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Background: Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects women of reproductive age and requires better treatment. N -acetylcysteine (NAC) is known to be beneficial under such conditions owing to its antioxidant potential and insulin-sensitizing properties. The effect of NAC on the reproductive outcomes of PCOS patients was examined in this meta-analysis., Methods: In accordance with PRISMA standards, this meta-analysis included studies that compared N -acetylcysteine, metformin, clomiphene citrate, and a placebo in patients with POCS. The main indicators were follicular growth, endometrial thickness, and hormone level. The risk of bias was evaluated using the Cochrane ROB2 tool., Results: Twenty-two studies ( n = 2515) were included. NAC was associated with a statistically significant increase in progesterone (SMD 0.95, 95% CI: 0.13-1.77, p = 0.02) and endometrial thickness (SMD 0.58, 95% CI: 0.10-1.06, p = 0.02) compared to the placebo and other drugs (SMD 0.71, 95% CI: 0.48-0.94, p < 0.0001). LH levels were significantly increased by NAC compared to metformin (SMD 0.67, 95% CI: 0.23-1.12, p = 0.003). However, no significant differences were observed in the estradiol, SHBG, or FSH levels., Conclusions: NAC had a major effect on progesterone, endometrial thickness, and LH levels in women with PCOS. Therefore, it may be a potential treatment option., Competing Interests: Authors Isabel Vi&ntilde;a and Macarena Carranza were employed by the company IVB Wellness Lab. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Tumor cells engage with the immune system in a complex manner, utilizing evasion and adaptability mechanisms. The development of cancer and resistance to treatment relies on the ability of immune cells to adjust their phenotype and function in response to cues from the tumor microenvironment, known as immunological cell plasticity. This study delves into the role of long non-coding RNAs (lncRNAs) in enhancing immune cell flexibility in cancer, focusing on their regulatory actions in the tumor microenvironment and potential therapeutic implications. Through a comprehensive review of existing literature, the study analyzes the impact of lncRNAs on macrophages, T-cells, and MDSCs, as well as the influence of cytokines and growth factors like TNF, IL-6, HGF, and TGFβ on immunological cell plasticity and tumor immunoediting. LncRNAs exert a strong influence on immune cell plasticity through mechanisms such as transcriptional regulation, post-transcriptional modifications, and chromatin remodeling. These RNA molecules intricately modulate gene expression networks, acting as scaffolding, decoys, guides, and sponges. Moreover, both direct cell-cell interactions and soluble chemicals in the tumor microenvironment contribute to enhancing immune cell activation and survival. Understanding the influence of lncRNAs on immune cell flexibility sheds light on the biological pathways of immune evasion and cancer progression. Targeting long non-coding RNAs holds promise for amplifying anti-tumor immunity and overcoming drug resistance in cancer treatment. However, further research is necessary to determine the therapeutic potential of manipulating lncRNAs in the tumor microenvironment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Membrane-based sensors (MePSs) exhibit remarkable precision and sensitivity in detecting pressure changes. MePSs are commonly used to monitor catalytic reactions in solution, generating gas products crucial for signal amplification in bioassays. They also allow for catalyst quantification by indirectly measuring the pressure generated by the gaseous products. This is particularly interesting for detecting enzymes in biofluids associated with disease onset. To enhance the performance of a MePS, various structural factors influence membrane flexibility and response time, ultimately dictating the device's pressure sensitivity. In this study, we fabricated MePSs using polydimethylsiloxane (PDMS) and investigated how structural modifications affect the Young's modulus ( E ) and residual stress ( σ 0 ) of the membranes. These modifications have a direct impact on the sensors' sensitivity to pressure variations, observed as a function of the volume of the chamber ( Σ ) or of the mechanical properties of the membrane itself ( S ). MePSs exhibiting the highest sensitivities were then employed to detect catalyst quantities inducing the dismutation of hydrogen peroxide, producing dioxygen as a gaseous product. As a result, a catalase enzyme was successfully detected using these optimized MePSs, achieving a remarkable sensitivity of (22.7 ± 1.2) µm/nM and a limit of detection (LoD) of 396 pM.

Optoelectronic and spinoptronic technologies benefit from flexible and tunable coherent light sources combining the best properties of nano- and material-engineering to achieve favorable properties such as chiral lasing and low threshold nonlinearities. In this work we demonstrate an electrically wavelength- and polarization-tunable room temperature polariton laser due to emerging photonic spin-orbit coupling. For this purpose, we design an optical cavity filled with both birefringent nematic liquid crystal and an inorganic perovskite. Our versatile growth method of single CsPbBr 3 inorganic perovskite crystals in polymer templates allows us to reach strong light-matter coupling and pump-induced condensation of exciton-polaritons resulting in coherent emission of light. The sensitivity of the liquid crystal to external voltage permits electrical tuning of the condensate energy across 7 nm; its threshold power, allowing us to electrically switch it on and off; and its state of polarization sweeping from linear to locally tilted circularly polarized emission., Competing Interests: Conflict of interest: Authors state no conflicts of interest., (© 2024 the author(s), published by De Gruyter, Berlin/Boston.)

