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Abstract: A growing body of evidence suggests that pro-inflammatory cytokines contribute to the pathogenesis of depression. Previously, it has been shown that cytokines (e.g. interferon-α therapy) induce major depression in humans. In addition, administration of the cytokine-inducer lipopolysaccharide (LPS) provokes anhedonia (i.e. the inability to experience pleasure) in rodents. Furthermore, serum pro-inflammatory cytokine levels are increased in depressed patients. Nevertheless, the etiology of cytokine-induced depression is largely unknown. Previously, it has been shown that selective serotonin re-uptake inhibitors decrease serum pro-inflammatory cytokine levels and that pro-inflammatory cytokines increase activity of the serotonin transporter (SERT). The purpose of this study was to explore the effect of partial and complete lack of the SERT in LPS-induced anhedonia assessed in the intracranial self-stimulation (ICSS) paradigm. A single intraperitoneal injection of LPS was used to induce a pro-inflammatory immune response in male serotonin transporter wild type (SERT+/+), heterozygous (SERT+/−) and knockout (SERT−/−) rats. Body weight and ICSS thresholds were measured daily. Although LPS reduced body weight in all genotypes, loss of body weight was less pronounced in SERT−/− compared to SERT+/+ rats. Remarkably, LPS-induced anhedonia was totally abolished in SERT−/− rats and as expected was still present in SERT+/+ and to a lesser extent in SERT+/− rats. Therefore, it is concluded that an intact SERT function is needed for pro-inflammatory cytokine-induced anhedonia and weight loss in rats. [Copyright &y& Elsevier]

Abstract: The first line of antidepressant treatment nowadays are selective serotonin reuptake inhibitors. Although they are relatively safe to use, selective serotonin reuptake inhibitors (SSRIs) can induce severe side effects. New promising antidepressants may be the triple monoamine reuptake inhibitors, which not only enhance serotonin and norepinephrine neurotransmission, but also increase brain dopamine levels. Recently it has been shown that one of the triple reuptake inhibitors, DOV 216,303 has antidepressant-like effects in the olfactory bulbectomy (OBX) model of depression, but the alterations in monoaminergic neurotransmission in these animals are still unknown. In the present study we investigated not only the effect of acute, but also chronic treatment of DOV 216,303 in OBX rats on monoamine and metabolite levels. The main results are decreased baseline dopamine levels in the prefrontal cortex one day after OBX, while 38days after OBX no difference could be observed in monoamine levels after vehicle treatment. Treatment with DOV 216,303 leads to increased extracellular levels of serotonin and norepinephrine neurotransmission, but also increased dopamine levels in OBX animals as well as their controls. This increase could be observed after one single administration, but also after chronic treatment. However, a DOV 216,303 challenge in chronically treated animals resulted in lower monoamine concentrations than the same challenge in untreated animals. More research is needed to investigate this seemingly hyporesponsivity to chronic DOV 216,303 treatment. [Copyright &y& Elsevier]

Background Current approaches for accurate blood pressure determination rely predominantly on invasive techniques. High Definition Oscillometry (HDO) was evaluated as a potential non-invasive approach for accurate blood pressure recordings in cynomolgus monkeys. Methods In conscious animals, systolic, diastolic, mean arterial blood pressure (MAP) and pulse/minute were determined 15 times within approx. 9 minutes per individual. This session was performed during 3 consecutive days. Anaesthesia induced hypotension was controlled simultaneously with HDO and telemetry as reference. Results Repeated measurements were highly reproducible. After procedural habituation, mean MAP was 96.2 ± 13.7 mmHg in males and 86.9 ± 4.3 mmHg in females. Mean intraindividual coefficients of variation ranged between 10.8% and 2.4% depending on the session and parameter. Values determined by HDO corresponded to those reported for invasive techniques. Conclusion Our results demonstrate, using telemetry as reference, the accuracy of HDO-based non-invasive blood pressure measurements in macaques to detect drug-related cardiovascular changes. [ABSTRACT FROM AUTHOR]

Abstract: Activity-based anorexia (ABA) is considered an animal model for anorexia nervosa (AN). By scheduled feeding and voluntary wheel running, it mimics severe body weight loss and increased physical activity in AN. Pharmacological, genetic and imaging studies implicate dopamine and serotonin in the regulation of feeding behavior, food-anticipatory activity, and food reward. Previous studies propose that the nucleus accumbens (NAc) plays an important role in these food-related processes. Here we determined dopamine and serotonin levels in the NAc upon exposure to the ABA model. Surprisingly, the release of dopamine and serotonin in the NAc were not increased during the initiation of food-anticipatory behavior in ABA rats. Dopamine release in the NAc was increased during feeding behavior in ABA rats. During ABA, levels of serotonin were low and circadian activity is blunted. We conclude that during the early stages of development of food-anticipatory activity, increased dopamine does not trigger hyperactivity. [Copyright &y& Elsevier]

Acute tryptophan depletion (ATD) transiently lowers central serotonin levels and can induce depressive mood states and cognitive defects. Previous studies have shown that ATD impairs object recognition in rats. As individual differences exist in central serotonin neurotransmission, the impact of ATD may vary accordingly. In this experiment, we investigated the hypothesis that male serotonin transporter knockout (SERT−/−), rats marked by a lower SERT function, are more vulnerable to the effects of ATD in an object recognition task than male wildtype (SERT+/+) and heterozygous (SERT+/−) rats. Twelve male SERT+/+, SERT+/−, and SERT−/− rats were treated with standard dose and low-dose ATD using a gelatine-based protein–carbohydrate mixture lacking tryptophan. In the control treatment, l-tryptophan was added to the mixture. Four hours after treatment, the rats were subjected to the object recognition task. In addition, the effects of ATD on plasma amino acid concentrations were measured, and concentrations of 5-HT and 5-HIAA were measured in the frontal cortex and hippocampus of these rats. Plasma TRP levels and central 5-HT and 5-HIAA levels were decreased in all genotypes after ATD, but effects were stronger in SERT−/− rats. The standard dose of ATD impaired object recognition in all genotypes. SERT−/− and SERT+/− rats were more vulnerable to low dose of ATD in the object recognition task compared to SERT+/+ rats. These results indicate a greater sensitivity to ATD in SERT−/− and SERT+/− rats, which may be related to stronger central depletion effects in these rats. [ABSTRACT FROM AUTHOR]

The article focuses on the recommendations for the registration of agents for the prevention and treatment of glucocorticoid-induced osteoporosis (GIOP) updated by the Group for the Respect of Ethics and Excellence in Science (GREEC). The update directed the design of clinical studies on the treatment of GIOP in postmenopausal women. Moreover, it aims to consider suitable recommendations for the registration of agents for use in GIOP in postmenopausal women, men, and premenopausal women.

