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Abstract Background Janus kinase (JAK) inhibition shows promise for treatment of patients with moderate to severe Crohn’s disease. We aimed to provide mechanistic insights into the JAK1-selective inhibitor upadacitinib through a transcriptomics substudy on biopsies from patients with Crohn's disease from CELEST. Methods Seventy-four patients consented to this optional substudy. Ileal and colonic biopsies were collected during endoscopy at screening and week 12 or 16. RNA isolated from 226 samples was analyzed by RNAseq, with additional qPCR analysis. Additional biopsies from patients with Crohn's disease receiving anti-tumor necrosis factor (anti-TNF; n = 34) and healthy controls (n = 10) were used for qPCR. Single-cell RNAseq public profiles were used to evaluate treatment effects on specific cellular subsets, associations with endoscopic improvement, and indirect comparisons with the anti-TNF-treated cohort. Results In involved areas of mucosa with endoscopic remission after upadacitinib treatment, 1156 and 76 protein-coding genes were significantly regulated (false discovery rate < 0.05) at week 12/16 in colonic and ileal biopsies, respectively (60 overlapped), compared with baseline. Upadacitinib did not significantly affect transcriptomes of noninvolved intestinal areas. CELEST patients (mostly anti-TNF-refractory) showed baseline differences in gene expression compared with a separate cohort of biologic-naïve patients. Notably, upadacitinib reversed overexpression of inflammatory fibroblast and interferon-γ effector signature markers. Conclusions Upadacitinib modulates inflammatory pathways in mucosal lesions of patients with anti-TNF-refractory Crohn's disease, including inflammatory fibroblast and interferon-γ-expressing cytotoxic T cell compartments. This substudy is the first to describe the molecular response to JAK1 inhibition in inflammatory bowel disease and differential effects relative to anti-TNF treatment. (Clinical trial identifier: NCT02365649)

Endophytic nitrogen-fixing bacteria are believed to contribute substantial amounts of N to certain gramineous crops. We have been interested to find (a) a diazotroph(s) in rice which can aggressively and stably persist and fix nitrogen in interior tissues and (b) unique rice-diazotrophic endophyte combinations. To achieve these objectives, it has been essential to find an efficient method to surface sterilize rice tissues. The method described here consists of exposing tissues to 1% Chloramine T for 15 min followed by shaking with glass beads. It has proven very efficient since (a) surface bacterial populations on the root and culm were found to be reduced by more than 90%, (b) the number of the internal colonizers was found to be significantly higher than the number of surface bacteria, and (c) colonization of root but not subepidermal tissue by gusA-marked Herbaspirillum seropedicae Z67 bacteria was found to be virtually eliminated. Nitrogen-fixing putative endophytic populations (MPN g dry wt⁻¹) in the root (7.94 × 10⁷) and culm (2.57 × 10⁶) on field-grown IR72 plants grown in the absence of N fertilizer was found to be significantly higher near heading stage. The corresponding total putative endophyte populations in the tissues of 25 highly diverse genotypes of rice and their relatives was found to range from 10⁵-10⁸ and 10⁴-10⁹, in the roots and culms, respectively. Generally, the resident bacteria were found to be non-diazotrophic, although in isolated cases diazotrophs were found, for example in the roots and culm of IR72 rice plants, or the culm of Zizaniopsis villanensis plants. The size of populations of diazotrophic bacteria in different rice genotypes was found to be 10³-10⁷ for the roots and 10⁴-10⁶ for the culms, respectively. The rice genera-related plants Potamophila pariffora and Rhynchoryza subulata showed the highest levels.

