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DPANN archaea have characteristically small cells and unique genomes that were long overlooked in diversity surveys. Their reduced genomes often lack essential metabolic pathways, requiring symbiotic relationships with other archaeal and bacterial hosts for survival. Yet a long-standing question remains, what is the advantage of maintaining ultrasmall cells. A recent study by Zhang et al. examined genomes of DPANN archaea from marine oxygen deficient zones (ODZs) (I. H. Zhang, B. Borer, R. Zhao, S. Wilbert, et al., mBio 15:e02918-23, 2024, https://doi.org/10.1128/mbio.02918-23). Surprisingly, these genomes contain a broad array of metabolic pathways including genes predicted to be involved in nitrous oxide (N 2 O) reduction. However, N 2 O levels are likely too low in ODZs to make this metabolically feasible. Modeling co-localization of DPANN archaea (N 2 O consumers) with other larger cells (N 2 O producers) demonstrates that N 2 O uptake rates can be optimized by maximizing the producer-to-consumer size ratio and proximity of consumer cells to producers. This may explain why such a diversity of archaea maintain extremely small cell sizes., Competing Interests: The authors declare no conflict of interest.

Alkanes, single carbon methane to long-chain hydrocarbons (e.g. hexadecane and tetradecane), are important carbon sources to anaerobic microbial communities. In anoxic environments, archaea are known to utilize and produce methane via the methyl-coenzyme M reductase enzyme (MCR). Recent explorations of new environments, like deep sea sediments, that have coupled metagenomics and cultivation experiments revealed divergent MCRs, also referred to as alkyl-coenzyme M reductases (ACRs) in archaea, with similar mechanisms as the C 1 utilizing canonical MCR mechanism. These ACR enzymes have been shown to activate other alkanes such as ethane, propane and butane for subsequent degradation. The reversibility of canonical MCRs suggests that these non-methane-activating homologues (ACRs) might have similar reversibility, perhaps mediated by undiscovered lineages that produce alkanes under certain conditions. The discovery of these alternative alkane utilization pathways holds significant promise for a breadth of potential biotechnological applications in bioremediation, energy production and climate change mitigation., (© 2024 The Author(s). Microbial Biotechnology published by John Wiley & Sons Ltd.)

Hepatocyte nuclear factor 4 α (HNF4α), a transcription factor (TF) essential for embryonic development, has been recently shown to regulate the expression of inflammatory genes. To characterize HNF4a function in immunity, we measured the effect of HNF4α antagonists on immune cell responses in vitro and in vivo. HNF4α blockade reduced immune activation in vitro and disease severity in the experimental model of multiple sclerosis (MS). Network biology studies of human immune transcriptomes unraveled HNF4α together with SP1 and c-myc as master TF regulating differential expression at all MS stages. TF expression was boosted by immune cell activation, regulated by environmental MS risk factors and higher in MS immune cells compared to controls. Administration of compounds targeting TF expression or function demonstrated non-synergic, interdependent transcriptional control of CNS autoimmunity in vitro and in vivo. Collectively, we identified a coregulatory transcriptional network sustaining neuroinflammation and representing an attractive therapeutic target for MS and other inflammatory disorders., Competing Interests: Declaration of competing interest The authors declare no competing interests related to the manuscript., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Adaptation plays an important role in sensory systems as it dynamically modifies sensitivity to allow the detection of stimulus changes. The vomeronasal system controls many social behaviors in most mammals by detecting pheromones released by conspecifics. Stimuli activate a transduction cascade in vomeronasal neurons that leads to spiking activity. Whether and how these neurons adapt to stimuli is still debated and largely unknown. Here, we measured short-term adaptation performing current-clamp whole-cell recordings by using diluted urine as a stimulus, as it contains many pheromones. We measured spike frequency adaptation in response to repeated identical stimuli of 2-10 s duration that was dependent on the time interval between stimuli. Responses to paired current steps, bypassing the signal transduction cascade, also showed spike frequency adaptation. We found that voltage-gated Na + channels in VSNs undergo slow inactivation processes. Furthermore, recovery from slow inactivation of voltage-gated Na + channels occurs in several seconds, a time scale similar to that measured during paired-pulse adaptation protocols, suggesting that it partially contributes to short-term spike frequency adaptation. We conclude that vomeronasal neurons do exhibit a time-dependent short-term spike frequency adaptation to repeated natural stimuli and that slow inactivation of Na + channels contributes to this form of adaptation. These findings not only increase our knowledge about adaptation in the vomeronasal system, but also raise the question of whether slow inactivation of Na + channels may play a role in other sensory systems., (Copyright © 2022 Sarno et al.)