Abstract: In anxiety research, the search for models with sufficient clinical predictive validity to support the translation of animal studies on anxiolytic drugs to clinical research is often challenging. This review describes the stress-induced hyperthermia (SIH) paradigm, a model that studies the activation of the autonomic nervous system in response to stress by measuring body temperature. The reproducible and robust SIH response, combined with ease of testing, make the SIH paradigm very suitable for drug screening. We will review the current knowledge on the neurobiology of the SIH response, discuss the role of GABAA and serotonin (5-HT) pharmacology, as well as how the SIH response relates to infectious fever. Furthermore, we will present novel data on the SIH response variance across different mice and their sensitivity to anxiolytic drugs. The SIH response is an autonomic stress response that can be successfully studied at the level of its physiology, pharmacology, neurobiology and genetics and possesses excellent animal-to-human translational properties. [Copyright &y& Elsevier]

Adherence to anti-osteoporosis medications is currently low and is associated with poor anti-fracture efficacy. This manuscript reviews the potential design of clinical studies that aim to demonstrate improved adherence, with new chemical entities to be used in the management of osteoporosis. Several medications have been unequivocally shown to decrease fracture rates in clinical trials. However, in real life settings, long-term persistence and compliance to anti-osteoporosis medication is poor, hence decreasing the clinical benefits for patients. An extensive search of Medline from 1985 to 2006 retrieved all trials including the keywords osteoporosis, compliance, persistence or adherence followed by a critical appraisal of the data obtained through a consensus expert meeting. The impact of non-adherence on the clinical development of interventions is reviewed, so that clinicians, regulatory agencies and reimbursement agencies might be better informed of the problem, in order to stimulate the necessary research to document adherence. Adherence to therapy is a major problem in the treatment of osteoporosis. Both patients and medication factors are involved. Adherence studies are an important aspect of outcomes studies, but study methodologies are not well developed at the moment and should be improved. Performing adherence studies will be stimulated when registration authorities accept the result of these studies and include the relevant information in Sect. 5.1 of the summary of product characteristics. Reimbursement authorities might also consider such studies as important information for decisions on reimbursement. [ABSTRACT FROM AUTHOR]

Abstract: In order to study mechanisms involved in the etiology of human affective disorders, there is an abundant use of various animal models. Next to genetic factors that predispose for psychopathologies, environmental stress is playing an important role in the etiology of these mental diseases. Since the majority of stress stimuli in humans that lead to psychopathology are of social nature, the study of consequences of social stress in experimental animal models is very valuable. The present review focuses on one of these models that uses the resident-intruder paradigm. In particular the long-lasting effects of social defeat in rats will be evaluated. Data from our laboratory on the consequences of social defeat on emotional behavior, stress responsivity and serotonergic functionality are presented. Furthermore, we will go into detail on hippocampal functioning in socially stressed rats. Very recent results show that there is a differential effect of a brief double social defeat and repetitive social defeat stress on dendritic remodeling in hippocampal CA3 neurons and that this has repercussions on hippocampal LTP and LTD. Both the structural and electrophysiological changes of principal neurons in the hippocampal formation after defeat are discussed as to their relationship with the maintenance in cognitive performance that was observed in socially stressed rats. The results are indicative of a large dynamic range in the adaptive plasticity of the brain, allowing the animals to adapt behaviorally to the previously occurred stressful situation with the progression of time. [Copyright &y& Elsevier]

Juvenile idiopathic arthritis (JIA) represents joint inflammation with an unknown cause that starts before the age of 16, resulting in stiff and painful joints. In addition, JIA patients often report symptoms of sickness behavior. Recent animal studies suggest that proinflammatory cytokines produce sickness behavior by increasing the activity of indoleamine-2,3-dioxygenase (IDO) and guanosinetriphosphate–cyclohydrolase-1 (GTP–CH1). Here, it is hypothesized that inflammation in JIA patients enhances the enzymatic activity of IDO and GTP-CH1 and decreases the co-factor tetrahydrobiopterin (BH4). These compounds play a crucial role in the synthesis and metabolism of neurotransmitters. The aim of our study was to reveal whether inflammation affects both the GTP-CH1 and IDO pathway in JIA patients. Serum samples were collected from twenty-four JIA patients. In these samples, the concentrations of tryptophan (TRP), kynurenine (KYN), tyrosine (TYR), neopterin, and phenylalanine (PHE) were measured. An HPLC method with electrochemical detection was developed to quantify tryptophan, kynurenine, and tyrosine. Neopterin and phenylalanine were quantified by ELISA. The KYN/TRP ratio was measured as an index of IDO activity, while the PHE/TYR ratio was measured as an index of BH4 activity. Neopterin concentrations were used as an indirect measure of GTP-CH1 activity. JIA patients with high disease activity showed higher levels of both neopterin and kynurenine, and a higher ratio of both KYN/TRP and PHE/TYR and lower tryptophan levels than clinically inactive patients. Altogether, these data support our hypothesis that inflammation increases the enzymatic activity of both IDO and GTP-CH1 but decreases the efficacy of the co-factor BH4. In the future, animal studies are needed to investigate whether inflammation-induced changes in these enzymatic pathways and co-factor BH4 lower the levels of the brain neurotransmitters glutamate, noradrenaline, dopamine, serotonin, and melatonin, and consequently, whether they may affect fatigue, cognition, anxiety, and depression. Understanding of these complex neuroimmune interactions provides new possibilities for Pharma-Food interventions to improve the quality of life of patients suffering from chronic inflammation. [ABSTRACT FROM AUTHOR]

A correction to the article "Mapping Quantitative Trait Loci Affecting Feather Pecking Behavior and Stress Response in Laying Hens" that was published in the 2003 issue is presented.

Mammals typically heal with fibrotic scars, and treatments to regenerate human skin and hair without a scar remain elusive. We discovered that mice lacking C-X-C motif chemokine receptor 2 (CXCR2 knockout [KO]) displayed robust and complete tissue regeneration across three different injury models: skin, hair follicle, and cartilage. Remarkably, wild-type mice receiving plasma from CXCR2 KO mice through parabiosis or injections healed wounds scarlessly. A comparison of circulating proteins using multiplex ELISA revealed a 24-fold higher plasma level of granulocyte colony stimulating factor (G-CSF) in CXCR2 KO blood. Local injections of G-CSF into wild-type (WT) mouse wound beds reduced scar formation and increased scarless tissue regeneration. G-CSF directly polarized macrophages into an anti-inflammatory phenotype, and both CXCR2 KO and G-CSF-treated mice recruited more anti-inflammatory macrophages into injured areas. Modulating macrophage activation states at early time points after injury promotes scarless tissue regeneration and may offer a therapeutic approach to improve healing of human skin wounds., Competing Interests: Declaration of interests A provisional patent has been filed with the US Patent and Trademark Office regarding CXCR2, G-CSF, and NETosis on reducing scar formation and promoting tissue regeneration., (Published by Elsevier Inc.)

