Miracle-dz/UniFAR-FTUs huggingface dataset:
Methionine restriction delays senescence and suppresses the senescence-associated secretory phenotype in the kidney through endogenous hydrogen sulfide

ABSTRACT Aging is a risk factor for various acute and chronic kidney injuries. Kidney aging is accompanied by the secretion of growth factors, proteases, and inflammatory cytokines, known as the senescence-associated secretory phenotype (SASP). These factors accelerate the aging process and senescence-associated changes. Delaying kidney senescence may prevent acute and chronic kidney injury. Methionine restriction (MR) was found to be an effective intervention for delaying senescence. However, the mechanism of MR remains unclear. In this study, we investigated the effect of MR on the survival rate and renal aging of C57BL/6 mice and examined the relevant mechanisms. MR increased the survival rate and decreased the levels of senescence markers in the aging kidney. Both in vivo and in vitro, MR upregulated the transsulfuration pathway to increase H2S production, downregulated senescence markers and the SASP, and activated AMPK. The ability of MR to delay aging was reduced when AMPK was inhibited. These results suggest that MR may slow animal aging and kidney senescence through H2S production and AMPK pathway activation. Abbreviations: DR: diet restriction; MR: methionine restriction; SASP: senescence-associated secretory phenotype; AL: ad libitum; CKD, chronic kidney disease; AKI: acute kidney disease; TSP: transsulfuration pathway; CGL: cystathionine g-lyase; H2S: hydrogen sulfide; AMPK: AMP-activated protein kinase; mTOR: mammalian target of rapamycin; IS: indoxyl sulfate; CC: compound C.
Sera collected before introduction of contaminated polio vaccine contain antibodies against SV40.

Anti-SV40 IgG antibodies were found by ELISA test in 6 out of 51 sera collected in 1952, i.e. before introduction of the polio vaccine. This indicates that the presence of SV40 in the human population whose footprints can be found in a fraction of human cerebral tumours need not be the consequence of contamination of early batches of polio vaccine with SV40.
Resting Energy Expenditure and Protein Balance in People with Epidermolysis Bullosa

Epidermolysis bullosa (EB) is a group of conditions characterized by severe fragility of the skin that causes recurring blistering. The recessive dystrophic subtype of EB (RDEB) has a strong impact on the nutritional status. We evaluated the resting energy expenditure (REE) and presence of protein catabolism in patients with RDEB. REE was assessed in 10 subjects (7 females; age range 4–33 years) by indirect calorimetry and using a predictive equation. Nitrogen balance was calculated by protein intake and 24 h urinary urea excretion estimations. An assessment of body surface area (BSA) with infected and non-infected skin lesions was applied to the nitrogen balance burn equation that was adapted to EB. The REE values predicted by the equation were consistently lower than the ones measured, except for two subjects. All subjects recorded high protein and energy intake, with protein intake being higher than 4 g protein/kg/day for five subjects. Even so, protein catabolism was observed in six subjects, three of whom had infected wounds. This study raises the hypothesis that the clinical and nutritional risks of people with RDEB are associated with an increased REE and negative nitrogen balance, which reinforces the importance of nutritional support.
Tumor Cells Hijack Macrophage-Produced Complement C1q to Promote Tumor Growth

