Optogenetic stimulation of medial septal glutamatergic neurons modulates theta-gamma coupling in the hippocampus.

Hippocampal cross-frequency theta-gamma coupling (TGC) is a basic mechanism for information processing, retrieval, and consolidation of long-term and working memory. While the role of entorhinal afferents in the modulation of hippocampal TGC is widely accepted, the influence of other main input to the hippocampus, from the medial septal area (MSA, the pacemaker of the hippocampal theta rhythm) is poorly understood. Optogenetics allows us to explore how different neuronal populations of septohippocampal circuits control neuronal oscillations in vivo. Rhythmic activation of septal glutamatergic neurons has been shown to drive hippocampal theta oscillations, but the role of these neuronal populations in information processing during theta activation has remained unclear. Here we investigated the influence of phasic activation of MSA glutamatergic neurons expressing channelrhodopsin II on theta-gamma coupling in the hippocampus. During the experiment, local field potentials of MSA and hippocampus of freely behaving mice were modulated by 470 nm light flashes with theta frequency (2-10) Hz. It was shown that both the power and the strength of modulation of gamma rhythm nested on hippocampal theta waves depend on the frequency of stimulation. The modulation of the amplitude of slow gamma rhythm (30-50 Hz) prevailed over modulation of fast gamma (55-100 Hz) during flash trains and the observed effects were specific for theta stimulation of MSA. We discuss the possibility that phasic depolarization of septal glutamatergic neurons controls theta-gamma coupling in the hippocampus and plays a role in memory retrieval and consolidation.

Significant reduction in the incidence of non-coronavirus infections in patients with chronic lymphocytic leukemia on ibrutinib and venetoclax treatment during the COVID-19 pandemic: An additional benefit of lockdown.

Effective treatment and prevention of infections challenge management of patients with chronic lymphicytic leukemia (CLL). The COVID-19 pandemic resulted in the reduction of outpatient hospital visits as a part of non-pharmaceutical interventions that could affect the incidence of infectious complications. Study enrolled patients with CLL receiving ibrutinib or/and venetoclax who were observed at the Moscow City Centre of Hematology from 01 April 2017 to 31 March 2021. We found a reduction in the incidence of infectious episodes after the implementation of the lockdown in Moscow in 01 April 2020, when compared to data on the year prior to the lockdown (p < 0.0001), as well as when compared to the predictive model (p = 0.02), and based on individual infection profiles using cumulative sums (p < 0.0001). Bacterial infections had 4.44-fold decrease, bacterial in combination with undefined infections had 4.89-fold decrease, viral infections had unsignificant changes. The decrease in the number of outpatient visits coincides with the time of the lockdown could be a likely factor, explaining a decline in the incidence of infection. Patients were clustered according incidence and severity of infectious episodes for subgroup mortality assessment. No differences in overall survival due to COVID-19 were observed. Typical respiratory infections, bacterial and undefined, the transmission of which may be affected by patient-to-patient contact in the settings of out-patient health care visits were decreased, possibly due to SARS-CoV-2 restrictive measures. A positive correlation between outpatient visits and the incidence of bronchial and upper respiratory tract infection points at the role of hospital-acquired infection and attests to the necessity of reorganizing care for all patients with CLL.

Differential Expression of Proteins Associated with Bipolar Disorder as Identified Using the PeptideShaker Software.

The prevalence of bipolar disorder (BD) in modern society is growing rapidly, but due to the lack of paraclinical criteria, its differential diagnosis with other mental disorders is somewhat challenging. In this regard, the relevance of proteomic studies is increasing due to the development of methods for processing large data arrays; this contributes to the discovery of protein patterns of pathological processes and the creation of new methods of diagnosis and treatment. It seems promising to search for proteins involved in the pathogenesis of BD in an easily accessible material-blood serum. Sera from BD patients and healthy individuals were purified via affinity chromatography to isolate 14 major proteins and separated using 1D SDS-PAGE. After trypsinolysis, the proteins in the samples were identified via HPLC/mass spectrometry. Mass spectrometric data were processed using the OMSSA and X!Tandem search algorithms using the UniProtKB database, and the results were analyzed using PeptideShaker. Differences in proteomes were assessed via an unlabeled NSAF-based analysis using a two-tailed Bonferroni-adjusted t-test. When comparing the blood serum proteomes of BD patients and healthy individuals, 10 proteins showed significant differences in NSAF values. Of these, four proteins were predominantly present in BD patients with the maximum NSAF value: 14-3-3 protein zeta/delta; ectonucleoside triphosphate diphosphohydrolase 7; transforming growth factor-beta-induced protein ig-h3; and B-cell CLL/lymphoma 9 protein. Further exploration of the role of these proteins in BD is warranted; conducting such studies will help develop new paraclinical criteria and discover new targets for BD drug therapy.