Patients with B-cell lymphomas have altered cellular components of vaccine responses due to malignancy and therapy, and the optimal timing of vaccination relative to therapy remains unknown. Severe acute respiratory syndrome coronavirus 2 vaccines created an opportunity for new insights in vaccine timing because patients were challenged with a novel antigen across multiple phases of treatment. We studied serologic messenger RNA vaccine response in retrospective and prospective cohorts with lymphoma and chronic lymphocytic leukemia, paired with clinical and research immune parameters. Reduced serologic response was observed more frequently during active treatment, but nonresponse was also common within observation and posttreatment groups. Total immunoglobulin A and immunoglobulin M correlated with successful vaccine response. In individuals treated with anti-CD19-directed chimeric antigen receptor-modified T cells, nonresponse was associated with reduced B and T follicular helper cells. Predictors of vaccine response varied by disease and therapeutic group, and therefore further studies of immune health during and after cancer therapies are needed to individualize vaccine timing., Competing Interests: Potential conflicts of interest. E. A. C. receives research support from Genentech/Roche and AbbVie and has served as a consultant for Beigene, AstraZeneca, and TG Therapeutics. J. S. has served as a consultant for ATARA, AstraZeneca, Celgene Corporation, Adaptive, and Genmab, and receives research support from AstraZeneca, Merck, Incyte, Bristol-Myers Squibb, Pharmacyclics, TG Therapeutics, Seattle Genetics, and Adaptive. S. K. B. received honoraria from Acrotech, Seagen, Kyowa Kirin, and Daiichi Sankyo. S. D. N. receives research support from Roche, Rafael, ATARA, Pharmacyclics, and Takeda/Millennium; is a data monitoring committee member for Merck; and has served as a consultant for Epizyme and Morphosys. D. J. L. received research funding from Curis and Triphase; is a data and safety monitoring board member for Karyopharm; and has served as a consultant for Morphosys/Incyte, Epizyme, and ADC Therapeutics. J. N. G. received research funding from Loxo and has served as a consultant for Genentech, AbbVie, and Kite. E. L. P. received funding from Roche Diagnostics Corporation for the evaluation of serologic tests for SARS-CoV-2. E. J. W. is consulting or is an advisor for Merck, Marengo, Janssen, Related Sciences, Synthekine, and Surface Oncology; is a founder of Surface Oncology, Danger Bio, and Arsenal Biosciences; and is an inventor on a patent (US patent number 10,370,446) submitted by Emory University that covers the use of PD-1 blockade to treat infections and cancer. S. J. S. reports research funding from Acerta, Celgene, Genentech/Roche, Merck, Novartis, Pharmacyclics, and TG Therapeutics; received honoraria/consulting fees from Acerta, AstraZeneca, Celgene, Incyte, Janssen, Loxo Oncology, Morphosys, and Nordic Nanovector; is a steering committee member for Celgene, Nordic Nanovector, and Novartis; and has a patent for combination therapies of CAR T cells and PD-1 inhibitors. M. R. holds patents related to CAR T cells; has served as a consultant for nanoString, BMS, GSK, Bayer, Sana Therapeutics, and AbClon; receives research funding from AbClon, nanoString, viTToria biotherapeutics, Oxford Nanoimaging, and Beckman Coulter; and is the scientific founder of viTToria Biotherapeutics. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Recent studies have examined the relations between the slope of pleasure experienced during exercise and remembered pleasure, forecasted pleasure, and enjoyment., Objectives: This study advances this line of research by examining the effects of exposing participants to exercise that increases in intensity and then decreases in intensity., Methods: In a within-subjects design, participants completed three exercise sessions matched for total and average work. One session steadily increased in intensity, another steadily decreased in intensity, and a third increased-then-decreased in intensity. Remembered pleasure, forecasted pleasure, and exercise enjoyment served as primary outcome variables., Results: Remembered pleasure, forecasted pleasure, and enjoyment did not differ between conditions. Remembered pleasure was positively associated with mean experienced pleasure, the overall slope of pleasure during the exercise session, affect experienced at the end of exercise, forecasted pleasure, accomplishment, and enjoyment., Conclusions: These data add to a growing literature on the effects of patterns of exercise intensity on affective responses to exercise. The results are discussed in context of previous and more recent research., Competing Interests: Declaration of competing interest There is no competing interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Direct delivery of therapeutics to the central nervous system (CNS) greatly expands opportunities to treat neurological diseases but is technically challenging. This opinion outlines principal technical aspects of direct CNS delivery via intracerebroventricular (ICV) or intrathecal (IT) injection to common nonclinical test species (rodents, dogs, and nonhuman primates) and describes procedure-related clinical and histopathological effects that confound interpretation of test article-related effects. Direct dosing is by ICV injection in mice due to their small body size, while other species are dosed IT in the lumbar cistern. The most frequent procedure-related functional effects are transient absence of lower spinal reflexes after IT injection or death soon after ICV dosing. Common procedure-related microscopic findings in all species include leukocyte infiltrates in CNS meninges or perivascular (Virchow-Robin) spaces; nerve fiber degeneration in the spinal cord white matter (especially dorsal and lateral tracts compressed by dosing needles or indwelling catheters), spinal nerve roots, and sciatic nerve; meningeal fibrosis at or near IT injection sites; hemorrhage; and gliosis. Findings typically are minimal to occasionally mild. Findings tend to be more severe and/or have a higher incidence in the spinal cord segments and spinal nerve roots at or close to the site of administration., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The healthcare needs of lesbian, gay, bisexual, trans*, queer, and intersex (LGBTQI+) persons are often overlooked, prompting national and international calls to include diversity-related competencies into medical students' training. However, LGBTQI+-focused healthcare education targets remain elusive, as surveys reveal considerable variability across national student populations. To generate empirical data and vocalize recommendations for medical education, we conducted the first nationwide online survey among 670 German medical students from 33 universities. Overall, most respondents reported low confidence regarding their medical training preparing them for LGBTQI+ patients, stated that LGBTQI+ themes were not covered during training, and agreed that the inclusion of such themes is urgently needed. In addition, we found gender and LGBTQI+ community member status to be key variables. Men scored lower in knowledge than women, while community members scored higher than non-community members. Similarly, community members reported higher comfort levels. Non-community men showed the highest levels of prejudice and efficacy beliefs, while at the same time had the lowest scores in contacts and the perceived importance of LGBTQI+-related teaching. Keeping subgroup differences in mind, we recommend that educational training should include LGBTQI+ healthcare aspects and address self-efficacy beliefs in future medical professionals to overcome LGBTQI+ healthcare disparities.

A university setting offers a unique opportunity to address physical activity for individuals with disabilities. The purpose of this case series was to highlight the development of a formal student-assisted exercise program and examine its impact on the perceived quality of life, exercise confidence, and functional mobility of college-aged individuals with intellectual and physical disabilities. Data from twelve participants was analyzed. Seven participants demonstrated an improvement in scores on the Self-Efficacy to Exercise scale and eight improved in functional measures associated with strength. Thus, a collaborative assisted exercise program in a university setting may positively impact health and physical activity, and exercise participation in young adults with physical and/or intellectual disabilities., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2022 The Author(s).)

