Longitudinal course of core cognitive domains in first-episode acute and transient psychotic disorders compared with schizophrenia.

Acute and transient psychotic disorder (ATPD) is characterized by acute onset of psychotic symptoms and early recovery. Contrastingly, schizophrenia (SZ) is a chronic mental disorder characterized by impaired functioning including a deficit in cognition. In SZ, the cognitive deficit is among the core symptoms, but in ATPDs, the existing evidence brings mixed results. Our primary aim was to compare three core cognitive domains (executive functioning/abstraction, speed of processing and working memory) of patients diagnosed with ATPD and SZ over a 12-month period. Moreover, we explored how these diagnostic subgroups differed in their clinical characteristics. We recruited 39 patients with a diagnosis of SZ and 31 with ATPD with schizophrenic symptoms. All patients completed clinical and neuropsychological assessments. At baseline, we used a one-way ANCOVA model with a group as the between-subjects factor. Mixed-model repeated-measures ANOVAs with time as the within-subjects factor and group as the between-subjects factor were run to test the overtime differences. At baseline, we did not find any differences in cognition - with sex, education and age as covariates - between ATPDs and SZ. After one year, all patients showed an improvement in all three domains, however, there were no significant overtime changes between ATPDs and SZ. Regarding clinical profiles, ATPDs demonstrated less severe psychopathology and better functioning compared to SZ both at baseline and after 12 months. The medication dosage differed at retest, but not at baseline between the groups. Our findings suggest clinical differences and a similar trajectory of cognitive performance between these diagnostic subgroups.

Inflammation and cognitive performance in first-episode schizophrenia spectrum disorders: The moderating effects of childhood trauma.

In this study, we aimed to determine whether childhood trauma moderated the relationship between inflammation and cognitive functioning in persons with first-episode schizophrenia spectrum disorders (SSDs). We included data from 92 individuals who participated in the nationwide Early-Stage Schizophrenia Outcome study. These individuals completed the Childhood Trauma Questionnaire, provided a fasting blood sample for high-sensitivity C-reactive protein analysis, and underwent extensive neuropsychological testing. The intervening effects of age, sex, education, smoking status, and body mass index were controlled. Results indicated that childhood trauma levels significantly moderated the relationship between inflammation and four cognitive domains: speed of processing, working memory, visual memory, and verbal memory. Inflammation also predicted verbal memory scores irrespective of childhood trauma levels or the covariates. Upon further exploration, the significant moderation effects appeared to be primarily driven by males. In conclusion, a history of childhood trauma may be an important determinant in evaluating how inflammation relates to the cognitive performance of people with first-episode SSDs, particularly in speed of processing, working memory, visual memory, and verbal memory. We recommend that future researchers examining the effect of inflammation on cognitive functioning in SSDs include trauma as a moderating variable in their models and further examine additional moderating effects of sex.

Association between cannabis use and symptom dimensions in schizophrenia spectrum disorders: an individual participant data meta-analysis on 3053 individuals.

