Explore the vast range of titles available.

The Notch receptor is an evolutionarily highly conserved transmembrane protein essential to a wide spectrum of cellular systems, and its deregulation has been linked to a vast number of developmental disorders and malignancies. Regulated Notch function is critical for the generation of T-cells, in which abnormal Notch signaling results in leukemia. Notch activation through -activation of the receptor by one of its ligands expressed on adjacent cells has been well defined. In this canonical ligand-dependent pathway, Notch receptor undergoes conformational changes upon ligand engagement, stimulated by a pulling-force on the extracellular fragment of Notch that results from endocytosis of the receptor-bound ligand into the ligand-expressing cell. These conformational changes in the receptor allow for two consecutive proteolytic cleavage events to occur, which release the intracellular region of the receptor into the cytoplasm. It can then travel to the nucleus, where it induces gene transcription. However, there is accumulating evidence that other pathways may induce Notch signaling. A ligand-independent mechanism of Notch activation has been described in which receptor processing is initiated cell-internal signals. These signals result in the internalization of Notch into endosomal compartments, where chemical changes existing in this microenvironment result in the conformational modifications required for receptor processing. This review will present mechanisms underlying both canonical ligand-dependent and non-canonical ligand-independent Notch activation pathways and discuss the latter in the context of Notch signaling in T-cells.

Benzodiazepine acute withdrawal syndrome is well known, but the long-term neurological consequences of benzodiazepine exposure are much less familiar. A scoping review was conducted of electronic databases for studies that reported on patient outcomes four or more weeks after complete cessation of benzodiazepine use. Forty-six results were retrieved in total, some of which provided signals for protracted symptoms, often reported as incidental findings, and others that showed benzodiazepine discontinuation was beneficial. Some overlap occurred in the outcomes, but these two groups of studies suggest that the benefits of benzodiazepine discontinuation for many patients tended to obscure the more prolonged, severe, and sometimes debilitating symptoms that persisted for months and years in a subpopulation of patients. The prevalence or trajectory of these enduring symptoms could not be determined from these studies. Further elucidation of the potential neurotoxicity of benzodiazepines is needed to better understand protracted symptoms and their treatment. Clinicians, patients, and the healthcare system must be cognizant of the risks of benzodiazepine exposure beyond two to four weeks.

Acute benzodiazepine withdrawal has been described, but literature regarding the benzodiazepine-induced neurological injury that may result in enduring symptoms and life consequences is scant. We conducted an internet survey of current and former benzodiazepine users and asked about their symptoms and adverse life events attributed to benzodiazepine use. This is a secondary analysis of the largest survey ever conducted with 1,207 benzodiazepine users from benzodiazepine support groups and health/wellness sites who completed the survey. Respondents included those still taking benzodiazepines (n = 136), tapering (n = 294), or fully discontinued (n = 763). The survey asked about 23 specific symptoms and more than half of the respondents who experienced low energy, distractedness, memory loss, nervousness, anxiety, and other symptoms stated that these symptoms lasted a year or longer. These symptoms were often reported as de novo and distinct from the symptoms for which the benzodiazepines were originally prescribed. A subset of respondents stated that symptoms persisted even after benzodiazepines had been discontinued for a year or more. Adverse life consequences were reported by many respondents as well. This was a self-selected internet survey with no control group. No independent psychiatric diagnoses could be made in participants. Many prolonged symptoms subsequent to benzodiazepine use and discontinuation (benzodiazepine-induced neurological dysfunction) have been shown in a large survey of benzodiazepine users. Benzodiazepine-induced neurological dysfunction (BIND) has been proposed as a term to describe symptoms and associated adverse life consequences that may emerge during benzodiazepine use, tapering, and continue after benzodiazepine discontinuation. Not all people who take benzodiazepines will develop BIND and risk factors for BIND remain to be elucidated. Further pathogenic and clinical study of BIND is needed.

The newly characterized sperm-specific Na + /H + exchanger stands out by its unique tripartite domain composition 1 , 2 . It unites a classical solute carrier unit with regulatory domains usually found in ion channels, namely, a voltage-sensing domain and a cyclic-nucleotide binding domain 1 , 3 , which makes it a mechanistic chimera and a secondary-active transporter activated strictly by membrane voltage. Our structures of the sea urchin SpSLC9C1 in the absence and presence of ligands reveal the overall domain arrangement and new structural coupling elements. They allow us to propose a gating model, where movements in the voltage sensor indirectly cause the release of the exchanging unit from a locked state through long-distance allosteric effects transmitted by the newly characterized coupling helices. We further propose that modulation by its ligand cyclic AMP occurs by means of disruption of the cytosolic dimer interface, which lowers the energy barrier for S4 movements in the voltage-sensing domain. As SLC9C1 members have been shown to be essential for male fertility, including in mammals 2 , 4 , 5 , our structure represents a potential new platform for the development of new on-demand contraceptives. This study proposes a molecular mechanism of voltage activation in SLC9C1, a transporter essential for male fertility.

