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Deep brain stimulation (DBS) for Parkinson’s disease (PD), essential tremor (ET), and dystonia is a well-established treatment option. The correlation between motor symptom improvement and effect on disability is inconclusive.

Patient satisfaction of deep brain stimulation (DBS) for cervical dystonia (CD) is heterogeneous. A high prevalence of psychiatric disorders in patients with CD is well-established. The presence of psychiatric classification in CD may affect the outcomes of DBS treatment.

Limited accessibility to language resources and technologies represents a challenge for the analysis, preservation, and documentation of natural languages other than English. Linguistic Linked (Open) Data (LLOD) holds the promise to ease the creation, linking, and reuse of multilingual linguistic data across distributed and heterogeneous resources. However, individual language resources and technologies accommodate or target different linguistic description levels, e.g., morphology, syntax, phonology, and pragmatics. In this comprehensive survey, the state-of-the-art of multilinguality and LLOD is being represented with a particular focus on linguistic description levels, identifying open challenges and gaps as well as proposing an ideal ecosystem for multilingual LLOD across description levels. This survey seeks to contribute an introductory text for newcomers to the field of multilingual LLOD, uncover gaps and challenges to be tackled by the LLOD community in reference to linguistic description levels, and present a solid basis for a future best practice of multilingual LLOD across description levels.

Currently, real-world data on doravirine are scarce. In a national prospective cohort, we assessed the effectiveness and tolerability of switching to doravirine-based antiretroviral therapy (ART) in people with HIV.

The adenosine triphosphate (ATP)-binding cassette (ABC) importer GlnPQ from Lactococcus lactishas two sequential covalently linked substrate-binding domains (SBDs), which capture the substrates and deliver them to the translocon. The two SBDs differ in their ligand specificities, binding affinities and the distance to the transmembrane domain; interestingly, both SBDs can bind their ligands simultaneously without affecting each other. In this work, we studied the binding of ligands to both SBDs using X-ray crystallography and molecular dynamics simulations. We report three high-resolution structures of SBD1, namely, the wild-type SBD1 with bound asparagine or arginine, and E184D SBD1 with glutamine bound. Molecular dynamics (MD) simulations provide a detailed insight into the dynamics associated with open-closed transitions of the SBDs.

The effect of water on the modification of acidic properties of Nb2O5and Nb1.3MnOxcatalysts was investigated using the cracking of cumene as model reaction, and compared to the behavior of a HZSM-5 catalyst. Nb1.3MnOxexhibited stronger Lewis acidity than Nb2O5, which translated into a higher selectivity towards α-methylstyrene formed on Lewis acid sites (LAS) by dehydrogenation of cumene. Steam enhanced strongly the conversion of cumene over both Nb-based catalysts. The products distribution on Nb-based catalysts was also deeply modified in the presence of steam, the selectivity towards α-methylstyrene decreasing strongly in favor of benzene, which is formed on Brønsted acid sites (BAS) by dealkylation of cumene. In contrast, the performances of HZSM-5 for cumene cracking and the products distribution were only marginally modified in the presence of steam. A kinetic model based on the elementary steps of the cumene reaction pathways (dealkylation and dehydrogenation) was used to estimate the ratio of LAS to BAS in absence and presence of water over Nb1.3MnOx. The activation energy of the cracking reaction was higher than that of the dehydrogenation reaction. The model described correctly the changes in the catalyst activity induced by addition of ≈2 V% of water, which resulted in a decrease in the [LAS]/[BAS] ratio from approximatively 3 to 1.

BackgroundThis study aims: (1) To compare cognitive and psychiatric outcomes after bilateral awake versus asleep subthalamic nucleus (STN) deep brain stimulation (DBS) surgery for Parkinson’s disease (PD). (2) To explore the occurrence of psychiatric diagnoses, cognitive impairment and quality of life after surgery in our whole sample. (3) To validate whether we can predict postoperative cognitive decline.Methods110 patients with PD were randomised to receive awake (n=56) or asleep (n=54) STN DBS surgery. At baseline and 6-month follow-up, all patients underwent standardised assessments testing several cognitive domains, psychiatric symptoms and quality of life.ResultsThere were no differences on neuropsychological composite scores and psychiatric symptoms between the groups, but we found small differences on individual tests and cognitive domains. The asleep group performed better on the Rey Auditory Verbal Learning Test delayed memory test (f=4.2, p=0.04), while the awake group improved on the Rivermead Behavioural Memory Test delayed memory test. (f=4.4, p=0.04). The Stroop III score was worse for the awake group (f=5.5, p=0.02). Worse scores were present for Stroop I (Stroop word card) (f=6.3, p=0.01), Stroop II (Stroop color card) (f=46.4, p<0.001), Stroop III (Stroop color-word card) (f=10.8, p=0.001) and Trailmaking B/A (f=4.5, p=0.04). Improvements were seen on quality of life: Parkinson’s Disease Questionnaire-39 (f=24.8, p<0.001), and psychiatric scales: Hamilton Depression Rating Scale (f=6.2, p=0.01), and Hamilton Anxiety Rating Scale (f=5.5, p=0.02).ConclusionsThis study suggests that the choice between awake and asleep STN DBS does not affect cognitive, mood and behavioural adverse effects, despite a minor difference in memory. STN DBS has a beneficial effect on quality of life, mood and anxiety symptoms.Trial registration numberNTR5809.