Complementary and Alternative medicine is known to have health benefits. Yoga nidra practice is an easy-to-do practice and has shown beneficial effects on stress reduction and is found to improve sleep in insomnia patients. Effect of yoga nidra practice on subjective sleep is known but its effect on sleep and cognition objectively is not documented. The aim of the study was to study the effect of yoga nidra practice on cognition and sleep using objective parameters. 41 participants were enrolled, and baseline sleep diary (SD) collected. Participants volunteered for overnight polysomnography (PSG) and cognition testing battery (CTB) comprising of Motor praxis test, emotion recognition task (ERT), digital symbol substitution task, visual object learning task (VOLT), abstract matching (AIM), line orientation task, matrix reasoning task, fractal-2-back test (NBACK), psychomotor vigilance task and balloon analog risk task. Baseline CTB and after one and two weeks of practice was compared. Power spectra density for EEG at central, frontal, and occipital locations during CTB was compared. Repeat SD and PSG after four weeks of practice were done. After yoga nidra practice, improved reaction times for all cognition tasks were seen. Post intervention compared to baseline (95%CI; p-value, effect size) showed a significant improvement in sleep efficiency of +3.62% (0.3, 5.15; p = 0.03, r = 0.42), -20min (-35.78, -5.02; p = 0.003, d = 0.84) for wake after sleep onset and +4.19 μV2 (0.5, 9.5; p = 0.04, r = 0.43) in delta during deep sleep. Accuracy increased in VOLT (95% CI: 0.08, 0.17; p = 0.002, d = 0.79), AIM (95% CI: 0.03, 0.12; p = 0.02, d = 0.61) and NBACK (95% CI: 0.02, 0.13; p = 0.04, d = 0.56); ERT accuracy increased for happy, fear and anger (95% CI: 0.07, 0.24; p = 0.004, d = 0.75) but reduced for neutral stimuli (95% CI: -0.31, -0.12; p = 0.04, r = 0.33) after yoga nidra practice. Yoga Nidra practice improved cognitive processing and night-time sleep., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Datta et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In mammals, the physiological activation of the glucocorticoid receptor (GR) by glucocorticoids (GCs) promotes the maturation of cardiomyocytes during late gestation, but the effect on postnatal cardiac growth and regenerative plasticity is unclear. Here we demonstrate that the GC-GR axis restrains cardiomyocyte proliferation during postnatal development. Cardiomyocyte-specific GR ablation in conditional knockout (cKO) mice delayed the postnatal cardiomyocyte cell cycle exit, hypertrophic growth and cytoarchitectural maturation. GR-cKO hearts showed increased expression of genes involved in glucose catabolism and reduced expression of genes promoting fatty acid oxidation and mitochondrial respiration. Accordingly, oxygen consumption in GR-cKO cardiomyocytes was less dependent on fatty acid oxidation, and glycolysis inhibition reverted GR-cKO effects on cardiomyocyte proliferation. GR ablation or transient pharmacological inhibition after myocardial infarction in juvenile and/or adult mice facilitated cardiomyocyte survival, cell cycle re-entry and division, leading to cardiac muscle regeneration along with reduced scar formation. Thus, GR restrains heart regeneration and may represent a therapeutic target., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Aromatic oils obtained during lubricant production (DAE) have high value as rubber extenders in tire manufacturing, but they have high carcinogenic potential due to the content of polycyclic aromatic compounds (PCAs). Legislation on PCA content requires additional treatment to reach treated oils (TDAE) with a PCA content lower than 3% according to the IP 346 method. IP 346 is a highly time-consuming and high uncertainty method, and several proposals have tried to replace it, but nowadays, there is no standard alternative. In this work, an extensive collection of samples covering a broad PCA content were obtained and characterized by physical properties, NMR, and aromatic and PCA content. Several correlations were tested to establish an optimum procedure to estimate the aromatic and the PCA content according to the requirement of high accuracy and low time and effort. The combination of several properties does not improve the accuracy of the correlation, and simpler equations were preferred. Integrated spectra appear as an acceptable characterization method as NMR percent of the total aromatic proton and polycyclic aromatic proton correlates satisfactory with the number of aromatic carbons and PCA content, respectively. The refractive index yields the best results for the correlation to PCA content. Obtained deviations compare favorably with methods previously described in the literature and with the uncertainty involved in the experimental method. They can be considered adequate methods to analyze such magnitudes routinely., (© 2022. Springer-Verlag GmbH Germany, part of Springer Nature.)

