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Background: Alzheimer’s disease (AD) patients frequently present with orthostatic hypotension. This inability to reflexively increase blood pressure on standing is a serious health concern and increases the risk of stroke and cardiovascular diseases. Objective: Since there are no clear mechanisms for orthostatic hypotension in human AD, the present study assessed the autonomic changes that could explain this comorbidity in an AD animal model. Methods: We used the established streptozotocin-induced rat model of AD (STZ-AD), which mimics many hallmark symptoms of sporadic AD in humans. Baroreflex responses were analyzed in anesthetized STZ-AD rats using femoral catheterization for blood pressure and heart rate, and autonomic activity was assessed using specific blockers and splanchnic sympathetic nerve recordings. Expression levels of autonomic receptors at the heart were examined using the western blot technique. Results: Baroreflex function in STZ-AD showed a blunted heart rate (HR) response to low blood pressure challenges, and the maximal sympathetic nerve activity was reduced. Conversely, HR responses to high blood pressure were similar to control, indicating no change in parasympathetic nerve activity. Under resting conditions, autonomic blockade demonstrated a baseline shift to increased sympathetic tone in STZ-AD. Protein expression levels of beta-1 adrenergic receptor and muscarinic acetylcholine receptor M2 in the heart were unchanged. Conclusion: Our study provides the first data on the pathological influence of AD on baroreflex function, which primarily affected the sympathetic nervous system in STZ-AD. These results represent the first mechanisms that may correlate with the orthostatic hypotension in human AD.

The authors hypothesize that particularly severely compromised and asphyctic term infants in need of resuscitation may benefit from delayed umbilical cord clamping (after several minutes). Although evidence is sparse, the underlying pathophysiological mechanisms support this assumption. For this review the authors have analyzed the available research. Based on these data they conclude that it may be unfavorable to immediately clamp the cord of asphyctic newborns (e.g., after shoulder dystocia) although recommended in current guidelines to provide quick neonatological support. Compression of the umbilical cord or thorax obstructs venous flow to the fetus more than arterial flow to the placenta. The fetus is consequently cut off from a supply of oxygenated, venous blood. This may cause not only hypoxemia and consecutive hypoxia during delivery but possibly also hypovolemia. Immediate cord clamping may aggravate the situation of the already compromised newborn, particularly if the cord is cut before the lungs are ventilated. By contrast, delayed cord clamping leads to fetoplacental transfusion of oxygenated venous blood, which may buffer an existing acidosis. Furthermore, it may enhance blood volume by up to 20%, leading to higher levels of various blood components, such as red and white blood cells, thrombocytes, mesenchymal stem cells, immunoglobulins, and iron. In addition, the resulting increase in pulmonary perfusion may compensate for an existing hypoxemia or hypoxia. Early cord clamping before lung perfusion reduces the preload of the left ventricle and hinders the establishment of sufficient circulation. Animal models and clinical trials support this opinion. The authors raise the question whether it would be better to resuscitate compromised newborns with intact umbilical cords. Obstetric and neonatal teams need to work even closer together to improve neonatal outcomes.

Figure S1: BCRA2 p.Y3035S Pedigrees. Figure S2: Western blot of ectopically expressed full-length wildtype and mutant hBRCA2 protein in VC8 DR-GFP cells subjected to HDR assay. Figure S3: Purification of wildtype and mutant BRCA2 from human cells. Figure S4: Position of BRCA2 DNA binding domain (DBD) variants on a ribbon diagram of the murine DBD crystal structure.

Table S1: Description of the BCAC studies contributing to COGS. Table S2: Predicted effects of BRCA1 and BRCA2 variants included in the iCOGS array on protein function. Table S3: Frequency of BRCA1 and BRCA2 variants from iCOGS in breast cancer cases and controls. Table S4: Family studies of Y3035S showing scores for each family by constant relative risk and 75% penetrance. Supplementary References.

Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case–control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; P = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; P = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; P = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants. Cancer Res; 77(11); 2789–99. ©2017 AACR.

Deep Brain Stimulation (DBS) is a therapy for various neurological movement disorders. It acts predominantly on motor symptoms, but may unfold a number of mostly subtle cognitive effects. In this regard, reports on particular language-related DBS sequels are comparably frequent, but difficult to overlook, given the heterogeneity of targeted structures in the brain, treated diseases, assessment methods and results reported. Accordingly, available knowledge was organized with respect to important aspects, such as the main DBS loci and surgical versus neuromodulatory therapy actions. Current views of biolinguistic underpinnings of the reviewed data, their clinical relevance and potential implications are discussed.