Coronavirus-Specific Antibody and T Cell Responses Developed after Sputnik V Vaccination in Patients with Chronic Lymphocytic Leukemia.

The clinical course of the new coronavirus disease 2019 (COVID-19) has shown that patients with chronic lymphocytic leukemia (CLL) are characterized by a high mortality rate, poor response to standard treatment, and low virus-specific antibody response after recovery and/or vaccination. To date, there are no data on the safety and efficacy of the combined vector vaccine Sputnik V in patients with CLL. Here, we analyzed and compared the magnitudes of the antibody and T cell responses after vaccination with the Sputnik V vaccine among healthy donors and individuals with CLL with different statuses of preexposure to coronavirus. We found that vaccination of the COVID-19-recovered individuals resulted in the boosting of pre-existing immune responses in both healthy donors and CLL patients. However, the COVID-19-naïve CLL patients demonstrated a considerably lower antibody response than the healthy donors, although they developed a robust T cell response. Regardless of the previous infection, the individuals over 70 years old demonstrated a decreased response to vaccination, as did those receiving anti-CD20 therapy. In summary, we showed that Sputnik V, like other vaccines, did not induce a robust antibody response in individuals with CLL; however, it provided for the development of a significant anti-COVID-19 T cell response.

The difference in serum proteomes in schizophrenia and bipolar disorder.

BACKGROUND: Purpose of study is revealing significant differences in serum proteomes in schizophrenia and bipolar disorder (BD). RESULTS: Quantitative mass-spectrometry based proteomic analysis was used to quantify proteins in the blood serum samples after the depletion of six major blood proteins. Comparison of proteome profiles of different groups revealed 27 proteins being specific for schizophrenia, and 18 - for BD. Protein set in schizophrenia was mostly associated with immune response, cell communication, cell growth and maintenance, protein metabolism and regulation of nucleic acid metabolism. Protein set in BD was mostly associated with immune response, regulating transport processes across cell membrane and cell communication, development of neurons and oligodendrocytes and cell growth. Concentrations of ankyrin repeat domain-containing protein 12 (ANKRD12) and cadherin 5 in serum samples were determined by ELISA. Significant difference between three groups was revealed in ANKRD12 concentration (p = 0.02), with maximum elevation of ANKRD12 concentration (median level) in schizophrenia followed by BD. Cadherin 5 concentration differed significantly (p = 0.035) between schizophrenic patients with prevailing positive symptoms (4.78 [2.71, 7.12] ng/ml) and those with prevailing negative symptoms (1.86 [0.001, 4.11] ng/ml). CONCLUSIONS: Our results are presumably useful for discovering the new pathways involved in endogenous psychotic disorders.

Functionalization of Carbon Nanotubes Surface by Aryl Groups: A Review.

The review is devoted to the methods of introducing aryl functional groups to the CNT surface. Arylated nanotubes are characterized by extended solubility, and are widely used in photoelectronics, semiconductor technology, and bioelectrocatalysis. The main emphasis is on arylation methods according to the radical mechanism, such as the Gomberg-Bachmann and Billups reactions, and the decomposition of peroxides. At the same time, less common approaches are also considered. For each of the described reactions, a mechanism is presented in the context of the effect on the properties of functionalized nanotubes and their application. As a result, this will allow us to choose the optimal modification method for specific practical tasks.

Ibrutinib in combination with rituximab is highly effective in treatment of chronic lymphocytic leukemia patients with steroid refractory and relapsed autoimmune cytopenias.

Autoimmune hemolytic anemia (AIHA) and pure red cell aplasia (PRCA) are common complications of CLL. The optimal treatment of steroid refractory AIHA/PRCA is not well established. We conducted a multicenter study of ibrutinib and rituximab in patients with relapsed/refractory to steroids AIHA/PRCA and underlying CLL. Protocol included induction (ibrutinib 420 mg/day and rituximab, 8 weekly and 4 monthly infusions) and maintenance phase with ibrutinib alone until progression or unacceptable toxicity. Fifty patients were recruited (44-warm AIHA, 2-cold AIHA, 4-PRCA). After the induction 34 patients (74%) have achieved complete response, 10 (21.7%) partial response. Median time to hemoglobin normalization was 85 days. With regards to CLL response 9 (19%) patients have achieved CR, 2 (4%) patients-stabilization and 39 (78%)-PR. The median follow-up was 37.56 months. In AIHA group 2 patients had a relapse. Among 4 patients with PRCA 1 patient did not respond, and 1 patient had a relapse after CR, 2 remained in CR. The most common adverse events were neutropenia (62%), infections (72%), gastrointestinal complications (54%). In conclusion ibrutinib in combination with rituximab is an active second-line treatment option for patients with relapsed or refractory AIHA/PRCA and underlying CLL.