We examined antibody and memory B cell responses longitudinally for ∼9-10 months after primary 2-dose SARS-CoV-2 mRNA vaccination and 3 months after a 3rd dose. Antibody decay stabilized between 6 and 9 months, and antibody quality continued to improve for at least 9 months after 2-dose vaccination. Spike- and RBD-specific memory B cells remained durable over time, and 40%-50% of RBD-specific memory B cells simultaneously bound the Alpha, Beta, Delta, and Omicron variants. Omicron-binding memory B cells were efficiently reactivated by a 3rd dose of wild-type vaccine and correlated with the corresponding increase in neutralizing antibody titers. In contrast, pre-3rd dose antibody titers inversely correlated with the fold-change of antibody boosting, suggesting that high levels of circulating antibodies may limit the added protection afforded by repeat short interval boosting. These data provide insight into the quantity and quality of mRNA-vaccine-induced immunity over time through 3 or more antigen exposures., Competing Interests: Declaration of interests S.E.H. has received consultancy fees from Sanofi Pasteur, Lumen, Novavax, and Merck for work unrelated to this study. A.R.G. is a consultant for Relation Therapeutics. E.J.W. is consulting for or is an advisor for Merck, Marengo, Janssen, Related Sciences, Synthekine, and Surface Oncology. E.J.W. is a founder of Surface Oncology, Danger Bio, and Arsenal Biosciences., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The capability of the adult central nervous system to self-repair/regenerate was demonstrated repeatedly throughout the last decades but remains in debate. Reduced neurogenic niche activity paralleled by a profound neuronal loss represents fundamental hallmarks in the disease course of neurodegenerative disorders. We and others have demonstrated the endogenous TGFβ system to represent a potential pathogenic participant in disease progression, of amyotrophic lateral sclerosis (ALS) in particular, by generating and promoting a disequilibrium of neurodegenerative and neuroregenerative processes. The novel human/primate specific LNA Gapmer Antisense Oligonucleotide "NVP-13", targeting TGFBR2, effectively reduced its expression and lowered TGFβ signal transduction in vitro and in vivo, paralleled by boosting neurogenic niche activity in human neuronal progenitor cells and nonhuman primate central nervous system. Here, we investigated NVP-13 in vivo pharmacology, safety, and tolerability following repeated intrathecal injections in nonhuman primate cynomolgus monkeys for 13 weeks in a GLP-toxicology study approach. NVP-13 was administered intrathecally with 1, 2, or 4 mg NVP-13/animal within 3 months on days 1, 15, 29, 43, 57, 71, and 85 in the initial 13 weeks. We were able to demonstrate an excellent local and systemic tolerability, and no adverse events in physiological, hematological, clinical chemistry, and microscopic findings in female and male Cynomolgus Monkeys. Under the conditions of this study, the no observed adverse effect level (NOAEL) is at least 4 mg/animal NVP-13.

The durability of immune memory after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccination remains unclear. In this study, we longitudinally profiled vaccine responses in SARS-CoV-2–naïve and –recovered individuals for 6 months after vaccination. Antibodies declined from peak levels but remained detectable in most subjects at 6 months. By contrast, mRNA vaccines generated functional memory B cells that increased from 3 to 6 months postvaccination, with the majority of these cells cross-binding the Alpha, Beta, and Delta variants. mRNA vaccination further induced antigen-specific CD4 + and CD8 + T cells, and early CD4 + T cell responses correlated with long-term humoral immunity. Recall responses to vaccination in individuals with preexisting immunity primarily increased antibody levels without substantially altering antibody decay rates. Together, these findings demonstrate robust cellular immune memory to SARS-CoV-2 and its variants for at least 6 months after mRNA vaccination.

SARS-CoV-2 mRNA vaccines have shown remarkable clinical efficacy, but questions remain about the nature and kinetics of T cell priming. We performed longitudinal antigen-specific T cell analyses on healthy SARS-CoV-2-naive and recovered individuals prior to and following mRNA prime and boost vaccination. Vaccination induced rapid antigen-specific CD4 + T cell responses in naive subjects after the first dose, whereas CD8 + T cell responses developed gradually and were variable in magnitude. Vaccine-induced Th1 and Tfh cell responses following the first dose correlated with post-boost CD8 + T cells and neutralizing antibodies, respectively. Integrated analysis revealed coordinated immune responses with distinct trajectories in SARS-CoV-2-naive and recovered individuals. Last, whereas booster vaccination improved T cell responses in SARS-CoV-2-naive subjects, the second dose had little effect in SARS-CoV-2-recovered individuals. These findings highlight the role of rapidly primed CD4 + T cells in coordinating responses to the second vaccine dose in SARS-CoV-2-naive individuals., Competing Interests: Declaration of interests S.E.H. has received consultancy fees from Sanofi Pasteur, Lumen, Novavax, and Merk for work unrelated to this study. E.J.W. is a consultant or an adviser for Merck, Elstar, Janssen, Related Sciences, Synthekine, and Surface Oncology. E.J.W. is a founder of Surface Oncology and Arsenal Biosciences. E.J.W. is an inventor on a patent (U.S. Patent No. 10,370,446) submitted by Emory University that covers the use of PD-1 blockade to treat infections and cancer. A.S. is a consultant for Gritstone, Flow Pharma, CellCarta, Arcturus, Oxfordimmunotech, and Avalia. La Jolla Institute for Immunology has filed for patent protection for various aspects of T cell epitope and vaccine design work., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Policymakers aim to move toward animal-free alternatives for scientific research and have introduced very strict regulations for animal research. We argue that, for neuroscience research, until viable and translational alternatives become available and the value of these alternatives has been proven, the use of animals should not be compromised., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Adult neurogenesis is a target for brain rejuvenation as well as regeneration in aging and disease. Numerous approaches showed efficacy to elevate neurogenesis in rodents, yet translation into therapies has not been achieved. Here, we introduce a novel human TGFβ-RII (Transforming Growth Factor-Receptor Type II) specific LNA-antisense oligonucleotide ("locked nucleotide acid"-"NVP-13"), which reduces TGFβ-RII expression and downstream receptor signaling in human neuronal precursor cells (ReNcell CX® cells) in vitro. After we injected cynomolgus non-human primates repeatedly i.th. with NVP-13 in a preclinical regulatory 13-week GLP-toxicity program, we could specifically downregulate TGFβ-RII mRNA and protein in vivo. Subsequently, we observed a dose-dependent upregulation of the neurogenic niche activity within the hippocampus and subventricular zone: human neural progenitor cells showed significantly (up to threefold over control) enhanced differentiation and cell numbers. NVP-13 treatment modulated canonical and non-canonical TGFβ pathways, such as MAPK and PI3K, as well as key transcription factors and epigenetic factors involved in stem cell maintenance, such as MEF2A and pFoxO3. The latter are also dysregulated in clinical neurodegeneration, such as amyotrophic lateral sclerosis. Here, we provide for the first time in vitro and in vivo evidence for a novel translatable approach to treat neurodegenerative disorders by modulating neurogenesis., (© 2021. The Author(s).)

