Miracle-dz/UniFAR-FTUs huggingface dataset:
14-3-3 Proteins in Guard Cell Signaling

Guard cells are specialized cells located at the leaf surface delimiting pores which control gas exchanges between the plant and the atmosphere. To optimize the CO2 uptake necessary for photosynthesis while minimizing water loss, guard cells integrate environmental signals to adjust stomatal aperture. The size of the stomatal pore is regulated by movements of the guard cells driven by variations in their volume and turgor. As guard cells perceive and transduce a wide array of environmental cues, they provide an ideal system to elucidate early events of plant signaling. Reversible protein phosphorylation events are known to play a crucial role in the regulation of stomatal movements. However, in some cases, phosphorylation alone is not sufficient to achieve complete protein regulation, but is necessary to mediate the binding of interactors that modulate protein function. Among the phosphopeptide-binding proteins, the 14-3-3 proteins are the best characterized in plants. The 14-3-3s are found as multiple isoforms in eukaryotes and have been shown to be involved in the regulation of stomatal movements. In this review, we describe the current knowledge about 14-3-3 roles in the regulation of their binding partners in guard cells: receptors, ion pumps, channels, protein kinases, and some of their substrates. Regulation of these targets by 14-3-3 proteins is discussed and related to their function in guard cells during stomatal movements in response to abiotic or biotic stresses.
PARP inhibitor olaparib sensitizes cholangiocarcinoma cells to radiation

Cholangiocarcinoma (CCA) is a highly malignant tumor with resistance to radiotherapy alone. Olaparib, a highly potent poly(ADP‐ribose) polymerase (PARP) inhibitor, has been shown to sensitize many types of tumor to radiotherapy. However, the effect of olaparib, either as monotherapy or as combination therapy with radiotherapy, on CCA is not known, and our study aimed to explore this. To assess radiosensitization in three CCA cell lines (QBC939, HuH28 and TFK‐1), viability and clonogenic assays were conducted. The absorbed radiation doses were 0 Gy, 2 Gy, 4 Gy, and 6 Gy; olaparib concentrations were 0 nmol/L, 1 nmol/L, 10 nmol/L, 100 nmol/L, 1000 nmol/L, 2500 nmol/L, 5000 nmol/L and 10 000 nmol/L. The mechanism of olaparib radiosensitization was explored by Western blotting. Immunofluorescence staining and flow cytometry were conducted to explore DNA damage and apoptosis. The radiosensitivity of CCA cells was enhanced by olaparib, which alone had little effect on the CCA cell lines without BRCA mutations. The degree of radiosensitization increased with increasing doses of olaparib by viability and clonogenic assays in vitro. Olaparib was able to enhance the effect of radiation by inhibiting PARP1, inducing DNA lesions and apoptosis. These findings emphasize the role of olaparib in the radiosensitization of CCA cells.
Delamination detection in wood - based composites, a methodological review.

Commonly observed damage in wood products and wood-based composites are: wood fibre fracture, delaminat ion between plies or debonding of wood‐adhesive layers. Delamination which is probably the most frequently observed damage, may be produced during manufacturing or, during in service loading such as accidental excessiv e loading produced for example by snow or, by fatigue in high ly variable environmental conditions of temperature and humidity. Damage detection in general and delamination i n particular is a very important issue in the conte xt of structural health monitoring for mechanical engineering infras tructure with elements in wood and wood-based composites. The development of computational techniques in the last twenty five years, and the progress achieved in me chanical characterisation of solids in general and of composites in particular, affected positively the development of the modelling of wood and wood-based composites mechanical behaviour. Related studies clearly suggest that delaminat ion in solid wood can occur between different layers of th e cell wall at submicroscopic, microscopic and macr oscopic structural levels. With respect to wood-based composites , the behaviour of two groups of products has been analysed: the laminated products and the fibre‐based products. De lamination detection studies were summarized in the context of structural health monitoring, The review of the the oretical aspects related to the detection of damage s induced by delamination in composites was oriented in two main d irections: the nondestructive evaluation method us ing an ultrasonic technique with Lamb waves, which is an experimental method able to provide local damage information and the model dependent method, at relatively low freq uency, which undertake analysis of structural model s implemented by finite element analysis and is able to pr ovide global damage information, for linear and non -linear mechanical behavior of the system The development of wood ‐ based composites testing methodologies for delamination detection should be encouraged as part of the efforts being made to control the performance of lo w cost building materials
Nonclinical comparability studies of recombinant human arylsulfatase A addressing manufacturing process changes

