Miracle-dz/UniFAR-FTUs huggingface dataset:
The rapidly evolving view of lysosomal storage diseases

Lysosomal storage diseases are a group of metabolic disorders caused by deficiencies of several components of lysosomal function. Most commonly affected are lysosomal hydrolases, which are involved in the breakdown and recycling of a variety of complex molecules and cellular structures. The understanding of lysosomal biology has progressively improved over time. Lysosomes are no longer viewed as organelles exclusively involved in catabolic pathways, but rather as highly dynamic elements of the autophagic‐lysosomal pathway, involved in multiple cellular functions, including signaling, and able to adapt to environmental stimuli. This refined vision of lysosomes has substantially impacted on our understanding of the pathophysiology of lysosomal disorders. It is now clear that substrate accumulation triggers complex pathogenetic cascades that are responsible for disease pathology, such as aberrant vesicle trafficking, impairment of autophagy, dysregulation of signaling pathways, abnormalities of calcium homeostasis, and mitochondrial dysfunction. Novel technologies, in most cases based on high‐throughput approaches, have significantly contributed to the characterization of lysosomal biology or lysosomal dysfunction and have the potential to facilitate diagnostic processes, and to enable the identification of new therapeutic targets.
Transcriptional repression of NFKBIA triggers constitutive IKK‐ and proteasome‐independent p65/RelA activation in senescence

The IκB kinase (IKK)‐NF‐κB pathway is activated as part of the DNA damage response and controls both inflammation and resistance to apoptosis. How these distinct functions are achieved remained unknown. We demonstrate here that DNA double‐strand breaks elicit two subsequent phases of NF‐κB activation in vivo and in vitro, which are mechanistically and functionally distinct. RNA‐sequencing reveals that the first‐phase controls anti‐apoptotic gene expression, while the second drives expression of senescence‐associated secretory phenotype (SASP) genes. The rapidly activated first phase is driven by the ATM‐PARP1‐TRAF6‐IKK cascade, which triggers proteasomal destruction of inhibitory IκBα, and is terminated through IκBα re‐expression from the NFKBIA gene. The second phase, which is activated days later in senescent cells, is on the other hand independent of IKK and the proteasome. An altered phosphorylation status of NF‐κB family member p65/RelA, in part mediated by GSK3β, results in transcriptional silencing of NFKBIA and IKK‐independent, constitutive activation of NF‐κB in senescence. Collectively, our study reveals a novel physiological mechanism of NF‐κB activation with important implications for genotoxic cancer treatment.
When POTS is the tip of the iceberg: Rare cases of dysautonomia as a possible manifestation of another disorder

Background Postural tachycardia syndrome (POTS) is a heterogenous disorder of the autonomic nervous system that is commonly associated with small fiber neuropathy, Ehlers-Danlos Syndrome and autoimmune disorders, but association with rare conditions may also occur. Methods Reported here are clinical features, diagnostic tests and treatment outcomes of 6 unique patients who presented with POTS and were subsequently diagnosed with Fabry disease, McArdle disease, Complex V mitochondrial disease, carcinoid tumor, Hodgkin’s lymphoma and chemotherapy-induced neuropathy. Results All patients (age range 15-57 years, 3 females, 3 males) presented with orthostatic intolerance of at least 6 months duration, and all patients had co-morbid small fiber neuropathy. Five patients presented with symptoms of POTS months to years before the underlying or associated medical condition was discovered, and three out of six patients experienced either complete resolution or significant improvement of POTS after treatment of the underlying or associated medical condition. Conclusion In rare cases, POTS can present as a possible manifestation of genetic, neoplastic or neurotoxic disorders. Unusual clinical features that fall outside of the typical spectrum of dysautonomia can point toward the presence of another disorder and help guide further diagnostic investigation.
GelMA/bioactive silica nanocomposite bioinks for stem cell osteogenic differentiation