The suprachiasmatic nucleus (SCN) is composed of functionally distinct subpopulations of GABAergic neurons which form a neural network responsible for synchronizing most physiological and behavioral circadian rhythms in mammals. To date, little is known regarding which aspects of SCN rhythmicity are generated by individual SCN neurons, and which aspects result from neuronal interaction within a network. Here, we utilize in vivo miniaturized microscopy to measure fluorescent GCaMP-reported calcium dynamics in arginine vasopressin (AVP)-expressing neurons in the intact SCN of awake, behaving mice. We report that SCN AVP neurons exhibit periodic, slow calcium waves which we demonstrate, using in vivo electrical recordings, likely reflect burst firing. Further, we observe substantial heterogeneity of function in that AVP neurons exhibit unstable rhythms, and relatively weak rhythmicity at the population level. Network analysis reveals that correlated cellular behavior, or coherence, among neuron pairs also exhibited stochastic rhythms with about 33% of pairs rhythmic at any time. Unlike single-cell variables, coherence exhibited a strong rhythm at the population level with time of maximal coherence among AVP neuronal pairs at CT/ZT 6 and 9, coinciding with the timing of maximal neuronal activity for the SCN as a whole. These results demonstrate robust circadian variation in the coordination between stochastically rhythmic neurons and that interactions between AVP neurons in the SCN may be more influential than single-cell activity in the regulation of circadian rhythms. Furthermore, they demonstrate that cells in this circuit, like those in many other circuits, exhibit profound heterogenicity of function over time and space.

Layered materials that perform mixed electron and ion transport are promising for energy harvesting, water desalination, and bioinspired functionalities. These functionalities depend on the interaction between ionic and electronic charges...

Modern work structures and organizations are often characterized by the simultaneous existence of multiple logics. Research has made profound efforts in describing a wide range of possible responses to different constellations of multiple logics in recent decades. But less is known about the subsequent effects of those responses. Since responses to multiple logics aim to change the initial constellation, they are likely to provoke counter-responses that alter the new constellation. Thus, as butterfly effect, certain strategies in dealing with multiple logics can initiate a series of responses that can lead to a fundamental change in the constellations of logics. The rise and fall of locum tenens physicians in Germany illustrate how series of responses can evolve, increase, and fundamentally alter the given constellation of logics. Thereby, our multi-method study also sheds light on the role of omnipresent actors and raises the question of how the actors can be theorized in a setting of multiple logics.

Embodied cognition theories posit direct interactions between sensorimotor and mental processing. Various clinical observations have been interpreted in this controversial framework, amongst others, low verb generation in word production tasks performed by persons with Parkinson’s disease (PD). If this were the consequence of reduced motor simulation of prevalent action semantics in this word class, reduced PD pathophysiology should result in increased verb production and a general shift of lexical contents towards particular movement-related meanings. 17 persons with PD and bilateral deep brain stimulation (DBS) of the subhtalamic nucleus (STN) and 17 healthy control persons engaged in a semantically unconstrained, phonemic verbal fluency task, the former in both DBS-off and DBS-on states. The analysis referred to the number of words produced, verb use, and the occurrence of different dimensions of movement-related semantics in the lexical output. Persons with PD produced fewer words than controls. In the DBS-off, but not in the DBS-on condition, the proportion of verbs within this reduced output was lower than in controls. Lowered verb production went in parallel with a semantic shift: in persons with PD in the DBS-off, but not the DBS-on condition, the relatedness of produced words to own body-movement was lower than in controls. In persons with PD, DBS induced-changes of the motor condition appear to go along with formal and semantic shifts in word production. The results are compatible with the idea of some impact of motor system states on lexical processing.