Catharanthus roseus (Madagascar periwinkle), a medicinal plant possessing high pharmacological attributes, is widely recognized for the biosynthesis of anticancer monoterpenoid indole alkaloids (MIAs) - vinblastine and vincristine. The plant is known to biosynthesize more than 130 different bioactive MIAs, highly acclaimed in traditional and modern medicinal therapies. The MIA biosynthesis is strictly regulated at developmental and spatial-temporal stages and requires a well-defined cellular and sub-cellular compartmentation for completion of the entire MIAs biosynthesis. However, due to their cytotoxic nature, the production of vinblastine and vincristine occurs in low concentrations in planta and the absence of chemical synthesis alternatives projects a huge gap in demand and supply, leading to high market price. With research investigations spanning more than four decades, plant tissue culture and metabolic engineering (ME)-based studies were attempted to explore, understand, explain, improve and enhance the MIA biosynthesis using homologous and heterologous systems. Presently, metabolic engineering and synthetic biology are the two powerful tools that are contributing majorly in elucidating MIA biosynthesis. This review concentrates mainly on the efforts made through metabolic engineering of MIAs in heterologous microbial factories. KEY POINTS: • Yeast engineering provides alternative production source of phytomolecules • Yeast engineering also helps to discover missing plant pathway enzymes and genes., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Chemical reactions are powerful molecular recognition machines. This power has been recently harnessed to build actual instances of each class of experimentally realizable computing automata, using exclusively small-molecule chemistry ( i.e. without requiring biomolecules). The most powerful of them, a programmable Turing machine, uses the Belousov-Zhabotinsky oscillatory chemistry, and accepts/rejects input sequences through a dual oscillatory and thermodynamic output signature. The time interval between the aliquots representing each letter of the input is the parameter that determines the time it takes to run the computation. Here, we investigate this critical performance parameter, and its effect not only on the computation speed, but also on the robustness of the accept/reject oscillatory and thermodynamic criteria. Our work demonstrates that the time interval is a non-trivial design parameter, whose choice should be made with great care. The guidelines we provide can be used in the optimization of the speed, robustness, and energy efficiency of chemical automata computations., Competing Interests: Marta Dueñas-Díez and Juan Pérez-Mercader have a patent related to the work presented here.18 There are no other conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Membrane contact sites (MCS) are subcellular regions where two organelles appose their membranes to exchange small molecules, including lipids. Structural information on how proteins form MCS is scarce. We designed an in vitro MCS with two membranes and a pair of tethering proteins suitable for cryo-tomography analysis. It includes VAP-A, an ER transmembrane protein interacting with a myriad of cytosolic proteins, and oxysterol-binding protein (OSBP), a lipid transfer protein that transports cholesterol from the ER to the trans Golgi network. We show that VAP-A is a highly flexible protein, allowing formation of MCS of variable intermembrane distance. The tethering part of OSBP contains a central, dimeric, and helical T-shape region. We propose that the molecular flexibility of VAP-A enables the recruitment of partners of different sizes within MCS of adjustable thickness, whereas the T geometry of the OSBP dimer facilitates the movement of the two lipid-transfer domains between membranes.

Objective: To explore the effects of low-frequency repetitive transcranial magnetic stimulation (LF rTMS) on cortico-striatal-cerebellar resting state functional connectivity in Parkinson's disease (PD), with and without dyskinesias., Methods: Because there is increasing evidence of an involvement of the pre-supplementary motor area (pre-SMA) in the pathophysiology of levodopa induced dyskinesias, we targeted the right pre-SMA with LF rTMS in 17 PD patients. We explored the effects of one sham-controlled LF rTMS session on resting state functional connectivity of interconnected brain regions by using functional MRI, and how it is modified by levodopa. The clinical effect on motor function and dyskinesias was documented., Results: As expected, one LF rTMS session did not alleviate dyskinesias. However, real, and not sham LF rTMS significantly increased the functional connectivity with the right putamen in patients with dyskinesias. In patients without dyskinesias, the real LF rTMS session significantly decreased functional connectivity in the right putamen and the cerebellum. We found no effects on functional connectivity after levodopa ingestion., Conclusion: One session of 1 Hz rTMS has opposing effects on pre-SMA functional connectivity depending on the PD patients' dyskinesia state., Significance: Patients dyskinesias state determines the way LF rTMS affects functional connectivity in late stage PD., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Purpose: To evaluate tear neuropeptides (NPs) (vasoactive intestinal peptide (VIP), neuropeptide Y (NPY), calcitonin gene-related peptide (CGRP), substance P (SP), nerve growth factor (NGF)) in chronic ocular topical hypotensive therapy with and without benzalkonium chloride (BAK) preservative., Methods: A comparative, open label, cross-sectional study of patients using antiglaucoma medications for > 6 months with BAK (group I), without BAK (group II) and controls was done. Tear NPs (ELISA), ocular surface evaluation tests (tear breakup time (TBUT), Schirmer's test, corneal and conjunctival staining score) and confocal central corneal subbasal nerve fibre layer (SBNFL) imaging was done., Results: Of 153 eyes evaluated, group 1 (82 eyes (41 patients; mean age 48±14.5 years)) and group 2 (71 eyes (36 patients; mean age 43.11±15 years)) were on therapy for a mean duration of 10.05±2.0 and 9.67±2.3 months, respectively. Tear analysis showed elevated SP and NGF (p<0.01); decreased CGRP (p=0.03), VIP and NPY (p<0.01) compared with controls (n=30, mean age 29.33±5.7 years). Tear NP levels (SP (p=0.1), NGF (p=0.33), CGRP (p=1), VIP (p=0.87), NPY (p=0.83)) and SBNFL (p=0.09) were comparable in both groups. There was no correlation seen between tear NP levels and clinical tests and SBNFL., Conclusion: Our study analysis points towards altered tear NP levels in eyes on chronic topical hypotensive therapy in comparison with controls with no significant difference in tear NP levels and central corneal SBNFL density between the BAK preservative and BAK-free antiglaucoma therapy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