Background: The association between cannabis use and positive symptoms in schizophrenia spectrum disorders is well documented, especially via meta-analyses. Yet, findings are inconsistent regarding negative symptoms, while other dimensions such as disorganization, depression, and excitement, have not been investigated. In addition, meta-analyses use aggregated data discarding important confounding variables which is a source of bias. Methods: PubMed, ScienceDirect and PsycINFO were used to search for publications from inception to September 27, 2022. We contacted the authors of relevant studies to extract raw datasets and perform an Individual Participant Data meta-analysis (IPDMA). Inclusion criteria were: psychopathology of individuals with schizophrenia spectrum disorders assessed by the Positive and Negative Syndrome Scale (PANSS); cannabis-users had to either have a diagnosis of cannabis use disorder or use cannabis at least twice a week. The main outcomes were the PANSS subscores extracted via the 3-factor (positive, negative and general) and 5-factor (positive, negative, disorganization, depression, excitement) structures. Preregistration is accessible via Prospero: ID CRD42022329172. Findings: Among the 1149 identified studies, 65 were eligible and 21 datasets were shared, totaling 3677 IPD and 3053 complete cases. The adjusted multivariate analysis revealed that relative to non-use, cannabis use was associated with higher severity of positive dimension (3-factor: Adjusted Mean Difference, aMD = 0.34, 95% Confidence Interval, CI = [0.03; 0.66]; 5-factor: aMD = 0.38, 95% CI = [0.08; 0.63]), lower severity of negative dimension (3-factor: aMD = -0.49, 95% CI [-0.90; -0.09]; 5-factor: aMD = -0.50, 95% CI = [-0.91; -0.08]), higher severity of excitement dimension (aMD = 0.16, 95% CI = [0.03; 0.28]). No association was found between cannabis use and disorganization (aMD = -0.13, 95% CI = [-0.42; 0.17]) or depression (aMD = -0.14, 95% CI = [-0.34; 0.06]). Interpretation: No causal relationship can be inferred from the current results. The findings could be in favor of both a detrimental and beneficial effect of cannabis on positive and negative symptoms, respectively. Longitudinal designs are needed to understand the role of cannabis is this association. The reported effect sizes are small and CIs are wide, the interpretation of findings should be taken with caution. Funding: This research did not receive any specific grant or funding. Primary financial support for authors was provided by Le Vinatier Psychiatric Hospital.

Cognitive flexibility in schizophrenia: A confirmatory factor analysis of neuropsychological measures.

Cognitive flexibility (CF) is the ability to adapt cognitive strategies according to the changing environment. The deficit in CF has often been linked to various neurological and psychiatric disorders including schizophrenia. However, the operationalization and assessment of CF have not been unified and the current research suggests that the available instruments measure different aspects of CF. The main objective of the present study was to compare three frequently used neuropsychological measures of CF-Wisconsin Card Sorting Test (WCST), Trail Making Test (TMT) and Stroop Color and Word Test (SCWT) in a population of patients (N = 220) with first-episode schizophrenia spectrum disorders in order to evaluate their convergent validity. The hypothesis of an underlying latent construct was tested via a confirmatory factor analysis. We used a one-factor CF model with scores from WCST, SCWT and TMT as observed variables. The established model showed a good fit to the data (χ2 = 1.67, p = 0.43, SRMR = 0.02, RMSEA = 0.0, CFI = 1.00). The highest factor loading was found in WCST as CF explained most of the variance in this neuropsychological measure compared to the other instruments. On the other hand, a TMT ratio index and a SCWT interference demonstrated lowest loadings in the model. The findings suggest that not all the frequently used measures share an underlying factor of CF or may capture different aspects of this construct.

Evolving acidic microenvironments during colitis provide selective analgesic targets for a pH-sensitive opioid.

ABSTRACT: Targeting the acidified inflammatory microenvironment with pH-sensitive opioids is a novel approach for managing visceral pain while mitigating side effects. The analgesic efficacy of pH-dependent opioids has not been studied during the evolution of inflammation, where fluctuating tissue pH and repeated therapeutic dosing could influence analgesia and side effects. Whether pH-dependent opioids can inhibit human nociceptors during extracellular acidification is unexplored. We studied the analgesic efficacy and side-effect profile of a pH-sensitive fentanyl analog, (±)- N -(3-fluoro-1-phenethylpiperidine-4-yl)- N -phenyl propionamide (NFEPP), during the evolution of colitis induced in mice with dextran sulphate sodium. Colitis was characterized by granulocyte infiltration, histological damage, and acidification of the mucosa and submucosa at sites of immune cell infiltration. Changes in nociception were determined by measuring visceromotor responses to noxious colorectal distension in conscious mice. Repeated doses of NFEPP inhibited nociception throughout the course of disease, with maximal efficacy at the peak of inflammation. Fentanyl was antinociceptive regardless of the stage of inflammation. Fentanyl inhibited gastrointestinal transit, blocked defaecation, and induced hypoxemia, whereas NFEPP had no such side effects. In proof-of-principle experiments, NFEPP inhibited mechanically provoked activation of human colonic nociceptors under acidic conditions mimicking the inflamed state. Thus, NFEPP provides analgesia throughout the evolution of colitis with maximal activity at peak inflammation. The actions of NFEPP are restricted to acidified layers of the colon, without common side effects in normal tissues. N -(3-fluoro-1-phenethylpiperidine-4-yl)- N -phenyl propionamide could provide safe and effective analgesia during acute colitis, such as flares of ulcerative colitis.