Leveraging 3D bioprinting for processing stem cell-laden biomaterials has unlocked a tremendous potential for fabricating living 3D constructs for bone tissue engineering. Even though several bioinks developed to date display suitable physicochemical properties for stem cell seeding and proliferation, they generally lack the nanosized minerals present in native bone bioarchitecture. To enable the bottom-up fabrication of biomimetic 3D constructs for bioinstructing stem cells pro-osteogenic differentiation, herein we developed multi-bioactive nanocomposite bioinks that combine the organic and inorganic building blocks of bone. For the organic component gelatin methacrylate (GelMA), a photocrosslinkable denaturated collagen derivative used for 3D bioprinting was selected due to its rheological properties display of cell adhesion moieties to which bone tissue precursors such as human bone marrow derived mesenchymal stem cells (hBM-MSCs) can attach to. The inorganic building block was formulated by incorporating mesoporous silica nanoparticles functionalized with calcium, phosphate and dexamethasone (MSNCaPDex), which previously proven to induce osteogenic differentiation. The newly formulated photocrosslinkable nanocomposite GelMA bioink incorporating MSNCaPDex nanoparticles and laden with hBM-MSCs was successfully processed into a 3D bioprintable construct with structural fidelity, and well dispersed nanoparticles throughout the hydrogel matrix. These nanocomposite constructs could induce the deposition of apatite in vitro, thus showing attractive bioactivity properties. Viability and differentiation studies showed that hBM-MSCs remained viable and exhibited osteogenic differentiation biomarkers when incorporated in GelMA/MSNCaPDex constructs and without requiring further biochemical, nor mechanical stimuli. Overall, our nanocomposite bioink has demonstrated excellent processability via extrusion bioprinting into osteogenic constructs with potential application in bone tissue repair and regeneration.
Identification of host factors binding to dengue and Zika virus subgenomic RNA by efficient yeast three-hybrid screens of the human ORFeome

ABSTRACT Flaviviruses such as the dengue (DENV) and the Zika virus (ZIKV) are important human pathogens causing around 100 million symptomatic infections each year. During infection, small subgenomic flavivirus RNAs (sfRNAs) are formed inside the infected host cell as a result of incomplete degradation of the viral RNA genome by cellular exoribonuclease XRN1. Although the full extent of sfRNA functions is to be revealed, these non-coding RNAs are key virulence factors and their detrimental effects on multiple cellular processes seem to consistently involve molecular interactions with RNA-binding proteins (RBPs). Discovery of such sfRNA-binding host-factors has followed established biochemical pull-down approaches skewed towards highly abundant proteins hampering proteome-wide coverage. Yeast three-hybrid (Y3H) systems represent an attractive alternative approach. To facilitate proteome-wide screens for RBP, we revisited and improved existing RNA-Y3H methodology by (1) implementing full-length ORF libraries in combination with (2) efficient yeast mating to increase screening depth and sensitivity, and (3) stringent negative controls to eliminate over-representation of non-specific RNA-binders. These improvements were validated employing the well-characterized interaction between DDX6 (DEAD-box helicase 6) and sfRNA of DENV as paradigm. Our advanced Y3H system was used to screen for human proteins binding to DENV and ZIKV sfRNA, resulting in a list of 69 putative sfRNA-binders, including several previously reported as well as numerous novel RBP host factors. Our methodology requiring no sophisticated infrastructure or analytic pipeline may be employed for the discovery of meaningful RNA–protein interactions at large scale in other fields.
Effects of last barrier thickness on the hot–cold factor of GaN-based light-emitting diodes

Abstract. The study of thermal properties for GaN-based light-emitting diodes (LEDs) with various last barrier thicknesses was reported. It was found that the LED output power decreased as we increased the thickness of the last barrier. It was also found that the LED output powers decrease with the increase of temperature for the LEDs with 12-, 24-, and 48-nm-thick last barriers. However, it was found that the LED output power increases with the increase of temperature for the LED with a 72-nm-thick last barrier due to the fact that more holes could enter the multiquantum well active region at elevated temperatures. Furthermore, it was found that the output power decreased by 0.15%/°C, 0.15%/°C, and 0.11%/°C for the LEDs with 12-, 24-, and 48-nm-thick last barriers, respectively, but increased by 0.09%/°C for the LED with a 72-nm-thick last barrier.
Male Fetal Sex Affects Uteroplacental Angiogenesis in Growth Restriction Mouse Model†.