AAA+ proteases are degradation machines that use ATP hydrolysis to unfold protein substrates and translocate them through a central pore toward a degradation chamber. FtsH, a bacterial membrane-anchored AAA+ protease, plays a vital role in membrane protein quality control. How substrates reach the FtsH central pore is an open key question that is not resolved by the available atomic structures of cytoplasmic and periplasmic domains. In this work, we used both negative stain TEM and cryo-EM to determine 3D maps of the full-length Aquifex aeolicus FtsH protease. Unexpectedly, we observed that detergent solubilization induces the formation of fully active FtsH dodecamers, which consist of two FtsH hexamers in a single detergent micelle. The striking tilted conformation of the cytosolic domain in the FtsH dodecamer visualized by negative stain TEM suggests a lateral substrate entrance between the membrane and cytosolic domain. Such a substrate path was then resolved in the cryo-EM structure of the FtsH hexamer. By mapping the available structural information and structure predictions for the transmembrane helices to the amino acid sequence we identified a linker of ∼20 residues between the second transmembrane helix and the cytosolic domain. This unique polypeptide appears to be highly flexible and turned out to be essential for proper functioning of FtsH as its deletion fully eliminated the proteolytic activity of FtsH., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Cetirizine, a major metabolite of hydroxyzine, became a marketed second-generation H 1 antihistamine that is orally active and has a rapid onset of action, long duration of effects and a very good safety record at recommended doses. The approved drug is a racemic mixture of (S)-cetirizine and (R)-cetirizine, the latter being the levorotary enantiomer that also exists in the market as a third-generation, non-sedating and highly selective antihistamine. Both enantiomers bind tightly to the human histamine H 1 receptor (hH 1 R) and behave as inverse agonists but the affinity and residence time of (R)-cetirizine are greater than those of (S)-cetirizine. In blood plasma, cetirizine exists in the zwitterionic form and more than 90% of the circulating drug is bound to human serum albumin (HSA), which acts as an inactive reservoir. Independent X-ray crystallographic work has solved the structure of the hH 1 R:doxepin complex and has identified two drug-binding sites for cetirizine on equine serum albumin (ESA). Given this background, we decided to model a membrane-embedded hH 1 R in complex with either (R)- or (S)-cetirizine and also the complexes of both ESA and HSA with these two enantiomeric drugs to analyze possible differences in binding modes between enantiomers and also among targets. The ensuing molecular dynamics simulations in explicit solvent and additional computational chemistry calculations provided structural and energetic information about all of these complexes that is normally beyond current experimental possibilities. Overall, we found very good agreement between our binding energy estimates and extant biochemical and pharmacological evidence. A much higher degree of solvent exposure in the cetirizine-binding site(s) of HSA and ESA relative to the more occluded orthosteric binding site in hH 1 R is translated into larger positional fluctuations and considerably lower affinities for these two nonspecific targets. Whereas it is demonstrated that the two known pockets in ESA provide enough stability for cetirizine binding, only one such site does so in HSA due to a number of amino acid replacements. At the histamine-binding site in hH 1 R, the distinct interactions established between the phenyl and chlorophenyl moieties of the two enantiomers with the amino acids lining up the pocket and between their free carboxylates and Lys179 in the second extracellular loop account for the improved pharmacological profile of (R)-cetirizine.

Scope: Fructose intake from added sugars correlates with the epidemic rise in metabolic syndrome and cardiovascular diseases (CVD). However, consumption of beverages containing fructose is allowed during gestation. Homocysteine (Hcy) is a well-known risk factor for CVD while hydrogen sulfide (H 2 S), a product of its metabolism, has been proved to exert opposite effects to Hcy., Methods and Results: First, it is investigated whether maternal fructose intake produces subsequent changes in Hcy metabolism and H 2 S synthesis of the progeny. Carbohydrates are supplied to pregnant rats in drinking water (10% wt/vol) throughout gestation. Adult female descendants from fructose-fed, control or glucose-fed mothers are studied. Females from fructose-fed mothers have elevated homocysteinemia, hepatic H 2 S production, cystathionine γ-lyase (CSE) (the key enzyme in H 2 S synthesis) expression and plasma H 2 S, versus the other two groups. Second, it is studied how adult female progeny from control (C/F), fructose- (F/F), and glucose-fed (G/F) mothers responded to liquid fructose and compared them to the control group (C/C). Interestingly, hepatic CSE expression and H 2 S synthesis are diminished by fructose intake, this effect being more pronounced in F/F females., Conclusion: Maternal fructose intake produces a fetal programming that increases hepatic H 2 S production and, in contrast, exacerbates its fructose-induced drop in female progeny., (© 2020 Wiley-VCH GmbH.)

Living systems process information using chemistry. Computations can be viewed as language recognition problems where both languages and automata recognizing them form an inclusive hierarchy. Chemical realizations, without using biochemistry, of the main classes of computing automata, Finite Automata (FA), 1-stack Push Down Automata (1-PDA) and Turing Machine (TM) have recently been presented. These use chemistry for the representation of input information, its processing and output information. The Turing machine uses the Belousov-Zhabotinsky (BZ) oscillatory reaction to recognize a representative Context-Sensitive Language (CSL), the 1-PDA uses a pH network to recognize a Context Free Language (CFL) and a FA for a Regular Language (RL) uses a precipitation reaction. By chemically reconfiguring them to recognize representative languages in the lower classes of the Chomsky hierarchy we illustrate the inclusiveness of the hierarchy of native chemical automata. These examples open the door for chemical programming without biochemistry. Furthermore, the thermodynamic metric originally introduced to identify the accept/reject state of the chemical output for the CSL, can equally be used for recognizing CFL and RL by the automata. Finally, we point out how the chemical and thermodynamic duality of accept/reject criteria can be used in the optimization of the energetics and efficiency of computations.

