Miracle-dz/UniFAR-FTUs huggingface dataset:
Acid sphingomyelinase inhibition results in profound rescue of neuronal function in glucocerebrosidase deficiency

The additive effect of genetic risk variants on overall disease risk is a plausible but frequently unproven hypothesis. Variants in the two lysosomal disease genes glucocerebrosidase1 (GBA1) and sphingomyelinase (SMPD1) are genetic risk factors for sporadic Parkinson disease (PD). We investigated the biological effect of combined glucocerebrosidase (GCase) and acid sphingomyelinase (ASM) deficiency in zebrafish (Danio rerio), an ideally suited vertebrate model system to study gene-gene interaction. Combined genetic inactivation of GCase and ASM resulted in marked synergistic increases of key sphingolipids in the gba1-/-;smpd1-/- double-mutant compared to gba1-/- or smpd1-/- single mutant zebrafish. However, the gba1-/-;smpd1-/- double-mutant zebrafish unexpectedly displayed a complete reciprocal rescue of mitochondrial respiratory chain function compared to the gba1-/- or smpd1-/- single mutant zebrafish. The mitochondrial rescue effect resulted in abolished lipid membrane peroxidation, normalisation of motor behaviour and prolonged survival in the gba1-/-;smpd1-/- double-mutant zebrafish compared to the gba1-/- single mutant zebrafish strain. RNAseq-based transcriptomic pathway analysis confirmed a profound rescue of neuronal function and intracellular homeostasis. Complementing in vitro experiments in a previously established model of GCase deficiency in dopaminergic SH-SY5Y cells demonstrated that the observed rescue effect is autophagy-independent. Our study highlights the importance of a functional validation for any putative interactions between PD risk genes and their overall effect on disease-relevant mechanisms rather than readily assuming an additive effect.
A digital mm-Wave PA architecture with Simultaneous Frequency and back-off Reconfigurability

Spectrally-efficient operation with high power and high efficiency at deep back-off will be critical for the next-generation mm-Wave transmitters for 5G and beyond. In addition, as larger non-contiguous chunks of the mm-Wave spectrum open up, dynamic frequency reconfiguration while ensuring high spectral and energy efficiency can become key towards optimal utilization of spectral resources. In this paper, we present a generalized asymmetrical multi-port combiner based network synthesis approach that enables both frequency and back-off reconfigurability in a mm-Wave power amplifier (PA) architecture to maintain high-efficiency operation with spectrally efficient codes across a wide frequency range. As a proof of concept, a silicon-based PA is presented which operates between 30–55 GHz with peak Psat of 23.7 dBm at 40 GHz and output collector efficiency (ηout) of 34.5 % and 22% at the 0 and −6 dB back-off respectively. The PA maintains ηout > 16% at −6 dB back-off across the range. Non-constant modulation is demonstrated with pulse shaping and with data rates upto 4 Gbps across the frequencies from 30–50 GHz.
Predictive maintenance based on event-log analysis: A case study

Predictive maintenance techniques are designed to help anticipate equipment failures to allow for advance scheduling of corrective maintenance, thereby preventing unexpected equipment downtime, improving service quality for customers, and also reducing the additional cost caused by over-maintenance in preventative maintenance policies. Many types of equipment--e.g., automated teller machines (ATMs), information technology equipment, medical devices, etc.--track run-time status by generating system messages, error events, and log files, which can be used to predict impending failures. Aiming at these types of equipment, we present a general classification-based failure prediction method. In our parameterized model, we systematically defined four categories of features to try to cover all possibly useful features, and then used feature selection to identify the most important features for model construction. The general solution is sufficiently flexible and complex to address failure prediction for target equipment types. We chose ATMs as the example equipment and used real ATM run-time event logs and maintenance records as experimental data to evaluate our method on the feasibility and effectiveness. In this paper, we also share insights on how to optimize the model parameters, select the most effective features, and tune classifiers to build a high-performance prediction model.
The Cation-π Box Is a Specific Phosphatidylcholine Membrane Targeting Motif*