This book provides a clear and understandable text for users and developers of advanced engineered materials, particularly in the area of thin films, and addresses fundamentals of modifying the optical, electrical, photo-electric, triboligical, and corrosion resistance of solid surfaces and adding functionality to solids by engineering their surface, structure, and electronic, magnetic and optical structure. Thin film applications are emphasized. Through the inclusion of multiple clear examples of the technologies, how to use them,and the synthesis processes involved, the reader will gain a deep understanding of the purpose, goals, and methodology of surface engineering and engineered materials. Virtually every advance in thin film, energy, medical, tribological materials technologies has resulted from surface engineering and engineered materials. Surface engineering involves structures and compositions not found naturally in solids and is used to modify the surface properties of solids and involves application of thin film coatings, surface functionalization and activation, and plasma treatment. Engineered materials are the future of thin film technology. Engineered structures such as superlattices, nanolaminates, nanotubes, nanocomposites, smart materials, photonic bandgap materials, metamaterials, molecularly doped polymers and structured materials all have the capacity to expand and increase the functionality of thin films and coatings used in a variety of applications and provide new applications. New advanced deposition processes and hybrid processes are being used and developed to deposit advanced thin film materials and structures not possible with conventional techniques a decade ago. Properties can now be engineered into thin films that achieve performance not possible a decade ago.

Background It remains unknown whether laparoscopic compared to open surgery translates into fewer incisional hernia repairs (IHR). The objectives of the current study were to compare the long-term incidence of IHR and the size of repaired hernias between patients subjected to laparoscopic or open resection of colonic cancer. Methods This was a nationwide cohort study comprised of patients undergoing resection for colonic cancer between January 2007 and March 2016 according to the Danish Colorectal Cancer Group database. Patients who subsequently underwent IHR were identified in the Danish Ventral Hernia Database, from which information about the priority of the hernia repair and the size of the fascial defect was retrieved. Results The study included 17,717 patients, of whom 482 (2.7%) underwent subsequent IHR during a median follow-up of 4.7 (interquartile range 2.8–6.9) years. There was no significant difference in the 5-year cumulative incidence of hernia repair after laparoscopic compared to open colonic resection (3.9%, CI 3.3–4.4% vs 4.1%, CI 3.5–4.6%). After adjustment for confounders, laparoscopic approach was associated with an increased rate of emergency IHR (HR 2.37, 95% CI 1.03–5.46, P  = 0.042) as opposed to elective IHR (HR 0.91, 95% CI 0.73–1.14, P  = 0.442). Laparoscopic surgery was significantly associated with a decreased fascial defect area compared to open surgery (mean difference −16.0 cm 2 , 95% CI −29.4 to −2.5, P  = 0.020). Conclusions There was no difference in the incidence of IHR after open compared to laparoscopic resection. Compared to the open approach, laparoscopic resection increased the rate of subsequent emergency IHR, suggesting that a more aggressive therapeutic approach may be warranted in this patient group upon diagnosis of an incisional hernia.

The tumour microenvironment and genetic alterations collectively influence drug efficacy in cancer, but current evidence is limited and systematic analyses are lacking. Using chronic lymphocytic leukaemia (CLL) as a model disease, we investigated the influence of 17 microenvironmental stimuli on 12 drugs in 192 genetically characterised patient samples. Based on microenvironmental response, we identified four subgroups with distinct clinical outcomes beyond known prognostic markers. Response to multiple microenvironmental stimuli was amplified in trisomy 12 samples. Trisomy 12 was associated with a distinct epigenetic signature. Bromodomain inhibition reversed this epigenetic profile and could be used to target microenvironmental signalling in trisomy 12 CLL. We quantified the impact of microenvironmental stimuli on drug response and their dependence on genetic alterations, identifying interleukin 4 (IL4) and Toll‐like receptor (TLR) stimulation as the strongest actuators of drug resistance. IL4 and TLR signalling activity was increased in CLL‐infiltrated lymph nodes compared with healthy samples. High IL4 activity correlated with faster disease progression. The publicly available dataset can facilitate the investigation of cell‐extrinsic mechanisms of drug resistance and disease progression. Synopsis Combined perturbation by microenvironmental stimuli and drugs of chronic lymphocytic leukaemia cells annotated for genetic alterations reveals distinct response patterns and molecular modulators. CLL samples fall into four subgroups with distinct progression dynamics based on their microenvironmental response. Trisomy 12 enhances the response to microenvironmental stimulation and has a distinct transcription factor activity profile which is inhibited by IBET‐762 treatment. Linear modelling reveals different types of drug ‐ stimuli interactions, the most common being drug resistance induced by microenvironmental stimulation. IL4 and TLR signalling is more active in CLL infiltrated lymph nodes, and higher IL4 signalling activity correlates with faster disease progression. Graphical Abstract Combined perturbation by microenvironmental stimuli and drugs of chronic lymphocytic leukaemia cells annotated for genetic alterations reveals distinct response patterns and molecular modulators.