Abnormally increased angiotensin II activity related to maternal angiotensinogen (AGT) genetic variants, or aberrant receptor activation, is associated with small-for-gestational-age (SGA) babies and abnormal uterine spiral artery remodeling in humans. Our group studies a murine AGT gene titration transgenic (TG; 3-copies of the AGT gene) model, which has a 20% increase in AGT expression mimicking a common human AGT genetic variant (A[-6]G) associated with intrauterine growth restriction (IUGR) and spiral artery pathology. We hypothesized that aberrant maternal AGT expression impacts pregnancy-induced uterine spiral artery angiogenesis in this mouse model leading to IUGR. We controlled for fetal sex and fetal genotype (e.g., only 2-copy wild-type [WT] progeny from WT and TG dams were included). Uteroplacental samples from WT and TG dams from early (days 6.5 and 8.5), mid (d12.5), and late (d16.5) gestation were studied to assess uterine natural killer cell (uNK) phenotypes, decidual metrial triangle angiogenic factors, placental growth and capillary density, placental transcriptomics, and placental nutrient transport. Spiral artery architecture was evaluated at day 16.5 by contrast-perfused three-dimensional micro-computed tomography (3D microCT). Our results suggest that uteroplacental angiogenesis is significantly reduced in TG dams at day 16.5. Males from TG dams are associated with significantly reduced uteroplacental angiogenesis from early to late gestation compared with their female littermates and WT controls. Angiogenesis was not different between fetal sexes from WT dams. We conclude that male fetal sex compounds the pathologic impact of maternal genotype in this mouse model of growth restriction.
Fine Particulate Matter and Markers of Alzheimer's Disease Neuropathology at Autopsy in a Community-Based Cohort.

BACKGROUND Evidence links fine particulate matter (PM2.5) to Alzheimer's disease (AD), but no community-based prospective cohort studies in older adults have evaluated the association between long-term exposure to PM2.5 and markers of AD neuropathology at autopsy. OBJECTIVE Using a well-established autopsy cohort and new spatiotemporal predictions of air pollution, we evaluated associations of 10-year PM2.5 exposure prior to death with Braak stage, Consortium to Establish a Registry for AD (CERAD) score, and combined AD neuropathologic change (ABC score). METHODS We used autopsy specimens (N = 832) from the Adult Changes in Thought (ACT) study, with enrollment ongoing since 1994. We assigned long-term exposure at residential address based on two-week average concentrations from a newly developed spatiotemporal model. To account for potential selection bias, we conducted inverse probability weighting. Adjusting for covariates with tiered models, we performed ordinal regression for Braak and CERAD and logistic regression for dichotomized ABC score. RESULTS 10-year average PM2.5 from death across the autopsy cohort was 8.2 (1.9) μg/m3. Average age at death was 89 (±7) years. Each 1μg/m3 increase in 10-year average PM2.5 prior to death was associated with a suggestive increase in the odds of worse neuropathology as indicated by CERAD score (OR: 1.35 (0.90, 1.90)) but a suggestive decreased odds of neuropathology as defined by the ABC score (OR: 0.79 (0.49, 1.19). There was no association with Braak stage (OR: 0.99 (0.64, 1.47). CONCLUSION We report inconclusive associations between PM2.5 and AD neuropathology at autopsy among a cohort where 94% of individuals experienced 10-year exposures below the current EPA standard. Prior studies of AD risk factors and AD neuropathology are similarly inconclusive, suggesting alternative mechanistic pathways for disease or residual confounding.
Selective cross-linking of coinciding protein assemblies by in-gel cross-linking mass-spectrometry

Cross-linking mass spectrometry has developed into an important method to study protein structures and interactions. The in-solution cross-linking workflows involve time and sample consuming steps and do not provide sensible solutions for differentiating cross-links obtained from co-occurring protein oligomers, complexes, or conformers. Here we developed a cross-linking workflow combining blue native PAGE with in-gel cross-linking mass spectrometry (IGX-MS). This workflow circumvents steps, such as buffer exchange and cross-linker concentration optimization. Additionally, IGX-MS enables the parallel analysis of co-occurring protein complexes using only small amounts of sample. Another benefit of IGX-MS observed by experiments on GroEL and purified bovine heart mitochondria, is the substantial reduction of artificial over-length cross-links when compared to in-solution cross-linking. We next used IGX-MS to investigate the complement components C5, C6, and their hetero-dimeric C5b6 complex. The obtained cross-links were used to generate a refined structural model of the complement component C6, resembling C6 in its inactivated state. This finding shows that IGX-MS can be used to provide new insights into the initial stages of the terminal complement pathway.
Remineralization potential and caries preventive efficacy of CPP-ACP/Xylitol/Ozone/Bioactive glass and topical fluoride combined therapy versus fluoride mono-therapy – a systematic review and meta-analysis