Antibody-mediated delivery of immunogenic epitopes to redirect virus-specific CD8+T-cells towards cancer cells is an emerging and promising new therapeutic strategy. These so-called antibody-epitope conjugates (AECs) rely on the proteolytic release of the epitopes close to the tumor surface for presentation by HLA class I molecules to eventually redirect and activate virus-specific CD8+T-cells towards tumor cells. We fused the immunogenic EBV-BRLF1 epitope preceded by a protease cleavage site to the C-terminus of the heavy and/or light chains of cetuximab and trastuzumab. We evaluated these AECs and found that, even though all AECs were able to redirect the EBV-specific T-cells, AECs with an epitope fused to the C-terminus of the heavy chain resulted in higher levels of T-cell activation compared to AECs with the same epitope fused to the light chain of an antibody. We observed that all AECs were depending on the presence of the antibody target, that the level of T-cell activation correlated with expression levels of the antibody target, and that our AECs could efficiently deliver the BRLF1 epitope to cancer cell lines from different origins (breast, ovarian, lung, and cervical cancer and a multiple myeloma). Moreover, in vivo, the AECs efficiently reduced tumor burden and increased the overall survival, which was prolonged even further in combination with immune checkpoint blockade. We demonstrate the potential of these genetically fused AECs to redirect the potent EBV-specific T-cells towards cancer in vitro and in vivo.

Abstract: METIS-II was an EU-FET MT project running from October 2004 to September 2007, which aimed at translating free text input without resorting to parallel corpora. The idea was to use “basic” linguistic tools and representations and to link them with patterns and statistics from the monolingual target-language corpus. The METIS-II project has four partners, translating from their “home” languages Greek, Dutch, German, and Spanish into English. The paper outlines the basic ideas of the project, their implementation, the resources used, and the results obtained. It also gives examples of how METIS-II has continued beyond its lifetime and the original scope of the project. On the basis of the results and experiences obtained, we believe that the approach is promising and offers the potential for development in various directions.

The dentato-rubro-thalamic tract (DRT) is currently considered as a potential target in deep brain stimulation (DBS) for various types of tremor. However, tractography depiction can vary depending on the included brain regions. The fast gray matter acquisition T1 inversion recovery (FGATIR) sequence, with excellent delineation of gray and white matter, possibly provides anatomical identification of rubro-thalamic DRT fibers.

In his book On Christian Teaching, David Smith offers multiple ways in which one’s Christian faith commitments influence pedagogical practices. Specific examples are drawn from the humanities, particularly from languages and literature. Some may conclude that such discussions are less appropriate in areas such as science, technology, engineering, and mathematics (STEM). We disagree and offer exemplars aligned with a set of six curricular criteria identified by Wayne Au. We argue that these exemplars emerge naturally from our Christian beliefs and are “faith-influenced” even if not every strategy embodies a narrower integration of faith and pedagogy.

Parkinson patients with chronic DBS routinely receive sensing-enabled implantable pulse generators upon battery replacement. Here we aimed to assess whether and/or how local field potential based reprogramming may be of use in this population.

Deep brain stimulation (DBS) of the ventral anterior limb of the internal capsule (vALIC) is a promising intervention for treatment-resistant depression (TRD). However, the working mechanisms of vALIC DBS in TRD remain largely unexplored. As major depressive disorder has been associated with aberrant amygdala functioning, we investigated whether vALIC DBS affects amygdala responsivity and functional connectivity. To investigate the long-term effects of DBS, eleven patients with TRD performed an implicit emotional face-viewing paradigm during functional magnetic resonance imaging (fMRI) before DBS surgery and after DBS parameter optimization. Sixteen matched healthy controls performed the fMRI paradigm at two-time points to control for test-retest effects. To investigate the short-term effects of DBS de-activation after parameter optimization, thirteen patients additionally performed the fMRI paradigm after double-blind periods of active and sham stimulation. Results showed that TRD patients had decreased right amygdala responsivity compared to healthy controls at baseline. Long-term vALIC DBS normalized right amygdala responsivity, which was associated with faster reaction times. This effect was not dependent on emotional valence. Furthermore, active compared to sham DBS increased amygdala connectivity with sensorimotor and cingulate cortices, which was not significantly different between responders and non-responders. These results suggest that vALIC DBS restores amygdala responsivity and behavioral vigilance in TRD, which may contribute to the DBS-induced antidepressant effect.

