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Evidence increasingly reveals that non-human animals in monotonous situations can show boredom-like states, distinctively manifesting as increases in both arousal-seeking, restless behaviour and low arousal, drowsy behaviour. However, task related boredom has been little investigated in animals, but could have implications for animal training efficacy, for animal welfare, and for modelling human task fatigue. We investigated whether varied sensory stimuli helped prevent boredom-like behaviour in a repetitive foraging scenario, compared with a monotonous equivalent. In a cross-over design, 20 rats searched pairs of containers for a small reward hidden within a digging material, with a new pair of containers presented every 2 min during a 20 min session. Multisensory cues distinguished the rewarded vs. non-rewarded containers. We hypothesized that, if rats became bored by sensory monotony, rats in a monotonous version of the scenario would show more arousal-seeking (e.g. exit-directed behaviour, jumping) and drowsy behaviour (e.g. standing still, yawning, task disengagement) than in a varied version. In the Monotony treatment, the digging material, reward flavour, and features of the cues remained constant in each presentation, whereas these changed throughout the Variety treatment. Behaviour was observed blind to treatment in a randomised order. Monotony significantly increased exit-directed behaviour compared with Variety, but no other treatment effects reached significance. Possible reasons for the relative lack of findings are discussed, including suggestions for future research. Here, sensory monotony during the task did not induce the full range of behaviours characterizing boredom, but it is of interest that it did increase exit-directed behaviour.

Intronic polymorphisms of the GABAA receptor β2 subunit gene (GABRB2) under adaptive evolution were associated with schizophrenia and reduced expression, especially of the long isoform which differs in electrophysiological properties from the short isoform. The present study was directed to examining the gene dosage effects of Gabrb2 in knockout mice of both heterozygous (HT) and homozygous (KO) genotypes with respect to possible schizophrenia-like and comorbid phenotypes. The KO mice, and HT mice to a lesser extent, were found to display prepulse inhibition (PPI) deficit, locomotor hyperactivity, stereotypy, sociability impairments, spatial-working and spatial-reference memory deficits, reduced depression and anxiety, and accelerated pentylenetetrazol (PTZ)-induced seizure. In addition, the KO mice were highly susceptible to audiogenic epilepsy. Some of the behavioral phenotypes showed evidence of imprinting, gender effect and amelioration by the antipsychotic risperidone, and the audiogenic epilepsy was inhibited by the antiepileptic diazepam. GABAergic parvalbumin (PV)-positive interneuron dystrophy, astrocyte dystrophy, and extensive microglia activation were observed in the frontotemporal corticolimbic regions, and reduction of newborn neurons was observed in the hippocampus by immunohistochemical staining. The neuroinflammation indicated by microglial activation was accompanied by elevated brain levels of oxidative stress marker malondialdehyde (MDA) and the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). These extensive schizophrenia-like and comorbid phenotypes brought about by Gabrb2 knockout, in conjunction with our previous findings on GABRB2 association with schizophrenia, support a pivotal role of GABRB2 in schizophrenia etiology.

Background Massive occurrences of interstitial loss of heterozygosity (LOH) likely resulting from gene conversions were found by us in different cancers as a type of single-nucleotide variations (SNVs), comparable in abundance to the commonly investigated gain of heterozygosity (GOH) type of SNVs, raising the question of the relationships between these two opposing types of cancer mutations. Methods In the present study, SNVs in 12 tetra sample and 17 trio sample sets from four cancer types along with copy number variations (CNVs) were analyzed by AluScan sequencing, comparing tumor with white blood cells as well as tissues vicinal to the tumor. Four published “nontumor”-tumor metastasis trios and 246 pan-cancer pairs analyzed by whole-genome sequencing (WGS) and 67 trios by whole-exome sequencing (WES) were also examined. Results Widespread GOHs enriched with CG-to-TG changes and associated with nearby CNVs and LOHs enriched with TG-to-CG changes were observed. Occurrences of GOH were 1.9-fold higher than LOH in “nontumor” tissues more than 2 cm away from the tumors, and a majority of these GOHs and LOHs were reversed in “paratumor” tissues within 2 cm of the tumors, forming forward-reverse mutation cycles where the revertant LOHs displayed strong lineage effects that pointed to a sequential instead of parallel development from “nontumor” to “paratumor” and onto tumor cells, which was also supported by the relative frequencies of 26 distinct classes of CNVs between these three types of cell populations. Conclusions These findings suggest that developing cancer cells undergo sequential changes that enable the “nontumor” cells to acquire a wide range of forward mutations including ones that are essential for oncogenicity, followed by revertant mutations in the “paratumor” cells to avoid growth retardation by excessive mutation load. Such utilization of forward-reverse mutation cycles as an adaptive mechanism was also observed in cultured HeLa cells upon successive replatings. An understanding of forward-reverse mutation cycles in cancer development could provide a genomic basis for improved early diagnosis, staging, and treatment of cancers.