Abstract Objective To compare the remineralization potential and caries preventive efficacy of CPP-ACP/bioactive glass/xylitol/ozone and topical fluoride (TF) combined therapy versus TF mono-therapy. Material and methods Embase, PubMed, Scopus, Web of Science and Cochrane databases were searched. 4457 records were screened and 26 trials were included. Data from 16 trials was pooled using Review Manager 5.4. Level of significance was p < . 05. The certainty of the evidence was evaluated using GRADE. Results Pooled analysis of two trials for white spot lesions (WSLs) regression (SMD −0.6, 95% CI: [−1.07 to −0.14], p = .01) and three trials for post-intervention DIAGNOdent values (SMD −1.24, 95% CI: [−1.96 to −0.52], p = .0007) significantly favoured CPP-ACP-TF combined therapy over TF mono-therapy. The sub-group analysis for caries increment (SMD −0.14, 95% CI: [−0.21 to −0.07], p < .0001) and the post intervention S mutans count (SMD −0.42, 95% CI: [−0.62 to −0.23], p < .0001) significantly favours ‘xylitol-TF’ and ‘CPP-ACP-TF’ combined therapy respectively. The high/unclear risk of bias, imprecision and indirectness of the included trials presented a low certainty of evidence. Conclusion CPP-ACP-TF exhibits superiority over TF monotherapy in remineralizing existing lesions and demonstrates better antibacterial effect, whereas it is not more effective for preventing caries incidence. However, Xylitol exerts an added benefit over fluoride alone in preventing caries increment. The low-certainty evidence highlights the need for more good quality trials.
A (conditional) role for labdane-related diterpenoid natural products in rice stomatal closure.

• Rice (Oryza sativa) is the staple food for over half the world's population. Drought stress imposes major constraints on rice yields. Intriguingly, labdane-related diterpenoid (LRD) phytoalexins in maize (Zea mays) affect drought tolerance, as indicated by the increased susceptibility of an insertion mutant of the class II diterpene cyclase ZmCPS2/An2 that initiates such biosynthesis. Rice also produces LRD phytoalexins, utilizing OsCPS2 and OsCPS4 to initiate a complex metabolic network. • For genetic studies of rice LRD biosynthesis the fast-growing Kitaake cultivar was selected for targeted mutagenesis via CRISPR/Cas9, with an initial focus on OsCPS2 and OsCPS4. The resulting cps2 and cps4 knock-out lines were further crossed to create a cps2x4 double-mutant. Both CPSs also were over-expressed. • Strikingly, all of the cv. Kitaake cps mutants exhibit significantly increased susceptibility to drought, which was associated with reduced stomatal closure that was evident even under well-watered conditions. However, CPS over-expression did not increase drought resistance, and cps mutants in other cultivars did not alter susceptibility to drought, although these also exhibited lesser effects on LRD production. • The results suggest that LRDs may act as a regulatory switch that triggers stomatal closure in rice, which might reflect the role of these openings in microbial entry.
Extrinsic Premelting at the Ice-Glass Interface

This paper describes an investigation into premelting at the ice-glass interface. Using ellipsometry to monitor the thickness of the iceglass interface, we show that no intrinsic premelting occurs at the interface between ice and smooth clean glass. However, premelting is observed at interfaces with roughened glass surfaces and with the introduction of surface impurities. Roughened glass which was made hydrophobic showed no premelting. The implications for theories of premelting are discussed.
Body Site and Body Orientation Preferences during Social Grooming: A Comparison between Wild and Captive Chimpanzees and Bonobos