Hintergrund: Es bestehen soziale Unterschiede in der Kenntnis und der Nutzung kommunaler Gesundheitsforderungs- und Praventionsangebote fur Kinder und Familien wie Bewegungsangebote und Elternedukation. Die Einflussfaktoren und mogliche Grunde dieser Unterschiede sind bislang jedoch nicht ausreichend untersucht. Fragestellungen: Der vorgestellten Studie lagen folgende Fragestellungen zugrunde. a) In welchem Umfang kennen soziookonomisch benachteiligte Familien und Familien mit Zuwanderungsgeschichte kommunale Angebote der Gesundheitsforderung und Pravention und nehmen sie in Anspruch? b) Welche Angebotsmerkmale fordern die Akzeptanz und die Teilnahmebereitschaft, welche Zugangsbarrieren wirken? Material und Methode: In den Ruhrgebietsstadten Moers (n = 201) und Oberhausen (n = 353) wurden an Kitas und Grundschulen teilstandardisierte Elternbefragungen zu kommunalen Angeboten aus den Handlungsfeldern Bewegungsforderung, Elternbildung und Sprachforderung durchgefuhrt. Anhand von t‑Tests wurden die Mittelwerte zu Angebotskenntnis und Inanspruchnahme von Elterngruppen verglichen. Bei Vorliegen signifikanter Gruppenunterschiede wurden die Effektstarken berechnet. Offene Elternfragen wurden inhaltsanalytisch ausgewertet. Ergebnisse: Familien, die armutsgefahrdet sind, ein niedriges Bildungsniveau oder einen Migrationshintergrund haben, kennen deutlich weniger Angebote und nehmen signifikant weniger teil. Bei Angeboten der Bewegungsforderung liegen die starksten Unterschiedseffekte vor. Die Antworten auf offene Fragen zeigen, dass Eltern einen Mangel an familienfreundlicher Infrastruktur wie Sport‑, Spiel- und Schwimmstatten identifizieren. Das Angebotsspektrum von Kitas und Grundschulen wird als unzureichend und wenig bedarfsorientiert wahrgenommen. Es werden Schlusselfaktoren evident, die die Angebotsnutzung fordern konnen. Diskussion: Angebote der Bewegungsforderung und Elternbildung mit Komm-Struktur, die eine hohe elterliche Eigenaktivitat erfordern, erreichen Risikogruppen mit hohem Praventionsbedarf kaum. Die sozialen Disparitaten illustrieren, dass individuumbezogene, verhaltenspraventive Masnahmen nicht zur Verringerung der sozialbedingten Ungleichheit von Gesundheitschancen im Kindesalter beitragen. Verhaltenspraventive Masnahmen sollten grundsatzlich in verhaltnispraventive Mehrkomponenten-Ansatze integriert werden, die strukturelle und umweltbezogene Veranderungen der Settings Kita, Schule und Wohnquartier beinhalten.

Sublattice melting is the loss of order of one lattice component in binary or ternary ionic crystals upon increase in temperature. A related transition has been predicted in colloidal crystals. To understand the nature of this transition, we study delocalization in self-assembled, size asymmetric binary colloidal crystals using a generalized molecular dynamics model. Focusing on BCC lattices, we observe a smooth change from localized-to-delocalized interstitial particles for a variety of interaction strengths. Thermodynamic arguments, mainly the absence of a discontinuity in the heat capacity, suggest that the passage from localization-to-delocalization is continuous and not a phase transition. This change is enhanced by lattice vibrations, and the temperature of the onset of delocalization can be tuned by the strength of the interaction between the colloid species. Therefore, the localized and delocalized regimes of the sublattice are dominated by enthalpic and entropic driving forces, respectively. This work sets the stage for future studies of sublattice melting in colloidal systems with different stoichiometries and lattice types, and it provides insights into superionic materials, which have potential for application in energy storage technologies., Hector Lopez-Rios and Ali Ehlen contributed equally