Text4baby in the United States and Russia: an opportunity for understanding how mHealth affects maternal and child health.

Text4baby uses new technology to deliver health messages and engage pregnant women and new mothers in healthy behaviors. The authors describe the need for carefully conducted early adopter epidemiologic evaluation and describe one such evaluation in a women, infant, and children clinic population in the United States and its proposed adaptation for use among early users of Text4baby in Russia. Collaborative efforts among countries can guide international understanding and use of best practices of this emerging technology.

Proteomic profile of serum from patients with schizophrenia spectrum disorders.

This article describes the most likely classes of proteins and molecular processes that specifically characterize schizophrenic spectrum disorders such as simple and paranoid schizophrenia, schizotypal disorder, and acute polymorphic psychotic disorder (APPD). The identification of patients' serum proteins was carried out using mass spectrometry. For patients with paranoid schizophrenia, the proteins responsible for translation and transcription are characteristic. A significant part of the proteins of patients with simple schizophrenia regulate the cell's main metabolic and transport processes. These are proteins of the receptor system, vesicular transport, and extracellular matrix, which mainly carry out catabolic processes. The proteins of patients with schizotypal disorder mostly coincided with the classes of other patients, apart from chaperone proteins, which were not found in other studied groups. These proteins are mainly involved in anabolic processes. The main classes of proteins found in patients with APPD are responsible for the metabolism of nucleic acids. Active apoptosis processes were also revealed in these patients. These results from our basic knowledge about the molecular mechanisms of the pathogenesis of these disorders.

COVID-19 in patients with chronic lymphocytic leukemia: a Moscow observational study.

We describe a retrospective cohort, 156 patients with chronic lymphocytic leukemia (CLL) diagnosed with COVID-19, analyze factors associated with a severe disease course and the effects of various treatment regimens. Anti-SARS-CoV-2 IgG and IgM levels are significantly lower. Patients with CLL are more likely to have a severe course of COVID-19, with IL-6 levels acting as a consistent biomarker of disease severity. Ten patients had recurrent episodes, fatality rate of 20%. Overall survival did not differ between patients receiving ibrutinib monotherapy and anti-CD20 antibodies ± chemotherapy. It seems that the immunodeficiency inherent to CLL influences outcomes to a larger degree than does the treatment. Glucocorticoids are not associated with significant OS improvement whereas anti-cytokine compounds usage seemed to be beneficial in patients with mild pulmonary involvement. Our data attest to the necessity of reorganizing health care for patients with CLL. Early administration of effective antiviral compounds and tailored vaccination protocols are warranted.

Oxidative Stress-Related Mechanisms in Schizophrenia Pathogenesis and New Treatment Perspectives.

Schizophrenia is recognized to be a highly heterogeneous disease at various levels, from genetics to clinical manifestations and treatment sensitivity. This heterogeneity is also reflected in the variety of oxidative stress-related mechanisms contributing to the phenotypic realization and manifestation of schizophrenia. At the molecular level, these mechanisms are supposed to include genetic causes that increase the susceptibility of individuals to oxidative stress and lead to gene expression dysregulation caused by abnormal regulation of redox-sensitive transcriptional factors, noncoding RNAs, and epigenetic mechanisms favored by environmental insults. These changes form the basis of the prooxidant state and lead to altered redox signaling related to glutathione deficiency and impaired expression and function of redox-sensitive transcriptional factors (Nrf2, NF-κB, FoxO, etc.). At the cellular level, these changes lead to mitochondrial dysfunction and metabolic abnormalities that contribute to aberrant neuronal development, abnormal myelination, neurotransmitter anomalies, and dysfunction of parvalbumin-positive interneurons. Immune dysfunction also contributes to redox imbalance. At the whole-organism level, all these mechanisms ultimately contribute to the manifestation and development of schizophrenia. In this review, we consider oxidative stress-related mechanisms and new treatment perspectives associated with the correction of redox imbalance in schizophrenia. We suggest that not only antioxidants but also redox-regulated transcription factor-targeting drugs (including Nrf2 and FoxO activators or NF-κB inhibitors) have great promise in schizophrenia. But it is necessary to develop the stratification criteria of schizophrenia patients based on oxidative stress-related markers for the administration of redox-correcting treatment.

Putative TAAR5 agonist alpha-NETA affects event-related potentials in oddball paradigm in awake mice.