Smoking and attention in schizophrenia spectrum disorders: What are we neglecting?

Introduction: Individuals with schizophrenia spectrum disorders (SSDs) record elevated rates of smoking, which is often attributed to their effort to self-medicate cognitive and attentional symptoms of their illness. Empirical evidence for this hypothesis is conflicting, however. In this study, we aimed to test predictions derived from the cognitive self-medication hypothesis. We predicted that cigarette smoking status and extent would predict the attentional performance of participants with SSDs. Simultaneously, we wished to address methodological gaps in previous research. We measured distinct attentional components and made adjustments for the effects of other, attention-modulation variables. Methods: Sixty-one smokers (82.0% males, 26.73 ± 6.05 years) and 61 non-smokers (50.8% males, 27.10 ± 7.90 years) with recent-onset SSDs completed an X-type Continuous Performance Test, which was used to derive impulsivity and inattention component scores. Relationships between the two component scores and cigarette smoking status and extent were assessed using hierarchical regression. Effects of estimated premorbid intellectual functioning and antipsychotic medication dosage were held constant. Results: Smokers had significantly higher inattention component scores than non-smokers when covariates were controlled (p = 0.026). Impulsivity remained unaffected by smoking status (p = 0.971). Cigarette smoking extent, i.e., the number of cigarettes smoked per day, was not associated with either inattention (p = 0.414) or impulsivity (p = 0.079). Conclusion: Models of smoking-related attentional changes can benefit from the inclusion of sample-specific component scores and attention-modulating covariates. Under these conditions, smokers with SSDs can show a partial attentional benefit. However, the limited scope of this benefit suggests that the cognitive self-medication hypothesis requires further testing or reconsidering.

The relationships between cognitive reserve, cognitive functioning and quality of life in first-episode schizophrenia spectrum disorders.

Cognitive reserve (CR) has been conceptualized as an individual's ability to optimize or maximize performance through differential recruitment of brain networks. As such, CR may contribute to the heterogeneity of cognitive deficits observed in schizophrenia. This study aimed to assess the relationships between CR, cognition and quality of life in first-episode (FES) patients. A total of 137 patients with either ICD-10 schizophrenia or "acute and transient psychotic disorders" diagnosis, and 62 healthy controls had completed a comprehensive assessment of six cognitive domains: speed of processing, attention, working memory/flexibility, verbal memory, visual memory, and abstraction/executive functioning. CR was calculated from the participants' education, premorbid IQ, and socioeconomic status. The results suggested that in patients, CR was positively related to cognitive performance in all domains, explaining 42.6% of the variance observed in cognition overall. Effects of CR in the control group were limited to three domains: speed of processing, abstraction/executive function and working memory/flexibility. These results suggest that CR largely contributes to cognitive variations present in FES patients. In addition, CR was negatively related to the social construct of patients' quality of life, and positively to symptom severity and general functioning.

Agonist that activates the µ-opioid receptor in acidified microenvironments inhibits colitis pain without side effects.