The density of C1q-producing TAMs and C4d deposits, hallmarks of complement activation, are negative prognostic factors in human clear-cell renal cell carcinoma. Thus, the classical complement pathway is a potential therapeutic target for this cancer. Clear-cell renal cell carcinoma (ccRCC) possesses an unmet medical need, particularly at the metastatic stage, when surgery is ineffective. Complement is a key factor in tissue inflammation, favoring cancer progression through the production of complement component 5a (C5a). However, the activation pathways that generate C5a in tumors remain obscure. By data mining, we identified ccRCC as a cancer type expressing concomitantly high expression of the components that are part of the classical complement pathway. To understand how the complement cascade is activated in ccRCC and impacts patients' clinical outcome, primary tumors from three patient cohorts (n = 106, 154, and 43), ccRCC cell lines, and tumor models in complement-deficient mice were used. High densities of cells producing classical complement pathway components C1q and C4 and the presence of C4 activation fragment deposits in primary tumors correlated with poor prognosis. The in situ orchestrated production of C1q by tumor-associated macrophages (TAM) and C1r, C1s, C4, and C3 by tumor cells associated with IgG deposits, led to C1 complex assembly, and complement activation. Accordingly, mice deficient in C1q, C4, or C3 displayed decreased tumor growth. However, the ccRCC tumors infiltrated with high densities of C1q-producing TAMs exhibited an immunosuppressed microenvironment, characterized by high expression of immune checkpoints (i.e., PD-1, Lag-3, PD-L1, and PD-L2). Our data have identified the classical complement pathway as a key inflammatory mechanism activated by the cooperation between tumor cells and TAMs, favoring cancer progression, and highlight potential therapeutic targets to restore an efficient immune reaction to cancer.
Distinct influence of omega-3 fatty acids on the plasma metabolome of healthy older adults.

Omega-3 polyunsaturated fatty acids (n3-PUFA) are well-recognized for their potent triglyceride-lowering effects, but the potential influence of these bioactive lipids on other biological processes, particularly in the context of healthy aging, remains unknown. With the goal of gaining new insight into some less well-characterized biological effects of n3-PUFAs in healthy older adults, we performed metabolomics of fasting peripheral blood plasma collected from 12 young adults and 12 older adults before and after an open-label intervention of n3-PUFA (3.9g/day, 2.7g EPA, 1.2g DHA). Proton nuclear magnetic resonance (1H-NMR) based lipoprotein subclass analysis revealed the expected reduction in total TG, but also demonstrated that n3-PUFA supplementation reduced VLDL particle number, modestly increased HDL cholesterol, and shifted the composition of HDL subclasses. Further metabolite profiling by 1H-NMR and mass spectrometry revealed pronounced changes in phospholipids, cholesterol esters, diglycerides, and triglycerides following n3-PUFA supplementation. Furthermore, significant changes in hydroxyproline, kynurenine, and 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF) following n3-PUFA supplementation provide further insight into some less well-recognized biological effects of n3-PUFA supplementation, including possible effects on protein metabolism, the kynurenine pathway, and glucose metabolism.
An Investigation into Picosecond Laser Micro-Trepanning of Alumina Ceramics Employing a Semi-Water-Immersed Scheme

Intense interest has been given to the fabrication of micro-through-holes with smaller tapering and higher aspect ratios in engineering ceramics due to their wide range of applications in MEMS and aerospace. A semi-water-immersed laser micro-trepanning (SWILT) scheme is proposed and investigated in this paper with alumina ceramics as the target material, and its performance is assessed and compared with the direct laser trepanning method. Relevant processing parameters influencing the trepanning process are explored through an orthogonally designed experiment, and their effects on hole profiles are adequately discussed to yield optimized parameters. It is revealed that SWILT is capable of producing micro-through-holes with minimized hole tapering and much straighter sidewalls compared with the direct trepanning results, whereas the ablated surface quality is relatively rougher. The micro-through-hole formation mechanisms are also amply analyzed, where the transition hole development may be purely attributed to the laser-material interaction in the direct laser trepanning condition, while the SWILT case features an enhanced material-removal rate, especially at the lower part of the through-hole. The latter is due to the strengthened mechanical effects coming from the water-confined plasma zone and the following cavitation bubble collapse, which may efficiently expel the molten material from sidewalls and result in significantly reduced hole tapering.
Protein folding state-dependent sorting at the Golgi apparatus

In eukaryotic cells, organelle-specific protein quality control (PQC) is critical for maintaining cellular homeostasis. Despite the Golgi apparatus being the major protein processing and sorting site within the secretory pathway, how it contributes to PQC has remained largely unknown. Using different chemical biology-based protein unfolding systems, we reveal the segregation of unfolded proteins from folded proteins in the Golgi. Quality control (QC) substrates are subsequently exported in distinct carriers, which likely contain unfolded proteins as well as highly oligomerized cargo that mimic protein aggregates. At an additional sorting step, oligomerized proteins are committed to lysosomal degradation, while unfolded proteins localize to the endoplasmic reticulum (ER) and associate with chaperones. These results highlight the existence of checkpoints at which QC substrates are selected for Golgi export and lysosomal degradation. Our data also suggest that the steady-state ER localization of misfolded proteins, observed for several disease-causing mutants, may have different origins.
Characteristics of Double-Gate Ga–In–Zn–O Thin-Film Transistor

