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Powered ankle prostheses have been proven to improve the walking economy of people with transtibial amputation. All commercial powered ankle prostheses that are currently available can only perform one-degree-of-freedom motion in a limited range. However, studies have shown that the frontal plane motion during ambulation is associated with balancing. In addition, as more advanced neural interfaces have become available for people with amputation, it is possible to fully recover ankle function by combining neural signals and a robotic ankle. Accordingly, there is a need for a powered ankle prosthesis that can have active control on not only plantarflexion and dorsiflexion but also eversion and inversion. We designed, built, and evaluated a two-degree-of-freedom (2-DoF) powered ankle–foot prosthesis that is untethered and can support level-ground walking. Benchtop tests were conducted to characterize the dynamics of the system. Walking trials were performed with a 77 kg subject that has unilateral transtibial amputation to evaluate system performance under realistic conditions. Benchtop tests demonstrated a step response rise time of less than 50 milliseconds for a torque of 40 N·m on each actuator. The closed-loop torque bandwidth of the actuator is 9.74 Hz. Walking trials demonstrated torque tracking errors (root mean square) of less than 7 N·m. These results suggested that the device can perform adequate torque control and support level-ground walking. This prosthesis can serve as a platform for studying biomechanics related to balance and has the possibility of further recovering the biological function of the ankle–subtalar–foot complex beyond the existing powered ankles.

The diagnostic criteria for fibromyalgia (FM) have relied heavily on subjective reports of experienced symptoms coupled with examination-based evidence of diffuse tenderness due to the lack of reliable biomarkers. Rheumatic disorders that are common causes of chronic pain such as rheumatoid arthritis, systemic lupus erythematosus, osteoarthritis, and chronic low back pain are frequently found to be comorbid with FM. As a result, this can make the diagnosis of FM more challenging. We aim to develop a reliable classification algorithm using unique spectral profiles of portable FT-MIR that can be used as a real-time point-of-care device for the screening of FM. A novel volumetric absorptive microsampling (VAMS) technique ensured sample volume accuracies and minimized the variation introduced due to hematocrit-based bias. Blood samples from 337 subjects with different disorders (179 FM, 158 non-FM) collected with VAMS were analyzed. A semi-permeable membrane filtration approach was used to extract the blood samples, and spectral data were collected using a portable FT-MIR spectrometer. The OPLS-DA algorithm enabled the classification of the spectra into their corresponding classes with 84% accuracy, 83% sensitivity, and 85% specificity. The OPLS-DA regression plot indicated that spectral regions associated with amide bands and amino acids were responsible for discrimination patterns and can be potentially used as spectral biomarkers to differentiate FM and other rheumatic diseases.

Altered myeloid inflammation and lymphopenia are hallmarks of severe infections. We identified the upregulated EN-RAGE gene program in airway and blood myeloid cells from patients with acute lung injury from SARS-CoV-2 or other causes across 7 cohorts. This program was associated with greater clinical severity and predicted future mechanical ventilation and death. EN-RAGEhi myeloid cells express features consistent with suppressor cell functionality, including low HLA-DR and high PD-L1. Sustained EN-RAGE program expression in airway and blood myeloid cells correlated with clinical severity and increasing expression of T cell dysfunction markers. IL-6 upregulated many EN-RAGE program genes in monocytes in vitro. IL-6 signaling blockade by tocilizumab in a placebo-controlled clinical trial led to rapid normalization of EN-RAGE and T cell gene expression. This identifies IL-6 as a key driver of myeloid dysregulation associated with worse clinical outcomes in COVID-19 patients and provides insights into shared pathophysiological mechanisms in non-COVID-19 ARDS.

With the continued promise of immunotherapy for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer screening and treatment strategies. Here, we study 1084 eQTLs affecting the TIME found through analysis of The Cancer Genome Atlas and literature curation. These TIME eQTLs are enriched in areas of active transcription, and associate with gene expression in specific immune cell subsets, such as macrophages and dendritic cells. Polygenic score models built with TIME eQTLs reproducibly stratify cancer risk, survival and immune checkpoint blockade (ICB) response across independent cohorts. To assess whether an eQTL-informed approach could reveal potential cancer immunotherapy targets, we inhibit CTSS, a gene implicated by cancer risk and ICB response-associated polygenic models; CTSS inhibition results in slowed tumor growth and extended survival in vivo. These results validate the potential of integrating germline variation and TIME characteristics for uncovering potential targets for immunotherapy.

Deafness affects 5% of the world's population, yet there is a lack of treatments to prevent hearing loss due to genetic causes. Norrie disease is a recessive X‐linked disorder, caused by NDP gene mutation. It manifests as blindness at birth and progressive sensorineural hearing loss, leading to debilitating dual sensory deprivation. To develop a gene therapy, we used a Norrie disease mouse model (Ndp$^{tm1Wbrg}$), which recapitulates abnormal retinal vascularisation and progressive hearing loss. We delivered human NDP cDNA by intravenous injection of adeno‐associated viral vector (AAV)9 at neonatal, juvenile and young adult pathological stages and investigated its therapeutic effects on the retina and cochlea. Neonatal treatment prevented the death of the sensory cochlear hair cells and rescued cochlear disease biomarkers as demonstrated by RNAseq and physiological measurements of auditory function. Retinal vascularisation and electroretinograms were restored to normal by neonatal treatment. Delivery of NDP gene therapy after the onset of the degenerative inner ear disease also ameliorated the cochlear pathology, supporting the feasibility of a clinical treatment for progressive hearing loss in people with Norrie disease.

Abstract Background We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in?~?80% of cases. Methods We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P?=?1.1?×?10?4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR?=?3.70[95%CI 1.3–8.2], P?=?2.1?×?10?4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR?

Headspace solid-phase microextraction coupled to gas chromatography-mass spectrometry (HS-SPME/GC-MS), sensory evaluation, and multivariate analysis were applied to monitor and compare the evolution of the aromatic profile of a lager beer in different types of containers (aluminum cans and glass bottles) during the natural ageing process. Samples were aged naturally for a year in the absence of light with a controlled temperature of around 14 °C +/? 0.5 °C. The sensory evaluation applied was a blind olfactometric triangle test between canned and bottled samples at different periods of aging: fresh, 6 months, and 11 months. The sensory evaluation showed that the panelists were able to differentiate between samples, except for the fresh samples from the brewery. A total of 34 volatile compounds were identified using the HS-SPME/GC-MS technique for both packaging types in this experiment. The application of multivariate analysis to the GC-MS data showed that the samples could not be differentiated according to the type of packaging but could be differentiated by the ageing time. The results showed that the combination of sensory, HS-SPME-GC-MS, and multivariate analysis seemed to be a valuable tool for monitoring and identifying possible changes in the aroma profile of a beer during its shelf life. Furthermore, the results showed that storing beer under optimal conditions helped preserve its quality during its shelf life, regardless of the type of packaging (aluminum can and glass bottle).