The University of Missouri (MU) has established a colony of dystrophin-deficient dogs with a mixed breed background to mirror the variable pathologic effects of dystrophinopathies between persons of a given kindred to further the understanding of the genetic and molecular basis of the variable phenotype; thus to facilitate discovery of an effective therapeutic strategy. Herein we report the phenotype and genotype of a normal-appearing 10-month-old colony female that died suddenly. At necropsy examination, there were reduced skeletal and laryngeal muscle volume and mild dilatation of the oesophagus. Microscopic findings consisted of extensive degeneration and regeneration of the axial skeletal, tongue, oesophageal, and laryngeal muscles that were characterized by considerable central nucleation, individual fibre mineralization and interstitial fibrosis. The myocardial findings were limited to infiltration of adipose cells in the interstitium. The female dog was a compound heterozygote with one X chromosome carrying a point mutation in intron 6 of the dystrophin gene and the other X chromosome carrying a repetitive element insertion in intron 13 of the dystrophin gene. Although the direct cause of death was uncertain, it might likely be due to sudden cardiac death as has been seen in Duchenne muscular dystrophy patients. This case demonstrated dystrophinopathy in female dogs that have no ameliorating normal X chromosome., (© 2021 The Authors Veterinary Medicine and Science Published by John Wiley & Sons Ltd.)

Novel mRNA vaccines for SARS-CoV-2 have been authorized for emergency use. Despite their efficacy in clinical trials, data on mRNA vaccine-induced immune responses are mostly limited to serological analyses. Here, we interrogated antibody and antigen-specific memory B cells over time in 33 SARS-CoV-2 naïve and 11 SARS-CoV-2 recovered subjects. SARS-CoV-2 naïve individuals required both vaccine doses for optimal increases in antibodies, particularly for neutralizing titers against the B.1.351 variant. Memory B cells specific for full-length spike protein and the spike receptor binding domain (RBD) were also efficiently primed by mRNA vaccination and detectable in all SARS-CoV-2 naive subjects after the second vaccine dose, though the memory B cell response declined slightly with age. In SARS-CoV-2 recovered individuals, antibody and memory B cell responses were significantly boosted after the first vaccine dose; however, there was no increase in circulating antibodies, neutralizing titers, or antigen-specific memory B cells after the second dose. This robust boosting after the first vaccine dose strongly correlated with levels of pre-existing memory B cells in recovered individuals, identifying a key role for memory B cells in mounting recall responses to SARS-CoV-2 antigens. Together, our data demonstrated robust serological and cellular priming by mRNA vaccines and revealed distinct responses based on prior SARS-CoV-2 exposure, whereby COVID-19 recovered subjects may only require a single vaccine dose to achieve peak antibody and memory B cell responses. These findings also highlight the utility of defining cellular responses in addition to serologies and may inform SARS-CoV-2 vaccine distribution in a resource-limited setting., (Copyright © 2021, American Association for the Advancement of Science.)

Intrathecal (IT) dosing (ie, injection into the subarachnoidal space at the lumbar region) is a common route of administration in cynomolgus monkey preclinical safety studies conducted for antisense oligonucleotides (ASO) that target central nervous system diseases. Herein we report on neurological signs that have been observed in 28 IT studies conducted in 1,016 cynomolgus monkeys. Neurological signs were classified into 5 groups: (1) A nonadverse transient absence of lower spinal reflexes. This observation occurred at low incidence in nontreated animals and in those that were injected artificial cerebrospinal fluid. The incidence increased in animals that were injected an ASO. Reflexes were present again at 24 hours or 48 hours after dosing. The incidence appeared to increase with dose. (2) Test-article-related adverse muscle tremor or muscle spasticity occurring during the injection procedure or immediately thereafter. In one-third of animals this finding responded to treatment with diazepam, in two-third it required euthanasia. (3) Neurological findings occurring between 30 minutes and 4 hours after dosing were characterized by any combination of ataxia, paresis, nystagmus, urinary incontinence, or muscle tremor. Those conditions either spontaneously resolved or they slowly worsened, eventually resulting in a poor general condition. (4) Neurological findings due to spinal cord injury were characterized by rapidly progressing paralysis of hind limbs. Magnetic resonance imaging revealed a focal hyperintense lesion, indicative of spinal cord necrosis. (5) Test-article-related adverse hind limb paresis or paralysis that occurred between 2 and 18 days after dosing. Those findings were rare and resulted in a poor general condition requiring euthanasia.

Many potential drugs for treatment of neurodegenerative diseases, particularly antisense oligonucleotides (ASOs), are administered via lumbar intrathecal injection, because these drugs do not cross the blood-brain barrier. Intrathecal injection is a well-established method in cynomolgus monkeys, a species that is used in preclinical safety assessment when other nonrodent species cannot be used. The authors completed intrathecal ASO administration in over 30 preclinical safety studies (>1000 animals and >4500 dose administrations) during which we observed 3 cases of procedure-related spinal cord necrosis (incidence <0.1%). We describe clinical symptoms, diagnostic approaches, morphological features, and prognosis of this rare injury, and compare these findings with typical drug-related findings of ASOs dosed by intrathecal injection. The low incidence of procedure-related and dose-limiting lesions confines this analysis to a small sample set. The pattern of effects is similar across all monkeys despite differences in age, body weight, and intrathecal injection site. All 3 cases presented a combination of the following findings: blood in cerebrospinal fluid at time of injection, clinical signs that increase in severity within a day of dosing, lameness of both hind limbs, reduced muscle tone, and loss of patellar, foot grip, and/or anal reflexes. In all cases, magnetic resonance imaging (MRI) showed a linear hyperintense lesion in the lumbar spinal cord. In 2 cases, this hyperintensity was associated with evidence of spinal cord edema. We conclude that a pattern of in-life and pathology findings, including noninvasive MRI assessment, is indicative of procedure-related effects.