Background: Specific interactions of peripheral membrane proteins with phosphatidylcholine (PC) are poorly characterized. Results: Staphylococcus aureus phosphatidylinositol-specific phospholipase C has poor affinity for PC. Introduction of two tyrosines generates a specific PC binding site. Conclusion: The PC choline cation interaction with amino acid π systems forms the PC-specific site. Significance: Well defined choline cation-aromatic π interactions may be a general motif to anchor proteins to PC-rich bilayers. Peripheral membrane proteins can be targeted to specific organelles or the plasma membrane by differential recognition of phospholipid headgroups. Although molecular determinants of specificity for several headgroups, including phosphatidylserine and phosphoinositides are well defined, specific recognition of the headgroup of the zwitterionic phosphatidylcholine (PC) is less well understood. In cytosolic proteins the cation-π box provides a suitable receptor for choline recognition and binding through the trimethylammonium moiety. In PC, this moiety might provide a sufficient handle to bind to peripheral proteins via a cation-π cage, where the π systems of two or more aromatic residues are within 4–5 Å of the quaternary amine. We prove this hypothesis by engineering the cation-π box into secreted phosphatidylinositol-specific phospholipase C from Staphylococcus aureus, which lacks specific PC recognition. The N254Y/H258Y variant selectively binds PC-enriched vesicles, and x-ray crystallography reveals N254Y/H258Y binds choline and dibutyroylphosphatidylcholine within the cation-π motif. Such simple PC recognition motifs could be engineered into a wide variety of secondary structures providing a generally applicable method for specific recognition of PC.
LRRK2 Kinase Inhibition Rescues Deficits in Lysosome Function Due to Heterozygous GBA1 Expression in Human iPSC-Derived Neurons

A growing number of genes associated with Parkinson’s disease are implicated in the regulation of lysosome function, including LRRK2, whose missense mutations are perhaps the most common monogenic cause of this neurodegenerative disease. These mutations are collectively thought to introduce a pathologic increase in LRRK2 kinase activity, which is currently a major target for therapeutic intervention. Heterozygous carriers of many missense mutations in the GBA1 gene have dramatically increased risk of Parkinson’s disease. A critical question has recently emerged regarding the potential interplay between the proteins encoded by these two disease-linked genes. Our group has recently demonstrated that knockin mutation of a Parkinson’s-linked GBA1 variant induces severe lysosomal and cytokine abnormalities in murine astrocytes and that these deficits were normalized via inhibition of wild-type LRRK2 kinase activity in these cells. Another group independently found that LRRK2 inhibition increases glucocerebrosidase activity in wild-type human iPSC-derived neurons, as well as those whose activity is disrupted by GBA1 or LRRK2 mutation. Fundamental questions remain in terms of the lysosomal abnormalities and the effects of LRRK2 kinase inhibition in human neurons deficient in glucocerebrosidase activity. Here, we further elucidate the physiological crosstalk between LRRK2 signaling and glucocerebrosidase activity in human iPSC-derived neurons. Our studies show that the allelic loss of GBA1 manifests broad defects in lysosomal morphology and function. Furthermore, our data show an increase in both the accumulation and secretion of oligomeric α-synuclein protein in these GBA1-heterozygous-null neurons, compared to isogenic controls. Consistent with recent findings in murine astrocytes, we observed that multiple indices of lysosomal dysfunction in GBA1-deficient human neurons were normalized by LRRK2 kinase inhibition, while some defects were preserved. Our findings demonstrate a selective but functional intersection between glucocerebrosidase dysfunction and LRRK2 signaling in the cell and may have implications in the pathogenesis and treatment of Parkinson’s disease.
Feasibility of MRI guided proton therapy: magnetic field dose effects

Many methods exist to improve treatment outcome in radiotherapy. Two of these are image-guided radiotherapy (IGRT) and proton therapy. IGRT aims at a more precise delivery of the radiation, while proton therapy is able to achieve more conformal dose distributions. In order to maximally exploit the sharp dose gradients from proton therapy it has to be combined with soft-tissue based IGRT. MRI-guided photon therapy (currently under development) offers unequalled soft-tissue contrast and real-time image guidance. A hybrid MRI proton therapy system would combine these advantages with the advantageous dose steering capacity of proton therapy. This paper addresses a first technical feasibility issue of this concept, namely the impact of a 0.5 T magnetic field on the dose distribution from a 90 MeV proton beam. In contrast to photon therapy, for MR-guided proton therapy the impact of the magnetic field on the dose distribution is very small. At tissue–air interfaces no effect of the magnetic field on the dose distribution can be detected. This is due to the low-energy of the secondary electrons released by the heavy protons.
XX Male – Testicular Disorder of Sexual Differentiation ( DSD ) : hormonal , molecular and cytogenetic studies Homem 46 , XX ( DSD testicular ) : estudos hormonal , molecular e citogenético