Breast cancer is considered the second-leading cancer after lung cancer and is the most prevalent cancer among women globally. Currently, cancer immunotherapy via vaccine has gained great attention due to specific and targeted immune cell activity that creates a potent immune response, thus providing long-lasting protection against the disease. Despite peptides being very susceptible to enzymatic degradation and poor immunogenicity, they can be easily customized with selected epitopes to induce a specific immune response and particulate with carriers to improve their delivery and thus overcome their weaknesses. With advances in nanotechnology, the peptide-based vaccine could incorporate other components, thereby modulating the immune system response against breast cancer. Considering that peptide-based vaccines seem to show remarkably promising outcomes against cancer, this review focuses on and provides a specific view of peptide-based vaccines used against breast cancer. Here, we discuss the benefits associated with a peptide-based vaccine, which can be a mainstay in the prevention and recurrence of breast cancer. Additionally, we also report the results of recent trials as well as plausible prospects for nanotechnology against breast cancer.

Background: In recent months, the current COVID-19 pandemic has generated thousands of studies directly or indirectly related with this disease and/or the coronavirus SARS-CoV-2 causing the infection. On August 22, 2022, the database PUBMED included 287,639 publications containing the term COVID-19. However, in spite of the importance of trace elements in human health, including the immune system, data on the levels of metals/metalloids in COVID-19 patients is very limited. Methods: The concentrations of As, Cd, Cr, Cu, Hg, Fe, Mg, Mn, Pb, Se, V and Zn were determined by inductively coupled plasma-mass spectrometry (ICP-MS) in 126 serum samples of individuals infected with SARS-CoV-2, as well as in 88 samples of non-infected individuals. Participants were divided into four groups: i) individuals COVID-19 positive (COVID-19 +) with an asymptomatic infection course; ii) individuals suffering mild COVID-19; iii) individuals suffering severe COVID-19, and iv) individuals COVID-19 negative (COVID-19-) (control group). The occurrence of the analyzed metals/metalloids was evaluated along with the biochemical profile, including blood cell counts, lipids, proteins and crucial enzymes. Results: Serum levels of Mg, V, Cr, Cu, Cd, and Pb were higher in COVID-19 positive patients than those in the control group. Although no significant differences were observed between the different groups of patients, the concentrations of Cd, Pb, V and Zn showed a tendency to be higher in individuals with severe COVID-19 than in those showing mild symptoms or being asymptomatic. Arsenic and Hg were rarely detected, regardless if the subjects were infected by SARS-CoV-2, or not. The current results did not show significant differences in the levels of the rest of analyzed elements according to the

Background This phase 1b study (NCT02323191) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of colony-stimulating factor-1 receptor-blocking monoclonal antibody (mAb) emactuzumab in combination with the programmed cell death-1 ligand (PD-L1)-blocking mAb atezolizumab in patients with advanced solid tumors naïve or experienced for immune checkpoint blockers (ICBs). Methods Emactuzumab (500–1350 mg flat) and atezolizumab (1200 mg flat) were administered intravenously every 3 weeks. Dose escalation of emactuzumab was conducted using the 3+3 design up to the maximum tolerated dose (MTD) or optimal biological dose (OBD). Extension cohorts to evaluate pharmacodynamics and clinical activity were conducted in metastatic ICB-naive urothelial bladder cancer (UBC) and ICB-pretreated melanoma (MEL), non-small cell lung cancer (NSCLC) and UBC patients. Results Overall, 221 patients were treated. No MTD was reached and the OBD was determined at 1000 mg of emactuzumab in combination with 1200 mg of atezolizumab. Grade ≥3 treatment-related adverse events occurred in 25 (11.3%) patients of which fatigue and rash were the most common (14 patients (6.3%) each). The confirmed objective response rate (ORR) was 9.8% for ICB-naïve UBC, 12.5% for ICB-experienced NSCLC, 8.3% for ICB-experienced UBC and 5.6% for ICB-experienced MEL patients, respectively. Tumor biopsy analyses demonstrated increased activated CD8 +tumor infiltrating T lymphocytes (TILs) associated with clinical benefit in ICB-naïve UBC patients and less tumor-associated macrophage (TAM) reduction in ICB-experienced compared with ICB-naïve patients. Conclusion Emactuzumab in combination with atezolizumab demonstrated a manageable safety profile with increased fatigue and skin rash over usual atezolizumab monotherapy. A considerable ORR was particularly seen in ICB-experienced NSCLC patients. Increase ofCD8 +TILs under therapy appeared to be associated with persistence of a TAM subpopulation.

The endometrium plays a crucial role in reproduction and, in humans, is cyclically remodeled under hormonal control. Estradiol favors tissue proliferation whereas progesterone inhibits tissue growth and induces morphological changes. Endometriosis is often associated with fertility issues and with exacerbated estrogen and reduced progesterone concentration or response in the eutopic endometrium. However, underlying mechanisms remain unclear. Progesterone Receptor Membrane Component (PGRMC) 1 is a protein able to modulate progesterone response and its murine knockout reduced fertility. However, the precise spatiotemporal pattern of PGRMC1 expression in the human endometrium is still poorly characterized. We investigated variations of eutopic endometrial PGRMC1 expression by combining RT-qPCR, immunofluorescence and in situ hybridization. We found that PGRMC1 expression progressively increases during the proliferative phase and decreases during the secretory phase. However, immunolabeling and identification of mRNA-containing cells were regularly heterogeneous in samples, according to tissue depth, with a gradient extending from the surface epithelium towards the basalis. There was no significant difference in PGRMC1 mRNA amounts between patients with or without endometriosis or adenomyosis, for any phase of the menstrual cycle, but cells with strong or moderate PGRMC1 immunolabeling were reduced during the proliferative phase in endometriotic patients. In conclusion, although the cyclical variation of PGRMC1 expression globally follows fluctuation of ovarian steroids, further work is required to precisely characterize hormonal control and identify the additional levels of regulation responsible for local adjustment of PGRMC1 concentration. This is particularly important in the light of recent studies emphasizing the correlation between adequate PGRMC1 amounts and fertility.