Purpose: To compare the dosimetric performances of intensity-modulated proton therapy (IMPT) plans generated with two different beam angle configurations (the Right-Left oblique posterior beams and the Superior-Inferior oblique posterior beams) for the treatment of distal esophageal carcinoma in the presence of uncertainties and interplay effect., Methods and Materials: Twenty patients' IMPT plans were retrospectively selected, with 10 patients treated with the R-L oblique posterior beams (Group R-L) and the other 10 patients treated with the S-I oblique posterior beams (Group S-I). Patients in both groups were matched by their clinical target volumes (CTVs-high and low dose levels) and respiratory motion amplitudes. Dose-volume-histogram (DVH) indices were used to assess plan quality. DVH bandwidth was calculated to evaluate plan robustness. Interplay effect was quantified using four-dimensional (4D) dynamic dose calculation with random respiratory starting phase of each fraction. Normal tissue complication probability (NTCP) for heart, liver, and lung was calculated, respectively, to estimate the clinical outcomes. Wilcoxon signed-rank test was used for statistical comparison between the two groups., Results: Compared with plans in Group R-L, plans in Group S-I resulted in significantly lower liver D mean and lung V 30Gy[RBE] with slightly higher but clinically acceptable spinal cord D max . Similar plan robustness was observed between the two groups. When interplay effect was considered, plans in Group S-I performed statistically better for heart D mean and V 30Gy[RBE] , lung Dmean and V 5Gy[RBE] , and liver D mean , with slightly increased but clinically acceptable spinal cord D max . NTCP for liver was significantly better in Group S-I., Conclusions: IMPT plans in Group S-I have better sparing of liver, heart, and lungs at the slight cost of spinal cord maximum dose protection, and are more interplay-effect resilient compared to IMPT plans in Group R-L. Our study supports the routine use of the S-I oblique posterior beams for the treatments of distal esophageal carcinoma., (© 2020 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Today, inflammatory rheumatic disorders are effectively treated, but many patients still suffer from residual fatigue. This work presents pathophysiological mechanisms of fatigue. First, cytokines can interfere with neurotransmitter release at the preterminal ending. Second, a long-term increase in serum concentrations of proinflammatory cytokines increase the uptake and breakdown of monoamines (serotonin, noradrenaline and dopamine). Third, chronic inflammation can also decrease monoaminergic neurotransmission via oxidative stress (oxidation of tetrahydrobiopterin [BH4]). Fourth, proinflammatory cytokines increase the level of enzyme indoleamine-2, 3-dioxygenase activity and shunt tryptophan away from the serotonin pathway. Fifth, oxidative stress stimulates astrocytes to inhibit excitatory amino acid transporters. Sixth, astrocytes produce kynurenic acid that acts as an antagonist on the α7-nicotinic acetylcholine receptor to inhibit dopamine release. Jointly, these actions result in increased glutamatergic and decreased monoaminergic neurotransmission. The above-described pathophysiological mechanisms negatively affect brain functioning in areas that are involved in fatigue., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: Esophageal carcinoma is the eighth most common cancer in the world. Volumetric-modulated arc therapy (VMAT) is widely used to treat distal esophageal carcinoma due to high conformality to the target and good sparing of organs at risk (OAR). It is not clear if small-spot intensity-modulated proton therapy (IMPT) demonstrates a dosimetric advantage over VMAT. In this study, we compared dosimetric performance of VMAT and small-spot IMPT for distal esophageal carcinoma in terms of plan quality, plan robustness, and interplay effects., Methods: 35 distal esophageal carcinoma patients were retrospectively reviewed; 19 patients received small-spot IMPT and the remaining 16 of them received VMAT. Both plans were generated by delivering prescription doses to clinical target volumes (CTVs) on phase-averaged 4D-CT's. The dose-volume-histogram (DVH) band method was used to quantify plan robustness. Software was developed to evaluate interplay effects with randomized starting phases for each field per fraction. DVH indices were compared using Wilcoxon rank-sum test. For fair comparison, all the treatment plans were normalized to have the same CTV high D 95% in the nominal scenario relative to the prescription dose., Results: In the nominal scenario, small-spot IMPT delivered statistically significantly lower liver D mean and V 30Gy[RBE] , lung D mean , heart D mean compared with VMAT. CTV high dose homogeneity and protection of other OARs were comparable between the two treatments. In terms of plan robustness, the IMPT and VMAT plans were comparable for kidney V 18Gy[RBE] , liver V 30Gy[RBE] , stomach V 45Gy[RBE] , lung D mean , V 5Gy[RBE] , and V 20Gy[RBE] , cord D max and D 0.03 c m 3 , liver D mean , heart V 20Gy[RBE] , and V 30Gy[RBE] , but IMPT was significantly worse for CTV high D 95% , D 2 c m 3 , and D 5% -D 95% , CTV low D 95% , heart D mean , and V 40Gy[RBE] , requiring careful and experienced adjustments during the planning process and robustness considerations. The small-spot IMPT plans still met the standard clinical requirements after interplay effects were considered., Conclusions: Small-spot IMPT decreases doses to heart, liver, and total lung compared to VMAT as well as achieves clinically acceptable plan robustness. Our study supports the use of small-spot IMPT for the treatment of distal esophageal carcinoma., (© 2019 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

The charge transport through GaAs nanowires, partially p-doped and partially intrinsic, is analyzed by four-point resistance profiling along freestanding nanowires using a multip-STM. The charge transport channel in the undoped segment is assigned to the surface conductivity, while the interior of the nanowire is the conductance channel in the p-doped segment. The convoluted interplay between conduction through the interior of the nanowire and surface state conduction is studied in detail. Measurements of the I-V curves along the nanowires provide the experimental basis for the proposed charge transport model for the transition of the conduction from the interior to the surface of the nanowire. A voltage drop along the surface state conduction channel leads to an upward shift of the band edges at the surface. This results, for higher applied voltages, in the removal of the depletion layer and an opening of a conductance channel between the interior of the nanowire and the surface states.

In scanning tunneling microscopy, we witness in recent years a paradigm shift from "just imaging" to detailed spectroscopic measurements at the nanoscale and multi-tip scanning tunneling microscope (STM) is a technique following this trend. It is capable of performing nanoscale charge transport measurements like a "multimeter at the nanoscale." Distance-dependent four-point measurements, the acquisition of nanoscale potential maps at current carrying nanostructures and surfaces, as well as the acquisition of I - V curves of nanoelectronic devices are examples of the capabilities of the multi-tip STM technique. In this review, we focus on two aspects: How to perform the multi-tip STM measurements and how to analyze the acquired data in order to gain insight into nanoscale charge transport processes for a variety of samples. We further discuss specifics of the electronics for multi-tip STM and the properties of tips for multi-tip STM, and present methods for a tip approach to nanostructures on insulating substrates. We introduce methods on how to extract the conductivity/resistivity for mixed 2D/3D systems from four-point measurements, how to measure the conductivity of 2D sheets, and how to introduce scanning tunneling potentiometry measurements with a multi-tip setup. For the example of multi-tip measurements at freestanding vapor liquid solid grown nanowires, we discuss contact resistances as well as the influence of the presence of the probing tips on the four point measurements.