A Ga-In-Zn-O thin-film transistor with double-gate structure is reported. Enhancement-mode operation that is essential to the constitution of a low-power digital circuitry is easily achieved when the upper and lower gate electrodes are tied together. The saturation mobility and the subthreshold swing are improved from 3.65 cm2/(V·s) and 0.44 V/dec to 18.9 cm2/(V·s) and 0.14 V/dec, respectively, compared with the single-gate structure. We can modulate the threshold voltage of either gate by adjusting the bias on the other gate.
Metagenomic Approaches for Public Health Surveillance of Foodborne Infections: Opportunities and Challenges

Abstract Foodborne disease surveillance in the United States is at a critical point. Clinical and diagnostic laboratories are using culture-independent diagnostic tests (CIDTs) to identify the pathogen causing foodborne illness from patient specimens. CIDTs are molecular tests that allow doctors to rapidly identify the bacteria causing illness within hours. CIDTs, unlike previous gold standard methods such as bacterial culture, do not produce an isolate that can be subtyped as part of the national molecular subtyping network for foodborne disease surveillance, PulseNet. Without subtype information, cases can no longer be linked using molecular data to identify potentially related cases that are part of an outbreak. In this review, we discuss the public health needs for a molecular subtyping approach directly from patient specimen and highlight different approaches, including amplicon and shotgun metagenomic sequencing.
FriWalk robotic walker: usability, acceptance and UX evaluation after a pilot study in a real environment

Abstract Background: Scientific evidence supports that prevention strategies like multicomponent physical exercise help avoiding functional decline, falls and frailty. The robotic walker FriWalk, developed within the ACANTO project, supports the execution of controlled physical activities during hospital admission to prevent functional deterioration associated to prolonged bedrest. FriWalk shows in a clinical validation study a positive relationship with improvement in physical performance, basic activities of daily living execution and frailty status. Usability, acceptance and user experience (UX) are key aspects to ease the adoption of assistive technologies in the elderly. Objective: This work pursues the evaluation of the usability, acceptance and UX of the FriWalk from the patients and clinical professionals’ perspectives. Methods: Data collected during the validation of FriWalk in a real environment have been used. Forty-two patients recruited at Getafe University Hospital (Acute Care and Orthogeriatric Units) and one clinical professional participated. SUS, TAM, UX and ad hoc questionnaires were administered. Results: Patients provided an average SUS of 52.86 and provided valuable information in the qualitative acceptance interviews. The clinical professional provided an averaged SUS and TAM of 67 and 46.6, respectively, and evaluated all UX categories as above average. Conclusions: Usability results do not qualify FriWalk as above average; the reasons explaining this have been identified and point out to the prototypical stage of the hardware. Acceptance and UX were positively evaluated and allowed the research team to propose a new organizational model to deliver the FriWalk-based prevention program. FriWalk will be soon evolved. Implications for rehabilitation FriWalk showed in a randomized clinical trial a positive relationship with improvement in physical performance, basic activities of daily living execution and frailty status. In terms of usability, user experience (UX) and acceptance, participants of the study have valued the FriWalk robotic walker as a promising help, considering that the device that has been under evaluation was still in a prototype stage. Clinical professional reported FriWalk and its corresponding exercise program description software regarding usability, acceptance and UX as satisfactory tool to prescribe and assess a rehabilitation program for hospitalized patients.
Multifunctional graphene oxide/iron oxide nanoparticles for magnetic targeted drug delivery dual magnetic resonance/fluorescence imaging and cancer sensing

