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In this paper we derive caloric smoothing estimates in Morrey smoothness spaces using decomposition techniques by means of wavelets and molecules. Our new estimate extends results for Gauss-Weierstrass, Cauchy-Poisson and fractional Gauss-Weierstrass semigroups.

Background: The increased stress the world experienced with the coronavirus disease (COVID-19) pandemic affected mental health, disproportionately affecting females. However, how perceived stress in the first year affected menstrual and menopausal symptoms has not yet been investigated. Objectives: This study evaluates the effect that the first year of the COVID-19 pandemic had on female reproductive and mental health. Methods: Residents in British Columbia, Canada, were surveyed online as part of the COVID-19 Rapid Evidence Study of a Provincial Population-Based Cohort for Gender and Sex. A subgroup of participants (n = 4171), who were assigned female sex at birth (age 25–69 years) and were surveyed within the first 6–12 months of the pandemic (August 2020–February 2021), prior to the widespread rollout of vaccines, was retrospectively asked if they noticed changes in their menstrual or menopausal symptoms, and completing validated measures of stress, depression and anxiety. Design: This is a population-based online retrospective survey. Results: We found that 27.8% reported menstrual cycle disturbances and 6.7% reported increased menopause symptoms. Those who scored higher on perceived stress, depression and anxiety scales were more likely to report reproductive cycle disturbances. Free-text responses revealed that reasons for disturbances were perceived to be related to the pandemic. Conclusion: The COVID-19 pandemic has highlighted the need to research female-specific health issues, such as menstruation. Our data indicate that in the first year of the pandemic, almost one-third of the menstruating population reported disturbances in their cycle, which was related to percieved stress, depression and anxiety scores.

Synchronized oscillations within and between brain areas facilitate normal processing, but are often amplified in disease. A prominent example is the abnormally sustained beta-frequency (∼20 Hz) oscillations recorded from the cortex and subthalamic nucleus of Parkinson's disease patients. Computational modeling suggests that the amplitude of such oscillations could be modulated by applying stimulation at a specific phase. Such a strategy would allow selective targeting of the oscillation, with relatively little effect on other activity parameters. Here, activity was recorded from 10 awake, parkinsonian patients (6 male, 4 female human subjects) undergoing functional neurosurgery. We demonstrate that stimulation arriving on a particular patient-specific phase of the beta oscillation over consecutive cycles could suppress the amplitude of this pathophysiological activity by up to 40%, while amplification effects were relatively weak. Suppressive effects were accompanied by a reduction in the rhythmic output of subthalamic nucleus (STN) neurons and synchronization with the mesial cortex. While stimulation could alter the spiking pattern of STN neurons, there was no net effect on firing rate, suggesting that reduced beta synchrony was a result of alterations to the relative timing of spiking activity, rather than an overall change in excitability. Together, these results identify a novel intrinsic property of cortico-basal ganglia synchrony that suggests the phase of ongoing neural oscillations could be a viable and effective control signal for the treatment of Parkinson's disease. This work has potential implications for other brain diseases with exaggerated neuronal synchronization and for probing the function of rhythmic activity in the healthy brain.SIGNIFICANCE STATEMENT In Parkinson's disease (PD), movement impairment is correlated with exaggerated beta frequency oscillations in the cerebral cortex and subthalamic nucleus (STN). Using a novel method of stimulation in PD patients undergoing neurosurgery, we demonstrate that STN beta oscillations can be suppressed when consecutive electrical pulses arrive at a specific phase of the oscillation. This effect is likely because of interrupting the timing of neuronal activity rather than excitability, as stimulation altered the firing pattern of STN spiking without changing overall rate. These findings show the potential of oscillation phase as an input for "closed-loop" stimulation, which could provide a valuable neuromodulation strategy for the treatment of brain disorders and for elucidating the role of neuronal oscillations in the healthy brain.

An intercomparison in the framework of the German Calibration Service (Deutscher Kalibrierdienst – DKD) was carried out. Two different travelling standards were used to measure the 10 % to 90 % rise time of a pulse generator and the 10 % to 90 % rise time, −3 dB bandwidth and attenuation at 500 MHz of an oscilloscope. Fourteen participants performed the measurements from September 2015 until May 2016.