A Light Detection and Ranging (LiDAR) sensor mounted on an Unmanned Aerial Vehicle (UAV) can map the overflown environment in point clouds. Mapped canopy heights allow for the estimation of crop biomass in agriculture. The work presented in this paper contributes to sensory UAV setup design for mapping and textual analysis of agricultural fields. LiDAR data are combined with data from Global Navigation Satellite System (GNSS) and Inertial Measurement Unit (IMU) sensors to conduct environment mapping for point clouds. The proposed method facilitates LiDAR recordings in an experimental winter wheat field. Crop height estimates ranging from 0.35–0.58 m are correlated to the applied nitrogen treatments of 0–300 kg N ha . The LiDAR point clouds are recorded, mapped, and analysed using the functionalities of the Robot Operating System (ROS) and the Point Cloud Library (PCL). Crop volume estimation is based on a voxel grid with a spatial resolution of 0.04 × 0.04 × 0.001 m. Two different flight patterns are evaluated at an altitude of 6 m to determine the impacts of the mapped LiDAR measurements on crop volume estimations.

Pulsed electron-electron double resonance spectroscopy (PELDOR/DEER) and single-molecule Förster resonance energy transfer spectroscopy (smFRET) are frequently used to determine conformational changes, structural heterogeneity, and inter probe distances in biological macromolecules. They provide qualitative information that facilitates mechanistic understanding of biochemical processes and quantitative data for structural modelling. To provide a comprehensive comparison of the accuracy of PELDOR/DEER and smFRET, we use a library of double cysteine variants of four proteins that undergo large-scale conformational changes upon ligand binding. With either method, we use established standard experimental protocols and data analysis routines to determine inter-probe distances in the presence and absence of ligands. The results are compared to distance predictions from structural models. Despite an overall satisfying and similar distance accuracy, some inconsistencies are identified, which we attribute to the use of cryoprotectants for PELDOR/DEER and label-protein interactions for smFRET. This large-scale cross-validation of PELDOR/DEER and smFRET highlights the strengths, weaknesses, and synergies of these two important and complementary tools in integrative structural biology. Pulsed electron-electron double resonance spectroscopy (PELDOR/DEER) and single-molecule Förster resonance energy transfer spectroscopy (smFRET) are used to determine conformational changes and probe distances in biological macromolecules. Here the authors compare the methods on a large set of samples.

BackgroundThe literature on transverse colonic cancer resection is sparse. The optimal surgical approach for this disease is thus unknown. This study aimed to examine laparoscopic versus open surgery for transverse colonic cancer.MethodsThis study was a nationwide, retrospective cohort study of all patients registered with a transverse colonic cancer in Denmark between 2010 and 2013. Data were obtained from the Danish Colorectal Cancer Group, the Danish Pathology Registry, Danish National Patient Registry, and patients’ records. Main outcome measures were surgical resection plane, lymph node yield, and long-term cancer recurrence and survival.ResultsIn total, 357 patients were included. Non-mesocolic resection was more frequent with laparoscopic compared with open resection (adjusted odds ratio 2.44, 95% CI 1.29–4.60, P = 0.006). Median number of harvested lymph nodes was higher after open compared with laparoscopic resection (22 versus 19, P = 0.03). Non-mesocolic resection (adjusted hazard ratio 2.45, 95% CI 1.25–4.79, P = 0.01) and increasing tumor stage (P < 0.001) were factors associated with recurrence. Cancer recurrence was significantly associated with an increased risk of mortality (adjusted hazard ratio 4.32, 95% CI 2.75–6.79, P < 0.001). Overall mortality was, however, not associated with the surgical approach or surgical plane.ConclusionsAlthough associated with a lower rate of mesocolic resection plane and fewer lymph nodes harvested, laparoscopic surgery for transverse colonic cancers led to similar long-term results compared with open resection.