OBJECTIVE: The effectiveness of µ-opioid receptor (MOPr) agonists for treatment of visceral pain is compromised by constipation, respiratory depression, sedation and addiction. We investigated whether a fentanyl analogue, (±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide (NFEPP), which preferentially activates MOPr in acidified diseased tissues, would inhibit pain in a preclinical model of inflammatory bowel disease (IBD) without side effects in healthy tissues. DESIGN: Antinociceptive actions of NFEPP and fentanyl were compared in control mice and mice with dextran sodium sulfate colitis by measuring visceromotor responses to colorectal distension. Patch clamp and extracellular recordings were used to assess nociceptor activation. Defecation, respiration and locomotion were assessed. Colonic migrating motor complexes were assessed by spatiotemporal mapping of isolated tissue. NFEPP-induced MOPr signalling and trafficking were studied in human embryonic kidney 293 cells. RESULTS: NFEPP inhibited visceromotor responses to colorectal distension in mice with colitis but not in control mice, consistent with acidification of the inflamed colon. Fentanyl inhibited responses in both groups. NFEPP inhibited the excitability of dorsal root ganglion neurons and suppressed mechanical sensitivity of colonic afferent fibres in acidified but not physiological conditions. Whereas fentanyl decreased defecation and caused respiratory depression and hyperactivity in mice with colitis, NFEPP was devoid of these effects. NFEPP did not affect colonic migrating motor complexes at physiological pH. NFEPP preferentially activated MOPr in acidified extracellular conditions to inhibit cAMP formation, recruit ß-arrestins and evoke MOPr endocytosis. CONCLUSION: In a preclinical IBD model, NFEPP preferentially activates MOPr in acidified microenvironments of inflamed tissues to induce antinociception without causing respiratory depression, constipation and hyperactivity.

Changes in signalling from faecal neuroactive metabolites following dietary modulation of IBS pain.

OBJECTIVE: Dietary therapies for irritable bowel syndrome (IBS) have received increasing interest but predicting which patients will benefit remains a challenge due to a lack of mechanistic insight. We recently found evidence of a role for the microbiota in dietary modulation of pain signalling in a humanised mouse model of IBS. This randomised cross-over study aimed to test the hypothesis that pain relief following reduced consumption of fermentable carbohydrates is the result of changes in luminal neuroactive metabolites. DESIGN: IBS (Rome IV) participants underwent four trial periods: two non-intervention periods, followed by a diet low (LFD) and high in fermentable carbohydrates for 3 weeks each. At the end of each period, participants completed questionnaires and provided stool. The effects of faecal supernatants (FS) collected before (IBS FS) and after a LFD (LFD FS) on nociceptive afferent neurons were assessed in mice using patch-clamp and ex vivo colonic afferent nerve recording techniques. RESULTS: Total IBS symptom severity score and abdominal pain were reduced by the LFD (N=25; p<0.01). Excitability of neurons was increased in response to IBS FS, but this effect was reduced (p<0.01) with LFD FS from pain-responders. IBS FS from pain-responders increased mechanosensitivity of nociceptive afferent nerve axons (p<0.001), an effect lost following LFD FS administration (p=NS) or when IBS FS was administered in the presence of antagonists of histamine receptors or protease inhibitors. CONCLUSIONS: In a subset of IBS patients with improvement in abdominal pain following a LFD, there is a decrease in pronociceptive signalling from FS, suggesting that changes in luminal mediators may contribute to symptom response.

A novel method for the in vitro assembly of virus-like particles and multimeric proteins.

OBJECTIVE: To develop a method for the efficient assembly of viral or multimeric proteins into virus-like particles (VLP) or other macro structures. RESULTS: Protein monomers were assembled by eliminating calcium ions through precipitation. The model protein, rotavirus VP6, assembled into stable, long nanotubes with better quality than the assemblies obtained directly from cell culture. Nanotube length was directly proportional to the initial concentration of VP6 monomers, in accordance with the classic nucleation theory of capsid assembly. The quality of the obtained assemblies was confirmed when the nanotubes were functionalized with metals, yielding unique nanobiomaterials. Assembly efficiency was improved in comparison with other previously proposed methods. CONCLUSIONS: The novel method presented here is simpler and faster than other reported methods for the assembly and disassembly of viral proteins, a step needed for most applications.

[National surveillance of clinical isolates of Enterococcus faecalis resistant to linezolid carrying the optrA gene in Colombia, 2014-2019]. / Vigilancia nacional de aislamientos clínicos de Enterococcus faecalis resistentes al linezolid portadores del gen optrA en Colombia, 2014-2019.