After nearly 50 years, the fabrication lines for the Z80 microprocessor have ceased. As an early processor in personal computing, the Z80 enabled budding computer scientists and engineers to tinker at home and discover the delight of computing.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a highly effective surgical treatment for patients with advanced Parkinson disease (PD). Combining 7.0-Tesla (7T) T2- and diffusion-weighted imaging (DWI) sequences allows for selective segmenting of the motor part of the STN and, thus, for possible optimization of DBS.

ABSTRACTThis research explores the conceptual integration of Living Labs (LLs) into the Regional Innovation Ecosystem (RIE) to understand their potential as facilitators of Responsible Innovation. While previous studies explored the role of Living Labs, they lack comprehensive integration strategies for addressing wicked problems. A conceptual framework is developed to understand the main role, detailed functions, and key elements for integration. Seven expert interviews were conducted to develop the conceptual framework, using the Interuniversity Microelectronics Centre (imec) within the Flemish Innovation Ecosystem as empirical context. The findings emphasise Living Labs as central orchestrators, enabling user-centric innovation, real-world experimentation, and stakeholder engagement. We identify four key elements that facilitate the proposed integration: government policy and funding, strategic integration, formal collaborations, and proof of concept. These findings have implications for advancing the theoretical understanding of Living Labs' integration into the Regional Innovation Ecosystem, and for practitioners who aim to foster Responsible Innovation.

ABSTRACTAntibody-mediated delivery of immunogenic viral CD8+T-cell epitopes to redirect virus-specific T cells toward cancer cells is a promising new therapeutic avenue to increase the immunogenicity of tumors. Multiple strategies for viral epitope delivery have been shown to be effective. So far, most of these have relied on a free C-terminus of the immunogenic epitope for extracellular delivery. Here, we demonstrate that antibody-epitope conjugates (AECs) with genetically fused epitopes to the N-terminus of the antibody can also sensitize tumors for attack by virus-specific CD8+T cells. AECs carrying epitopes genetically fused at the N-terminus of the light chains of cetuximab and trastuzumab demonstrate an even more efficient delivery of the T-cell epitopes compared to AECs with the epitope fused to the C-terminus of the heavy chain. We demonstrate that this increased efficiency is not caused by the shift in location of the cleavage site from the N- to the C-terminus, but by its increased proximity to the cell surface. We hypothesize that this facilitates more efficient epitope delivery. These findings not only provide additional insights into the mechanism of action of AECs but also broaden the possibilities for genetically fused AECs as an avenue for the redirection of multiple virus-specific T cells toward tumors.

The selective hydrodesulfurization (HDS) of fluidized catalytic cracking gasoline still represents a challenging step to minimize hydrogen overconsumption and maintain high octane numbers. To better understand the competition between desulfurization and hydrogenation reactions, a Langmuir–Hinshelwood kinetic model is established, based on high-throughput HDS experiments of a model feedstock of 3-methyl-thiophene (3MT) and 2,3-dimethyl-but-2-ene over CoMoS/Al2O3catalysts. To reduce the model's dimensionality, some key enthalpies of adsorption are determined by density functional theory (DFT) calculations. The model takes into account 16 different reactions (hydrogenation, hydrodesulfurization, isomerization) for which rate constants and adsorption constants are determined to reproduce adequately the experimental product distribution. The model is finally used to predict and discuss the impact of operating conditions (partial pressures of key reactants and temperature) on the selectivity. The selectivity is most affected by the conversion levels of the reactants, with an optimum desulfurization selectivity at approximately 30–50% 3MT conversion. Operating at low temperature (170 °C) is also favorable for the HDS selectivity.

Introduction The benefit of radiographs or steroid injection for idiopathic carpal tunnel syndrome (CTS) or ulnar neuropathy at the elbow (UNE) is open to debate. We assessed: (1) Radiographs ordered and injections performed at a new patient visit for patients presenting with either idiopathic CTS or UNE; (2) The estimated payment reduction if we omit these interventions; and (3) Patient age, sex, geographic region, and work status associated with radiographs or injections at a new patient visit for patients presenting with either idiopathic CTS or UNE.