The XX male syndrome – Testicular Disorder of Sexual Differentiation (DSD) is a rare condition characterized by a spectrum of clinical presentations, ranging from ambiguous to normal male genitalia. We report hormonal, molecular and cytogenetic evaluations of a boy presenting with this syndrome. Examination of the genitalia at age of 16 months, showed: penis of 3.5 cm, proximal hypospadia and scrotal testes. Pelvic ultrasound did not demonstrate Mullerian duct structures. Karyotype was 46,XX. Gonadotrophin stimulation test yielded insufficient testosterone production. Gonadal biopsy showed seminiferous tubules without evidence of Leydig cells. Molecular studies revealed that SRY and TSPY genes and also DYZ3 sequences were absent. In addition, the lack of deletions or duplications of SOX9, NR5A1, WNT4 and NROB1 regions was verified. The infant was heterozygous for all microsatellites at the 9p region, including DMRT1 gene, investigated. Only 10% of the patients are SRY-negative and usually they have ambiguous genitalia, as the aforementioned patient. The incomplete masculinization suggests gain of function mutation in one or more genes downstream to SRY gene. Arq Bras Endocrinol Metab. 2010;54(8):685-9
Activation of the Epithelial Sodium Channel (ENaC) by the Alkaline Protease from Pseudomonas aeruginosa*

Background: Pseudomonas aeruginosa alkaline protease is a virulence factor that contributes to cystic fibrosis pathology. Results: The ENaC channel is activated by alkaline protease. Conclusion: Alkaline protease secretion may contribute to bacterial virulence by altering ENaC activity. Significance: The results provide insight into patho-mechanisms associated with alkaline protease secretion. Pseudomonas aeruginosa is an opportunistic pathogen that significantly contributes to the mortality of patients with cystic fibrosis. Chronic infection by Pseudomonas induces sustained immune and inflammatory responses and damage to the airway. The ability of Pseudomonas to resist host defenses is aided, in part, by secreted proteases, which act as virulence factors in multiple modes of infection. Recent studies suggest that misregulation of protease activity in the cystic fibrosis lung may alter fluid secretion and pathogen clearance by proteolytic activation of the epithelial sodium channel (ENaC). To evaluate the possibility that proteolytic activation of ENaC may contribute to the virulence of Pseudomonas, primary human bronchial epithelial cells were exposed to P. aeruginosa and ENaC function was assessed by short circuit current measurements. Apical treatment with a strain known to express high levels of alkaline protease (AP) resulted in an increase in basal ENaC current and a loss of trypsin-inducible ENaC current, consistent with sustained activation of ENaC. To further characterize this AP-induced ENaC activation, AP was purified, and its folding, activity, and ability to activate ENaC were assessed. AP folding was efficient under pH and calcium conditions thought to exist in the airway surface liquid of normal and cystic fibrosis (CF) lungs. Short circuit measurements of ENaC in polarized monolayers indicated that AP activated ENaC in immortalized cell lines as well as post-transplant, primary human bronchial epithelial cells from both CF and non-CF patients. This activation was mapped to the γ-subunit of ENaC. Based on these data, patho-mechanisms associated with AP in the CF lung are proposed wherein secretion of AP leads to decreased airway surface liquid volume and a corresponding decrease in mucocilliary clearance of pulmonary pathogens.
Pulmonary infection interrupts acute cutaneous wound healing through disruption of chemokine signals