Resilience, the ability to overcome stressful conditions, is found in most mammals and varies significantly among individuals. A lack of resilience can lead to the development of neuropsychiatric and sleep disorders, often within the same individual. Despite extensive research into the brain mechanisms causing maladaptive behavioral-responses to stress, it is not clear why some individuals exhibit resilience. To examine if sleep has a determinative role in maladaptive behavioral-response to social stress, we investigated individual variations in resilience using a social-defeat model for male mice. Our results reveal a direct, causal relationship between sleep amount and resilience-demonstrating that sleep increases after social-defeat stress only occur in resilient mice. Further, we found that within the prefrontal cortex, a regulator of maladaptive responses to stress, pre-existing differences in sleep regulation predict resilience. Overall, these results demonstrate that increased NREM sleep, mediated cortically, is an active response to social-defeat stress that plays a determinative role in promoting resilience. They also show that differences in resilience are strongly correlated with inter-individual variability in sleep regulation.To many of us, it may seem obvious that sleep is restorative: we feel better after a good night’s rest. However, exactly how sleep benefits the brain and body remains poorly understood. One clue may lie in neuropsychiatric disorders: these conditions – such as depression and anxiety – are often accompanied by disrupted sleep. Additionally, these neuropsychiatric disorders are frequently caused or worsened by stress, which can also interfere with sleep. This close association between stress and sleep has led some to hypothesize that sleep serves to overcome the adverse effects of stress on the brain, but this hypothesis remains largely untested. One type of stress that is common to all mammals is social stress, defined as stress caused by social interactions. This means that mice and other rodents can be subjected to social stress in the laboratory to test hypotheses about the effects of stress on the brain. Importantly, in both animals and humans, there are individual differences in resilience, or the ability to overcome the adverse effects of stress. Based on this information, Bush et al. set out to establish whether sleep can regulate resilience to social stress in mice. When the mice were gently kept awake during their normal sleep time, resilience decreased and so the mice were less able to overcome the negative effects of stress. Conversely, increasing sleep, by activating an area of the brain responsible for initiating sleep, increased the mice’s resilience to social stress. Thus, Bush et al. showed that changes in sleep do lead to changes in resilience. To find out whether resilience can be predicted by changes in sleeping patterns, Bush et al. studied how both resilient mice and those susceptible to stress slept before and after social stress. Resilient mice would often sleep more after social stress; meanwhile, few changes were observed in susceptible mice. Surprisingly, sleep quality also predicted resilience, with resilient mice sleeping better than susceptible mice even before exposure to social stress. To determine whether the differences in sleep that predict resilience can be detected as brain activity, Bush et al. placed electrodes in two regions of the prefrontal cortex – a part of the brain important for decision-making and social behaviors – to measure how mice recovered lost sleep. This experiment revealed that the changes in sleep that predict resilience are prominent in the prefrontal cortex. Overall, Bush et al. reveal that sleeping more and sleeping better promote resilience to social stress. Furthermore, the results suggests that lack of sleep may lead to increased risk of stress-related psychiatric conditions. Humans are one of the few species that choose to deprive themselves of sleep: Bush, et al. provide evidence that this choice may have significant consequences on mental health. Furthermore, this work creates a new model that lays the groundwork for future studies investigating how sleep can overcome stress on the brain.

Motor signs such as dyspraxia and abnormal gait are characteristic features of autism spectrum disorder (ASD). However, motor behavior in adults with ASD has scarcely been quantitatively characterized. In this pilot study, we aim to quantitatively examine motor signature of adults with ASD without intellectual impairment using marker-less visual-perceptive motion capture. 82 individuals (37 ASD and 45 healthy controls, HC) with an IQ > 85 and aged 18 to 65 years performed nine movement tasks and were filmed by a 3D-infrared camera. Anatomical models were quantified via custom-made software and resulting kinematic parameters were compared between individuals with ASD and HCs. Furthermore, the association between specific motor behaviour and severity of autistic symptoms (Autism Diagnostic Observation Schedule 2, Autism Spectrum Quotient) was explored. Adults with ASD showed a greater mediolateral deviation while walking, greater sway during normal, tandem and single leg stance, a reduced walking speed and cadence, a greater arrhythmicity during jumping jack tasks and an impaired manual dexterity during finger tapping tasks (p 0.48) compared to HC. Furthermore, in the ASD group, some of these parameters correlated moderately to severity of ASD symptoms. Adults with ASD seem to display a specific motor signature in this disorder affecting movement timing and aspects of balance. The data appear to reinforce knowledge about motor signs reported in children and adolescents with ASD. Also, quantitative motor assessment via visual-perceptive computing may be a feasible instrument to detect subtle motor signs in ASD and perhaps suitable in the diagnosis of ASD in the future.

A magnetic field modifies optical properties and provides valley splitting in a molybdenum disulfide (MoS

Circadian clocks enable organisms to predict and align their behaviors and physiologies to constant daily day-night environmental cycle. Because the ubiquitin ligase Siah2 has been identified as a potential regulator of circadian clock function in cultured cells, we have used SIAH2-deficient mice to examine its function in vivo. Our experiments demonstrate a striking and unexpected sexually dimorphic effect of SIAH2-deficiency on the regulation of rhythmically expressed genes in the liver. The absence of SIAH2 in females, but not in males, altered the expression of core circadian clock genes and drastically remodeled the rhythmic transcriptome in the liver by increasing the number of day-time expressed genes, and flipping the rhythmic expression from nighttime expressed genes to the daytime. These effects are not readily explained by effects on known sexually dimorphic pathways in females. Moreover, loss of SIAH2 in females, not males, preferentially altered the expression of transcription factors and genes involved in regulating lipid and lipoprotein metabolism. Consequently, SIAH2-deficient females, but not males, displayed disrupted daily lipid and lipoprotein patterns, increased adiposity and impaired metabolic homeostasis. Overall, these data suggest that SIAH2 may be a key component of a female-specific circadian transcriptional output circuit that directs the circadian timing of gene expression to regulate physiological rhythms, at least in the liver. In turn, our findings imply that sex-specific transcriptional mechanisms may closely interact with the circadian clock to tailor overt rhythms for sex-specific needs.