Graphene Oxide (GO) has recently attracted substantial attention in biomedical field as an effective platform for biological sensing, tissue scaffolds and in vitro fluorescence imaging. However, the targeting modality and the capability of its in vivo detection have not been explored. To enhance the functionality of GO, we combine it with superparamagnetic iron oxide nanoparticles (Fe3O4 NPs) serving as a biocompatible magnetic drug delivery addends and magnetic resonance contrast agent for MRI. Synthesized GO-Fe3O4 conjugates have an average size of 260 nm and show low cytotoxicity comparable to that of GO. Fe3O4 nanoparticles provide superparamagnetic properties for magnetic targeted drug delivery allowing simple manipulation by the magnetic field and magnetic resonance imaging with high r2/r1 relaxivity ratios of ~10.7. GO-Fe3O4 retains pH-sensing capabilities of GO used in this work to detect cancer versus healthy environments in vitro and exhibits fluorescence in the visible for bioimaging. As a drug delivery platform GO-Fe3O4 shows successful fluorescence-tracked transport of hydrophobic doxorubicin non-covalently conjugated to GO with substantial loading and 2.5-fold improved efficacy. As a result, we propose GO-Fe3O4 nanoparticles as a novel multifunctional magnetic targeted platform for high efficacy drug delivery traced in vitro by GO fluorescence and in vivo via MRI capable of optical cancer detection.
Casein Phosphopeptide-Amorphous Calcium Phosphate Attenuates Virulence and Modulates Microbial Ecology of Saliva-Derived Polymicrobial Biofilms

Background: Casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) acts as a salivary biomimetic that provides bioavailable calcium and phosphate ions to augment fluoride-mediated remineralisation of early caries lesions. However, there are indications that it may also have beneficial ecological effects on the oral microbiome. Objective: This in vitro study investigated whether CPP-ACP could influence microbial counts, acidogenicity, and the relative abundance of specific caries- and health-associated bacterial species in polymicrobial biofilms. Methods: Saliva-derived polymicrobial biofilms were grown for 96 h in a cariogenic environment and treated every 12 h with 2% CPP-ACP or vehicle control. Colony forming units (CFUs) and acidogenicity were estimated from the treated biofilms. Microbial ecological effects of CPP-ACP were assessed based on the relative abundance of 14 specific caries- and health-associated bacterial species using a real-time quantitative PCR assay. Results: CPP-ACP-treated biofilms showed relatively modest, but significant, reductions in microbial CFUs (21% reduction, p = 0.008) and acidogenicity (33% reduction, p < 0.001), compared to the control-treated biofilms. The CPP-ACP treated biofilms also exhibited significantly lower bacterial loads of cariogenic Scardovia wiggsiae (fold change 0.017, p < 0.001) and Prevotella denticola(fold change 0.005, p < 0.001), and higher bacterial loads of commensal Streptococcus sanguinis(fold change 30.22, p < 0.001), S. mitis/oralis(fold change 9.66, p = 0.012), and S. salivarius/thermophilus(fold change 89.35, p < 0.001) than the control-treated biofilms. Conclusions: The results indicate that CPP-ACP has virulence-attenuating attributes that can influence a beneficial microbial ecological change in the biofilm.
TRAF6 and A20 Regulate Lysine 63–Linked Ubiquitination of Beclin-1 to Control TLR4-Induced Autophagy