Deep brain stimulation (DBS) of the ventral anterior limb of the internal capsule (vALIC) is effective for refractory obsessive-compulsive disorder (OCD). Retrospective evaluation showed that stimulation closer to the supero-lateral branch of the medial forebrain bundle (slMFB), within the vALIC, was associated with better response to DBS. The present study is the first to compare outcomes of DBS targeted at the vALIC using anatomical landmarks and DBS with connectomic tractography-based targeting of the slMFB. We included 20 OCD-patients with anatomical landmark-based DBS of the vALIC that were propensity score matched to 20 patients with tractography-based targeting of electrodes in the slMFB. After one year, we compared severity of OCD, anxiety and depression symptoms, response rates, time to response, number of parameter adjustments, average current, medication usage and stimulation-related adverse effects. There was no difference in Y-BOCS decrease between patients with anatomical landmark-based and tractography-based DBS. Nine (45%) patients with anatomical landmark-based DBS and 13 (65%) patients with tractography-based DBS were responders (BF10= 1.24). The course of depression and anxiety symptoms, time to response, number of stimulation adjustments or medication usage did not differ between groups. Patients with tractography-based DBS experienced fewer stimulation-related adverse effects than patients with anatomical landmark-based DBS (38 vs 58 transient and 1 vs. 17 lasting adverse effects; BF10= 14.968). OCD symptoms in patients with anatomical landmark-based DBS of the vALIC and tractography-based DBS of the slMFB decrease equally, but patients with tractography-based DBS experience less adverse effects.

ABSTRACTIntroduction:Oligosaccharides found in mammalian milk have shown the potential to alter brain development across multiple species. The diversity and concentration of these oligosaccharides is species-specific and varies greatly between individuals, thus understanding their role in cognitive development is warranted. We investigated the impact of early life dietary fucosylated/neutral or sialylated human milk oligosaccharides (HMO) on behaviours in tasks assessing anxiety, motivation, appetite, learning, and memory.Methods:Sixty-four female Göttingen minipigs were artificially reared from 2 weeks postnatal and provided milk replacers. The study used four groups: no additional oligosaccharides (Con), fucosylated and neutral oligosaccharides (FN, 4 g/L), sialylated oligosaccharides (SL, 0.68 g/L), or both FN and SL (FN + SL, 4 g/L) from 2 to 11 weeks postnatal. One reference group was sow-reared. Weaning occurred between 10 and 11 weeks postnatal, and thereafter an obesogenic diet was provided. Behavioral tasks were conducted over three periods: 1) 0–11 weeks; 2) 16–29 weeks; 3) 39–45 weeks. Tasks included a spatial holeboard task, open field task, exposure to a novel object, runway task, single-feed task, and home pen behaviour observation.Results:In the holeboard, the SL group demonstrated improved reference memory during reversal trials between 16-29 weeks. All groups demonstrated equivalent behavior in open field, novel object, runway, and single-feed tasks, as well as in their home pens (Ps > 0.05).Discussion:These results suggest that early life dietary intake of sialylated oligosaccharides may provide an improvement to cognition during the equivalent developmental stage of adolescence.

Antibodies are the cardinal effector molecules of the immune system and are being leveraged with enormous success as biotherapeutic drugs. A key part of the adaptive immune response is the production of an epitope-diverse, polyclonal antibody mixture that is capable of neutralizing invading pathogens or disease-causing molecules through binding interference and by mediating humoral and cellular effector functions. Avidity — the accumulated binding strength derived from the affinities of multiple individual non-covalent interactions — is fundamental to virtually all aspects of antibody biology, including antibody–antigen binding, clonal selection and effector functions. The manipulation of antibody avidity has since emerged as an important design principle for enhancing or engineering novel properties in antibody biotherapeutics. In this Review, we describe the multiple levels of avidity interactions that trigger the overall efficacy and control of functional responses in both natural antibody biology and their therapeutic applications. Within this framework, we comprehensively review therapeutic antibody mechanisms of action, with particular emphasis on engineered optimizations and platforms. Overall, we describe how affinity and avidity tuning of engineered antibody formats are enabling a new wave of differentiated antibody drugs with tailored properties and novel functions, promising improved treatment options for a wide variety of diseases.

Deep brain stimulation is an effective treatment for obsessive–compulsive disorder but is rarely used. Action is needed by psychologists, psychiatrists and insurers so that patients with otherwise intractable cases can receive this therapy to improve their mental health.