The mouse vomeronasal system controls several social behaviors. Pheromones and other social cues are detected by sensory neurons in the vomeronasal organ (VNO). Stimuli activate a transduction cascade that leads to membrane potential depolarization, increase in cytosolic Ca 2+ level, and increased firing. The Ca 2+ -activated chloride channels TMEM16A and TMEM16B are co-expressed within microvilli of vomeronasal neurons, but their physiological role remains elusive. Here, we investigate the contribution of each of these channels to vomeronasal neuron firing activity by comparing wild-type (WT) and knock-out (KO) mice. Performing loose-patch recordings from neurons in acute VNO slices, we show that spontaneous activity is modified by Tmem16a KO, indicating that TMEM16A, but not TMEM16B, is active under basal conditions. Upon exposure to diluted urine, a rich source of mouse pheromones, we observe significant changes in activity. Vomeronasal sensory neurons (VSNs) from Tmem16a cKO and Tmem16b KO mice show shorter interspike intervals (ISIs) compared with WT mice, indicating that both TMEM16A and TMEM16B modulate the firing pattern of pheromone-evoked activity in VSNs., (Copyright © 2021 Hernandez-Clavijo et al.)

Background: International Classification Functioning (ICF) Core Sets represent a holistic approach to functioning within rehabilitation field. Information-reporting efficacy of a rehabilitation-based Respiratory ICF set applied on a large scale throughout the ICS Maugeri network was tested., Methods: A prospective multi-center study (May-November 2018) was conducted for all respiratory inpatients consecutively admitted for rehabilitation. Doctors, physiotherapists, psychologists, nurses used an electronic Respiratory ICF set (33 items among the ICF body functions, activity and participations components) at admission and at discharge to assess the disability changes. The ICF report qualifiers, from 0 (no impairment) to 4 (maximum impairment), guided clinical, diagnostic and rehabilitation prescriptions., Results: 1886 patients (69.6±10.8 years; M=1045) were admitted (589 chronic obstructive pulmonary disease, 494 chronic respiratory failure [CRF], 21 prolonged mechanical ventilation [PMV], 496 with other respiratory diseases), of whom 15 died, and 117 were transferred to acute care. The mean length of stay was 23.1±11.8 days (range 1-122). The mean time to fill in the ICF set was 23.16±0.70 min. The rate of filled charts improved from 16% in May to 100% in November. The baseline distribution of the more severe qualifiers (>2) progressively increased from the whole sample to the PMV subgroup. After rehabilitation, in the whole sample and in the CRF and PMV subgroups, the severity qualifiers significantly decreased (P<0.0001), showing a positive effect of the intervention on patients' disability., Conclusions: Routine use of a Respiratory ICF set for chronic respiratory diseases helps to prepare a personalized rehabilitation program discriminating disability level in different respiratory diseases and assessing disability outcomes pre-post rehabilitation.