Background: Resting-state functional magnetic resonance imaging (fMRI) studies have demonstrated that basal ganglia functional connectivity is altered in Parkinson's disease (PD) as compared to healthy controls. However, such functional connectivity alterations have not been related to the dopaminergic deficits that occurs in PD over time., Objectives: To examine whether functional connectivity impairments are correlated with dopaminergic deficits across basal ganglia subdivisions in patients with PD both cross-sectionally and longitudinally., Methods: We assessed resting-state functional connectivity of basal ganglia subdivisions and dopamine transporter density using 11 C-PE2I PET in thirty-four PD patients at baseline. Of these, twenty PD patients were rescanned after 19.9 ± 3.8 months. A seed-based approach was used to analyze resting-state fMRI data. 11 C-PE2I binding potential (BP ND ) was calculated for each participant. PD patients were assessed for disease severity., Results: At baseline, PD patients with greater dopaminergic deficits, as measured with 11 C-PE2I PET, showed larger decreases in posterior putamen functional connectivity with the midbrain and pallidum. Reduced functional connectivity of the posterior putamen with the thalamus, midbrain, supplementary motor area and sensorimotor cortex over time were significantly associated with changes in DAT density over the same period. Furthermore, increased motor disability was associated with lower intraregional functional connectivity of the posterior putamen., Conclusions: Our findings suggest that basal ganglia functional connectivity is related to integrity of dopaminergic system in patients with PD. Application of resting-state fMRI in a large cohort and longitudinal scanning may be a powerful tool for assessing underlying PD pathology and its progression., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Microbial communities recurrently establish metabolic associations resulting in increased fitness and ability to perform complex tasks, such as xenobiotic degradation. In a previous study, we have described a sulfonamide-degrading consortium consisting of a novel low-abundant actinobacterium, named strain GP, and Achromobacter denitrificans PR1. However, we found that strain GP was unable to grow independently and could not be further purified., Results: Previous studies suggested that strain GP might represent a new putative species within the Leucobacter genus (16S rRNA gene similarity < 97%). In this study, we found that average nucleotide identity (ANI) with other Leucobacter spp. ranged between 76.8 and 82.1%, further corroborating the affiliation of strain GP to a new provisional species. The average amino acid identity (AAI) and percentage of conserved genes (POCP) values were near the lower edge of the genus delimitation thresholds (65 and 55%, respectively). Phylogenetic analysis of core genes between strain GP and Leucobacter spp. corroborated these findings. Comparative genomic analysis indicates that strain GP may have lost genes related to tetrapyrrole biosynthesis and thiol transporters, both crucial for the correct assembly of cytochromes and aerobic growth. However, supplying exogenous heme and catalase was insufficient to abolish the dependent phenotype. The actinobacterium harbors at least two copies of a novel genetic element containing a sulfonamide monooxygenase (sadA) flanked by a single IS1380 family transposase. Additionally, two homologs of sadB (4-aminophenol monooxygenase) were identified in the metagenome-assembled draft genome of strain GP, but these were not located in the vicinity of sadA nor of mobile or integrative elements., Conclusions: Comparative genomics of the genus Leucobacter suggested the absence of some genes encoding for important metabolic traits in strain GP. Nevertheless, although media and culture conditions were tailored to supply its potential metabolic needs, these conditions were insufficient to isolate the PR1-dependent actinobacterium further. This study gives important insights regarding strain GP metabolism; however, gene expression and functional studies are necessary to characterize and further isolate strain GP. Based on our data, we propose to classify strain GP in a provisional new species within the genus Leucobacter, 'Candidatus Leucobacter sulfamidivorax'.

Every problem in computing can be cast as decision problems of whether strings are in a language or not. Computations and language recognition are carried out by three classes of automata, the most complex of which is the Turing machine. Living systems compute using biochemistry; in the artificial, computation today is mostly electronic. Thinking of chemical reactions as molecular recognition machines, and without using biochemistry, we realize one automaton in each class by means of one-pot, table top chemical reactors: from the simplest, Finite automata, to the most complex, Turing machines. Language acceptance/rejection criteria by automata can be formulated using energy considerations. Our Turing machine uses the Belousov-Zhabotinsky chemical reaction and checks the same symbol in an Avogadro's number of processors. Our findings have implications for chemical and general computing, artificial intelligence, bioengineering, the study of the origin and presence of life on other planets, and for artificial biology., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

The ros1 kinase is an oncogenic driver in non-small-cell lung cancer (nsclc). Fusion events involving the ROS1 gene are found in 1%-2% of nsclc patients and lead to deregulation of a tyrosine kinase-mediated multi-use intracellular signalling pathway, which then promotes the growth, proliferation, and progression of tumour cells. ROS1 fusion is a distinct molecular subtype of nsclc, found independently of other recognized driver mutations, and it is predominantly identified in younger patients (<50 years of age), women, never-smokers, and patients with adenocarcinoma histology. Targeted inhibition of the aberrant ros1 kinase with crizotinib is associated with increased progression-free survival (pfs) and improved quality-of-life measures. As the sole approved treatment for ROS1- rearranged nsclc, crizotinib has been demonstrated, through a variety of clinical trials and retrospective analyses, to be a safe, effective, well-tolerated, and appropriate treatment for patients having the ROS1 rearrangement. Canadian physicians endorse current guidelines which recommend that all patients with nonsquamous advanced nsclc, regardless of clinical characteristics, be tested for ROS1 rearrangement. Future integration of multigene testing panels into the standard of care could allow for efficient and cost-effective comprehensive testing of all patients with advanced nsclc. If a ROS1 rearrangement is found, treatment with crizotinib, preferably in the first-line setting, constitutes the standard of care, with other treatment options being investigated, as appropriate, should resistance to crizotinib develop., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare the following interests: JA, SB, ACS have received personal fees from Pfizer, outside the submitted work; RA received personal fees from Pfizer during the conduct of the study; DGB received grants from Pfizer during the conduct of the study and personal fees from AstraZeneca, Roche, Bristol–Myers Squibb, Boehringer Ingelheim, Pfizer, Merck, Bayer, Lilly, and Takeda outside the submitted work; GB and WM are members of the Pfizer advisory board; CB and CC have received other consideration from Pfizer outside the submitted work; PD received grants from Pfizer during the conduct of the study and other consideration from Bayer, Bristol–Myers Squibb, AstraZeneca, and Pfizer outside the submitted work; HSS has received other consideration from Pfizer Canada, Bayer, Merck, and EMD Serono Canada outside the submitted work; TLS has received grants and personal fees from AstraZeneca and personal fees from Bristol–Myers Squibb, Janssen, Pfizer, and Novartis outside the submitted work; ET has received grants from, and been an advisory board member for, Pfizer, Bristol–Myers Squibb, Merck, AstraZeneca, Roche, and Janssen outside the submitted work; MST received grants and personal fees from Pfizer during the conduct of the study and has received grants and personal fees from AstraZeneca and Merck, and personal fees from Bristol–Myers Squibb and Bayer outside the submitted work; JCC, DNI, NBL, BM, FRK, and ZX have no conflicts to disclose.