ObjectivesThe SARS-CoV-2 (COVID-19) pandemic has had profound physical and mental health effects on populations around the world. Limited empirical research has used a gender-based lens to evaluate the mental health impacts of the pandemic, overlooking the impact of public health measures on marginalized groups, such as women, and the gender diverse community. This study used a gender-based analysis to determine the prevalence of psychosocial symptoms and substance use (alcohol and cannabis use in particular) by age, ethnicity, income, rurality, education level, Indigenous status, and sexual orientation.MethodsParticipants in the study were recruited from previously established cohorts as a part of the COVID-19 Rapid Evidence Study of a Provincial Population-Based Cohort for Gender and Sex (RESPPONSE) study. Those who agreed to participate were asked to self-report symptoms of depression, anxiety, pandemic stress, loneliness, alcohol use, and cannabis use across five phases of the pandemic as well as retrospectively before the pandemic.ResultsFor all psychosocial outcomes, there was a significant effect of time with all five phases of the pandemic being associated with more symptoms of depression, anxiety, stress, and loneliness relative to pre-COVID levels (p < .0001). Gender was significantly associated with all outcomes (p < .0001) with men exhibiting lower scores (i.e., fewer symptoms) than women and gender diverse participants, and women exhibiting lower scores than the gender diverse group. Other significant predictors were age (younger populations experiencing more symptoms, p < .0001), ethnicity (Chinese/Taiwanese individuals experiencing fewer symptoms, p = .005), and Indigenous status (Indigenous individuals experiencing more symptoms, p < .0001). Alcohol use and cannabis use increased relative to pre-pandemic levels, and women reported a greater increase in cannabis use than men (p < .0001).ConclusionsOur findings highlight the need for policy makers and leaders to prioritize women, gender-diverse individuals, and young people when tailoring public health measures for future pandemics.

Abnormally sustained beta-frequency synchronisation between the motor cortex and subthalamic nucleus (STN) is associated with motor symptoms in Parkinson's disease (PD). It is currently unclear whether STN neurons have a preference for beta-frequency input (12-35 Hz), rather than cortical input at other frequencies, and how such a preference would arise following dopamine depletion. To address this question, we combined analysis of cortical and STN recordings from awake human PD patients undergoing deep brain stimulation surgery with recordings of identified STN neurons in anaesthetised rats. In these patients, we demonstrate that a subset of putative STN neurons is strongly and selectively sensitive to magnitude fluctuations of cortical beta oscillations over time, linearly increasing their phase-locking strength with respect to the full range of instantaneous amplitude in the beta-frequency range. In rats, we probed the frequency response of STN neurons in the cortico-basal-ganglia-network more precisely, by recording spikes evoked by short bursts of cortical stimulation with variable frequency (4-40 Hz) and constant amplitude. In both healthy and dopamine-depleted rats, only beta-frequency stimulation led to a progressive reduction in the variability of spike timing through the stimulation train. This suggests, that the interval of beta-frequency input provides an optimal window for eliciting the next spike with high fidelity. We hypothesize, that abnormal activation of the indirect pathway, via dopamine depletion and/or cortical stimulation, could trigger an underlying sensitivity of the STN microcircuit to beta-frequency input.

Loss-of-function mutations in the parkin-encoding PARK2 gene are a frequent cause of young-onset, autosomal recessive Parkinson's disease (PD). Parkin knockout mice have no nigro-striatal neuronal loss but exhibit abnormalities of striatal dopamine transmission and cortico-striatal synaptic function. How these predegenerative changes observed in vitro affect neural dynamics at the intact circuit level, however, remains hitherto elusive. Here, we recorded from motor cortex, striatum and globus pallidus (GP) of anesthetized parkin-deficient mice to assess cortex-basal ganglia circuit dynamics and to dissect cell type-specific functional connectivity in the presymptomatic phase of genetic PD.While ongoing activity of presumed striatal spiny projection neurons and their downstream counterparts in the GP was not different from controls, parkin deficiency had a differential impact on striatal interneurons: In parkin-mutant mice, tonically active neurons displayed elevated activity levels. Baseline firing rates of transgenic striatal fast spiking interneurons (FSI), on the contrary, were reduced and the correlational structure of the FSI microcircuitry was disrupted. The entire transgenic striatal microcircuit showed enhanced and phase-shifted phase coupling to slow (1-3 Hz) cortical population oscillations. Unexpectedly, local field potentials recorded from striatum and GP of parkin-mutant mice robustly displayed amplified beta oscillations (~22 Hz), phase-coupled to cortex. Parkin deficiency selectively increased spike-field coupling of FSIs to beta oscillations.Our findings suggest that loss of parkin function leads to amplifications of synchronized cortico-striatal oscillations and an intrastriatal reconfiguration of interneuronal circuits. This presymptomatic disarrangement of dynamic functional connectivity may precede nigro-striatal neurodegeneration and predispose to imbalance of striatal outflow accompanying symptomatic PD.