Study Objectives: There are few studies evaluating (1) exercise capacity as assessed by the 6-minute walking distance (6MWD) test in large populations with obstructive sleep apnea (OSA); and (2) correlations with patients' comorbidities., Methods: This study presents a cluster analysis performed on the data of 1,228 patients. Severity of exercise limitation was defined on the basis of 6MWD., Results: Sixty-one percent showed exercise limitation (29.2% and 31.9% mild and severe exercise limitation, respectively). About 60% and 40% of patients were included in cluster 1 (CL1) and 2 (CL2), respectively. CL1 included younger patients with high prevalence of apneas, desaturations, and hypertension with better exercise tolerance. CL2 included older patients, all with chronic obstructive pulmonary disease (COPD), high prevalence of chronic respiratory failure (CRF), fewer apneas but severe mean desaturation, daytime hypoxemia, more severe exercise limitation, and exercise-induced desaturations. Only CRF and COPD significantly (P < .001) correlated with 6MWD < 85% of predicted value. 6MWD correlated positively with apnea-hypopnea index, oxygen desaturation index, nocturnal pulse oxygen saturation (SpO₂), resting arterial oxygen tension, mean SpO₂ on exercise, and negatively with age, body mass index, time spent during night with SpO₂ < 90%, mean nocturnal desaturation, arterial carbon dioxide tension, and number of comorbidities. Patients without severe comorbidities had higher exercise capacity than those with severe comorbidities, (P < .001). Exercise limitation was significantly worse in OSA severity class I when compared to other classes (P < .001)., Conclusions: A large number of patients with OSA experience exercise limitation. Older age, comorbidities such as COPD and CRF, OSA severity class I, severe mean nocturnal desaturation, and daytime hypoxemia are associated with worse exercise tolerance., (© 2020 American Academy of Sleep Medicine.)

Recent evidence suggests that the primary progressive form of multiple sclerosis (PP-MS) may present with specific immunological alterations. In this study we focused our attention on CD161, an NK and T cell marker upregulated in relapsing-remitting MS, and investigated its transcript and protein levels in blood cells from PP-MS and healthy individuals. We demonstrated transcriptional downregulation of CD161 in PP-MS and described concomitant mRNA reduction for RORgt, CCR6, CXCR6, KLRK1/NKG2D and many other markers typical of mucosa associated invariant T (MAIT) cells. Targeted multiparametric flow cytometry on fresh blood cells from an independent cohort of case-control subjects confirmed the selective loss of circulating CD8 CD161 high T cells, which consist mainly of MAIT cells, and not of CD8 CD161 int T cells in PP-MS. These data demonstrate alterations in a specific circulating immune cell subset in MS patients with progressive onset.

Background: Lung diffusing capacity (DLCO) and lung volume distribution predict exercise performance and are altered in COPD patients. If pulmonary rehabilitation (PR) can modify DLCO parameters is unknown., Objectives: To investigate changes in DLCO and ventilation inhomogeneity following a PR program and their relation with functional outcomes in patients with COPD., Methods: This was a prospective, observational, multicentric study. Patients were evaluated before and after a standardized 3-week PR program. Functional assessment included body plethysmography, DLCO, transfer factor (KCO) and alveolar volume (VA), gas exchange, the 6-min walking test (6MWT) and exercise-related dyspnea. Patients were categorized according to the severity of airflow limitation and presence of ventilation inhomogeneity, identified by a VA/TLC <0.8., Results: Two hundred and fifty patients completed the study. Baseline forced expiratory volume in 1 s (FEV1) % predicted (mean ± SD) was 50.5 ± 20.1 (76% males); 137 patients had a severe disease. General study population showed improvements in 6MWT (38 ± 55 m; p < 0.01), DLCO (0.12 ± 0.63 mmol × min-1 kPa-1; p < 0.01), lung function and dyspnea. Comparable improvements in DLCO were observed regardless of the severity of disease and the presence of ventilation inhomogeneity. While patients with VA/TLC <0.8 improved the DLCO increasing their VA (177 ± 69 ml; p < 0.01), patients with VA/TLC >0.8 improved their KCO (8.1 ± 2.8%; p = 0.019). The latter had also better baseline lung function and higher improvements in 6MWT (14.6 ± 6.7 vs. 9.0 ± 1.8%; p = 0.015). Lower DLCO at baseline was associated with lower improvements in 6MWT, the greatest difference being between subjects with very severe and mild DLCO impairment (2.7 ± 7.4 vs. 14 ± 2%; p = 0.049)., Conclusions: In COPD patients undergoing a PR program, different pathophysiological mechanisms may drive improvements in DLCO, while ventilation inhomogeneity may limit improvements in exercise tolerance., (© 2016 S. Karger AG, Basel.)