Regulation of the ubiquitination of Beclin-1 may be a general mechanism that controls autophagy. Controlling the Inner Pac-Man Autophagy is a process by which cellular components can be recycled to provide much-needed raw materials to help cells survive conditions of acute stress. But if a cell has to rely on this process for too long, the cell will die. TLR4 is a receptor that responds to a bacterial component called LPS to activate the transcription factor NF-κB, which drives the expression of pro-inflammatory genes in a process that requires a modifying enzyme called TRAF6 to switch on the pathway and an opposing enzyme called A20 to switch it off. Shi and Kehrl now show that these two enzymes play an analogous role in regulating TLR4-induced autophagy: TRAF6 modifies (ubiquitinates) a protein called Beclin-1, which initiates autophagy, whereas A20 counters the effects of TRAF6 and shuts the process down. The authors’ examination of other pro-autophagy pathways suggests that regulation of the ubiquitination state of Beclin-1 may be a general mechanism for the induction of autophagy by pro-inflammatory stimuli. Autophagy delivers cytoplasmic constituents to autophagolysosomes and is linked to both innate and adaptive immunity. Toll-like receptor 4 (TLR4) signaling induces autophagy and recruits Beclin-1, the mammalian homolog of yeast Atg6, to the receptor complex. We found that tumor necrosis factor receptor (TNFR)–associated factor 6 (TRAF6)–mediated, Lys63 (K63)–linked ubiquitination of Beclin-1 is critical for TLR4-triggered autophagy in macrophages. Two TRAF6-binding motifs in Beclin-1 facilitated the binding of TRAF6 and the ubiquitination of Beclin-1. Lys117, which is strategically located in the Bcl-2 homology 3 (BH3) domain of Beclin-1, was a major site for K63-linked ubiquitination. The deubiquitinating enzyme A20 reduced the extent of K63-linked ubiquitination of Beclin-1 and limited the induction of autophagy in response to TLR signaling. Treatment of macrophages with either interferon-γ or interleukin-1 also triggered the K63-linked ubiquitination of Beclin-1 and the formation of autophagosomes. These results indicate that the status of K63-linked ubiquitination of Beclin-1 plays a key role in regulating autophagy during inflammatory responses.
Investigation of Single pMOSFET Gate Oxide Degradation on NOR Logic Circuit Operability

The impact of gate oxide degradation of a single pMOSFET on the performance of the CMOS NOR logic circuit has been examined using a switch matrix technique. A constant voltage stress of -4.0V was used to induce a low level of degradation to the 2.0nm gate oxide of the pMOSFET. Characteristics of the CMOS NOR logic circuit following gate oxide degradation are analyzed in both the DC and V-t domains. The NOR gate rise time increases by approximately 30%, which may lead to timing or logic errors in high frequency digital circuits. Additionally, the voltage switching point of the NOR logic circuit shifts by 9% which could affect operation of analog or mixed signal designs. This shift in NOR logic circuit performance is correlated to an increased channel resistance of the stressed pMOSFET.
Evaluating Reach, Acceptability, Utility, and Engagement with An App-Based Intervention to Improve Medication Adherence in Patients with Coronary Heart Disease in the MedApp-CHD Study: A Mixed-Methods Evaluation

Objective: The aim of this study was to assess the reach, acceptability, utility, and engagement with the apps that were used in the MEDication reminder APPlications (apps) to improve medication adherence in Coronary Heart Disease (MedApp-CHD) study, a randomised clinical trial to improve medication adherence, using a mixed-methods approach. Methods: The MedApp-CHD study randomised 163 patients with coronary heart disease (CHD) to one of three groups: (i) usual care (n = 56), (ii) a basic medication reminder app (n = 54), or (iii) an advanced medication reminder app (n = 53). For this mixed-methods evaluation, the data sources included patient screening logs, feedback questionnaires collected at three-month follow-up, focus groups discussions, and analytical data from the app software. Results: Ninety-four percent (98/104) of participants who received a medication reminder app completed the three-month feedback questionnaire and 15 participated in the focus group discussions. The themes that were identified included that participants (i) found the medication reminders useful in reminding them to take the medications on the correct time every day, (ii) liked having the medication list as an easily-accessible record of medications’ names and dosages, (iii) reported being likely to continue to use the apps after the study completion, (iv) would be likely to recommend the apps to their family and friends, and (v) those who used the clinical measurements feature found it useful as a tool to track and graph the blood pressure and glucose levels over time (especially those with diabetes and/or hypertension). In addition, analytical data from the app software demonstrated that the participants used the medication-related features more than the clinical measurements feature. Furthermore, data from the patient screening logs showed that the main reason for exclusion, other than not meeting the CHD criteria, was not having a suitable smartphone, and those that were excluded for this reason were older and had a higher proportion of females than those enrolled in the study. Conclusion: This study provides important insights regarding the features that are most useful in apps that aim to improve medication adherence. This mixed-methods evaluation suggests that, currently, young male patients with CHD are more likely to use such apps, that the apps were well-accepted and useful in reminding the patients to take the medications, and that the patients were engaged in regularly using the apps.