2D electron crystallography can be used to study small membrane proteins in their native environment. Obtaining highly ordered 2D crystals is difficult and time-consuming. However, 2D crystals diffracting to only 10-12 Å can be prepared relatively conveniently in most cases. We have developed image-processing algorithms allowing to generate a high resolution 3D structure from cryo-electron crystallography images of badly ordered crystals. These include movie-mode unbending, refinement over sub-tiles of the images in order to locally refine the sample tilt geometry, implementation of different CTF correction schemes, and an iterative method to apply known constraints in the real and reciprocal space to approximate amplitudes and phases in the so-called missing cone regions. These algorithms applied to a dataset of the potassium channel MloK1 show significant resolution improvements to better than 5 Å., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Functional, flexible, and integrated lab-on-chips, based on elastic membranes, are capable of fine response to external stimuli, so to pave the way for many applications as multiplexed sensors for a wide range of chemical, physical and biomedical processes. Here, we report on the use of elastic thin membranes (TMs), integrated with a reaction chamber, to fabricate a membrane-based pressure sensor (MePS) for reaction monitoring. In particular, the TM becomes the key-element in the design of a highly sensitive MePS capable to monitor gaseous species production in dynamic and temporally fast processes with high resolution and reproducibility. Indeed, we demonstrate the use of a functional MePS integrating a 2 μm thick polydimethylsiloxane TM by monitoring the dioxygen evolution resulting from catalytic hydrogen peroxide dismutation. The operation of the membrane, explained using a diffusion-dominated model, is demonstrated on two similar catalytic systems with catalase-like activity, assembled into polyelectrolyte multilayers capsules. The MePS, tested in a range between 2 and 50 Pa, allows detecting a dioxygen variation of the μmol L -1 s -1 order. Due to their structural features, flexibility of integration, and biocompatibility, the MePSs are amenable of future development within advanced lab-on-chips.

Purpose: Reliable and reproducible methods for identifying PD-L1 expression on tumor cells are necessary to identify responders to anti-PD-1 therapy. We tested the reproducibility of the assessment of PD-L1 expression in non-small cell lung cancer (NSCLC) tissue samples by pathologists. Experimental Design: NSCLC samples were stained with PD-L1 22C3 pharmDx kit using the Dako Autostainer Link 48 Platform. Two sample sets of 60 samples each were designed to assess inter- and intraobserver reproducibility considering two cut points for positivity: 1% or 50% of PD-L1 stained tumor cells. A randomization process was used to obtain equal distribution of PD-L1 positive and negative samples within each sample set. Ten pathologists were randomly assigned to two subgroups. Subgroup 1 analyzed all samples on two consecutive days. Subgroup 2 performed the same assessments, except they received a 1-hour training session prior to the second assessment. Results: For intraobserver reproducibility, the overall percent agreement (OPA) was 89.7% [95% confidence interval (CI), 85.7-92.6] for the 1% cut point and 91.3% (95% CI, 87.6-94.0) for the 50% cut point. For interobserver reproducibility, OPA was 84.2% (95% CI, 82.8-85.5) for the 1% cut point and 81.9% (95% CI, 80.4-83.3) for the 50% cut point, and Cohen's κ coefficients were 0.68 (95% CI, 0.65-0.71) and 0.58 (95% CI, 0.55-0.62), respectively. The training was found to have no or very little impact on intra- or interobserver reproducibility. Conclusions: Pathologists reported good reproducibility at both 1% and 50% cut points. More adapted training could potentially increase reliability, in particular for samples with PD-L1 proportion, scores around 50%. Clin Cancer Res; 23(16); 4569-77. ©2017 AACR ., (©2017 American Association for Cancer Research.)