Chiral molecules are challenging for the pharmaceutical industry because although physical properties of the enantiomers are the same in achiral systems, they exhibit different effects in chiral systems, such as the human body. The separation of enantiomers is desired but complex, as enantiomers crystallize most often as racemic compounds. A technique to enable the chiral separation of racemic compounds is to create an asymmetry in the thermodynamic system by generating chiral cocrystal(s) using a chiral coformer and using the solubility differences to enable separation through crystallization from solution. However, such quaternary systems are complex and require analytical methods to quantify different chiral molecules in solution. Here, we develop a new chiral quantification method using ultraviolet-circular dichroism spectroscopy and multivariate partial least squares calibration models, to build multicomponent chiral phase diagrams. Working on the quaternary system of (R)- and (S)-2-(2-oxopyrrolidin-1-yl)butanamide enantiomers with (S)-mandelic acid in acetonitrile, we measure accurately the full quaternary phase diagram for the first time. By understanding the phase stabilities of the racemic compound and the enantiospecific cocrystal, the chiral resolution of levetiracetam could be designed due to a large asymmetry in overall solubility between both sides of the racemic composition. This new method offers improvements for chiral molecule quantification in complex multicomponent chiral systems and can be applied to other chiral spectroscopy techniques.

High mobility group box 1 (HMGB1) was first identified as a chromatin-associated protein and later discovered to initiate and regulate inflammation by inducing cytokine production, cell migration and cell differentiation. HMGB1 forms complexes with a variety of proteins (e.g. C1q, LPS, CXCL12, IL-1a, IL1b, Beclin-6, p53) that in turn play a role in different cellular mechanisms. However, most HMGB1-protein complexes identified are found in the extracellular space whereas intracellular HMGB1-protein complexes are far less defined. Firstly, data of HMGB1 interactome was previously generated by Rebecka Heinbäck, Erlandsson Harris group at KI. The HMGB1 interactome was identified in resting and in LPS-stressed THP-1 cells using a method called BioID. The objective was to explore possible intracellular HMGB1 protein-protein interactions during resting and inflammatory conditions. HMGB1 in complex with other proteins have been known to exhibit crucial functions, therefore our investigation can lead to important knowledge in developing promising future therapeutics targeting HMGB1 in addition to further knowledge on intracellular functions of HMGB1. In this project, we used a combination of different computational analysis tools to explore the roles of HMGB1 and its interactome. Thereafter, we selected proteins within the BioID dataset that were further investigated for direct protein-protein interactions with HMGB1 using computational modelling as well as laboratory techniques, such as co-immunoprecipitation. Our data reveals functional and biological differences of HMGB1 in resting and LPS activated THP-1 cells. Within resting cells, the HMGB1 interactome is involved in transduction and transcription processes whereas under LPS-stressed conditions HMGB1 is indicated in apoptosis, HATs, and processes in antiviral mechanisms, mainly when localised in the cytosol. Additionally, we revealed potential direct interaction of HMGB1 to S100A6 and HCLS1, in which both can induc

High mobility group box 1 (HMGB1) was first identified as a chromatin-associated protein and later discovered to initiate and regulate inflammation by inducing cytokine production, cell migration and cell differentiation. HMGB1 forms complexes with a variety of proteins (e.g. C1q, LPS, CXCL12, IL-1a, IL1b, Beclin-6, p53) that in turn play a role in different cellular mechanisms. However, most HMGB1-protein complexes identified are found in the extracellular space whereas intracellular HMGB1-protein complexes are far less defined. Firstly, data of HMGB1 interactome was previously generated by Rebecka Heinbäck, Erlandsson Harris group at KI. The HMGB1 interactome was identified in resting and in LPS-stressed THP-1 cells using a method called BioID. The objective was to explore possible intracellular HMGB1 protein-protein interactions during resting and inflammatory conditions. HMGB1 in complex with other proteins have been known to exhibit crucial functions, therefore our investigation can lead to important knowledge in developing promising future therapeutics targeting HMGB1 in addition to further knowledge on intracellular functions of HMGB1. In this project, we used a combination of different computational analysis tools to explore the roles of HMGB1 and its interactome. Thereafter, we selected proteins within the BioID dataset that were further investigated for direct protein-protein interactions with HMGB1 using computational modelling as well as laboratory techniques, such as co-immunoprecipitation. Our data reveals functional and biological differences of HMGB1 in resting and LPS activated THP-1 cells. Within resting cells, the HMGB1 interactome is involved in transduction and transcription processes whereas under LPS-stressed conditions HMGB1 is indicated in apoptosis, HATs, and processes in antiviral mechanisms, mainly when localised in the cytosol. Additionally, we revealed potential direct interaction of HMGB1 to S100A6 and HCLS1, in which both can induc

Neurofibromatosis type 1 (NF1, von Recklinghausen), is an autosomal dominant disease with 1/2500 incidence and occurs symptoms such as café au laits spots, axillary and inguinal freckling, benign tumors with different sizes which are called neurofibroma, and malignant peripheral nerve sheat tumors (MPNST). In addition, tumor development may happen in the spinal cord, cranial nerves, and brain, also bone deformities such as scoliosis. There is no correlation between mutations in NF1 patients and disease phenotype. It shows quite a variety of clinical manifestations. It is also known that the same mutation in the same family has different clinical manifestations. One of the views about these clinical variations is the existence of modifier factors in the NF1 gene. MicroRNAs (miRNAs) are one of these modifier factors. Also, studies in recent years show that changes in mitochondrial function may play a role as modifier factors to NF1 patients' different phenotypes. Mitochondria are important organelles due to their unique signaling pathways and being the energy production center of the cell. In recent years, studies with mitochondria have increased greatly. Mitochondria are known to originate from a bacterium that was taken into the cell by an ancestral anaerobic eukaryotic cell. Mitochondrial physiological processes and possible involvement of bacteria are reviewed with comparative analyses. One of the small non-coding RNA, miRNAs are functioning as post-transcriptional regulators of gene expression. It has been shown that mitochondrial miRNAs (mitomiRs) modulate the mitochondrial genome's translational activation, and regulate mitochondrial protein expression and function. Although mitochondria have been confirmed to be vital for the development, the role of mitomiRs in the crucial biological processes including energy metabolism, oxidative stress, inflammation, and apoptosis has been understood recently. This thesis study aimed to compare the selected 11 mitomiR's is, Nörofibromatozis tip 1 (NF1, von Recklinghausen), toplumda 1/2500 insidansı ile ortaya çıkan bir otozomal dominant hastalık olup ciltte sütlü kahve lekeler (café au lait - CALM), çillenmeler, nörofibrom olarak isimlendirilen farklı boyutlarda iyi huylu tümörler ve malin periferik sinir kılıfı tümörleri (MPNST) gibi belirtiler verir. Bunun yanı sıra omurilikte, kafa sinirlerinde, beyinde tümörler gelişebilmekte ve omurga eğriliği gibi kemik şeklinde bozukluklar meydana gelebilmektedir. NF1 hastalarında saptanan mutasyonlar ile hastalığın fenotipi arasında bir ilişki mevcut değildir. Klinik çok değişkenlik gösterir. Hatta aynı aile içinde bile aynı mutasyonu gösteren bireylerin farklı klinik tablo gösterdiği de bilinen bir durumdur. Bu klinik değişkenliğin ortaya çıkmasındaki görüşlerden biri NF1 geni üzerindeki modifiye edici faktörlerin varlığıdır. Bu aday modifiye edici faktörlerden bir tanesi mikroRNA'lardır (miRNA). Ayrıca son yıllarda yapılan çalışmalar mitokondrilerin fonksiyonundaki değişikliklerin de bir modifiye edici faktör olarak NF1 hastalarının farklı fenotipler göstermesinde rol oynayabileceğini göstermektedir. Mitokondriler, kendine özgü sinyal yolaklarının varlığı ve hücrenin enerji üretim merkezi olmaları nedeniyle önemli organellerdir. Son yıllarda mitokondrilerle yapılan çalışmalar büyük oranda artmıştır. Mitokondrilerin, atasal bir anaerobik ökaryotik hücre tarafından hücre içine alınan bir bakteriden köken aldığı bilinmektedir, karşılaştırmalı analizler ile mitokondriyel fizyolojik süreçler ve bakterilerin olası katılımı gözden geçirilmektedir. Küçük kodlanmayan RNA'lardan olan miRNA'lar, gen ifadesinin post transkripsiyonel düzenleyicileri olarak fonksiyon gösteren RNA'lardır. Son zamanlarda, mitokondriyel miRNA'ların (mitomiR), mitokondriyel genomun translasyonel aktivitesini modüle ettiği ve mitokondriyel protein ifadesini ve fonksiyonunu düzenlediği gösterilmiştir. Mitokondrinin gelişim için gerekli olduğu doğrulanmış olsada, mitomiR'lerin en