Background Follow-up visits with clinic providers after hospital discharge may not be feasible for some patients due to functional limitations, transportation challenges, need for physical distancing, or fear of exposure especially during the current COVID-19 pandemic. Methods The aim of the study was to determine the effects of post- h ospital clinic (POSH) and telephone (TPOSH) follow-up provider visits versus no visit on 30-day readmission. We used a retrospective cohort design based on data from 1/1/2017 to 12/31/2019 on adult patients ( n  = 213,513) discharged home from 15 Kaiser Permanente Southern California hospitals . Completion of POSH or TPOSH provider visits within 7 days of discharge was the exposure and all-cause 30-day inpatient and observation stay readmission was the primary outcome. We used matching weights to balance the groups and Fine-Gray subdistribution hazard model to assess for readmission risk. Results Unweighted all-cause 30-day readmission rate was highest for patients who completed a TPOSH (17.3%) followed by no visit (14.2%), non-POSH (evaluation and management visits that were not focused on the hospitalization: 13.6%) and POSH (12.6%) visits. The matching weighted models showed that the effects of POSH and TPOSH visits varied across patient subgroups. For high risk (LACE 11+) medicine patients, both POSH (HR: 0.77, 95% CI: 0.71, 0.85, P  < .001) and TPOSH (HR: 0.91, 95% CI: 0.83, 0.99, P  = .03) were associated with 23 and 9% lower risk of 30-day readmission, respectively, compared to no visit. For medium to low risk medicine patients (LACE< 11) and all surgical patients regardless of LACE score or age, there were no significant associations for either visit type with risk of 30-day readmission. Conclusions Post-hospital telephone follow-up provider visits had only modest effects on 30-day readmission in high-risk medicine patients compared to clinic visits. It remains to be determined if greater use and comfort with virtual visits by providers and patients as a result of the pandemic might improve the effectiveness of these encounters.

Newborn screening (NBS) for spinal muscular atrophy (SMA) and severe combined immunodeficiency (SCID) faces challenges. Accurate and precise SMN1 and SMN2 copy number determination, confirmed by two orthogonal methods, are vital for SMA prognostication and treatment. Single SMN1 copy detection also enables the further feasibility to screen for compound heterozygotes. In SCID, low-level T-cell receptor excision circle (TREC) quantification by quantitative PCR is imprecise, necessitating replicates for reliable results. An assay with enhanced accuracy, precision, and high throughput is warranted for NBS SMA and SCID. False positive of SMN1 deletions due to allele dropout are also a potential pitfall in PCR-based methods. We evaluated a first-tier fully automated quadruplex droplet digital PCR (ddPCR) assay detecting SMN1, SMN2, TREC, and RPP30 using dried blood spots together with a second-tier Sanger sequencing to exclude SMN1 allele dropout. Five proficiency test samples and six patient samples with known SMN1 and SMN2 copy numbers confirmed by multiplex ligation-dependent probe amplification were used for accuracy evaluation with full concordance. The ddPCR assay showed high precision for SMN1 and SMN2 (<7% coefficient of variation (CV) for ≥0 copy) and TREC (14.6% CV at 37 copies/µL blood). Second-tier Sanger sequencing identified all SMA cases with homozygous deletions. Accuracy for TREC classification was concordant with 10 proficiency samples. The reference interval of TREC concentration was established for newborns ≥ 34 weeks (n = 1812) and the 2.5th percentile was 57 copies/µL blood. A two-tiered approach with fully automated quadruplex ddPCR and Sanger sequencing delivers accurate and precise quantitation for NBS SMA and SCID, enabling early treatment and counseling.

