Proof Generation in QAP-Based zk-SNARKs

Zero-knowledge succinct non-interactive argument of knowledge (zkSNARK) allows a party, known as the prover, to convince another party, known as the verifier, that he knows a private value <inline-formula> <tex-math notation="LaTeX">$v$ </tex-math></inline-formula>, without revealing it, such that <inline-formula> <tex-math notation="LaTeX">$F(u,v)=y$ </tex-math></inline-formula> for some function <inline-formula> <tex-math notation="LaTeX">$F$ </tex-math></inline-formula> and public values <inline-formula> <tex-math notation="LaTeX">$u$ </tex-math></inline-formula> and <inline-formula> <tex-math notation="LaTeX">$y$ </tex-math></inline-formula>. There are various versions of zk-SNARK, among them, Quadratic Arithmetic Program (QAP)-based zk-SNARK has been widely used in practice, especially in Blockchain technology. This is attributed to two desirable features; its fixed-size proof and the very light computation load of the verifier. However, the computation load of the prover in QAP-based zkSNARKs is very heavy, even-though it is designed to be very efficient. This load can be beyond the prover’s computation power to handle, and has to be offloaded to some external servers. In the existing offloading solutions, either (i) the load of computation, offloaded to each sever, is a fraction of the prover’s primary computation (e.g., DZIK), however the servers need to be trusted, (ii) the servers are not required to be trusted, but the computation complexity imposed to each one is the same as the prover’s primary computation (e.g., Trinocchio). In this paper, we present a scheme, which has the benefits of both solutions. In particular, we propose a secure multi-party proof generation algorithm where the prover can delegate its task to <inline-formula> <tex-math notation="LaTeX">$N $ </tex-math></inline-formula> servers, where (i) even if a group of <inline-formula> <tex-math notation="LaTeX">$T \in \mathbb {N}$ </tex-math></inline-formula> servers, <inline-formula> <tex-math notation="LaTeX">$T < N$ </tex-math></inline-formula>, collude, they cannot gain any information about the secret value <inline-formula> <tex-math notation="LaTeX">$v$ </tex-math></inline-formula>, (ii) the computation complexity of each server is less than <inline-formula> <tex-math notation="LaTeX">$1/(N-T)$ </tex-math></inline-formula> of the prover’s primary computation. The design is such that we don’t lose the efficiency of the prover’s algorithm in the process of delegating the tasks to external servers.
SME: ReRAM-based Sparse-Multiplication-Engine to Squeeze-Out Bit Sparsity of Neural Network

Resistive Random-Access-Memory (ReRAM) cross-bar is a promising technique for deep neural network (DNN) accelerators, thanks to its in-memory and in-situ analog computing abilities for Vector-Matrix Multiplication-and-Accumulations (VMMs). However, it is challenging for crossbar architecture to exploit the sparsity in DNNs. It inevitably causes complex and costly control to exploit fine-grained sparsity due to the limitation of tightly-coupled crossbar structure.As the countermeasure, we develop a novel ReRAM-based DNN accelerator, named Sparse-Multiplication-Engine (SME), based on a hardware and software co-design framework. First, we orchestrate the bit-sparse pattern to increase the density of bit-sparsity based on existing quantization methods. Second, we propose a novel weight mapping mechanism to slice the bits of a weight across the crossbars and splice the activation results in peripheral circuits. This mechanism can decouple the tightly-coupled crossbar structure and cumulate the sparsity in the crossbar. Finally, a superior squeeze-out scheme empties the crossbars mapped with highly-sparse non-zeros from the previous two steps. We design the SME architecture and discuss its use for other quantization methods and different ReRAM cell technologies. Compared with prior state-of-the-art designs, the SME shrinks the use of crossbars up to 8.7× and 2.1× using ResNet-50 and MobileNet-v2, respectively, with ≤ 0.3% accuracy drop on ImageNet.