Neurofibromatosis type 1 (NF1, von Recklinghausen), is an autosomal dominant disease with 1/2500 incidence and occurs symptoms such as café au laits spots, axillary and inguinal freckling, benign tumors with different sizes which are called neurofibroma, and malignant peripheral nerve sheat tumors (MPNST). In addition, tumor development may happen in the spinal cord, cranial nerves, and brain, also bone deformities such as scoliosis. There is no correlation between mutations in NF1 patients and disease phenotype. It shows quite a variety of clinical manifestations. It is also known that the same mutation in the same family has different clinical manifestations. One of the views about these clinical variations is the existence of modifier factors in the NF1 gene. MicroRNAs (miRNAs) are one of these modifier factors. Also, studies in recent years show that changes in mitochondrial function may play a role as modifier factors to NF1 patients' different phenotypes. Mitochondria are important organelles due to their unique signaling pathways and being the energy production center of the cell. In recent years, studies with mitochondria have increased greatly. Mitochondria are known to originate from a bacterium that was taken into the cell by an ancestral anaerobic eukaryotic cell. Mitochondrial physiological processes and possible involvement of bacteria are reviewed with comparative analyses. One of the small non-coding RNA, miRNAs are functioning as post-transcriptional regulators of gene expression. It has been shown that mitochondrial miRNAs (mitomiRs) modulate the mitochondrial genome's translational activation, and regulate mitochondrial protein expression and function. Although mitochondria have been confirmed to be vital for the development, the role of mitomiRs in the crucial biological processes including energy metabolism, oxidative stress, inflammation, and apoptosis has been understood recently. This thesis study aimed to compare the selected 11 mitomiR's is, Nörofibromatozis tip 1 (NF1, von Recklinghausen), toplumda 1/2500 insidansı ile ortaya çıkan bir otozomal dominant hastalık olup ciltte sütlü kahve lekeler (café au lait - CALM), çillenmeler, nörofibrom olarak isimlendirilen farklı boyutlarda iyi huylu tümörler ve malin periferik sinir kılıfı tümörleri (MPNST) gibi belirtiler verir. Bunun yanı sıra omurilikte, kafa sinirlerinde, beyinde tümörler gelişebilmekte ve omurga eğriliği gibi kemik şeklinde bozukluklar meydana gelebilmektedir. NF1 hastalarında saptanan mutasyonlar ile hastalığın fenotipi arasında bir ilişki mevcut değildir. Klinik çok değişkenlik gösterir. Hatta aynı aile içinde bile aynı mutasyonu gösteren bireylerin farklı klinik tablo gösterdiği de bilinen bir durumdur. Bu klinik değişkenliğin ortaya çıkmasındaki görüşlerden biri NF1 geni üzerindeki modifiye edici faktörlerin varlığıdır. Bu aday modifiye edici faktörlerden bir tanesi mikroRNA'lardır (miRNA). Ayrıca son yıllarda yapılan çalışmalar mitokondrilerin fonksiyonundaki değişikliklerin de bir modifiye edici faktör olarak NF1 hastalarının farklı fenotipler göstermesinde rol oynayabileceğini göstermektedir. Mitokondriler, kendine özgü sinyal yolaklarının varlığı ve hücrenin enerji üretim merkezi olmaları nedeniyle önemli organellerdir. Son yıllarda mitokondrilerle yapılan çalışmalar büyük oranda artmıştır. Mitokondrilerin, atasal bir anaerobik ökaryotik hücre tarafından hücre içine alınan bir bakteriden köken aldığı bilinmektedir, karşılaştırmalı analizler ile mitokondriyel fizyolojik süreçler ve bakterilerin olası katılımı gözden geçirilmektedir. Küçük kodlanmayan RNA'lardan olan miRNA'lar, gen ifadesinin post transkripsiyonel düzenleyicileri olarak fonksiyon gösteren RNA'lardır. Son zamanlarda, mitokondriyel miRNA'ların (mitomiR), mitokondriyel genomun translasyonel aktivitesini modüle ettiği ve mitokondriyel protein ifadesini ve fonksiyonunu düzenlediği gösterilmiştir. Mitokondrinin gelişim için gerekli olduğu doğrulanmış olsada, mitomiR'lerin en

The genetic background of each person might affect the severity of radiotherapy (RT)-induced normal tissue toxicity. The aim of study was to evaluate the influence of TGFB1 C-509T and Leu10Pro, XRCC1 Arg280His and XRCC3 Thr241Met polymorphisms as well as the level of radiation-induced CD8 T-lymphocyte apoptosis (RILA) on adverse effects of RT for prostate cancer (PCa). The study included 88 patients with localized or locally advanced PCa who were treated with RT. The polymorphisms were determined by PCR–RFLP analysis on DNA from peripheral blood mononuclear cells. RILA values were measured by flow cytometry. We found that CT genotype of TGFB1 C-509T could be protective biomarker for acute genitourinary (GU) and gastrointestinal (GI) radiotoxicity, while Thr variant of XRCC3 Thr241Met could predict the risk for acute GU radiotoxicity. Correlation between RILA values and toxicity was not detected. Univariate logistic regression analysis showed that Gleason score and risk group were risk factors for late GU, while for late GI radiotoxicity it was diabetes mellitus type 2. However, in multivariate model those were not proven to be significant and independent risk factors. Identification of assays combination predicting individual radiosensitivity is a crucial step towards personalized RT approach.