We present a new software package called Focus that interfaces cryo-transmission electron microscopy (cryo-EM) data collection with computer image processing. Focus creates a user-friendly environment to import and manage data recorded by direct electron detectors and perform elemental image processing tasks in a high-throughput manner while new data is being acquired at the microscope. It provides the functionality required to remotely monitor the progress of data collection and data processing, which is essential now that automation in cryo-EM allows a steady flow of images of single particles, two-dimensional crystals, or electron tomography data to be recorded in overnight sessions. The rapid detection of any errors that may occur greatly increases the productivity of recording sessions at the electron microscope., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

Once penetrated into the lungs of exposed people, asbestos induces an in vivo biomineralisation process that leads to the formation of a ferruginous coating embedding the fibres. The ensemble of the fibre and the coating is referred to as asbestos body and is believed to be responsible for the high toxicological outcome of asbestos. Lung tissue of two individuals subjected to prolonged occupational exposure to crocidolite asbestos was investigated using synchrotron radiation micro-probe tools. The distribution of K and of elements heavier than Fe (Zn, Cu, As, and Ba) in the asbestos bodies was observed for the first time. Elemental quantification, also reported for the first time, confirmed that the coating is highly enriched in Fe (~20% w/w), and x-ray absorption spectroscopy indicated that Fe is in the 3+ oxidation state and that it is present in the form of ferritin or hemosiderin. Comparison of the results obtained studying the asbestos bodies upon removing the biological tissue by chemical digestion and those embedded in histological sections, allowed unambiguously distinguishing the composition of the asbestos bodies, and understanding to what extent the digestion procedure altered their chemical composition. A speculative model is proposed to explain the observed distribution of Fe.

Migratory waterfowl are natural reservoirs for low pathogenic avian influenza viruses (AIVs) and may contribute to the long-distance dispersal of these pathogens as well as spillover into domestic bird populations. Surveillance for AIVs is critical to assessing risks for potential spread of these viruses among wild and domestic bird populations. The Delmarva Peninsula on the east coast of the United States is both a key convergence point for migratory Atlantic waterfowl populations and a region with high poultry production (>4,700 poultry meat facilities). Sampling of key migratory waterfowl species occurred at 20 locations throughout the Delmarva Peninsula in fall and winter of 2013-14. Samples were collected from 400 hunter-harvested or live-caught birds via cloacal and oropharyngeal swabs. Fourteen of the 400 (3.5%) birds sampled tested positive for the AIV matrix gene using real-time reverse transcriptase PCR, all from five dabbling duck species. Further characterization of the 14 viral isolates identified two hemagglutinin (H3 and H4) and four neuraminidase (N2, N6, N8, and N9) subtypes, which were consistent with isolates reported in the Influenza Research Database for this region. Three of 14 isolates contained multiple HA or NA subtypes. This study adds to the limited baseline information available for AIVs in migratory waterfowl populations on the Delmarva Peninsula, particularly prior to the highly pathogenic AIV A(H5N8) and A(H5N2) introductions to the United States in late 2014.

Social housing has often been recommended as one-way to address the psychological well-being of captive non-human primates. Published reports have examined methods to socialize compatible animals by forming pairs or groups. Successful socialization rates vary depending on the species, gender, and environment. This study presents a retrospective look at pairing attempts in two species of owl monkeys, Aotus nancymaae and A. azarae, which live in monogamous pairs in the wild. The results of 477 pairing attempt conducted with captive, laboratory housed owl monkeys and 61 hr of behavioral observations are reported here. The greatest success pairing these owl monkeys occurred with opposite sex pairs, with an 82% success rate. Opposite sex pairs were more successful when females were older than males. Female-female pairs were more successful than male-male (MM) pairs (62% vs 40%). Successful pairs stayed together between 3 and 7 years before the animals were separated due to social incompatibility. Vigilance, eating, and sleeping during introductions significantly predicted success, as did the performance of the same behavior in both animals. The results of this analysis show that it is possible to give captive owl monkeys a social alternative even if species appropriate social partners (i.e., opposite sex partners) are not available. The focus of this report is a description of one potential way to enhance the welfare of a specific new world primate, the owl monkey, under laboratory conditions. More important is how the species typical social structure of owl monkeys in nature affects the captive management of this genus. Am. J. Primatol. 79:e22521, 2017. © 2015 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

The structural defects in two-dimensional transition metal dichalcogenides, including point defects, dislocations and grain boundaries, are scarcely considered regarding their potential to manipulate the electrical and optical properties of this class of materials, notwithstanding the significant advances already made. Indeed, impurities and vacancies may influence the exciton population, create disorder-induced localization, as well as modify the electrical behaviour of the material. Here we report on the experimental evidence, confirmed by ab initio calculations, that sulfur vacancies give rise to a novel near-infrared emission peak around 0.75 eV in exfoliated MoS 2 flakes. In addition, we demonstrate an excess of sulfur vacancies at the flake's edges by means of cathodoluminescence mapping, aberration-corrected transmission electron microscopy imaging and electron energy loss analyses. Moreover, we show that ripplocations, extended line defects peculiar to this material, broaden and redshift the MoS 2 indirect bandgap emission.

The synthesis of ZnO porous nanobelts with high surface-to-volume ratio is envisaged to enhance the zinc oxide sensing and photocatalytic properties. Yet, controlled stoichiometry, doping and compensation of as-grown n-type behavior remain open problems for this compound. Here, we demonstrate the effect of residual sulfur atoms on the optical properties of ZnO highly porous, albeit purely wurtzite, nanobelts synthesized by solvothermal decomposition of ZnS hybrids. By means of combined cathodoluminescence analyses and density functional theory calculations, we attribute a feature appearing at 2.36 eV in the optical emission spectra to sulfur related intra-gap states. A comparison of different sulfur configurations in the ZnO matrix demonstrates the complex compensating effect on the electronic properties of the system induced by S-inclusion.

Surface defect or damage is one of the critical factors leading to the failure of engineering materials and structures. The methodologies for the measurement of surface shape and feature or defect have been extensively explored and developed over the past few decades, including both contact and non-contact methods. Speckle pattern interferometry, as a non-contact optical method, has been demonstrated to effectively contour the surface shape through adjusting the illumination vector. However, few studies have been made to investigate the effect of the initial position of the illumination source as well as the source translation direction. In this paper, we report to carry out a study of measuring the surface form and feature using digital speckle pattern interferometry system via a slight translation of illumination source. Through theoretically analyzing the sensitivity factor along with the experimental validation, it is shown that the contouring fringe is more sensitive to the surface height with an off-axis illumination than the paraxial illumination. It is also found that translating the source along axial and lateral direction can be both used for the surface shape re-construction.