In this paper we describe the design of an exposure setup used to study possible non-thermal effects due to the exposure of human hematopoietic stem cells to GSM, UMTS and LTE mobile communication signals. The experiments are performed under fully blinded conditions in a TEM waveguide located inside an incubator to achieve defined environmental conditions as required for the living cells. Chamber slides containing the cells in culture medium are placed on the septum of the waveguide. The environmental and exposure parameters such as signal power, temperatures, relative humidity and CO2 content of the surrounding atmosphere are monitored permanently during the exposure experiment. The power of the exposure signals required to achieve specific absorption rates of 0.5, 1, 2 and 4 W kg−1 are determined by numerical calculation of the field distribution inside the cell culture medium at 900 MHz (GSM), 1950 MHz (UMTS) and 2535 MHz (LTE). The dosimetry is verified both with scattering parameter measurements on the waveguide with and without containers filled with cell culture medium and with temperature measurements with non-metallic probes in separate heating experiments.

Abstract Background Chronic inflammation emerges as a feature of the pathogenesis of pulmonary arterial hypertension (PAH) in experimental models. Alterations of circulating cell subsets have been observed in patients with PAH. We aimed to assess associations of the white blood cell count with disease severity and outcome in patients with PAH. Methods The total and differential white blood cell count was related to functional parameters, pulmonary hemodynamics and transplantation-free survival in 77 patients with PAH in an observational single center study. Results An increased neutrophil/lymphocyte ratio was associated with poor World Health Organization functional class and shorter 6-minute walking distance, as well as with elevated right atrial pressure and high level of N-terminal prohormone of brain natriuretic peptide. During a median follow-up period of 31 months (range 16-56) 23 patients died and 2 patients were referred to lung transplantation. Using uni- and subsequent bivariate Cox proportional hazards analyses an increased neutrophil/lymphocyte ratio was associated with unfavorable transplantation-free survival independent of hemodynamic parameters and C-reactive protein. The prognostic implication sustained in subsets of patients with incident PAH and in the absence of cardiovascular risk factors. Conclusions The results of this analysis indicate that a neutrophilic inflammation may be associated with clinical deterioration and poor outcome in patients with PAH. Assessing the composition of the differential white blood cell count may render prognostic information and could represent a step towards incorporating an inflammatory marker into the clinical management of patients with PAH.

Genetically determined cerebellar ataxias (CA) are a heterogeneous group of disorders with progressive decline of cerebellar functions. The cerebellum influences internal forward models that play a role in cognitive control, but whether these processes are dysfunctional in CA is unclear. Here, we examined sensory predictive coding processes and response adaptation in CA and healthy controls (HC) using behavioral tests with concomitant EEG recordings. N = 23 patients and N = 29 age- and sex-matched HC were studied. Sensory prediction coding was tested with an auditory distraction paradigm and error-related behavioral adaptation with a visual flanker task. As neurophysiological markers we studied different event-related potentials: the P3a for orientation of attention; the N2 and the error-related negativity (ERN) for cognitive adaptation processes/consequences of response errors; error-related positivity (Pe) for error-awareness; the mismatch negativity (MMN) for sensory predictive coding; and reorientation negativity (RON) for reorientation after unexpected events. Overall reaction times were slower in patients compared to HC, but error rates did not differ. Both in patients and HC, P3a amplitudes were larger in distraction trials, but the P3a amplitude was smaller in patients compared to HC. The MMN as well as behavioral and EEG-correlates of response adaptation (ERN/N2) did not differ between groups, while the Pe was attenuated in patients. During sensory predictive coding, RON amplitudes were significantly larger in HC compared to patients. In HC, but not in patients, RON amplitudes were also larger in deviant compared to frequent trials. Processes generating internal forward models are largely intact in genetically determined CA, whereas updating of mental models and error awareness are disturbed in these patients. Keywords: Cerebellar ataxia, Forward model, EEG, Cognitive control