The evolving nature of electricity production, transmission, and consumption necessitates an update to the IEEE's Reliability Test System (RTS), which was last modernized in 1996. The update presented here introduces a generation mix more representative of modern power systems, with the removal of several nuclear and oil-generating units and the addition of natural gas, wind, solar photovoltaics, concentrating solar power, and energy storage. The update includes assigning the test system a geographic location in the southwestern United States to enable the integration of spatio-temporally consistent wind, solar, and load data with forecasts. Additional updates include common RTS transmission modifications in published literature, definitions for reserve product requirements, and market simulation descriptions to enable benchmarking of multi-period power system scheduling problems. The final section presents example results from a production cost modeling simulation on the updated RTS system data.

Supplemental material, sj-pdf-1-eid-10.1177_0143831X221120534 for Labour market collectivism: New solidarities of highly skilled freelance workers in medicine, IT and the film industry by Birgit Apitzsch, Maximiliane Wilkesmann, Caroline Ruiner, Mona Bassyiouny, Ronny Ehlen and Lena Schulz in Economic and Industrial Democracy

Impaired performance in verbal fluency (VF) tasks is a frequent observation in Parkinson's disease (PD). As to the nature of the underlying cognitive deficit, it is commonly attributed to a frontal-type dysexecutive syndrome due to nigrostriatal dopamine depletion. Whereas dopaminergic medication typically improves VF performance in PD, e.g., by ameliorating impaired lexical switching, its effect on semantic network activation is unclear. Data from priming studies suggest that dopamine causes a faster decay of semantic activation spread. The aim of the current study was to examine the impact of dopaminergic medication on the dynamic change of word frequency during VF performance as a measure of semantic spreading activation. To this end, we performed a median split analysis of word frequency during phonemic and semantic VF task performance in a PD group tested while receiving dopaminergic medication (ON) as well as after drug withdrawal (i.e., OFF), and in a sample of age-matched healthy volunteers (both groups n = 26). Dopaminergic medication in the PD group significantly affected phonemic VF with improved word production as well as increased error-rates. The expected decrease of word frequency during VF task performance was significantly smaller in the PD group ON medication than in healthy volunteers across semantic and phonemic VF. No significant group-difference emerged between controls and the PD group in the OFF condition. The comparison between both treatment conditions within the PD group did not reach statistical significance. The observed pattern of results indicates a faster decay of semantic network activation during lexical access in PD patients on dopaminergic medication. In view of improved word generation, this finding is consistent with a concept of more focused neural activity by an increased signal-to-noise ratio due to dopaminergic neuromodulation. However, the effect of dopaminergic stimulation on VF output suggests a trade-off between these beneficial effects and increased error-rates.

The Suprachiasmatic Nucleus (SCN) is composed of functionally distinct sub-populations of GABAergic neurons which form a neural network responsible for synchronizing most physiological and behavioral circadian rhythms in mammals. To date, little is known regarding which aspects of SCN rhythmicity are generated by individual SCN neurons, and which aspects result from neuronal interaction within a network. Here, we utilize in vivo miniaturized microscopy to measure fluorescent GCaMP-reported calcium dynamics in AVP-expressing neurons in the intact SCN of awake, behaving mice. We report that SCN AVP neurons exhibit periodic, slow calcium waves which we demonstrate, using in vivo electrical recordings, likely reflect burst-firing. Further, we observe substantial heterogeneity of function in that AVP neurons exhibit unstable rhythms, and relatively weak rhythmicity at the population level. Network analysis reveals that correlated cellular behavior, or coherence, among neuron pairs also exhibited stochastic rhythms with about 33% of pairs rhythmic at any time. Unlike single-cell variables, coherence exhibited a strong rhythm at the population level with time of maximal coherence among AVP neuronal pairs at CT/ZT 6 and 9, coinciding with the timing of maximal neuronal activity for the SCN as a whole. These results demonstrate robust circadian variation in the coordination between stochastically rhythmic neurons and that interactions between AVP neurons in the SCN may be more influential than single-cell activity in the regulation of circadian rhythms. Furthermore, they demonstrate that cells in this circuit, like those in many other circuits imaged in vivo, exhibit profound heterogenicity of function over time and space.Significance StatementThis work is the first to employ two novel in vivo recording techniques, miniaturized calcium microscopy and optogentically-targeted single unit activity recording, to examine the rhythmic behavior of AVP expressing neurons both at the individual neuronal and network level. These results suggest that while AVP neurons are important for organismal rhythmicity, individual cellular rhythms are unstable and diverse. However, we observed correlated activity among these neurons which appears more reliably rhythmic, suggesting that emergent network properties of the SCN may be more relevant for organismal rhythmicity than individual neuronal characteristics.