Grooming site preferences have been relatively well studied in monkey species in order to investigate the function of social grooming. They are not only influenced by the amount of ectoparasites, but also by different social variables such as the dominance rank between individuals or their levels of affiliation. However, studies on this topic mainly come from monkey species, with almost no report on great apes. This study aimed to explore whether body site and body orientation preferences during social grooming show species-specific differences (bonobos vs. chimpanzees) and environment-specific differences (captivity vs. wild). Results showed that bonobos groomed the head, the front and faced each other more often than chimpanzees, while chimpanzees groomed the back, anogenitals and more frequently in face-to-back positions. Moreover, captive individuals were found to groom facing one another more often than wild ones, whereas wild individuals groomed the back and in face-to-back positions more. While future studies should expand their scope to include more populations per condition, our preliminary 2 by 2 comparison study highlights the influence of (i) species-specific social differences such as social tolerance, social attention and facial communication, and (ii) socioenvironmental constraints such as risk of predation, spatial crowding and levels of hygiene, that might be the two important factors determining the grooming patterns in two Panspecies.
Thin‐film silicon solar cell technology

This paper describes the use, within p–i–n‐ and n–i–p‐type solar cells, of hydrogenated amorphous silicon (a‐Si:H) and hydrogenated microcrystalline silicon (μc‐Si:H) thin films (layers), both deposited at low temperatures (200°C) by plasma‐assisted chemical vapour deposition (PECVD), from a mixture of silane and hydrogen. Optical and electrical properties of the i‐layers are described. These properties are linked to the microstructure and hence to the i‐layer deposition rate, that in turn, affects throughput in production. The importance of contact and reflection layers in achieving low electrical and optical losses is explained, particularly for the superstrate case. Especially the required properties for the transparent conductive oxide (TCO) need to be well balanced in order to provide, at the same time, for high electrical conductivity (preferably by high electron mobility), low optical absorption and surface texture (for low optical losses and pronounced light trapping). Single‐junction amorphous and microcrystalline p–i–n‐type solar cells, as fabricated so far, are compared in their key parameters (Jsc, FF, Voc) with the [theoretical] limiting values. Tandem and multijunction cells are introduced; the μc‐Si: H/a‐Si: H or [micromorph] tandem solar cell concept is explained in detail, and recent results obtained here are listed and commented. Factors governing the mass‐production of thin‐film silicon modules are determined both by inherent technical reasons, described in detail, and by economic considerations. The cumulative effect of these factors results in distinct efficiency reductions from values of record laboratory cells to statistical averages of production modules. Finally, applications of thin‐film silicon PV modules, especially in building‐integrated PV (BIPV) are shown. In this context, the energy yields of thin‐film silicon modules emerge as a valuable gauge for module performance, and compare very favourably with those of other PV technologies. Copyright © 2004 John Wiley & Sons, Ltd.
miR-365 inhibits the progression of gallbladder carcinoma and predicts the prognosis of Gallbladder carcinoma patients

ABSTRACT Gallbladder carcinoma (GBC) is one of the most common fatal biliary tract tumors in the world. Its 3-year survival rate is 30% and the recurrence rate remains very high. miR-365 was downregulated in numerous tumors and worked as tumor suppressor gene. However, the role of miR-365 in GBC was unclear. In this study, our results found that the expression of miR-365 in GBC tissues was reduced rather than that in non-cancerous tissues. miR-365 overexpression inhibited the proliferation, metastasis and expansion of GBC CSCs. Mechanically, bioinformatic and luciferase reporter analysis identified Ras-related C3 botulinum toxin substrate 1 (RAC1) as a direct target of miR-365. Overexpression of miR-365 in GBC cells reduced the RAC1 mRNA and protein expression. The special RAC1 inhibitor EHop-106 abolished the discrepancy of growth, metastasis and self-renewal ability between miR-365-overexpression GBC cells and their control cells, which further demonstrated that RAC1 was involved in miR-365-disrupted GBC cells growth, metastasis and self-renewal. More importantly, reduced expression of miR-365 was a predictor of poor prognosis of GBC patients. In conclusion, miR-365 inhibited GBC cell growth, metastasis and self-renewal capacity by directly targeting RAC1, and may therefore prove to be a novel prognosis biomarker for GBC patients.