The advent of dose intensified interval compressed therapy has improved event-free survival for patients with localized Ewing sarcoma (EwS) to 78% at 5 years. However, nearly a quarter of patients with localized tumors and 60-80% of patients with metastatic tumors suffer relapse and die of disease. In addition, those who survive are often left with debilitating late effects. Clinical features aside from stage have proven inadequate to meaningfully classify patients for risk-stratified therapy. Therefore, there is a critical need to develop approaches to risk stratify patients with EwS based on molecular features. Over the past decade, new technology has enabled the study of multiple molecular biomarkers in EwS. Preliminary evidence requiring validation supports copy number changes, and loss of function mutations in tumor suppressor genes as biomarkers of outcome in EwS. Initial studies of circulating tumor DNA demonstrated that diagnostic ctDNA burden and ctDNA clearance during induction are also associated with outcome. In addition, fusion partner should be a pre-requisite for enrollment on EwS clinical trials, and the fusion type and structure require further study to determine prognostic impact. These emerging biomarkers represent a new horizon in our understanding of disease risk and will enable future efforts to develop risk-adapted treatment.

A dynamic mutation in exon 1 of the FMR1 gene causes Fragile X-related Disorders (FXDs), due to the expansion of an unstable CGG repeat sequence. Based on the CGG sequence size, two types of FMR1 alleles are possible: "premutation" (PM, with 56-200 CGGs) and "full mutation" (FM, with >200 triplets). Premutated females are at risk of transmitting a FM allele that, when methylated, epigenetically silences FMR1 and causes Fragile X syndrome (FXS), a very common form of inherited intellectual disability (ID). Expansions events of the CGG sequence are predominant over contractions and are responsible for meiotic and mitotic instability. The CGG repeat usually includes one or more AGG interspersed triplets that influence allele stability and the risk of transmitting FM to children through maternal meiosis. A unique mechanism responsible for repeat instability has not been identified, but several processes are under investigations using cellular and animal models. The formation of unusual secondary DNA structures at the expanded repeats are likely to occur and contribute to the CGG expansion. This review will focus on the current knowledge about CGG repeat instability addressing the CGG sequence expands.

We report a medium-throughput drug-screening platform (METPlatform) based on organotypic cultures that allows to evaluate inhibitors against metastases growing in situ. By applying this approach to the unmet clinical need of brain metastasis, we identified several vulnerabilities. Among them, a blood-brain barrier permeable HSP90 inhibitor showed high potency against mouse and human brain metastases at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis applied to metastases treated with the chaperone inhibitor uncovered a novel molecular program in brain metastasis, which includes biomarkers of poor prognosis and actionable mechanisms of resistance. Our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is compatible with human samples. Thus, this clinically relevant strategy is aimed to personalize the management of metastatic disease in the brain and elsewhere. Keywords: drug-screen; metastasis; organotypic cultures; patient-derived; resistance

Usher syndrome (USH) is the most common form of monogenic deaf-blindness. Loss of vision is untreatable and there are no suitable animal models for testing therapeutic strategies of the ocular constituent of USH, so far. By introducing a human mutation into the harmonin-encoding USH1C gene in pigs, we generated the first translational animal model for USH type 1 with characteristic hearing defect, vestibular dysfunction, and visual impairment. Changes in photoreceptor architecture, quantitative motion analysis, and electroretinography were characteristics of the reduced retinal virtue in USH1C pigs. Fibroblasts from USH1C pigs or USH1C patients showed significantly elongated primary cilia, confirming USH as a true and general ciliopathy. Primary cells also proved their capacity for assessing the therapeutic potential of CRISPR/Cas-mediated gene repair or gene therapy in vitro. AAV-based delivery of harmonin into the eye of USH1C pigs indicated therapeutic efficacy in vivo.

Herein we report the synthesis of a new class of compounds associating Keggin and Dawson-type Polyoxometalates (POMs) with a derivative of the anionic decahydro-closo-decaborate cluster [B10H10]2? through aminopropylsilyl ligand (APTES) acting as both a linker and a spacer between the two negatively charged species. Three new adducts were isolated and fully characterized by various NMR techniques and MALDI-TOF mass spectrometry, notably revealing the isolation of an unprecedented monofunctionalized SiW10 derivative stabilized through intramolecular H-H dihydrogen contacts. DFT as well as electrochemical studies allowed studying the electronic effect of grafting the decaborate cluster on the POM moiety and its consequences on the hydrogen evolution reaction (HER) properties.

Ozone has been successfully employed in water treatment due to its ability to oxidize a wide variety of refractory compounds. In order to increase the process efficiency and optimize its economy, the implementation of heterogeneous catalysts has been encouraged. In this context, the use of cheap and widely available natural materials is a promising option that would promote the utilization of ozone in a cost-effective water treatment process. This review describes the use of natural clays, zeolites and oxides as supports or active catalysts in the ozonation process, with emphasis on the structural characteristics and modifications performed in the raw natural materials; the catalytic oxidation mechanism; effect of the operating parameters and degradation efficiency outcomes. According to the information compiled, more research in realistic scenarios is needed (i.e., real wastewater matrix or continuous operation in pilot scale) in order to transfer this technology to the treatment of real wastewater streams.

Background and aim The appearance of alterations in normal metabolic activity has been increasingly considered a risk factor for the development of sporadic and late-onset neurodegenerative diseases. In this report, we induced chronic metabolic stress by feeding of a high-fat diet (HFD) in order to study its consequences in cognition. We also studied the effects of a loss of function of isoforms 1 and 3 of the c-Jun N-terminal Kinases (JNK), stress and cell death response elements. Methods Animals were fed either with conventional chow or with HFD, from their weaning until their sacrifice at 9 months. Before sacrifice, body weight, intraperitoneal glucose and insulin tolerance test (IP-GTT and IP-ITT) were performed to evaluate peripheral biometrics. Additionally, cognitive behavioral tests and analysis of spine density were performed to assess cognitive function. Molecular studies were carried out to confirm the effects of metabolic stressors in the hippocampus relative to cognitive loss. Results Our studies demonstrated that HFD in Jnk3(-/-) lead to synergetic responses. Loss of function of JNK3 led to increased body weight, especially when exposed to an HFD and they had significantly decreased response to insulin. These mice also showed increased stress in the endoplasmic reticulum and diminished cognitive capacity. However, loss of function of JNK1 promoted normal or heightened energetic metabolism and preserved cognitive function even when chronically metabolically stressed. Conclusions Downregulation of JNK3 does not seem to be a suitable target for the modulation of energetic-cognitive dysregulations while loss of function of JNK1 seems to promote a good metabolic-cognitive profile, just like resistance to the negative effects of chronic feeding with HFD.