In this paper, we present a fast and accurate kernel-based supervised algorithm referred to as the Reduced Kernel Extreme Learning Machine (RKELM). In contrast to the work on Support Vector Machine (SVM) or Least Square SVM (LS-SVM), which identifies the support vectors or weight vectors iteratively, the proposed RKELM randomly selects a subset of the available data samples as support vectors (or mapping samples). By avoiding the iterative steps of SVM, significant cost savings in the training process can be readily attained, especially on Big datasets. RKELM is established based on the rigorous proof of universal learning involving reduced kernel-based SLFN. In particular, we prove that RKELM can approximate any nonlinear functions accurately under the condition of support vectors sufficiency. Experimental results on a wide variety of real world small instance size and large instance size applications in the context of binary classification, multi-class problem and regression are then reported to show that RKELM can perform at competitive level of generalized performance as the SVM/LS-SVM at only a fraction of the computational effort incurred., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The species Thuris depressus Sakakibara (1975) is proposed as a syn. n. of Thuris binodosus (Goding 1926), comb. n. The distribution of the genus is expanded from Brazil and Peru to include Ecuador and Venezuela, and the immature is described based on 75 characters.

Background and Objective: The aim of this paper is to provide an efficient, parametric, general, and completely automatic real time classification method of electroencephalography (EEG) signals obtained from self-induced emotions. The particular characteristics of the considered low-amplitude signals (a self-induced emotion produces a signal whose amplitude is about 15% of a really experienced emotion) require exploring and adapting strategies like the Wavelet Transform, the Principal Component Analysis (PCA) and the Support Vector Machine (SVM) for signal processing, analysis and classification. Moreover, the method is thought to be used in a multi-emotions based Brain Computer Interface (BCI) and, for this reason, an ad hoc shrewdness is assumed., Method: The peculiarity of the brain activation requires ad-hoc signal processing by wavelet decomposition, and the definition of a set of features for signal characterization in order to discriminate different self-induced emotions. The proposed method is a two stages algorithm, completely parameterized, aiming at a multi-class classification and may be considered in the framework of machine learning. The first stage, the calibration, is off-line and is devoted at the signal processing, the determination of the features and at the training of a classifier. The second stage, the real-time one, is the test on new data. The PCA theory is applied to avoid redundancy in the set of features whereas the classification of the selected features, and therefore of the signals, is obtained by the SVM., Results: Some experimental tests have been conducted on EEG signals proposing a binary BCI, based on the self-induced disgust produced by remembering an unpleasant odor. Since in literature it has been shown that this emotion mainly involves the right hemisphere and in particular the T8 channel, the classification procedure is tested by using just T8, though the average accuracy is calculated and reported also for the whole set of the measured channels., Conclusions: The obtained classification results are encouraging with percentage of success that is, in the average for the whole set of the examined subjects, above 90%. An ongoing work is the application of the proposed procedure to map a large set of emotions with EEG and to establish the EEG headset with the minimal number of channels to allow the recognition of a significant range of emotions both in the field of affective computing and in the development of auxiliary communication tools for subjects affected by severe disabilities., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

The immatures stages of 8 of the 11 genera (Amastris Stål, Bajulata Ball, Erosne Stål, Harmonides Kirkaldy, Idioderma Van Duzee, Neotynelia Creão-Duarte & Sakakibara, Tynelia Stål, and Vanduzea Goding) of the tribe Amastrini are described for the first time along with brief diagnoses of Membracidae and the subfamily Smiliinae. A key to genera and notes on biology are provided. Multiple species of most genera are illustrated. Based on its distinct nymphal morphology, Vanduzea laeta nolina Ball is elevated to specific rank as Vanduzea nolina stat. n., and Bajulata, despite the superficial similarity of its adults to those of Vanduzea, is confirmed as warranting generic rank based on its unique nymphal morphology. Colombia is a new country record for Tynelia.

Although it has long been known that mitochondria take up Ca2+, the molecular identities of the channels and transporters involved in this process were revealed only recently. Here, we discuss the recent work that has led to the characterization of the mitochondrial calcium uniporter complex, which includes the channel-forming subunit MCU (mitochondrial calcium uniporter) and its regulators MICU1, MICU2, MCUb, EMRE, MCUR1 and miR-25. We review not only the biochemical identities and structures of the proteins required for mitochondrial Ca2+ uptake but also their implications in different physiopathological contexts.

Although clinical atherosclerosis is fairly common, it is a surprisingly uncommon finding in anthropology. Several cases have been reported in the anthropological literature but most of them are referred to X-ray studies and to computerized tomographic imaging but, as far as we know, no macroscopic findings useful to anthropologists have been published before. We present a case of an adult male skeleton scattered on a wooded area with remains of partially mummified soft tissues between right tibia and fibula in which macroscopic findings showed a cylindrical structure that could be confused with a root or a branch. This cylindrical structure was diagnosed as an arterial segment and microscopic findings revealed calcified eccentric fibroatheromatosis. We hope this case will improve the knowledge of this macroscopic appearance and thus be useful to anthropologists., (Copyright © 2012 Elsevier Inc. All rights reserved.)