Background: DSM-IV identifies three stress response disorders (acute stress (ASD), post-traumatic stress (PTSD) and adjustment disorders (AD)) that derive from specific life events. An additional condition of complicated grief (CG), well described in the literature, is triggered by bereavement., Methods: This paper reports on the reliability and validity of the Structured Clinical Interview for Trauma and Loss Spectrum (SCI-TALS) developed to assess the spectrum of stress response. The instrument is based on a spectrum model that emphasizes soft signs, low-grade symptoms, subthreshold syndromes, as well as temperamental and personality traits comprising clinical and subsyndromal manifestations. Study participants, enrolled at 6 Italian Departments of Psychiatry, included consecutive patients with PTSD (N = 48), CG (N = 44), and controls (N = 48)., Results: We showed good reliability and validity of the SCI-TALS. Domain scores were significantly higher in participants with PTSD or CG compared to controls. There were high correlations between specific SCI-TALS domains and corresponding scores on established measures of similar constructs. Participants endorsing grief and loss events reported similar scores on all instruments, except those with CG who scored significantly higher on the domain of grief reactions., Conclusion: These results support the existence of a specific grief-related condition and the proposal that different forms of stress response have similar manifestations.

Steady-state plasma concentrations of clozapine and norclozapine, its major metabolite, as well as their sum and ratio (norclozapine/clozapine), were evaluated in 50 in- and outpatients taking clozapine and naturalistically recruited. Drug plasma concentrations were measured by means of a reversed-phase high-performance liquid chromatography (RPLC) method with an ultraviolet detection. Daily doses (milligrams per kilogram of body weight) of clozapine correlated positively with clozapine plasma parameters, except with the norclozapine/clozapine ratio, in all patients. When the patients were divided in subgroups with respect to gender, the corresponding plasma concentrations were no longer dose-related in men. A lack of significant correlation was observed also in patients (n=23) co-treated with typical neuroleptics. Conversely, dose-concentration correlations were significant in either smoker or nonsmoker patients. No significant relationship between body weight and clozapine plasma parameters was reported. Further, we observed (1) a trend towards higher medians of clozapine or total analytes in women than those reported in men (P=.09 and .07); (2) no significant difference in plasma levels obtained in subjects younger than 34 years and subjects 34 years old or older; (3) a trend towards higher norclozapine and clozapine plus norclozapine levels (P=.05 and .08) in nonsmoker than smoker patients; (4) no significant difference between clozapine plasma parameters measured in patients co-medicated with typical neuroleptics and in patients receiving clozapine alone.

The present report analyzes the agreement between the interview and the self-report formats of the instruments Structured Clinical Interview for Social Anxiety Spectrum (SCI-SHY) and Structured Clinical Interview for Obsessive Compulsive Spectrum (SCI-OBS), already validated, in three psychiatric patient samples and controls. Thirty patients (10 with obsessive-compulsive disorder [OCD], 10 with social anxiety disorder [SAD], 10 with recurrent unipolar depression in remission) and 20 control subjects (10 university students, 10 ophthalmologic patients) were assessed using the SCI-SHY, the SCI-OBS, and the self report version of the two instruments. Agreement between the two versions was very good for the seven SCI-OBS domains (with intraclass correlation coefficients [ICCs] ranging from 0.80 to 0.96) and the four SCI-SHY domains (ICCs from 0.74 to 0.90). When items were analyzed individually, subjects tended to under-report some phobia-related problems in the interview. The total number of items endorsed in the SCI-SHY, but not in the SCI-OBS, was affected by the order of administration: when the SCI-SHY interview was administered first, subjects reported a median of five more symptoms; when the self-report was administered first, there was no significant difference in the number of symptoms endorsed in the two formats. However, this difference is not clinically important, given the large number of items comprising the instruments, and might be explained by the fact that subjects are likely to overemphasize occasional symptoms or behaviors when they are asked by the interviewer to answer a long series of "new" questions as accurately as possible. Given the high agreement between domain scores in the two formats of the instruments and the fact that scores are virtually identical when the self-report is administered first, we recommend the use of the self-report versions in clinical and research settings.