The unstable proteins in white wine cause haze in bottles of white wine, degrading its quality. Thaumatins and chitinases are grape pathogenesis-related (PR) proteins that remain stable during vinification but can precipitate at high temperatures after bottling. The white wine protein stabilization process can prevent haze by removing these unstable proteins. Traditionally, bentonite is used to remove these proteins; however, it is labor-intensive, generates wine losses, affects wine quality, and harms the environment. More efficient protein stabilization technologies should be based on a better understanding of the main factors and mechanisms underlying protein precipitation. This review focuses on recent developments regarding the instability and removal of white wine proteins, which could be helpful to design more economical and environmentally friendly protein stabilization methods that better preserve the products´ quality.

Methods that site-selectively attach multivalent carbohydrate moieties to proteins can be used to generate homogeneous glycodendriproteins as synthetic functional mimics of glycoproteins. Here, we study aspects of the scope and limitations of some common bioconjugation techniques that can give access to well-defined glycodendriproteins. A diverse reactive platform was designed via use of thiol-Michael-type additions, thiol-ene reactions, and Cu(I)-mediated azide-alkyne cycloadditions from recombinant proteins containing the non-canonical amino acids dehydroalanine, homoallylglycine, homopropargylglycine, and azidohomoalanine.© 2022 Wiley-VCH GmbH.

According to the American Cancer Society, roughly 54,000 new cases of oral cavity or oropharyngeal cancers have been detected in the United States of America in 2021, and they will cause about 10,850 deaths. The main therapies for cancer management, such as surgery and radio- and chemotherapy, have some own benefits, albeit they are often destructive for surrounding tissues; thus, deep investigations into non-surgical treatments for oral cavities are needed. Biologically active compounds (BACs) extracted from European Spruce needles were analyzed to determine the total phenolic and flavonoid content and were used as additional ingredients for oral hygiene products. An anti-proliferation investigation was carried out using extracts containing BACs with the use of several cell lines (cancer and a normal one). ESI-MS studies on BACs showed that luteolin, a natural flavonoid compound with anti-tumorigenic properties against various types of tumors, is the predominant component of the extracts. MTT, BrdU, and LIVE/DEAD studies demonstrated that BAC extracts obtained from Christmas tree needles possess anticancer properties against squamous cell carcinoma (with epithelial origins). We proved that BAC extracts contain high amounts of luteolin, which induces cytotoxicity toward cancer cells; along with their high selectivity, robustness, and nontoxicity, they are very promising materials in oral health applications.

Organophosphate triesters are compounds widely used in industries and are ubiquitous in the environment, where they can be transformed into organophosphate diesters. Some organophosphate diesters are also used by industry. Several studies suggest organophosphate diesters can have toxic effects for reproduction, and hazardous and mutagenic properties. Due to the impact these compounds can have on marine biota and human beings through the consumption of fish and shellfish, it is necessary to study their presence in widely consumed seafood species. We therefore developed an analytical method for determining six of the most common organophosphate diesters in seafood. The procedure is based on the Quick, Easy, Cheap, Effective, Rugged and Safe extraction method and a solid phase extraction clean-up, followed by liquid chromatography coupled to high-resolution mass spectrometry. The method was optimised and validated for seafood with different lipid content, providing satisfactory relative recoveries (from 89 to 138%) and limits of detection (1.0-50 ng g-1 dry weight), as well as repeatability values (RSD% (n = 5, 100 ng g-1 (dry weight)) lower than 15%. Eight seafood species were analysed using this method and two organophosphate diesters were detected and quantified in all the samples, demonstrating the suitability of the method.

The photocatalytic and electrocatalytic conversion of CO2 has the potential to provide valuable products, such as chemicals or fuels of interest, at low cost while maintaining a circular carbon cycle. In this context, carbon dots possess optical and electrochemical properties that make them suitable candidates to participate in the reaction, either as a single component or forming part of more elaborate catalytic systems. In this review, we describe several strategies where the carbon dots participate, both with amorphous and graphitic structures, in the photocatalysis or electrochemical catalysis of CO2 to provide different carbon-containing products of interest. The role of the carbon dots is analyzed as a function of their redox and light absorption characteristics and their complementarity with other known catalytic systems. Moreover, detailed information about synthetic procedures is also reviewed.

The constant search for the proper management of non-degradable waste in conjunction with the circular economy makes the thermal pyrolysis of plastics an important technique for obtaining products with industrial interest. The present study aims to produce pyrolytic oil from thermoplastics and their different mixtures in order to determine the best performance between these and different mixtures, as well as to characterize the liquid fraction obtained to analyze its use based on said properties. This was carried out in a batch type reactor at a temperature of 400 degrees C for both individual plastics and their mixtures, from which the yields of the different fractions are obtained. The liquid fraction of interest is characterized by gas chromatography and its properties are characterized by ASTM standards. The product of the pyrolysis of mixtures of 75% polystyrene and 25% polypropylene presents a yield of 82%, being the highest, with a viscosity of 1.12 cSt and a calorific power of 42.5 MJ/kg, which has a composition of compounds of carbon chains ranging between C6 and C20, for which it is proposed as a good additive agent to conventional fuels for industrial use.

This review makes a critical evaluation of 61 peer-reviewed manuscripts that use a docking step in a virtual screening (VS) protocol to predict SARS-CoV-2 M-pro (M-pro) inhibitors in approved or investigational drugs. Various manuscripts predict different compounds, even when they use a similar initial dataset and methodology, and most of them do not validate their methodology or results. In addition, a set of known 150 SARS-CoV-2 M-pro inhibitors extracted from the literature and a second set of 81 M-pro inhibitors and 113 inactive compounds obtained from the COVID Moonshot project were used to evaluate the reliability of using docking scores as feasible predictors of the potency of a SARS-CoV-2 M-pro inhibitor. Using two SARS-CoV-2 M-pro structures and five protein-ligand docking programs, we proved that the correlation between the pIC(50) and docking scores is not good. Neither was any correlation found between the pIC(50) and the increment G calculated with an MM-GBSA method. When a group of experimentally known inactive compounds was added, neither the docking scores or the increment G were able to distinguish between compounds with or without M-pro experimental inhibitory activity. Performances improved when covalent and noncovalent inhibitors were treated separately, but were not good enough to fully support using a docking score as a cutoff value for selecting new putative M-pro inhibitors or predicting the relative bioactivity of a compound by comparison with a reference compound. The two sets of known SARS-CoV-2 M-pro inhibitors presented here could be used for validating future VS protocols which aim to predict M-pro inhibitors.