Halogenation of bioactive peptides via incorporation of non-natural amino acid derivatives during chemical synthesis is a common strategy to enhance functionality. Bacterial tyrptophan halogenases efficiently catalyze regiospecific halogenation of the free amino acid tryptophan, both in vitro and in vivo. Expansion of their substrate scope to peptides and proteins would facilitate highly-regulated post-synthesis/expression halogenation. Here, we demonstrate novel in vitro halogenation (chlorination and bromination) of peptides by select halogenase enzymes and identify the C-terminal (G/S)GW motif as a preferred substrate. In a first proof-of-principle experiment, we also demonstrate chemo-catalyzed derivatization of an enzymatically chlorinated peptide, albeit with low efficiency. We further rationally derive PyrH halogenase mutants showing improved halogenation of the (G/S)GW motif, both as a free peptide and when genetically fused to model proteins with efficiencies up to 90%.

High‐risk acute pulmonary embolism (PE) is associated with significant in‐hospital mortality. Large‐Bore Mechanical Thrombectomy (LBMT) is a treatment option for acute PE, but data on its efficacy in high‐risk PE was limited. This prospective case series reported the outcomes of 14 patients with high‐risk PE treated using a novel multipurpose mechanical aspiration system (MMAS). Most patients were in hemodynamic decompensation, requiring inotropic or mechanical circulatory support. The mean procedural time was 73.5 ± 39.2 min. Complete procedural success was achieved in 78.6% of the cases, while two patients required bailout therapies. The mean pulmonary arterial pressure decreased by 27.2%, and the right‐ventricle/left‐ventricle ratio normalized in 85.7% of patients. The primary endpoint—in‐hospital mortality—was 0%, while the major bleeding rate was 27.2%. These findings suggest that MMAS is a safe and effective intervention for acute high‐risk PE.

Combination therapy with radioembolization (yttrium-90)-resin microspheres) followed by nivolumab has shown a promising response rate of 30.6% in a Phase II trial (CA209-678) for advanced hepatocellular carcinoma (HCC); however, the response mechanisms and relevant biomarkers remain unknown. By collecting both pretreatment and on-treatment samples, we performed multimodal profiling of tissue and blood samples and investigated molecular changes associated with favorable responses in 33 patients from the trial. We found that higher tumor mutation burden, mutations and higher expression of interferon gamma pathways occurred more frequently in responders. Meanwhile, non-responders tended to be enriched for a novel Asian-specific transcriptomic subtype (Kaya_P2) with a high frequency of chromosome 16 deletions and upregulated cell cycle pathways. Strikingly, unlike other cancer types, we did not observe any association between T-cell populations and treatment response, but tumors from responders had a higher proportion of CXCL9 /CXCR3 macrophages. Moreover, biomarkers discovered in previous immunotherapy trials were not predictive in the current cohort, suggesting a distinctive molecular landscape associated with differential responses to the combination therapy. This study unraveled extensive molecular changes underlying distinctive responses to the novel treatment and pinpointed new directions for harnessing combination therapy in patients with advanced HCC.

ObjectiveAs the current therapeutic strategies for human hepatocellular carcinoma (HCC) have been proven to have limited effectiveness, immunotherapy becomes a compelling way to tackle the disease. We aim to provide humanised mouse (humice) models for the understanding of the interaction between human cancer and immune system, particularly for human-specific drug testing.DesignPatient-derived xenograft tumours are established with type I human leucocyte antigen matched human immune system in NOD-scid Il2rg−/− (NSG) mice. The longitudinal changes of the tumour and immune responses as well as the efficacy of immune checkpoint inhibitors are investigated.ResultsSimilar to the clinical outcomes, the human immune system in our model is educated by the tumour and exhibits exhaustion phenotypes such as a significant declination of leucocyte numbers, upregulation of exhaustion markers and decreased the production of human proinflammatory cytokines. Notably, cytotoxic immune cells decreased more rapidly compared with other cell types. Tumour infiltrated T cells have much higher expression of exhaustion markers and lower cytokine production compared with peripheral T cells. In addition, tumour-associated macrophages and myeloid-derived suppressor cells are found to be highly enriched in the tumour microenvironment. Interestingly, the tumour also changes gene expression profiles in response to immune responses by upregulating immune checkpoint ligands. Most importantly, in contrast to the NSG model, our model demonstrates both therapeutic and side effects of immune checkpoint inhibitors pembrolizumab and ipilimumab.ConclusionsOur work provides a model for immune-oncology study and a useful parallel-to-human platform for anti-HCC drug testing, especially immunotherapy.