Embodied cognition theories posit direct interactions between sensorimotor and mental processing. Various clinical observations have been interpreted in this controversial framework, amongst others, low verb generation in word production tasks performed by persons with Parkinson’s disease (PD). If this were a sequel of reduced motor simulation of prevalent action semantics in this word class, reduced PD pathophysiology should result in increased verb production and a general shift of lexical contents towards particular movement-related meanings. 17 persons with PD and bilateral Deep Brain Stimulation (DBS) of the subhtalamic nucleus (STN) and 17 healthy control persons engaged in a semantically unconstrained, phonemic verbal fluency task, the former in both DBS-off and DBS-on states. The analysis referred to the number of words produced, verb use, and the occurrence of different dimensions of movement-related semantics in the lexical output. Persons with PD produced fewer words than controls. In the DBS-off, but not in the DBS-on condition, the proportion of verbs within this reduced output was lower than in controls. Lowered verb production went in parallel with a semantic shift. In persons with PD in the DBS-off, but not the DBS-on condition, the relatedness of produced words to own body-movement was lower than in controls. In persons with PD, DBS induced-changes of the motor condition appear to go along with formal and semantic shifts in word production. The results support the idea of a direct connection between the motor system and lexical processing.

Highly skilled freelance workers are mainly depicted as a challenge to trade unionism because of their mobility, market power and specific interests in organisational support. The authors explore the manifestations of collectivism of highly skilled freelance workers on the basis of semi-structured interviews with 14 highly skilled freelancers and 35 representatives of intermediaries such as trade unions, professional associations, staffing agencies and cooperatives in medicine, IT and film in Germany. The results reveal new forms and dynamics of labour market collectivism arising from concurrent conflicts and negotiations of job access and working conditions.

Here we study the recently introduced notion of a locally harmonic Maass form and its applications to the theory of $L$-functions. In particular, we find finite formulas for certain twisted central $L$-values of a family of elliptic curves in terms of finite sums over canonical binary quadratic forms. This yields vastly simpler formulas related to work of Birch and Swinnerton-Dyer for such $L$-values, and extends beyond their framework to special non-CM elliptic curves., 29 pages, 4 tables and 1 diagram

Background Colorectal cancer is one of the most common malignancies worldwide. There is an urgent need for simple and fast methods to improve tumor detection in the diagnostic and intraoperative setting to avoid complications and provide objective information in distinguishing malignant and benign colorectal tissue. Optical spectroscopy methods have recently shown a great potential for this discrimination in different organs. Materials and methods In this pilot study, fluorescence emission spectra (excitation: 473 nm) and diffuse reflectance spectra (DRS) of normal and tumor tissues from resected colorectal cancer specimen were measured using fiber optical probes in an ex vivo setting, and the data were subjected to multivariate analysis. Results Substantial spectral differences were found in the fluorescence and DRS spectra of colorectal cancer tissue in comparison to benign tissue. The diagnostic potential of a multimode optical system combining both spectroscopic methods was investigated by mathematical combination. Compared with the individual techniques, a higher sensitivity of the joint DRS-fluorescence optical system in the discrimination between malignant and benign colorectal tissue could be observed. Conclusions In the pilot study presented herein, a quick and reliable method to differentiate malignant and benign colorectal tissue ex vivo with different spectroscopic techniques using spectral fiber probes could be established. Joint fluorescence and near-infrared spectroscopy had a higher sensitivity in tissue discrimination and showed to be a promising combination of two spectroscopic methods. Further studies using the synergic effect of fluorescence and DRS spectroscopy are needed to transfer these findings into the in vivo situation.