Engineering Management involves an extremely diverse range of topics, problems, and questions. Many of the problems and topics of interest in engineering management involve both human and non-human elements.  These Chapters are relevant to engineering management and describes and categorizes the methods used in investigations where the primary emphasis was the behavior and characteristics of things other than people. Relative frequencies of methods as well as trends are reported. Implications for the field generally and for methodological training for doctoral students specifically are discussed. Altogether, 13 studies were included and synthesized.

Machine learning has greatly facilitated the analysis of medical data, while the internal operations usually remain intransparent. To better comprehend these opaque procedures, a convolutional neural network for optical coherence tomography image segmentation was enhanced with a Traceable Relevance Explainability (T-REX) technique. The proposed application was based on three components: ground truth generation by multiple graders, calculation of Hamming distances among graders and the machine learning algorithm, as well as a smart data visualization ('neural recording'). An overall average variability of 1.75% between the human graders and the algorithm was found, slightly minor to 2.02% among human graders. The ambiguity in ground truth had noteworthy impact on machine learning results, which could be visualized. The convolutional neural network balanced between graders and allowed for modifiable predictions dependent on the compartment. Using the proposed T-REX setup, machine learning processes could be rendered more transparent and understandable, possibly leading to optimized applications.

Removal of heavy metals from drinking water sources and rivers is of strategic health importance and is essential for sustainable ecosystem development, in particular in polluted areas around the globe. In this work, new hybrid inorganic-organic material adsorbents made of ortho- (Si-o-OR) or para-Schiff base silica (Si-p-OR) were synthesized and characterized in depth. These hybrid adsorbents show a high selectivity to Cu(II), even in the presence of competing heavy metals (Zn(II), Cd(II), and Pb(II)), and also demonstrate great reusability after five adsorption-desorption cycles. Maximum sorption capacity for Cu(II) was found for Si-o-OR (79.36 mg g−1) and Si-p-OR (36.20 mg g−1) in no less than 25 min. Energy dispersive X-ray fluorescence and Fourier transform-infrared spectroscopy studies demonstrate that this uptake occurs due to a chelating effect, which allows these adsorbents to trap Cu(II) ions on their surfaces; this result is supported by a theoretical study for Si-o-OR. The new adsorbents were tested against real water samples extracted from two rivers from the Oriental region of Morocco

Objectives: To further elucidate the role of the MHC in ankylosing spondylitis by typing 17 genes, searching for HLA-B∗27 independent associations and assessing the impact of sex on this male biased disease. Methods: High-confidence two-field resolution genotyping was performed on 310 cases and 2196 controls using an n-1 concordance method. Protein-coding variants were called from next-generation sequencing reads using up to four software programs and the consensus result recorded. Logistic regression tests were applied to the dataset as a whole, and also in stratified sets based on sex or HLA-B∗27 status. The amino acids driving association were also examined. Results: Twenty-five HLA protein-coding variants were significantly associated to disease in the population. Three novel protective associations were found in a HLA-B∗27 positive population, HLA-A∗24:02 (OR = 0.4, CI = 0.2–0.7), and HLA-A amino acids Leu95 and Gln156. We identified a key set of seven loci that were common to both sexes, and robust to change in sample size. Stratifying by sex uncovered three novel risk variants restricted to the female population (HLA-DQA1∗04.01, -DQB1∗04:02, -DRB1∗08:01; OR = 2.4–3.1). We also uncovered a set of neutral variants in the female population, which in turn conferred strong effects in the male set, highlighting how population composition can lead to the masking of true associations. Conclusion: Population stratification allowed for a nuanced investigation into the tightly linked MHC region, revealing novel HLA-B∗27 signals as well as replicating previous HLA-B∗27 dependent results. This dissection of signals may help to elucidate sex biased disease predisposition and clinical progression.

Signaling pathways are frequently activated through signal-receiving membrane proteins, and the discovery ofsmall molecules targeting these receptors may yield insights into their biology. However, due to their intrinsicproperties,membrane protein targets often cannot be identified bymeans of established approaches, in particularaffinity-based proteomics, calling for the exploration of new methods. Here, we report the identification ofindophagolin as representative member of an indoline-based class of autophagy inhibitors through a targetagnosticphenotypic assay. Thermal proteome profiling and subsequent biochemical validation identified thepurinergic receptor P2X4 as a target of indophagolin, and subsequent investigations suggest that indophagolintargets further purinergic receptors. These results demonstrate that thermal proteome profiling may enable thede novo identification of membrane-bound receptors as cellular targets of bioactive small molecules.

Signaling pathways are frequently activated through signal-receiving membrane proteins, and the discovery ofsmall molecules targeting these receptors may yield insights into their biology. However, due to their intrinsicproperties,membrane protein targets often cannot be identified bymeans of established approaches, in particularaffinity-based proteomics, calling for the exploration of new methods. Here, we report the identification ofindophagolin as representative member of an indoline-based class of autophagy inhibitors through a targetagnosticphenotypic assay. Thermal proteome profiling and subsequent biochemical validation identified thepurinergic receptor P2X4 as a target of indophagolin, and subsequent investigations suggest that indophagolintargets further purinergic receptors. These results demonstrate that thermal proteome profiling may enable thede novo identification of membrane-bound receptors as cellular targets of bioactive small molecules.

Fungicides are used to suppress the growth of fungi for crop protection. The most widely used fungicides are succinate dehydrogenase inhibitors (SDHIs) that act by blocking succinate dehydrogenase, the complex II of the mitochondrial electron transport chain. As recent reports suggested that SDHI-fungicides could not be selective for their fungi targets, we tested the mitochondrial function of human cells (Peripheral Blood Mononuclear Cells or PBMCs, HepG2 liver cells, and BJ-fibroblasts) after exposure for a short time to Boscalid and Bixafen, the two most used SDHIs. Electron Paramagnetic Resonance (EPR) spectroscopy was used to assess the oxygen consumption rate (OCR) and the level of mitochondrial superoxide radical. The OCR was significantly decreased in the three cell lines after exposure to both SDHIs. The level of mitochondrial superoxide increased in HepG2 after Boscalid and Bixafen exposure. In BJ-fibroblasts, mitochondrial superoxide was increased after Bixafen exposure, but not after Boscalid. No significant increase in mitochondrial superoxide was observed in PBMCs. Flow cytometry revealed an increase in the number of early apoptotic cells in HepG2 exposed to both SDHIs, but not in PBMCs and BJ-fibroblasts, results consistent with the high level of mitochondrial superoxide found in HepG2 cells after exposure. In conclusion, short-term exposure to Boscalid and Bixafen induces a mitochondrial dysfunction in human cells.