Recombinant human arylsulfatase A (rhASA) is in clinical development for the treatment of patients with metachromatic leukodystrophy (MLD). Manufacturing process changes were introduced to improve robustness and efficiency, resulting in higher levels of mannose-6-phosphate and sialic acid in post-change (process B) compared with pre-change (process A) rhASA. A nonclinical comparability program was conducted to compare process A and process B rhASA. All doses were administered intrathecally. Pharmacodynamic comparability was evaluated in immunotolerant MLD mice, using immunohistochemical staining of lysosomal-associated membrane protein-1 (LAMP-1). Pharmacokinetic comparability was assessed in juvenile cynomolgus monkeys dosed once with 6.0 mg (equivalent to 100 mg/kg of brain weight) process A or process B rhASA. Biodistribution was compared by quantitative whole-body autoradiography in rats. Potential toxicity of process B rhASA was evaluated by repeated rhASA administration at doses of 18.6 mg in juvenile cynomolgus monkeys. The specific activities for process A and process B rhASA were 89 U/mg and 106 U/mg, respectively, which were both well within the target range for the assay. Pharmacodynamic assessments showed no statistically significant differences in LAMP-1 immunohistochemical staining in the spinal cord and in most of the brain areas assessed between process A and B rhASA-dosed mice. LAMP-1 staining was reduced with both process A and B rhASA compared with vehicle, supporting its activity. Concentration–time curves in cerebrospinal fluid and serum of cynomolgus monkeys were similar with process A and B rhASA. Process A and B rhASA were similar in terms of their pharmacokinetic parameters and biodistribution data. No process B rhASA-related toxicity was detected. In conclusion, manufacturing process changes did not affect the pharmacodynamic, pharmacokinetic or safety profiles of process B rhASA relative to process A rhASA.
Cytoplasmic Translocation of Nucleolar Protein NOP53 Promotes Viral Replication by Suppressing Host Defense

NOP53 is a tumor suppressor protein located in the nucleolus and is translocated to the cytoplasm during infection by vesicular stomatitis virus (VSV) and herpes simplex virus type 1 (HSV-1), as shown in our previous study. Cytoplasmic NOP53 interacts with the retinoic acid-inducible gene I (RIG-I) to remove its K63-linked ubiquitination, leading to attenuation of type I interferon IFN-β. In the present study, we found no obvious translocation of NOP53 in infection by a mutant virus lacking ICP4 (HSV-1/d120, replication inadequate). Blocking cytoplasmic translocation of NOP53 by the deletion of its nuclear export sequence (NES) abrogated its ability to support viral replication. These results demonstrated that NOP53 redistribution is related to viral replication. It is interesting that treatment with poly (I:C) or RIG-I-N (a constitutively-active variant) directly induced NOP53 cytoplasmic translocation. To better assess the function of cytoplasmic NOP53 in viral replication, the NOP53-derived protein N3-T, which contains a human immunodeficiency virus (HIV)-derived cell-penetrating Tat peptide at the C-terminal region of N3 (residues 330–432), was constructed and expressed. The recombinant N3-T protein formed trimers, attenuated the expression of IFN-β and IFN-stimulated genes, as well as decreased the phosphorylation level of interferon regulatory factor 3 (IRF3). Furthermore, N3-T promoted the efficient replication of enveloped and non-enveloped DNA and RNA viruses belonging to 5 families. Our findings expand the understanding of the mechanism by which viruses utilize the nucleolar protein NOP53 for optimal viral replication.
Adverse Mandibular Bone Effects Associated with Kidney Disease Are Only Partially Corrected with Bisphosphonate and/or Calcium Treatment