OBJECTIVE: To describe the epidemiological, phenotypical and genetic characteristics of clinical isolates carrying the optrA gene identified in antimicrobial resistance surveillance by the laboratory of the National Institute of Health of Colombia. METHODS: Between October 2014 and February 2019, 25 isolates of Enterococcus spp. resistant to linezolid were received. Antimicrobial identification and sensitivity were determined using Vitek 2 and the minimum inhibitory concentration (MIC) to linezolid was established with E-test. The optrA gene was detected by PCR, and the genetic diversity of optrA-positive isolates was tested with Diversilab®. Six isolates were selected to perform whole genome sequencing. RESULTS: The optrA gene was confirmed in 23/25 isolates of E. faecalis from seven departments in Colombia. The isolates presented a MIC to linezolid between 8 and >256µg/mL. Typing by Diversilab® showed a wide genetic variability. All the isolates analyzed by whole genome sequencing showed the resistance genes fexA, ermB, lsaA, tet(M), tet(L) and dfrG in addition to optrA and were negative for other mechanisms of resistance to linezolid. Three type sequences and three optrA variants were identified: ST16 (optrA-2), ST476 (optrA-5) and ST618 (optrA-6). The genetic environment of the optrA-2 (ST16) isolates presented the impB, fex, optrA segment, associated with plasmid, while in two isolates (optrA-6 and optrA-5) the transferable chromosomal element Tn6674-like was found. CONCLUSION: OptrA-positive clinical isolates present a high genetic diversity, with different optrA clones and variants related to two types of structures and different mobile genetic elements.

From discourse to pathology: Automatic identification of Parkinson's disease patients via morphological measures across three languages.

Embodied cognition research on Parkinson's disease (PD) points to disruptions of frontostriatal language functions as sensitive targets for clinical assessment. However, no existing approach has been tested for crosslinguistic validity, let alone by combining naturalistic tasks with machine-learning tools. To address these issues, we conducted the first classifier-based examination of morphological processing (a core frontostriatal function) in spontaneous monologues from PD patients across three typologically different languages. The study comprised 330 participants, encompassing speakers of Spanish (61 patients, 57 matched controls), German (88 patients, 88 matched controls), and Czech (20 patients, 16 matched controls). All subjects described the activities they perform during a regular day, and their monologues were automatically coded via morphological tagging, a computerized method that labels each word with a part-of-speech tag (e.g., noun, verb) and specific morphological tags (e.g., person, gender, number, tense). The ensuing data were subjected to machine-learning analyses to assess whether differential morphological patterns could classify between patients and controls and reflect the former's degree of motor impairment. Results showed robust classification rates, with over 80% of patients being discriminated from controls in each language separately. Moreover, the most discriminative morphological features were associated with the patients' motor compromise (as indicated by Pearson r correlations between predicted and collected motor impairment scores that ranged from moderate to moderate-to-strong across languages). Taken together, our results suggest that morphological patterning, an embodied frontostriatal domain, may be distinctively affected in PD across languages and even under ecological testing conditions.

Expansin-like Exl1 from Pectobacterium is a virulence factor required for host infection, and induces a defence plant response involving ROS, and jasmonate, ethylene and salicylic acid signalling pathways in Arabidopsis thaliana.

Expansins are encoded by some phytopathogenic bacteria and evidence indicates that they act as virulence factors for host infection. Here we analysed the expression of exl1 by Pectobacterium brasiliense and Pectobacterium atrosepticum. In both, exl1 gene appears to be under quorum sensing control, and protein Exl1 can be observed in culture medium and during plant infection. Expression of exl1 correlates with pathogen virulence, where symptoms are reduced in a Δexl1 mutant strain of P. atrosepticum. As well as Δexl1 exhibiting less maceration of potato plants, fewer bacteria are observed at distance from the inoculation site. However, bacteria infiltrated into the plant tissue are as virulent as the wild type, suggesting that this is due to alterations in the initial invasion of the tissue. Additionally, swarming from colonies grown on MacConkey soft agar was delayed in the mutant in comparison to the wild type. We found that Exl1 acts on the plant tissue, probably by remodelling of a cell wall component or altering the barrier properties of the cell wall inducing a plant defence response, which results in the production of ROS and the induction of marker genes of the JA, ET and SA signalling pathways in Arabidopsis thaliana. Exl1 inactive mutants fail to trigger such responses. This defence response is protective against Pectobacterium brasiliense and Botrytis cinerea in more than one plant species.