This study investigated a series of clinical characteristics, including the level of insight into illness and axis I comorbidity, in 125 patients with bipolar disorder with psychotic features categorized in three groups: 62 patients with mania, 28 patients with mixed mania, and 35 patients with depression. All patients were hospitalized and were assessed in the week preceding discharge. The three groups did not differ in the severity of psychopathology as assessed by the Brief Psychiatric Rating Scale (BPRS). The mania group had a lower level of insight into the social consequences of illness than the other two groups, and compared with the group with depression, they had a lower level of insight of poor attention and of poor social judgment. As to axis I comorbidity, obsessive-compulsive disorder was found to be significantly more frequent in depression than in mania. Patients with depression more frequently reported a history of suicidality than those with mania, whereas they did not significantly differ from patients with mixed mania. Our results suggest that mixed mania as assessed at the time of the patient's discharge differs from mania and from depression with respect to a limited number of features among those examined. However, the overall level of insight into illness significantly discriminated mixed mania from mania, but not from depression.

A simple reversed-phase liquid chromatographic method enabling the simultaneous analysis in plasma of the tricyclic antidepressant clomipramine, its demethylated metabolite, and the selective serotonin reuptake inhibitor fluvoxamine, was developed. The drugs and dibenzepine, the internal standard, were extracted from 1 mL plasma through an automated solid-phase procedure, eluted in a total chromatographic time of approximately 14 min and detected by means of an ultraviolet spectrophotometer preset at 254 nm. An assay sensitivity of 10 microg/L was observed for all analytes. Recoveries for these drugs and their metabolites ranged between 65% and 98% and their coefficient of variation (within-day and day-to-day) between 1.9% and 2.9%. In spiked plasma, within-day and day-to-day imprecision data were less than 5%. The simultaneous determination of clomipramine, N-desmethylclomipramine, and fluvoxamine with adequate sensitivity and accuracy may be useful for the monitoring of drug treatment in depression and obsessive-compulsive disorder, where combinations of such drugs are employed.

Some patients with disabling and potentially fatal lung disease, who are nonresponders to conventional treatment, could benefit from lung transplantation (LT). It is, therefore, necessary to know the number of patients who are potentially eligible for such a therapeutic procedure. A retrospective study of the mortality rate of the Italian population from 1989-1991 was carried out. Groups of non-neoplastic chronic respiratory diseases, for which LT is indicated, were identified according to the Italian Central Statistical Institute (ISTAT), analytical international classification of diseases, trauma and causes of death (9th revision of 1975). The distribution of these diseases was considered both in terms of the total number of deaths (all ages) and in the relative number prior to 60 yrs of age (the maximum acceptable age for LT). Twenty five ISTAT codes referring to chronic non-neoplastic lung diseases for which LT is indicated were identified, and grouped according to disease type. The total national mortality rate from 1989-1991 due to selected lung diseases for which transplant is indicated was 44,915 (14,335 in 1989, 15,271 in 1990, and 15,309 in 1991), and 2,774 (6%) of these deaths occurred below the age limit of 60 yrs (986 in 1989, 889 in 1990, and 899 in 1981). Considering the normal limitations of retrospective studies on mortality rate, and the fact that only one eligibility criterion for LT (age) was considered, the results obtained provide an indirect evaluation and overestimation of the potential candidates for such treatment in Italy, and the relative need for organ donation.

Total cases of fatal asthma in the occupational setting reported in the literature are reviewed and the case of a 39-year-old foundry worker who died at work is described. A diagnosis of occupational asthma induced by diphenylmethane diisocyanate (MDI) had been assessed 5 years in advance through a 0.005-ppm exposure inhalation challenge. Postmortem microscopic examination of the lung showed epithelial desquamation, eosinophilic/neutrophilic infiltration of the mucosa, dilatation of bronchial vessels, edema, hypertrophy and disarray of smooth muscle. Fatal asthma attack in a MDI-sensitized individual, to our knowledge, has not been previously described.