Background/Aims: Patients with chronic kidney disease (CKD) have a high prevalence of periodontal disease that may predispose to tooth loss and inflammation. The goal of this study was to test the hypotheses that a genetic rat model of progressive CKD would exhibit altered oral bone properties and that treatment with either bisphosphonates or calcium could attenuate these adverse changes. Methods: At 25 weeks of age, rats were treated with zoledronate (ZOL), calcium gluconate, or their combination for 5 or 10 weeks. Mandible bone properties were assessed using micro-computed tomography to determine bone volume (BV/TV) and cementum-enamel junction to alveolar crest distance (CEJ-AC). Results: Untreated CKD animals had significantly lower BV/TV at both 30 (-5%) and 35 (-14%) weeks of age and higher CEJ-AC (+27 and 29%) compared to normal animals. CKD animals had a significantly higher parathyroid hormone (PTH) compared to normal animals, yet similar levels of C-reactive protein (CRP). ZOL treatment normalized BV/TV over the first 5 weeks but this benefit was lost by 10 weeks. Calcium treatment, alone or in combination with ZOL, was effective in normalizing BV/TV at both time points. Neither ZOL nor calcium was able to correct the higher CEJ-AC caused by CKD. Calcium, but not ZOL, significantly reduced serum PTH, while neither treatment affected CRP. Conclusions: (i) This progressive animal model of CKD shows a clear mandibular skeletal phenotype consistent with periodontitis, (ii) the periodontitis is not associated with systemic inflammation as measured by CRP, and (iii) reducing PTH has positive effects on the mandible phenotype.
Environmental Isolation of Cryptococcus gattii VGII from Indoor Dust from Typical Wooden Houses in the Deep Amazonas of the Rio Negro Basin

Cryptococcosis is a human fungal infection of significant mortality and morbidity, especially in the meningoencephalitis form. Cryptococcosis is distributed worldwide and its agents, C. neoformans and C. gattii, present eight major molecular types—VNI-VNIV and VGI-VGIV respectively. The primary cryptococcosis caused by molecular type VGII (serotype B, MAT alpha) prevails in immunocompetent patients in the North and Northeast of Brazil, revealing an endemic regional pattern to this molecular type. Since 1999, C. gattii VGII has been involved in an ongoing outbreak in Canada, and is expanding to the Northwest of the United States, two temperate regions. Exposure to propagules dispersed in the environment, related to various organic substrates, mainly decomposing wood in and around dwellings, initiates the infection process. The present study investigated the presence of the agents of cryptococcosis in dust from dwellings in the upper Rio Negro, municipality of Santa Isabel do Rio Negro in Amazonas state. Indoor dust was collected from 51 houses, diluted and plated on bird seed agar. Dark brown colonies were identified phenotypically, and genotypically by URA5 restriction fragment length polymorphism analysis and multilocus sequence typing (MLST). The mating type was identified using pheromone-specific primers. Three of the 51 houses were positive for C. gattii molecular type VGII, MATα and MATa, showing a high prevalence of this agent. MLST studies identified eight subtypes, VGIIb (ST7), VGIIa (ST20), (ST5) and 5 new subtypes unique to the region. For the first time in the state of Amazonas, C. gattii VGII MATα and MATa were isolated from the environment and correlates with endemic cryptococcosis in this state. This is the first description of MLST subtypes on environmental isolates in the Brazilian Amazon, indicating domiciliary dust as a potential source for human infection with different subtypes of C. gattii VGII MATα and MATa.
The role of empagliflozin in the management of type 2 diabetes by patient profile

Current recommendations for the management of type 2 diabetes mellitus (T2DM) include patient-centered approach, ie, targeting glycemic control based on patient and disease characteristics. Ten different classes of oral and injectable anti-hyperglycemic agents have been developed for T2DM, including the newest class – sodium–glucose cotransporter 2 (SGLT2) inhibitors. Four members of the class with comparable glycemic efficacy and side effects have gained approval in the US and the rest of the world. This review covers empagliflozin – third approved SGLT2 inhibitor in the US. The drug has shown rapid absorption reaching peak levels in ~2 hours and an elimination half-life of ~13 hours. Empagliflozin is a highly selective SGLT2 inhibitor with 2600-fold higher affinity for SGLT2 compared with SGLT1. Oral administration results in a dose-dependent inhibition of the transporters with increased urinary glucose excretion and resultant reduction in plasma glucose. Its efficacy and safety have been shown in a number of studies conducted in many countries. Across the trials, significant improvements in primary and secondary efficacy end points have been demonstrated, including reductions in HbA1c (~−0.8%), fasting plasma glucose (~−2 mmol/L), body weight (~−2 kg), and blood pressure (systolic −4 mmHg and diastolic −2 mmHg). Similar to other SGLT2 inhibitors, empagliflozin does not increase the risk for hypoglycemia, and the most commonly reported side effects are urinary and genital tract infections. Although empagliflozin can be used as the first-line monotherapy, its current place in the treatment of T2DM appears to be as an add-on to other oral anti-hyperglycemic agent(s) or insulin at any stage of the disease.
ROAST: An Open-Source, Fully-Automated, Realistic Volumetric-Approach-Based Simulator For TES