Analysis of two Mexican Pectobacterium brasiliense strains reveals an inverted relationship between c-di-GMP levels with exopolysaccharide production and swarming motility.

Pectobacterium is a diverse genus of phytopathogenic species from soil and water that cause infection either to restricted or multiple plant hosts. Phylogenetic analysis and metabolic fingerprinting of large numbers of genomes have expanded classification of Pectobacterium members. Pectobacterium brasiliense sp. nov has been elevated to the species level having detached from P. carotovorum. Here we present two P. brasiliense strains BF20 and BF45 isolated in Mexico from Opuntia and tobacco, respectively, which cluster into two different groups in whole genome comparisons with other Pectobacterium. We found that BF20 and BF45 strains are phenotypically different as BF45 showed more severe and rapid symptoms in comparison to BF20 in the host models celery and broccoli. Both strains produced similar levels of the main autoinducers, but BF45 shows an additional low abundant autoinducer compared to strain BF20. The two strains had different levels of c-di-GMP, which regulates the transition from motile to sessile lifestyle. In contrast to BF45, BF20 had the highest levels of c-di-GMP, was more motile (swarming), non-flocculant and less proficient in biofilm formation and exopolysaccharide production. Genomic comparisons revealed that differences in c-di-GMP accumulation and perhaps the associated phenotypes might be due to unique c-di-GMP metabolic genes in these two strains. Our results improve our understanding of the associations between phenotype and genotype and how this has shaped the physiology of Pectobacterium strains.

Neuroactive Steroids and Cognitive Functions in First-Episode Psychosis Patients and Their Healthy Siblings.

Background: Neuroactive steroids (NAS) affect neurotransmitter systems and cognition; thus, they play role in etiopathogenesis of psychiatric disorders. Aims: The primary aim was to examine cognition and effects of NAS on cognitive functioning in first-episode psychosis patients and in their healthy siblings. The secondary aims were to verify whether cognitive deficit is an endophenotype of psychosis and whether higher NAS levels represent a high-risk factor for psychosis. Methods: Studied participants were 1) patients with first episode of psychosis, 2) healthy siblings of the patients, and 3) matching healthy controls. Study procedures included administration of a battery of neuropsychological tests assessing six cognitive domains and examination of NAS plasma levels [cortisol (CORT), 11-deoxycorticosterone (DOC), testosterone (TEST), dehydroepiandrostendione (DHEA), dihydrotestosterone (DHT), and progesterone (PROG)]. Results: A total of 67 subjects were analyzed (16 patients, 22 siblings, and 29 controls). Significant group differences were found in most of the cognitive domains; the patients had the lowest scores. The Kruskal-Wallis test revealed significant group differences in CORT levels (p < 0.01), TEST (p < 0.01), and DHT (p < 0.001); no difference was found in PROG, DHEA, and DOC. All cognitive domains, except for attention, were affected by the NAS levels. CORT levels of patients correlated with speed of processing (r = 0.55) and working memory (r = 0.52), while PROG levels correlated with abstraction (r = -0.63). In siblings, there was a negative correlation between TEST levels and verbal memory (r = -0.51) and PROG with attention (r = -0.47). Conclusions: Our results verified that individual domains of cognitive deficit (abstraction and verbal memory) can be considered as an endophenotype of psychosis. Higher levels of cortisol and testosterone in siblings are consistent with high-risk states for psychosis. Multiple interactions between NAS and cognitive functioning, particularly memory functions, were observed. Study limitations (small sample size and administration of antipsychotic medication) did not allow us to establish unequivocally NAS as an endophenotype.

Cognitive Profiles and Functional Connectivity in First-Episode Schizophrenia Spectrum Disorders - Linking Behavioral and Neuronal Data.