Asymmetric microsphere resonant cavities (ARCs) allow for free-space coupling to high quality (Q) whispering gallery modes (WGMs) while exhibiting highly directional light emission, enabling WGM resonance measurements in the far-field. These remarkable characteristics make “stand-off” biodetection in which no coupling device is required in near-field contact with the resonator possible. Here we show asymmetric microsphere resonators fabricated from optical fibers which support dynamical tunneling to excite high-Q WGMs, and demonstrate free-space coupling to modes in an aqueous environment. We characterize the directional emission by fluorescence imaging, demonstrate coupled mode effects due to free space coupling by dynamical tunneling, and detect adsorption kinetics of a protein in aqueous solution. Based on our approach, new, more robust WGM biodetection schemes involving microfluidics and in-vivo measurements can be designed.

This paper introduces a parameter estimation method for a general class of statistical models. The method exclusively relies on the possibility to conduct simulations for the construction of interpolation-based metamodels of informative empirical characteristics and some subjectively chosen correlation structure of the underlying spatial random process. In the absence of likelihood functions for such statistical models, which is often the case in stochastic geometric modelling, the idea is to follow a quasi-likelihood (QL) approach to construct an optimal estimating function surrogate based on a set of interpolated summary statistics. Solving these estimating equations one can account for both the random errors due to simulations and the uncertainty about the meta-models. Thus, putting the QL approach to parameter estimation into a stochastic simulation setting the proposed method essentially consists of finding roots to a sequence of approximating quasiscore functions. As a simple demonstrating example, the proposed method is applied to a special parameter estimation problem of a planar Boolean model with discs. Here, the quasi-score function has a half-analytical, numerically tractable representation and allows for the comparison of the model parameter estimates found by the simulation-based method and obtained from solving the exact quasi-score equations.

Describes the North Suburban Library System (Chicago) experience of becoming a Learning Organization which involves issues relating to management, decision making, knowledge transfer, and empowerment at all staff levels. Discusses teamwork, collaborative efforts, communication, information sharing, annual planning, and staff development and training. (LRW)

Airway epithelial cells reduce cytosolic ATP content in response to treatment with S. aureus alpha-toxin (hemolysin A, Hla). This study was undertaken to investigate whether this is due to attenuated ATP generation or to release of ATP from the cytosol and extracellular ATP degradation by ecto-enzymes. Exposure of cells to rHla did result in mitochondrial calcium uptake and a moderate decline in mitochondrial membrane potential, indicating that ATP regeneration may have been attenuated. In addition, ATP may have left the cells through transmembrane pores formed by the toxin or through endogenous release channels (e.g., pannexins) activated by cellular stress imposed on the cells by toxin exposure. Exposure of cells to an alpha-toxin mutant (H35L), which attaches to the host cell membrane but does not form transmembrane pores, did not induce ATP release from the cells. The Hla-mediated ATP-release was completely blocked by IB201, a cyclodextrin-inhibitor of the alpha-toxin pore, but was not at all affected by inhibitors of pannexin channels. These results indicate that, while exposure of cells to rHla may somewhat reduce ATP production and cellular ATP content, a portion of the remaining ATP is released to the extracellular space and degraded by ecto-enzymes. The release of ATP from the cells may occur directly through the transmembrane pores formed by alpha-toxin.

Membrane proteins, particularly G-protein coupled receptors (GPCRs), are notoriously difficult to express. Using commercial E. coli cell-free systems with the detergent Brij-35, we could rapidly produce milligram quantities of 13 unique GPCRs. Immunoaffinity purification yielded receptors at >90% purity. Secondary structure analysis using circular dichroism indicated that the purified receptors were properly folded. Microscale thermophoresis, a novel label-free and surface-free detection technique that uses thermal gradients, showed that these receptors bound their ligands. The secondary structure and ligand-binding results from cell-free produced proteins were comparable to those expressed and purified from HEK293 cells. Our study demonstrates that cell-free protein production using commercially available kits and optimal detergents is a robust technology that can be used to produce sufficient GPCRs for biochemical, structural, and functional analyses. This robust and simple method may further stimulate others to study the structure and function of membrane proteins.