Label-free in situ X-ray scattering from protein spherical nucleic acids (Pro-SNAs, consisting of protein cores densely functionalized with covalently bound DNA) was used to elucidate the enzymatic reaction pathway for the DNase I-induced degradation of DNA. Time-course small-angle X-ray scattering (SAXS) and gel electrophoresis reveal a two-state system with time-dependent populations of intact and fully degraded DNA in the Pro-SNAs. SAXS shows that in the fully degraded state, the DNA strands forming the outer shell of the Pro-SNA were completely digested. SAXS analysis of reactions with different Pro-SNA concentrations reveals a reaction pathway characterized by a slow, rate determining DNase I-Pro-SNA association, followed by rapid DNA hydrolysis. Molecular dynamics (MD) simulations provide the distributions of monovalent and divalent ions around the Pro-SNA, relevant to the activity of DNase I. Taken together, in situ SAXS in conjunction with MD simulations yield key mechanistic and structural insights into the interaction of DNA with DNase I. The approach presented here should prove invaluable in probing other enzyme-catalyzed reactions on the nanoscale.

Polydispersity and random sequences are ubiquitous features of polymers, and molecular dynamics simulations can help elucidate the impact of disorder in polymer systems. However, currently available packages for building polymer topologies do not enable the user to include randomness in a straightforward fashion. Here, we introduce Hoobas, a molecular builder package that easily handles polydispersity using a prototype-builder design pattern. This enables fast and easy building of systems comprised of thousands of distinct objects. It is written in the Python programming language, which ensures compatibility with a wide range of molecular dynamics packages and tools, as well as easy integration into most workflows.

There are no Food and Drug Administration approved pharmacotherapies for methamphetamine (METH) overdose, thus identifying novel drug targets to prevent this devastating adverse event is a public-health imperative. Previous research suggests that serotonin and sigma receptors may contribute to the adverse effects of METH. The present study assessed whether pretreatment with the 5-HT2A receptor antagonist M100907 or the sigma 1 (σ1) receptor antagonist BD 1047 attenuated METH-induced lethality, hyperthermia, convulsions, and seizures. Male, Swiss-Webster mice received intraperitoneal injections of M100907 (1 and 10 mg/kg), BD 1047 (10 mg/kg), or a combination of M100907 (1 mg/kg) and BD 1047 (10 mg/kg) prior to treatment with METH (78 mg/kg). Convulsions and lethality were assessed by observation, core body temperature was assessed by surgically implanted telemetric probes, and seizures were assessed by electroencephalography. M100907 reduced METH-elicited lethality from 67% to 33%, BD1047 reduced METH-elicited lethality from 67% to 50%, and combined administration of both agents eliminated lethality in all mice tested. Similarly, both agents and their combination reduced METH-elicited seizures and convulsions. None of the treatments decreased METH-induced hyperthermia. This research suggests that reducing METH-induced seizures is an important factor in reducing lethality associated with METH overdose. However, future studies should examine whether M100907 and BD 1047 modulate METH-induced hypertension and other adverse effects that may also contribute to METH overdose. Our data support the continued investigation of compounds that target 5-HT2A and σ1 receptors in METH-induced overdose, including their potential to yield emergency reversal agents.

Introduction:Stress can have a variety of detrimental effects on humans. From depression and anxiety to schizophrenia, stress plays a factor in the development of these diseases through neurochemical changes in the brain and elevated levels of hormones. Among the geriatric population, decreased sleep levels are known to be a frequent issue; insomnia rates among the senior population are much higher in frequency compared to any other age group. Sleep deprivation also leads to major consequences in the brain and sleep disruption is linked to neuropsychological illness; however, the specific mechanisms involved in these effects are not understood. This study focuses on the resilient effects of ΔFosB, a protein known to mediate resilience to stress and the direct effect of sleep deprivation on ΔFosB expression in areas known to mediate resilience to social stress. We hypothesize that ΔFosB may be part of the mechanism through which sleep alters resilience to social stress.Methods:Mice were sleep-deprived for an eight-hour period for five days. After sleep deprivation they were subject to social defeat and underwent avoidance testing. The brains of these mice were removed, and immunohistochemistry analysis was conducted to determine ∆FosB expression in various sections of the brain.Results:The preliminary findings of this study indicates that sleep is altered in resilient animals and that sleep deprivation may lead to increased resilience to social defeat. The most significant decrease in ∆FosB expression was found in the prelimbic cortex, a change associated with resilience, and which was observed after chronic sleep deprivation. Contrarily, there was also an increase of ∆FosB expression in the nucleus accumbens.Conclusion:These findings indicate that changes in ∆FosB activation in the brain is a significant factor for promoting resilient behavior in situations of social stress. In particular, a decrease in ∆FosB activation in the PLC plays a role in explaining how sleep deprivation contributes to decreased social resilience in situations of social stress.