Trace amines have been reported to be neuromodulators of monoaminergic systems. Trace amines receptor 5 (TAAR5) is expressed in several regions of mice central nervous system, such as amygdala, arcuate nucleus and ventromedial hypothalamus, but very limited information is available on its functional role. The purpose of this study is to examine the effect of TAAR5 agonist alpha-NETA on the generation of mismatch negativity (MMN) analogue in C57BL/6 mice. Event-related potentials have been recorded from awake mice in oddball paradigms before and after the alpha-NETA administration. Alpha-NETA has been found to decrease N40 MMN-like difference, which resulted from the increased response to standard stimuli. An opposite effect has been found for the P80 component: the amplitude increased in response both to standard and deviant stimuli. A significant increase in N40 peak latency after the alpha-NETA administration has been found. This may suggest a reduced speed of information processing similar to the increase in P50 and N100 components latencies in schizophrenia patients. These results provide new evidence for a role of TAAR5 in cognitive processes.

Platelet function and bleeding in chronic lymphocytic leukemia and mantle cell lymphoma patients on ibrutinib.

BACKGROUND: Therapy with irreversible Bruton's tyrosine kinase inhibitor ibrutinib in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) is associated with bleeding. OBJECTIVES: To propose the predictive markers of such bleeding, as well as mechanisms responsible for decreased bleeding at later therapy stages. PATIENTS/METHODS: We investigate platelet functional activity in 50 CLL and 16 MCL patients on ibrutinib using flow cytometry and light transmission aggregometry. RESULTS: Prior to treatment, both patient groups had decreased platelet counts; impaired aggregation with adenosine diphosphate (ADP); and decreased binding of CD62P, PAC1, and annexin V upon stimulation. Bleeding in patients treated with ibrutinib was observed in 28 (56%) CLL patients, who had decreased aggregation with ADP and platelet count before therapy. Their platelet count on therapy did not change, platelet aggregation with ADP steadily improved, and aggregation with collagen first decreased and then increased in anticorrellation with bleeding. Bleeding in MCL was observed in 10 (62%) patients, who had decreased dense granule release before therapy. ADP and ristocetin induced platelet aggregation in ibrutinib-treated MCL patients increased on therapy, while collagen-induced aggregation evolved similarly to CLL patients. CONCLUSIONS: Our results suggest that ibrutinib-dependent bleeding in CLL patients involves three mechanisms: decreased platelet count (the most important discriminator between bleeding and non-bleeding patients), impaired platelet response to ADP caused by CLL, and inhibition by ibrutinib. Initially, ibrutinib shifts the balance to bleeding, but then it is restored because of the improved response to ADP.

Trace Amine-Associated Receptor 1 Agonist Modulates Mismatch Negativity-Like Responses in Mice.

The trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor widely expressed in the mammalian brain, particularly in limbic system and monoaminergic areas. It has proven to be an important modulator of dopaminergic, serotoninergic, and glutamatergic neurotransmission and is considered to be a potential useful target for the pharmacotherapy of neuropsychiatric disorders, including schizophrenia. One of the promising schizophrenia endophenotypes is a deficit in neurocognitive abilities manifested as mismatch negativity (MMN) deficit. This study examines the effect of TAAR1 partial agonist RO5263397 on the MMN-like response in freely moving C57BL/6 mice. Event-related potentials (ERPs) were recorded from awake mice in the oddball paradigm before and after RO5263397 administration. The RO5263397 (but not saline) administration increased the N40 amplitude in response to deviant stimuli. That provided the MMN-like difference at the 36-44 ms interval after the injection. The pitch deviance-elicited changes before the injection and in the control paradigm were established for the P68 component. After TAAR1 agonist administration the P68 amplitude in response both to standard and deviant stimuli was increased. These results suggest that the MMN-like response in mice may be modulated through TAAR1-dependent processes (possibly acting through the direct or indirect glutamate NMDA receptor modulation), indicating the TAAR1 agonists potential antipsychotic and pro-cognitive activity.

Effect of trace amine-associated receptor 1 agonist RO5263397 on sensory gating in mice.

The trace amine-associated receptor 1 (TAAR1) agonist RO5263397 effect on sensory gating in C57BL/6 mice was studied. Sensory gating is a mechanism for dosing and filtering the incoming information, by which the brain regulates the responses to sensory stimuli coming from the environment. Sensory gating deficit is considered to be one of the schizophrenia endophenotypes. TAAR1 agonist at a 1 mg/kg dosage contributed to the sensory gating index (S1-S2) increase. Sensory gating index rose due to the N40 amplitude increase in response to the first stimulus in a pair, whereas the amplitude of the second stimulus remained unchanged. These results suggest that the sensory gating in mice may be modulated through TAAR1-dependent processes, indicating potential contribution of TAAR1 and trace amines in general to the neuropharmacology of cognitive processes.