Studies of the immune response typically focus on single-insult systems, with little known about how multi-insult encounters are managed. Pneumonia in patients recovering from surgery is a clinical situation that exemplifies the need for the patient to mount two distinct immune responses. Examining this, we have determined that poor wound healing is an unreported complication of pneumonia in laparotomy patients. Using mouse models, we found that lung infection suppressed the trafficking of innate leukocytes to wounded skin, while pulmonary resistance to the bacterial infection was maintained. The dual insults caused distinct systemic and local changes to the inflammatory response, the most striking being a rapid and sustained decrease in chemokine levels at the wound site of mice with pneumonia. Remarkably, replenishing wound chemokine levels completely rescued the wound-healing rate in mice with a pulmonary infection. These findings have broad implications for understanding the mechanisms guiding the innate immune system to prioritize inflammatory sites. One Sentence Summary Chemokine-mediated signaling drives the prioritization of innate immune responses to bacterial pulmonary infection over cutaneous wound healing. Highlights Human laparotomy patients with pneumonia have an increased rate of incision dehiscence, and this observation can be recapitulated in mouse models of bacterial lung infections and skin wounds. Lung infection causes rapid and sustained suppression of skin wound chemokine and inflammatory cytokine production as well as leukocyte recruitment. Unique systemic shifts in the immune compartment occur with two inflammatory insults, including the cytokine/chemokine signature and the mobilization, recruitment, and phenotype of innate leukocytes. Restoration of chemokine signaling in the wounds of mice that have a lung infection results in increased neutrophil trafficking to the wound site and rescues the rate of healing. Graphical Abstract
Fuel choices in urban Indian households

ABSTRACT This paper applies an ordered discrete choice framework to model fuel choices and patterns of cooking fuel use in urban Indian households. The choices considered are for three main cooking fuels: firewood, kerosene, and LPG (liquid petroleum gas). The models, estimated using a large microeconomic dataset, show a reasonably good performance in the prediction of households’ primary and secondary fuel choices. This suggests that ordered models can be used to analyze multiple fuel use patterns in the Indian context. The results show that lack of sufficient income is one of the main factors that retard households from using cleaner fuels, which usually also require the purchase of relatively expensive equipments. The results also indicate that households are sensitive to LPG prices. In addition to income and price, several socio-demographic factors such as education and sex of the head of the household are also found to be important in determining household fuel choice.
Embolization of cerebral arteriovenous malformations: Part II--Aspects of complications and late outcome.

OBJECTIVE From 1987 through 1993, we performed embolizations on 150 patients with cerebral arteriovenous malformations (AVMs) at Sahlgrenska University Hospital. The patients ranged in age from 5 to 70 years (35.5 +/- 14.8 yr, mean +/- standard deviation) and were selected by neurosurgeons in Scandinavia. We analyzed the risk of complications and late outcome to have a better basis for the decision to perform embolization. METHODS The follow-up was a personal clinical examination of all surviving patients by a neurologist. Files for all patients were also studied. RESULTS In 34 patients, the AVMs were eliminated by embolization alone (20 patients) or by supplementary surgery (14 patients). In 66 patients, the AVMs were embolized to a size suitable for supplementary stereotactic radiation. The clinical course was stable for those 100 patients. Another group of 50 patients who had undergone embolization was only partially treated, and as a group, those patients had less favorable outcomes. The manifestations or symptoms leading to diagnosis were in concordance with other studies. Headache and epilepsy showed a positive response to treatment in patients whose AVMs had been eliminated as well as in those who received only partial treatment. A history of cerebral bleeding did not influence the prognosis of recurrent bleeding. Conversely, AVMs with feeder or nidus aneurysms were related to an increased risk of bleeding. If there was a history of bleeding in a patient with large, partially treated AVMs, the prognosis for survival was diminished. CONCLUSION The indication for treatment increases with the occurrence of AVMs with associated aneurysms. For patients with large AVMs, a history of bleeding justifies a more aggressive approach to treatment. The reduced risk of complications during the last years of the study also increases the indication for embolization.
Subclinical Hypothyroidism and Associated Cardiovascular Risk Factor in Perimenopausal Females