The character of cognitive deficit in schizophrenia is not clear due to the heterogeneity in research results. In heterogeneous conditions, the cluster solution allows the classification of individuals based on profiles. Our aim was to examine the cognitive profiles of first-episode schizophrenia spectrum disorder (FES) subjects based on cluster analysis, and to correlate these profiles with clinical variables and resting state brain connectivity, as measured with magnetic resonance imaging. A total of 67 FES subjects were assessed with a neuropsychological test battery and on clinical variables. The results of the cognitive domains were cluster analyzed. In addition, functional connectivity was calculated using ROI-to-ROI analysis with four groups: Three groups were defined based on the cluster analysis of cognitive performance and a control group with a normal cognitive performance. The connectivity was compared between the patient clusters and controls. We found different cognitive profiles based on three clusters: Cluster 1: decline in the attention, working memory/flexibility, and verbal memory domains. Cluster 2: decline in the verbal memory domain and above average performance in the attention domain. Cluster 3: generalized and severe deficit in all of the cognitive domains. FES diagnoses were distributed among all of the clusters. Cluster comparisons in neural connectivity also showed differences between the groups. Cluster 1 showed both hyperconnectivity between the cerebellum and precentral gyrus, the salience network (SN) (insula cortex), and fronto-parietal network (FPN) as well as between the PreCG and SN (insula cortex) and hypoconnectivity between the default mode network (DMN) and seeds of SN [insula and supramarginal gyrus (SMG)]; Cluster 2 showed hyperconnectivity between the DMN and cerebellum, SN (insula) and precentral gyrus, and FPN and IFG; Cluster 3 showed hypoconnectivity between the DMN and SN (insula) and SN (SMG) and pallidum. The cluster solution confirms the prevalence of a cognitive decline with different patterns of cognitive performance, and different levels of severity in FES. Moreover, separate behavioral cognitive subsets can be linked to patterns of brain functional connectivity.

Analysis of the Binding of Expansin Exl1, from Pectobacterium carotovorum, to Plant Xylem and Comparison to EXLX1 from Bacillus subtilis.

The plant xylem is a preferred niche for some important bacterial phytopathogens, some of them encoding expansin proteins, which bind plant cell walls. Yet, the identity of the substrate for bacterial expansins within the plant cell wall and the nature of its interaction with it are poorly known. Here, we determined the localization of two bacterial expansins with differing isoelectric points (and with differing binding patterns to cell wall extracts) on plant tissue through in vitro fluorophore labeling and confocal imaging. Differential localization was observed, in which Exl1 from Pectobacterium carotovorum located into the intercellular spaces between xylem vessels and adjacent cells of the plant xylem, whereas EXLX1 from Bacillus subtilis bound cell walls of most cell types. In isolated vascular tissue, however, both PcExl1 and BsEXLX1 preferentially bound to tracheary elements over the xylem fibers, even though both are composed of secondary cell walls. Fluorescence correlation spectroscopy, employed to analyze the interaction of expansins with isolated xylem, indicates that binding is governed by more than one factor, which could include interaction with more than one type of polymer in the fibers, such as cellulose and hemicellulose or pectin. Binding to different polysaccharides could explain the observed reduction of cellulolytic and xylanolytic activities in the presence of expansin, possibly because of competition for the substrate. Our findings are relevant for the comprehensive understanding of the pathogenesis by P. carotovorum during xylem invasion, a process in which Exl1 might be involved.

Using bioreactors to study the effects of drugs on the human microbiota.

The study of complex microbial communities has become a major research focus as mounting evidence suggests the pivotal role microbial communities play in host health and disease. Microbial communities of the gastrointestinal tract, known as the gut microbiota, have been implicated in aiding the host with vitamin biosynthesis, regulation of host energy metabolism, immune system development, and resistance to pathogen invasion. Conversely, disruptions of the gut microbiota have been linked to host morbidity, including the development of inflammatory diseases, metabolic disorders, increased cardiovascular risk, and increased risk of infectious diseases. However, studying the gut microbiota in humans and animals is challenging, as many microorganisms are fastidious with unique nutritional or environmental requirements that are often not met using conventional culture techniques. Bioreactors provide a unique solution to overcome some of the limitations of conventional culture techniques. Bioreactors have been used to propagate and establish complex microbial communities in vitro by recapitulating the physiological conditions found in the GI tract. These systems further our understanding of microbial physiology and facilitate our understanding of the impact of medications and xenobiotics on microbial communities. Here, we review the versatility and breadth of bioreactor systems that are currently available and how they are being used to study faecal and defined microbial communities. Bioreactors provide a unique opportunity to study complex microbial interactions and perturbations in vitro in a controlled environment without confounding biotic and abiotic variables.