Addressing hazardous drinking during medical-surgical care improves patients’ health. This formative evaluation examined patients’ consideration of options to change drinking and engage in treatment. It explored whether interventions such as “DO-MoST” overcome treatment barriers. We interviewed 20 medical-surgical patients with hazardous drinking in a trial of DO-MoST, and 16 providers. Analyses used a directed content approach. Patients were receptive to and comfortable discussing drinking during medical-surgical care. Interventions like DO-MoST (patient-centered, motivational approach to shared decision making) addressed some treatment barriers. Patients and providers viewed such interventions as helpful by building a relationship with a psychologist who facilitated self-awareness of drinking behaviors, and discussing connections between alcohol- and physical health-related problems and potential strategies to address drinking. However, both groups expressed concerns about individual and system-level barriers to long-term change. Interventions like DO-MoST bridge the gap between the patient’s medical treatment episode and transition to other health care settings. Trial Registration The study is registered on ClinicalTrials.gov (ID: NCT03258632).

This book gives an overview of recent integrated and inter-disciplinary approaches between chemical experiment and theory in a variety of fields, from polymer science to materials chemistry and ranging from the design of tailored properties to catalysis and reactivity, building on the well-established success of Density Functional Theory as.

The Interuniversity Attraction Pole (IAP) ‘PLANET TOPERS’ (Planets: Tracing the Transfer, Origin, Preservation, and Evolution of their Reservoirs) addresses the fundamental understanding of the thermal and compositional evolution of the different reservoirs of planetary bodies (core, mantle, crust, atmosphere, hydrosphere, cryosphere, and space) considering interactions and feedback mechanisms. Here we present the first results after 2 years of project work.

Twelve male lambs (30.5±2.1 kg) with cannulas in the rumen were divided into three groups to evaluate the accidental toxicity of selenium (Se) via digestive tract. The first group received intraruminal bolus without a Se source; the second group received intraruminal bolus with sodium selenite (SS: Na SeO ); the third group received intraruminal bolus with barium selenate (BS: BaSeO ). The ruminal boluses were immediately degraded by a manufacturing defect, releasing an amount of 366 mg Se via rumen. All lambs had tachypnea (80 cycles per minute), a metallic smell in the oral cavity and laminitis foot. Analyses of necropsy and histopathology showed frequencies of lesions in the myocardium and skeletal muscle, lesions in the myocardium were more common in lambs intoxicated with SS or BS than the control group (P<0.05); the tissues were swollen and there were hyaline fibres (Zenker degeneration), as well as fragments and proliferation of the nuclei with necrosis. Se concentration in lambs intoxicated with SS and BS were: myocardium: 0.389 and 0.332; skeletal muscle: 0.583 and 0.492; and kidney: 2.871 and 2.841 μg/g fresh tissue, respectively. The Se concentration in blood increased over 2.5 times in the intoxicated lambs with both sources of Se (0.14 vs. 0.36 μg/mL) from baseline to the 22 days of sampling. There was a lower correlation (r=0.46) in SS intoxication group than the control and BS group (r≥0.93). As a conclusion, high dosages of 366 mg Se or 12 mg Se/kg BW in an accidental dosage did not cause a severe mortality but all lambs immediately showed reduced feed intake, metallic smell exhalation and depression.

Explores the effects of the acculturation process on these families, using questionnaires distributed to 61 college students and their mothers. Finds no significant relationship between level of individual acculturation and family conflict, cohesion, and satisfaction, although mothers of traditional subjects reported higher family satisfaction than mothers of acculturated subjects. Discusses the results and offers cultural explanations. (Original abstract-amended)