A crucial bottleneck in membrane protein studies, particularly G-protein coupled receptors, is the notorious difficulty of finding an optimal detergent that can solubilize them and maintain their stability and function. Here we report rapid production of 12 unique mammalian olfactory receptors using short designer lipid-like peptides as detergents. The peptides were able to solubilize and stabilize each receptor. Circular dichroism showed that the purified olfactory receptors had alpha-helical secondary structures. Microscale thermophoresis suggested that the receptors were functional and bound their odorants. Blot intensity measurements indicated that milligram quantities of each olfactory receptor could be produced with at least one peptide detergent. The peptide detergents' capability was comparable to that of the detergent Brij-35. The ability of 10 peptide detergents to functionally solubilize 12 olfactory receptors demonstrates their usefulness as a new class of detergents for olfactory receptors, and possibly other G-protein coupled receptors and membrane proteins.

Abstract Purpose To evaluate the efficacy of low-dose radiotherapy in painful gonarthritis. Methods We assessed the medical records of 1037 patients with painful gonarthritis who had undergone low-dose radiotherapy between 1981 and 2008. The subjective patient perception of the response to irradiation as graded immediately or up to two months after the completion of a radiotherapy series was evaluated and correlated with age, gender, radiological grading and the duration of symptoms before radiotherapy. Moreover, we performed a mail survey to obtain additional long-term follow-up information and received one hundred and six evaluable questionnaires. Results We assessed 1659 series of radiotherapy in 1037 patients. In 79.3% of the cases the patients experienced a slight, marked or complete pain relief immediately or up to two months after the completion of radiotherapy. Gender, age and the duration of pain before radiotherapy did not have a significant influence on the response to irradiation. In contrast, severe signs of osteoarthritis were associated with more effective pain relief. In more than 50% of the patients who reported a positive response to irradiation a sustained period of symptomatic improvement was observed. Conclusions Our results confirm that low-dose radiotherapy is an effective treatment for painful osteoarthritis of the knee. In contrast to an earlier retrospective study, severe signs of osteoarthritis constituted a positive prognostic factor for the response to irradiation. A randomized trial is urgently required to compare radiotherapy with other treatment modalities.

Abstract Background Male breast cancer (MBC) is a rare disease accounting for approximately 1% of all breast carcinomas. Presently treatment recommendations are derived from the standards for female breast cancer. However, those approaches might be inadequate because of distinct gender specific differences in tumor biology of breast cancer. This study was planned in order to contrast potential differences between female and male breast cancer in both tumor biological behavior and clinical management. Methods MBC diagnosed between 1995-2007 (region Chemnitz/Zwickau, Saxony, Germany) was retrospectively analyzed. Tumor characteristics, treatment and follow-up of the patients were documented. In order to highlight potential differences each MBC was matched with a female counterpart (FBC) that showed accordance in at least eight tumor characteristics (year of diagnosis, age, tumor stage, nodal status, grade, estrogen- and progesterone receptors, HER2 status). Results 108 male/female matched-pairs were available for survival analyses. In our study men and women with breast cancer had similar disease-free (DFS) and overall (OS) survival. The 5-years DFS was 53.4% (95% CI, range 54.1-66.3) in men respectively 62.6% (95% CI, 63.5-75.3) in women (p > 0.05). The 5-years OS was 71.4% (95% CI, 62.1-72.7%) and 70.3% (95% CI, 32.6-49.6) in women (p > 0.05). In males DFS analyses revealed progesterone receptor expression as the only prognostic relevant factor (p = 0.006). In multivariate analyses for OS both advanced tumor size (p = 0.01) and a lack of progesterone receptor expression were correlated (p = 0.01) with poor patients outcome in MBC. Conclusion Our comparative study revealed no survival differences between male and female breast cancer patients and gives evidence that gender is no predictor for survival in breast cancer. This was shown despite of significant gender specific differences in terms of frequency and intensity of systemic therapy in favor to female breast cancer.