Theoretical Modeling of Cognitive Dysfunction in Schizophrenia by Means of Errors and Corresponding Brain Networks.

The current evidence of cognitive disturbances and brain alterations in schizophrenia does not provide the plausible explanation of the underlying mechanisms. Neuropsychological studies outlined the cognitive profile of patients with schizophrenia, that embodied the substantial disturbances in perceptual and motor processes, spatial functions, verbal and non-verbal memory, processing speed and executive functioning. Standardized scoring in the majority of the neurocognitive tests renders the index scores or the achievement indicating the severity of the cognitive impairment rather than the actual performance by means of errors. At the same time, the quantitative evaluation may lead to the situation when two patients with the same index score of the particular cognitive test, demonstrate qualitatively different performances. This may support the view why test paradigms that habitually incorporate different cognitive variables associate weakly, reflecting an ambiguity in the interpretation of noted cognitive constructs. With minor exceptions, cognitive functions are not attributed to the localized activity but eventuate from the coordinated activity in the generally dispersed brain networks. Functional neuroimaging has progressively explored the connectivity in the brain networks in the absence of the specific task and during the task processing. The spatio-temporal fluctuations of the activity of the brain areas detected in the resting state and being highly reproducible in numerous studies, resemble the activation and communication patterns during the task performance. Relatedly, the activation in the specific brain regions oftentimes is attributed to a number of cognitive processes. Given the complex organization of the cognitive functions, it becomes crucial to designate the roles of the brain networks in relation to the specific cognitive functions. One possible approach is to identify the commonalities of the deficits across the number of cognitive tests or, common errors in the various tests and identify their common "denominators" in the brain networks. The qualitative characterization of cognitive performance might be beneficial in addressing diffuse cognitive alterations presumably caused by the dysconnectivity of the distributed brain networks. Therefore, in the review, we use this approach in the description of standardized tests in the scope of potential errors in patients with schizophrenia with a subsequent reference to the brain networks.

Evaluation of dried blood spot sampling for pharmacokinetic research and therapeutic drug monitoring of anti-tuberculosis drugs in children.

BACKGROUND: Dried blood spot (DBS) sampling for pharmacokinetic (PK) studies and therapeutic drug monitoring have unique advantages over venous sampling. This study aimed to evaluate a DBS method for first-line anti-tuberculosis drugs in children, and DBS sampling to assess PK parameters. METHODS: Paraguayan children were treated according to the revised paediatric dosing scheme of the World Health Organization. A PK curve was performed both with DBS sampling and conventional venous sampling for rifampicin, pyrazinamide and ethambutol. Passing-Bablok regression, Bland-Altman plots and predictive performance evaluation were used to assess agreement between DBS and plasma concentrations. The percentages of patients attaining population PK values for Cmax and AUC0-24h were calculated. RESULTS: After use of a conversion factor, Passing-Bablok regression showed no significant proportional or systematic bias between DBS and plasma concentrations. Bland-Altman plots showed that 95% of the ratios of the DBS predicted:observed plasma concentrations lay between 0.6 and 1.4 for rifampicin, 0.5 and 1.6 for pyrazinamide and -0.4 and 2.8 for ethambutol. DBS measurements showed acceptable predictive performance for rifampicin and pyrazinamide, but not for ethambutol. Assessment of Cmax target attainment was 62.5% for isoniazid, 25% for rifampicin, 100% for pyrazinamide and 75% for ethambutol. CONCLUSION: For rifampicin and pyrazinamide, the DBS method was accurate in predicting plasma concentrations, and was used successfully for PK parameter assessment. However, predicting ethambutol plasma concentrations with DBS measurement was associated with too much imprecision. Despite higher dosing, only 25% of the population reached average target adult rifampicin exposures.