Purpose: To investigate how spot size and spacing affect plan quality, robustness, and interplay effects of robustly optimized intensity modulated proton therapy (IMPT) for lung cancer., Methods and Materials: Two robustly optimized IMPT plans were created for 10 lung cancer patients: first by a large-spot machine with in-air energy-dependent large spot size at isocenter (σ: 6-15 mm) and spacing (1.3 σ), and second by a small-spot machine with in-air energy-dependent small spot size (σ: 2-6 mm) and spacing (5 mm). Both plans were generated by optimizing radiation dose to internal target volume on averaged 4-dimensional computed tomography scans using an in-house-developed IMPT planning system. The dose-volume histograms band method was used to evaluate plan robustness. Dose evaluation software was developed to model time-dependent spot delivery to incorporate interplay effects with randomized starting phases for each field per fraction. Patient anatomy voxels were mapped phase-to-phase via deformable image registration, and doses were scored using in-house-developed software. Dose-volume histogram indices, including internal target volume dose coverage, homogeneity, and organs at risk (OARs) sparing, were compared using the Wilcoxon signed-rank test., Results: Compared with the large-spot machine, the small-spot machine resulted in significantly lower heart and esophagus mean doses, with comparable target dose coverage, homogeneity, and protection of other OARs. Plan robustness was comparable for targets and most OARs. With interplay effects considered, significantly lower heart and esophagus mean doses with comparable target dose coverage and homogeneity were observed using smaller spots., Conclusions: Robust optimization with a small spot-machine significantly improves heart and esophagus sparing, with comparable plan robustness and interplay effects compared with robust optimization with a large-spot machine. A small-spot machine uses a larger number of spots to cover the same tumors compared with a large-spot machine, which gives the planning system more freedom to compensate for the higher sensitivity to uncertainties and interplay effects for lung cancer treatments., (Copyright © 2018 Elsevier Inc. All rights reserved.)

We present a four-point probe resistance measurement technique which uses four equivalent current measuring units, resulting in minimal hardware requirements and corresponding sources of noise. Local sample potentials are measured by a software feedback loop which adjusts the corresponding tip voltage such that no current flows to the sample. The resulting tip voltage is then equivalent to the sample potential at the tip position. We implement this measurement method into a multi-tip scanning tunneling microscope setup such that potentials can also be measured in tunneling contact, allowing in principle truly non-invasive four-probe measurements. The resulting measurement capabilities are demonstrated for [Formula: see text] and [Formula: see text] samples.

Severe feather pecking (SFP) in chickens is a detrimental behaviour with possibly neurochemical deficits at its base. Recent neurological studies depicted conflicting results on the role of serotonin (5-hydroxytryptamine, 5-HT) and dopamine (DA) in the development and display of feather pecking. We studied brain monoamine levels and behaviour in domestic chickens divergently genetically selected on feather pecking behaviour, the Low Feather Pecking (LFP) and High Feather Pecking (HFP) lines, both at a young age and when adult, to elucidate the role of 5-HT and DA in feather pecking. Also pecking behaviour and the behavioural response to challenging test situations was determined. At 8 weeks of age, HFP had lower 5-HT and DA turnover in several brain areas than LFP, whereas these differences had disappeared or were even reversed at 25 weeks of age. Line differences in central monoamine activity were found both in emotion-regulating and motor-regulating areas. As expected from previous generations, HFP exceeded LFP in most types of pecking at other birds, including severe feather pecking. Furthermore, HFP responded more actively in most behavioural tests conducted, and seem more impulsive or (hyper)active in their way of coping with challenges. This paper shows different developmental trajectories of the neurochemical systems (5-HT and DA) for chickens divergently selected on feather pecking behaviour, and a remarkable reversion of differences in monoamine activity at a later stage of life. Whether this is a cause or consequence of SFP needs further investigation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

To safeguard patients, regulatory authorities require that new drugs that are to be given by the intravitreal (IVT) route are assessed for their safety in a laboratory species using the same route of administration. Due to the high similarity of ocular morphology and physiology between humans and nonhuman primates (NHPs) and due to the species specificity of many biotherapeutics, the monkey is often the only appropriate model. To this end, intravitreal administration and assessment of ocular toxicity are well established in cynomolgus monkeys ( Macaca fascicularis ). In contrast, the common marmoset monkey ( Callithrix jacchus ) is not a standard model for ocular toxicity studies due to its general sensitivity to laboratory investigations and small eye size. It was the purpose of the present work to study whether the marmoset is a useful alternative to the cynomolgus monkey for use in intravitreal toxicological studies. Six marmoset monkeys received repeated (every 2 weeks for a total of four doses) intravitreal injections of 10 or 20  µ L of a placebo. The animals were assessed for measurements of intraocular pressure (IOP), standard ophthalmological investigations and electroretinography (ERG). At the end of the dosing period, the animals were sacrificed and the eyes were evaluated histologically. ERG revealed similar results when comparing predose to end-of-study data, and there was no difference between the two dose volumes. A transient increase in the IOP was seen immediately after dosing, which was more pronounced after dosing of 20  µ L compared to 10  µ L. Ophthalmologic and microscopic observations did not show any significant changes. Therefore, it can be concluded that 10  µ L as well as 20  µ L intravitreal injections of a placebo are well tolerated in the marmoset. These results demonstrate that the common marmoset is an alternative to the cynomolgus monkey for intravitreal toxicity testing., Competing Interests: The authors declare that they have no conflict of interest., (Copyright: © 2017 Birgit Korbmacher et al.)

The 5-HT 1A/1B -receptor agonist eltoprazine has a behavioral drug signature that resembles that of a variety of psychostimulant drugs, despite the differences in receptor binding profile. These psychostimulants are effective in treating impulsivity disorders, most likely because they increase norepinephrine (NE) and dopamine (DA) levels in the prefrontal cortex. Both amphetamine and methylphenidate, however, also increase dopamine levels in the nucleus accumbens (NAc), which has a significant role in motivation, pleasure, and reward. How eltoprazine affects monoamine release in the medial prefrontal cortex (mPFC), the orbitofrontal cortex (OFC), and the NAc is unknown. It is also unknown whether eltoprazine affects different forms of impulsivity and brain reward mechanisms. Therefore, in the present study, we investigate the effects of eltoprazine in rats in the following sequence: 1) the activity of the monoaminergic systems using in vivo microdialysis, 2) motivation for reward measured using the intracranial self-stimulation (ICSS) procedure, and finally, 3) "waiting" impulsivity in the delay-aversion task, and the "stopping" impulsivity in the stop-signal task. The microdialysis studies clearly showed that eltoprazine increased DA and NE release in both the mPFC and OFC, but only increased DA concentration in the NAc. In contrast, eltoprazine decreased 5-HT release in the mPFC and NAc (undetectable in the OFC). Remarkably, eltoprazine decreased impulsive choice, but increased impulsive action. Furthermore, brain stimulation was less rewarding following eltoprazine treatment. These results further support the long-standing hypothesis that "waiting" and "stopping" impulsivity are regulated by distinct neural circuits, because 5-HT 1A/1B -receptor activation decreases impulsive choice, but increases impulsive action., (Copyright © 2016 Elsevier B.V. All rights reserved.)