The advent of high-throughput single-cell transcriptomic analysis of microglia has revealed different phenotypes that are inherently associated with disease conditions. A common feature of some of these activated phenotypes is the upregulation of galectin-3. Representative examples of these phenotypes include disease-associated microglia (DAM) and white-associated microglia (WAM), whose role(s) in neuroprotection/neurotoxicity is a matter of high interest in the microglia community. In this review, we summarise the main findings that demonstrate the ability of galectin-3 to interact with key pattern recognition receptors, including, among others, TLR4 and TREM2 and the importance of galectin-3 in the regulation of microglia activation. Finally, we discuss increasing evidence supporting the involvement of this lectin in the main neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, multiple sclerosis, traumatic brain injury, and stroke.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease in which the formation of extracellular aggregates of amyloid beta (Aβ) peptide, fibrillary tangles of intraneuronal tau and microglial activation are major pathological hallmarks. One of the key molecules involved in microglial activation is galectin-3 (gal3), and we demonstrate here for the first time a key role of gal3 in AD pathology. Gal3 was highly upregulated in the brains of AD patients and 5xFAD (familial Alzheimer’s disease) mice and found specifically expressed in microglia associated with Aβ plaques. Single-nucleotide polymorphisms in the LGALS3 gene, which encodes gal3, were associated with an increased risk of AD. Gal3 deletion in 5xFAD mice attenuated microglia-associated immune responses, particularly those associated with TLR and TREM2/DAP12 signaling. In vitro data revealed that gal3 was required to fully activate microglia in response to fibrillar Aβ. Gal3 deletion decreased the Aβ burden in 5xFAD mice and improved cognitive behavior. Interestingly, a single intrahippocampal injection of gal3 along with Aβ monomers in WT mice was sufficient to induce the formation of long-lasting (2 months) insoluble Aβ aggregates, which were absent when gal3 was lacking. High-resolution microscopy (stochastic optical reconstruction microscopy) demonstrated close colocalization of gal3 and TREM2 in microglial processes, and a direct interaction was shown by a fluorescence anisotropy assay involving the gal3 carbohydrate recognition domain. Furthermore, gal3 was shown to stimulate TREM2–DAP12 signaling in a reporter cell line. Overall, our data support the view that gal3 inhibition may be a potential pharmacological approach to counteract AD.

The effects of constant-current deep brain stimulation (DBS) have not been studied in controlled trials in patients with Parkinson's disease. We aimed to assess the safety and efficacy of bilateral constant-current DBS of the subthalamic nucleus. This prospective, randomised, multicentre controlled trial was done between Sept 26, 2005, and Aug 13, 2010, at 15 clinical sites specialising in movement disorders in the USA. Patients were eligible if they were aged 18–80 years, had Parkinson's disease for 5 years or more, and had either 6 h or more daily off time reported in a patient diary of moderate to severe dyskinesia during waking hours. The patients received bilateral implantation in the subthalamic nucleus of a constant-current DBS device. After implantation, computer-generated randomisation was done with a block size of four, and patients were randomly assigned to the stimulation or control group (stimulation:control ratio 3:1). The control group received implantation without activation for 3 months. No blinding occurred during this study, and both patients and investigators were aware of the treatment group. The primary outcome variable was the change in on time without bothersome dyskinesia (ie, good quality on time) at 3 months as recorded in patients' diaries. Patients were followed up for 1 year. This trial is registered with ClinicalTrials.gov, number NCT00552474. Of 168 patients assessed for eligibility, 136 had implantation of the constant-current device and were randomly assigned to receive immediate (101 patients) or delayed (35 patients) stimulation. Both study groups reported a mean increase of good quality on time after 3 months, and the increase was greater in the stimulation group (4·27 h vs 1·77 h, difference 2·51 [95% CI 0·87–4·16]; p=0·003). Unified Parkinson's disease rating scale motor scores in the off-medication, on-stimulation condition improved by 39% from baseline (24·8 vs 40·8). Some serious adverse events occurred after DBS implantation, including infections in five (4%) of 136 patients and intracranial haemorrhage in four (3%) patients. Stimulation of the subthalamic nucleus was associated with dysarthria, fatigue, paraesthesias, and oedema, whereas gait problems, disequilibrium, dyskinesia, and falls were reported in both groups. Constant-current DBS of the subthalamic nucleus produced significant improvements in good quality on time when compared with a control group without stimulation. Future trials should compare the effects of constant-current DBS with those of voltage-controlled stimulation. St Jude Medical Neuromodulation Division.