Research in the area of transcranial electrical stimulation (TES) often relies on computational models of current flow in the brain. Models are built on magnetic resonance images (MRI) of the human head to capture detailed individual anatomy. To simulate current flow, MRIs have to be segmented, virtual electrodes have to be placed on the scalp, the volume is tessellated into a mesh, and the finite element model is solved numerically to estimate the current flow. Various software tools are available for each step, as well as processing pipelines that connect these tools for automated or semi-automated processing. The goal of the present tool - ROAST – is to provide an end-to-end pipeline that can automatically process individual heads with realistic volumetric anatomy leveraging open-source software (SPM8, iso2mesh and getDP) and custom scripts to improve segmentation and execute electrode placement. When we compare the results on a standard head with other major commercial software for finite element modeling (ScanIP, Abaqus), ROAST only leads to a small difference of 9% in the estimated electric field in the brain. We obtain a larger difference of 47% when comparing results with SimNIBS, an automated pipeline that is based on surface segmentation of the head. We release ROAST as an open-source, fully-automated pipeline at https://www.parralab. org/roast/.
Viral vectors for cystic fibrosis gene therapy: What does the future hold?

Correspondence: Uta Griesenbach Department of Gene Therapy, Faculty of Medicine at the National Heart and Lung institute, imperial College London, Manresa Road, London Sw3 6LR, UK Tel +44 207 351 8339 Fax +44 207 351 8340 email u.griesenbach@imperial.ac. uk Abstract: Gene transfer to the airway epithelium has been more difficult than originally anticipated, largely because of significant extraand intracellular barriers in the lung. In general, viral vectors are more adapted to overcoming these barriers than nonviral gene transfer agents and are, therefore, more efficient in transferring genes into recipient cells. Viral vectors derived from adenovirus, adeno-associated virus, and Sendai virus, which all have a natural tropism for the airway epithelium, have been evaluated for cystic fibrosis (CF) gene therapy. Although these vectors transduce airway epithelial cells efficiently, gene expression is transient and repeated administration is inefficient. They are, therefore, unlikely to be suitable for CF gene therapy. More recently, lentiviruses (LV) have been assessed for lung gene transfer. In contrast to retroviruses, they transduce nondividing cells and randomly integrate into the genome. However, LVs do not have a natural tropism for the lung, and a significant amount of effort has been put into pseudotyping these vectors with proteins suitable for airway gene transfer. Several studies have shown that LV-mediated transduction leads to persistent gene expression (for the lifetime of the animal) in the airways and, importantly, repeated administration is feasible. Thus, appropriately pseudotyped LV vectors are promising candidates for CF gene therapy. Here, we will review preclinical and clinical research related to viral CF gene therapy.
Product sounds: Basic concepts and categories

In this paper we investigated which categories of product sounds listeners can distinguish. We explored the perceptual domain of product sounds in order to be able to derive perceptually similar categories and determine how users are able to describe these categories by merely listening to them. Employing two different experimental paradigms (free categorization and pairwise comparison), we determined six perceptually relevant product sound categories (air, alarm, cyclic, impact, liquid, mechanical) and nine basic concepts that mentally represent these categories (sound source, action, location, sound type, onomatopoeias, psychoacoustics, temporal descriptions, emotions, abstract meaning). The results indicate that these categories are not only a direct consequence of perceptual similarities in the spectral temporal structure but also result from similarities based on cognitive, emotional, and contextual evaluations of the sound. We conclude that sound is an intrinsic property of a product and, with the knowledge gathered in this study, designers will be able to relate the auditory property of a product to the overall product experience. In addition, this paper presents two methods for the perceptual evaluation of product sounds.
Proliferation accurately identifies the high-risk patients among small, low-grade, lymph node-negative invasive breast cancers.