Cytochrome P450 3A4 (CYP3A4) is the most important drug metabolizing enzyme in the liver, responsible for the oxidative metabolism of ∼50% of clinically prescribed drugs. Therefore, genetic variation in CYP3A4 could potentially affect the pharmacokinetics, toxicity and clinical outcome of drug treatment. Thus far, pharmacogenetics for CYP3A4 has not received much attention. However, the recent discovery of the intron 6 single-nucleotide polymorphism (SNP) rs35599367C > T, encoding the CYP3A4∗22 allele, led to several studies into the pharmacogenetic effect of CYP3A4∗22 on different drugs. This allele has a relatively minor allele frequency of 3-5% and an effect on CYP3A4 enzymatic activity. Thus far, no review summarizing the data published on several drugs is available yet. This article therefore addresses the current knowledge on CYP3A4∗22. This information may help in deciding if, and for which drugs, CYP3A4∗22 genotype-based dosing could be helpful in improving drug therapy. CYP3A4∗22 was shown to significantly influence the pharmacokinetics of several drugs, with currently being most thoroughly investigated tacrolimus, cyclosporine, and statins. Additional studies, focusing on toxicity and clinical outcome, are warranted to demonstrate clinical utility of CYP3A4∗22 genotype-based dosing.

Cytochrome P450 3A4 (CYP3A4) is the most important drug metabolizing enzyme in the liver, responsible for the oxidative metabolism of ∼50% of clinically prescribed drugs. Therefore, genetic variation in CYP3A4 could potentially affect the pharmacokinetics, toxicity and clinical outcome of drug treatment. Thus far, pharmacogenetics for CYP3A4 has not received much attention. However, the recent discovery of the intron 6 single-nucleotide polymorphism (SNP) rs35599367C > T, encoding the CYP3A4∗22 allele, led to several studies into the pharmacogenetic effect of CYP3A4∗22 on different drugs. This allele has a relatively minor allele frequency of 3-5% and an effect on CYP3A4 enzymatic activity. Thus far, no review summarizing the data published on several drugs is available yet. This article therefore addresses the current knowledge on CYP3A4∗22. This information may help in deciding if, and for which drugs, CYP3A4∗22 genotype-based dosing could be helpful in improving drug therapy. CYP3A4∗22 was shown to significantly influence the pharmacokinetics of several drugs, with currently being most thoroughly investigated tacrolimus, cyclosporine, and statins. Additional studies, focusing on toxicity and clinical outcome, are warranted to demonstrate clinical utility of CYP3A4∗22 genotype-based dosing.

The provision of safe water for people is a human right; historically, a major number of people depend on groundwater as a source of water for their needs, such as agricultural, industrial or human activities. Water resources have recently been affected by organic and/or inorganic contaminants as a result of population growth and increased anthropogenic activity, soil leaching and pollution. Water resource remediation has become a serious environmental concern, since it has a direct impact on many aspects of people’s lives. For decades, the pump-and-treat method has been considered the predominant treatment process for the remediation of contaminated groundwater with organic and inorganic contaminants. On the other side, this technique missed sustainability and the new concept of using renewable energy. Permeable reactive barriers (PRBs) have been implemented as an alternative to conventional pump-and-treat systems for remediating polluted groundwater because of their effectiveness and ease of implementation. In this paper, a review of the importance of groundwater, contamination and biological, physical as well as chemical remediation techniques have been discussed. In this review, the principles of the permeable reactive barrier’s use as a remediation technique have been introduced along with commonly used reactive materials and the recent applications of the permeable reactive barrier in the remediation of different contaminants, such as heavy metals, chlorinated solvents and pesticides. This paper also discusses the characteristics of reactive media and contaminants’ uptake mechanisms. Finally, remediation isotherms, the breakthrough curves and kinetic sorption models are also being presented. It has been found that groundwater could be contaminated by different pollutants and must be remediated to fit human, agricultural and industrial needs. The PRB technique is an efficient treatment process that is an inexpensive alternative for the pump-and-treat procedure, Validerad;2021;Nivå 2;2021-10-01 (johcin)

Signaling pathways are frequently activated through signal-receiving membrane proteins, and the discovery ofsmall molecules targeting these receptors may yield insights into their biology. However, due to their intrinsicproperties,membrane protein targets often cannot be identified bymeans of established approaches, in particularaffinity-based proteomics, calling for the exploration of new methods. Here, we report the identification ofindophagolin as representative member of an indoline-based class of autophagy inhibitors through a targetagnosticphenotypic assay. Thermal proteome profiling and subsequent biochemical validation identified thepurinergic receptor P2X4 as a target of indophagolin, and subsequent investigations suggest that indophagolintargets further purinergic receptors. These results demonstrate that thermal proteome profiling may enable thede novo identification of membrane-bound receptors as cellular targets of bioactive small molecules.

The provision of safe water for people is a human right; historically, a major number of people depend on groundwater as a source of water for their needs, such as agricultural, industrial or human activities. Water resources have recently been affected by organic and/or inorganic contaminants as a result of population growth and increased anthropogenic activity, soil leaching and pollution. Water resource remediation has become a serious environmental concern, since it has a direct impact on many aspects of people’s lives. For decades, the pump-and-treat method has been considered the predominant treatment process for the remediation of contaminated groundwater with organic and inorganic contaminants. On the other side, this technique missed sustainability and the new concept of using renewable energy. Permeable reactive barriers (PRBs) have been implemented as an alternative to conventional pump-and-treat systems for remediating polluted groundwater because of their effectiveness and ease of implementation. In this paper, a review of the importance of groundwater, contamination and biological, physical as well as chemical remediation techniques have been discussed. In this review, the principles of the permeable reactive barrier’s use as a remediation technique have been introduced along with commonly used reactive materials and the recent applications of the permeable reactive barrier in the remediation of different contaminants, such as heavy metals, chlorinated solvents and pesticides. This paper also discusses the characteristics of reactive media and contaminants’ uptake mechanisms. Finally, remediation isotherms, the breakthrough curves and kinetic sorption models are also being presented. It has been found that groundwater could be contaminated by different pollutants and must be remediated to fit human, agricultural and industrial needs. The PRB technique is an efficient treatment process that is an inexpensive alternative for the pump-and-treat procedure, Validerad;2021;Nivå 2;2021-10-01 (johcin)