This paper introduces the equivalent discrete-time channel model (EDTCM) to the area of diffusion-based molecular communication (DBMC). Emphasis is on an absorbing receiver, which is based on the so-called first passage time concept. In the wireless communications community the EDTCM is well known. Therefore, it is anticipated that the EDTCM improves the accessibility of DBMC and supports the adaptation of classical wireless communication algorithms to the area of DBMC. Furthermore, the EDTCM has the capability to provide a remarkable reduction of computational complexity compared to random walk based DBMC simulators. Besides the exact EDTCM, three approximations thereof based on binomial, Gaussian, and Poisson approximation are proposed and analyzed in order to further reduce computational complexity. In addition, the Bahl-Cocke-Jelinek-Raviv (BCJR) algorithm is adapted to all four channel models. Numerical results show the performance of the exact EDTCM, illustrate the performance of the adapted BCJR algorithm, and demonstrate the accuracy of the approximations.

Depression is highly prevalent in COPD patients, and both diseases are believed to be associated with inflammation. The aim of this study was to elucidate the role of the immune system alterations in pathogenesis of depression in COPD patients. Blood was collected from patients diagnosed with chronic obstructive pulmonary disease and comorbid depressive symptoms [COPD + DS, (N = 13)], from individuals with either COPD (N = 16) or recurrent depressive disorder (rDD) alone (N = 15), and from healthy controls (N = 19). Surface phenotype expression of T regulatory and T effector cells was analyzed with a flow cytometry, and IL-2, IL-6, IL-8, IFN-γ, IL-17, and neopterin were detected with ELISA. We demonstrated that COPD, depression, and COPD with comorbid depression are associated with increased IL-6 levels when compared with healthy controls 42.2 ± 1.87, 40.9 ± 2.12, 41.7 ± 1.31, and 33.2 ± 1.23 pg/ml, respectively (p < 0.05). A significant increase in neopterin levels was observed both in rDD and COPD patients when compared with controls (15.69 ± 0.095, 13.98 ± 0.887 vs. 9.22 ± 0.466 nmol/l, p < 0.001 and p < 0.05, respectively). Concentrations of IFN-γ were significantly increased in COPD + DS patients when compared with controls (24.3 ± 1.49 and 17.8 ± 0.70 pg/ml, respectively, p < 0.05). IL-2 levels were highest in COPD + DS (3.20 ± 0.389 pg/ml) and differed significantly when this group was compared with controls (2.20 ± 0.184 pg/ml), p ≤ 0.05). In this study, we demonstrated for the first time that depressive symptoms in COPD patients may be related to inflammatory state as confirmed by increased levels of IL-6 both in COPD and depression and also in COPD with comorbid depressive symptoms, despite the fact that the patients were treated with anti-inflammatory drugs and/or antidepressants. We also identified IFN-γ and IL-2 as putative inflammatory agents associated with depressive symptoms in COPD patients. Prospective studies will need to confirm whether measuring IL-2 and IFN-γ can identify COPD patients at risk of depression. These findings suggest that T helper cell 1-derived cellular immune activation may play significant role in developing depressive symptoms in COPD patients., Competing Interests: None to declare.

Functional hemispheric asymmetries can vary over time and steroid hormones have been shown to be one of the factors that can modulate them. Research into this matter has mainly focused on sex steroid hormones (androgens, estrogens and progestogens), although there is increasing evidence that glucocorticoids which are related to the body's response to stress (e.g. cortisol or corticosterone) might also modulate functional hemispheric asymmetries. Here, we review studies in humans and non-human model species investigating the relation of stress and laterality. Results indicate a dual relationship of the two parameters. Both acute and chronic stress can affect different forms of lateralization in the human brain, often (but not always) resulting in greater involvement of the right hemisphere. Moreover, lateralization as a form of functional brain architecture can also represent a protective factor against adverse effects of stress., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Many central nervous system (CNS) diseases are inadequately treated by systemically administered therapies due to the blood brain barrier (BBB), which prevents achieving adequate drug concentrations at sites of action. Due to the increasing prevalence of neurodegenerative diseases and the inability of most systemically administered therapies to cross the BBB, direct CNS delivery will likely play an increasing role in treatment. Administration of large molecules, cells, viral vectors, oligonucleotides, and other novel therapies directly to the CNS via the subarachnoid space, ventricular system, or parenchyma overcomes this obstacle. Clinical experience with direct CNS administration of small molecule therapies suggests that this approach may be efficacious for the treatment of neurodegenerative disorders using biological therapies. Risks of administration into the brain tissue or cerebrospinal fluid include local damage from implantation of the delivery system and/or administration of the therapeutic and reactions affecting the CNS. Preclinical safety studies on CNS administered compounds must differentiate between the effects of the test article, the delivery device, and/or the vehicle, and assess exacerbations of reactions due to combinations of effects. Animal models characterized for safety assessment of CNS administered therapeutics have enabled human trials, but interpretation can be challenging. This manuscript outlines the challenges of preclinical intrathecal/intracerebroventricular/intraparenchymal studies, evaluation of results, considerations for special endpoints, and translation of preclinical findings to enable first-in-human trials. Recommendations will be made based on the authors' collective experience with conducting these studies to enable clinical development of CNS-administered biologics., (© The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

For the control of norovirus outbreaks, it is widely recommended that exposed but asymptomatic patients should be cohorted separately from unexposed patients and from symptomatic patients. The frequency of subsequent symptomatic norovirus infection in contact patients has not been investigated systematically. We retrospectively investigated the development of typical norovirus symptoms in contact patients during seven norovirus outbreaks affecting 57 patients between November 2014 and May 2015. Only one of 14 contact patients developed typical norovirus symptoms, calling into question current recommendations to isolate contact patients., (Copyright © 2016 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.)

A method which allows scanning tunneling microscopy (STM) tip biasing independent of the sample bias during frequency modulated atomic force microscopy (AFM) operation is presented. The AFM sensor is supplied by an electronic circuit combining both a frequency shift signal and a tunneling current signal by means of an inductive coupling. This solution enables a control of the tip potential independent of the sample potential. Individual tip biasing is specifically important in order to implement multi-tip STM/AFM applications. An extensional quartz sensor (needle sensor) with a conductive tip is applied to record simultaneously topography and conductivity of the sample. The high resonance frequency of the needle sensor (1 MHz) allows scanning of a large area of the surface being investigated in a reasonably short time. A recipe for the amplitude calibration which is based only on the frequency shift signal and does not require the tip being in contact is presented. Additionally, we show spectral measurements of the mechanical vibration noise of the scanning system used in the investigations.

We present a multi-tip scanning tunneling potentiometry technique that can be implemented into existing multi-tip scanning tunneling microscopes without installation of additional hardware. The resulting setup allows flexible in situ contacting of samples under UHV conditions and subsequent measurement of the sample topography and local electric potential with resolution down to Å and μV, respectively. The performance of the potentiometry feedback is demonstrated by thermovoltage measurements on the Ag/Si(111)-(√3×√3)R30° surface by resolving a standing wave pattern. Subsequently, the ability to map the local transport field as a result of a lateral current through the sample surface is shown on Ag/Si(111)-(√3×√3)R30° and Si(111) - (7 × 7) surfaces.