Background: Perimenopause refers to the period around menopause (40-55 years). This includes the period before menopause and the first year after menopause. Perimenopausal age is an important stage in a women's life. Many women are diagnosed with hypothyroidism at midlife. Hypothyroidism - both overt and subclinical are associated with increased risk of CVS diseases. Subclinical hypothyroidism is more important as this stage is usually ignored from treatment point of view and if early intervention is done in SCH worsening of metabolic derangement may be avoided. Objectives: The present study was aimed to know the prevalence of subclinical hypothyroidism and associated dyslipidemia in perimenopausal females. Material and Methods: In our retrospective study we took 100 perimenopausal females (40-55years) who were investigated for thyroid and lipid profile. Atherogenic indices like TC/HDL-c, LDL-c/HDL-c, TG/HDL-c ratios were calculated from the individual lipid profile parameters. The reference guidelines for lipid profile was according to NCEP ATP III. Result: Subclinical hypothyroidism was found to be present in 18% of perimenopausal females The mean TSH levels were found to be higher in SCH as compared to euthyroid females with a mean value of 7.56±3.54(μIU/ml). Dyslipidemia was seen in patients with SCH. TSH levels were found to be positively correlated with total cholesterol. Conclusion: We conclude that subclinical hypothyroidism is present in 18% females of perimenopausal age group. Increased TSH levels are associated with hypertension, hypertriglyceridemia, and elevated TC/HDL-C ratio and non cholesterol HDL. In perimenopausal women the condition is usually underdiagnosed and ignored but subclinical hypothyroidism in these females should be screened and treated timely to decrease the risk of accelerated atherosclerosis and premature coronary artery disease in them.
Clothed particle representation in quantum field theory: Mass renormalization

We consider the neutral pion and nucleon fields interacting via the pseudoscalar (PS) Yukawa-type coupling. The method of unitary clothing transformations is used to handle the so-called clothed particle representation, where the total field Hamiltonian and the three boost operators in the instant form of relativistic dynamics take on the same sparse structure in the Hilbert space of hadronic states. In this approach the mass counterterms are cancelled (at least, partly) by commutators of the generators of clothing transformations and the field interaction operator. This allows the pion and nucleon mass shifts to be expressed through the corresponding three-dimensional integrals whose integrands depend on certain covariant combinations of the relevant three-momenta. The property provides the momentum independence of mass renormalization. The present results prove to be equivalent to the results obtained by Feynman techniques.
ISOLATION AND SCREENING OF THERMO-STABLE CELLULASE ENZYME FUNGAL PRODUCER AT DIFFERENT TEMPERATURE ( Pengasingan dan Saringan Enzim Selulosa Tahan Haba dari Kulat pada Suhu yang Berbeza )

Thermostable cellulase from fungi has high potential for industrial application. In this study, wild -type of fungal were isolate from different sources such as hot spring water, sea water, soft wood, rice straw and cow dung. The isolates were characterized by cultural and morphological observation. Based on morphological characteristics, the genera of all fungal cultures were identified namely Aspergillus fumigatus. The screening for thermostable cellulase were done using 2% carboxymethyl cellulose and congo red as an indicator at temperature 30 ̊C, 37 ̊C, 45 ̊C and 50 ̊C respectively. Out of 26 fungal isolates, only eight isolates were selected for further screening and showed the abilities to secrete cellulases by forming distinct halo zones on selective agar plate. The maximum halo zone ranging from 32mm to 35mm were obtained after 72 hour incubation at 50 ̊C by H2, SW1 and C1 isolates. As contrary other isolates showed halo zone range from 22 mm to 29 mm at same temperature. All the isolates showed the abilities to secrete cellulase enzyme at other temperature but lower when compared to 50 ̊C referred to the halo zone obtained. The SW1 isolates showed highest celluloytic index which was 2.93measured at 37 ̊C and 2.67 at 50 ̊C respectively.
Dynamic interactive framework to link business intelligence with strategy

Business Intelligence (BI) has been a popular manner for companies in the information age. Previous literatures have focused on technologies of BI like data warehouse, On Line Analytical Processing (OLAP) and data mining but a few cases explained how to link BI with strategic goals. This paper illustrates a whole picture to describe different levels of BI from a globalisation perspective. Furthermore, the combination of value creation process of Balanced Scorecard (BSC) and BI units will become the connection processes of strategic goals and BI. In this paper, System Dynamics plays an important role of causation validity and dynamic feedback interaction. Finally, a dynamic interactive framework of global BI is proposed for practical operation to improve conventional BSC Systems in industry.