BACKGROUND The proliferation factor mitotic activity index (MAI) is the strongest prognosticator in lymph node-negative invasive breast cancer patients under age 71. The question remains, whether this also holds for 'favourable prognosis' subgroups. PATIENTS AND METHODS The study was a multicentre prospective analysis of the MAI for recurrence-free survival and overall cancer-related survival of grade, MAI, and other prognosticators in 853 long-term follow-up, T1-3N0M0 breast cancer patients under 71 years. RESULTS In all tumours together (N = 853), in grade 3 (n = 269), in tumours <1 cm all grades (n = 84), 1-2 cm, grades 1 + 2 (n = 300), and 2-3 cm, grades 1 + 2 (n = 124), the MAI is prognostically superior. Other features [grade, estrogen receptor (ER), diameter, and age] did not enhance its prognostic value except in grades 1 + 2 tumours 2-3 cm diameter with MAI <10, where ER has an additional prognostic value. CONCLUSIONS In women <71 years with T1-3N0M0 small or low-grade invasive breast cancer usually not receiving systemic treatment, MAI > or =10 accurately identifies those at high risk. These high-risk patients should be considered for adjuvant systemic therapy.
Spatiotemporal Expression of MANF in the Developing Rat Brain

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an evolutionarily conserved neurotrophic factor which exhibited neuroprotective properties. Recent studies suggested that MANF may play a role in the neural development of Drosophila and zebra fishes. In this study, we investigated the spatiotemporal expression of MANF in the brain of postnatal and adult rats. MANF expression appeared wide spread and mainly localized in neurons. In the cerebral cortex, neurons in layer IV and VI displayed particularly strong MANF immunoreactivity. In the hippocampus, intensive MANF expression was observed throughout the subfields of Cornu Amonis (CA1, CA2, and CA3) and the granular layer of the dentate gyrus (DG). In the substantia nigra, high MANF expression was shown in the substantia nigra pars compacta (SNpc). In the thalamus, the anterodorsal thalamic nucleus (ADTN) exhibited the highest MANF immunoreactivity. In the hypothalamus, intensive MANF immunoreactivity was shown in the supraoptic nucleus (SON) and tuberomammillary nucleus (TMN). In the cerebellum, MANF was localized in the external germinal layer (EGL), Purkinje cell layer (PCL), internal granule layer (IGL) and the deep cerebellar nuclei (DCN). We examined the developmental expression of MANF on postnatal day (PD) 3, 5, 7, 9, 15, 21, 30 and adulthood. In general, the levels of MANF were high in the early PDs (PD3 and PD5), and declined gradually as the brain matured; MANF expression in the adult brain was the lowest among all time points examined. However, in some structures, such as PCL, IGL, SON, TMN and locus coeruleus (LC), high expression of MANF sustained throughout the postnatal period and persisted into adulthood. Our results indicated that MANF was developmentally regulated and may play a role in the maturation of the central nervous system (CNS).
The Distortion Rate Function of Cyclostationary Gaussian Processes

A general expression for the quadratic distortion rate function (DRF) of cyclostationary Gaussian processes in terms of their spectral properties is derived. This expression can be seen as the result of orthogonalization over the different components in the polyphase decomposition of the process. We use this expression to derive, in a closed form, the DRF of several cyclostationary processes arising in practice. We first consider the DRF of a combined sampling and source coding problem. It is known that the optimal coding strategy for this problem involves source coding applied to a signal with the same structure as one resulting from pulse amplitude modulation (PAM). Since a PAM-modulated signal is cyclostationary, our DRF expression can be used to solve for the minimal distortion in the combined sampling and source coding problem. We also analyze in more detail the DRF of a source with the same structure as a PAM-modulated signal, and show that it is obtained by reverse waterfilling over an expression that depends on the energy of the pulse and the baseband process modulated to obtain the PAM signal. This result is then used to explore the effect of the symbol rate in PAM on the DRF of its output. In addition, we also study the DRF of sources with an amplitude-modulation structure, and show that the DRF of a narrow-band Gaussian stationary process modulated by either a deterministic or a random phase sine-wave equals the DRF of the baseband process.