Effect of alpha-NETA on auditory event related potentials in sensory gating study paradigm in mice.

The potential contribution of trace amines (TA) to the pathophysiology of neuropsychiatric disorders makes it interesting to examine the effect of TA receptor ligands on schizophrenia biomarkers. We studied the effect of systemic administration of a putative Trace Amine-Associated Receptor 5 (TAAR5) agonist, alpha-NETA (2-(alpha-naphthoyl) ethyltrimethylammonium iodide), on the amplitude of the N40 event related potentials component and on the sensory gating (SG) index in C57BL/6 mice. It was found that low doses of alpha-NETA (2.5 mg/kg and 5 mg/kg) do not elicit a significant effect on the parameters of the N40 component and the SG index. However, the higher dose of alpha-NETA (10 mg/kg) induces a significant effect on the N40 component, but since a decrease in amplitude is observed on both the first and second stimuli in the pair, the SG index does not change. Thus, alpha-NETA administration causes a steady decrease in the N40 amplitude in response to both the first and second stimuli in the paired-click paradigm, and an increase in the N40 peak latency.

TAAR5 receptor agonist affects sensory gating in rats.

Trace amines are structurally close to classical monoamines and dysregulation in trace amines and/or their receptors might contribute to pathology of mental disorders. The study was aimed to investigate the effect of recently identified Trace Amine-Associated Receptor 5 (TAAR5) agonist 2-(alpha-naphthoyl)ethyltrimethylammonium iodide (alpha-NETA) on sensory gating (SG) in awake freely moving rats. SG was studied in paired-click paradigm and SG index was calculated as difference in event related potentials component N40 amplitudes to the first and second stimulus in the pair. The 1 mg/kg dose of alpha-NETA as well as the control injection of saline had no significant effects on the SG index. However, higher doses of alpha-NETA (3 and 5 mg/kg) significantly decreased the SG index. The change in the SG index was mainly due to a decrease in the N40 amplitude, and the 5 mg/kg dose caused the N40 decrease both in response to the first and second stimulus in the pair. Thus, TAAR5 activation can influence SG, indicating the potential role of trace amines and TAAR5 in sensory information dosing.

Identification of TAAR5 Agonist Activity of Alpha-NETA and Its Effect on Mismatch Negativity Amplitude in Awake Rats.

Mismatch negativity (MMN) is a well-defined component of human event-related potentials that reflects the pre-attentive, stimulus-discrimination process and is associated with involuntary switching of attention. MMN-like responses detected in animal models provide an opportunity to investigate the neural mechanisms of this process that involves several neurotransmitter and neuromodulator systems. Trace amines are believed to play a significant role in neuromodulation of synaptic transmission. The present study aimed to determine the role of trace amine-associated receptor 5 (TAAR5) in the MMN-like response in rats. First, using a bioluminescence resonance energy transfer (BRET) cAMP biosensor, we performed unbiased screening of TAAR5 ligands from a commercially available compound library (661 compounds) and identified 2-(alpha-naphthoyl)ethyltrimethylammonium iodide (alpha-NETA) as a potent (EC50 150 nM) TAAR5 agonist. Then, we recorded auditory event-related potentials during an oddball paradigm in awake freely moving rats that were intraperitoneally injected with a vehicle or two doses of the putative TAAR5 agonist alpha-NETA. The MMN-like response was increased by alpha-NETA 3 mg/kg dose, but not by 1 mg/kg dose or 0.9% saline solution. These results suggest that the MMN-like response in rats may be modulated, at least in part, through TAAR5-dependent processes.

The Development of Muscle Fatigue Suppresses Auditory Sensory Gating (P50) during Sustained Contraction.

Our aim was to study the influence of fatigue development on sensory gating during a muscle load. The fatiguing task was sustained contraction of a handgrip dynamometer with 7 and 30% maximum voluntary contraction (MVC). The suppression of P50, an auditory event-related potential, was used as the sensory gating index in the paired-click paradigm with a 500 ms interstimulus interval; the difference between the P50 amplitudes of the first and the second stimuli of the pair was used as the sensory gating index. We found that the 30% MVC fatigue development strongly decreased sensory gating, sometimes totally suppressing it. We concluded that central fatigue impaired motor performance and strongly suppressed inhibitory processes, as shown by the decreased P50 amplitude to the second stimulus. Therefore, muscle central fatigue influences sensory gating, similar to schizophrenia spectrum disorders.