Colloidal crystals formed by size-asymmetric binary particles co-assemble into a wide variety of colloidal compounds with lattices akin to ionic crystals. Recently, a transition from a compound phase with a sublattice of small particles to a metal-like phase in which the small particles are delocalized has been predicted computationally and observed experimentally. In this colloidal metallic phase, the small particles roam the crystal maintaining the integrity of the lattice of large particles, as electrons do in metals. A similar transition also occurs in superionic crystals, termed sublattice melting. Here, we use energetic principles and a generalized molecular dynamics model of a binary system of functionalized nanoparticles to analyze the transition to sublattice delocalization in different co-assembled crystal phases as a function of T, number of grafted chains on the small particles, and number ratio between the small and large particles $n_s$:$n_l$. We find that $n_s$:$n_l$ is the primary determinant of crystal type due to energetic interactions and interstitial site filling, while the number of grafted chains per small particle determines the stability of these crystals. We observe first-order sublattice delocalization transitions as T increases, in which the host lattice transforms from low- to high-symmetry crystal structures, including A20 to BCT to BCC, Ad to BCT to BCC, and BCC to BCC/FCC to FCC transitions and lattices. Analogous sublattice transitions driven primarily by lattice vibrations have been seen in some atomic materials exhibiting an insulator-metal transition also referred to as metallization. We also find minima in the lattice vibrations and diffusion coefficient of small particles as a function of $n_s$:$n_l$, indicating enhanced stability of certain crystal structures for $n_s$:$n_l$ values that form compounds., Comment: AE and HL-R contributed equally to this work

Additional file 3: Figure S2. Core body temperature time series of the septic shock patients. Core body temperature was measured every hour during a 24-h period during the blood draw. The raw time series in (A) was linearly detrended (trend is shown in blue) to obtain (B).

Background: Although intensive efforts to improve diagnosis and therapy of sepsis over the last decade, the mortality of septic shock remains high and causes substantial socioeconomical burden of disease. The function of immune cells is time-of-day-dependent and is regulated by several circadian clock genes. This study aims to investigate whether the rhythmicity of clock gene expression is altered in patients with septic shock.Methods: This prospective pilot study was performed at the university hospital Charité – Universitätsmedizin Berlin, Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK). We included 20 patients with septic shock between May 2014 and January 2018, from whom blood was drawn every 4 hours over a 24-hour period to isolate CD14-positive monocytes and to measure expression of 17 clock and clock-associated genes. Of these patients, 3 whose samples expressed fewer than 8 clock genes were excluded from the final analysis. Expression data were compared to data of a healthy study population and a rhythmicity score SP was calculated, which comprises values between -1 (arrhythmic) and 1 (rhythmic). Results: Overall, the rhythmicity scores for septic shock patients were significantly (p < 0.0001) lower (0.23 ± 0.26) compared to the control group (12 healthy young men, 0.70 ± 0.18). 77% of the measured clock genes were classified as having inconclusive rhythms, i.e. neither rhythmic nor arrhythmic. The clock genes NR1D1, NR1D2 and CRY2 were the most rhythmic, while CLOCK and ARNTL were the least rhythmic. In addition, the expression of clock genes CRY1, NR1D1, NR1D2, DBP, and PER2 was suppressed in septic shock patients and CRY2 was significantly upregulated compared to controls.Conclusion: Compared to young healthy men, molecular rhythms in immune cells of septic shock patients were substantially decreased. The decrease in rhythmicity was clock gene-dependent. The loss of rhythmicity and downregulation of clock gene expression might be caused by sepsis and might further deteriorate immune responses and organ injury, but further studies are necessary to understand underlying pathophysiological mechanisms.Clinical trial registered with www.ClinicalTrials.gov (NCT02044575) on 24 January 2014.

The aim of this study was to synthesize quantitative research that identified ranking lists of the most severe stressors of patients in the intensive care unit, as perceived by patients, relatives, and health care professionals (HCP). We conducted a systematic literature search in PubMed, MEDLINE, EMBASE, PsycInfo, CINAHL, and Cochrane Library from 1989 to 15 May 2020. Data were analyzed with descriptive and semi-quantitative methods to yield summarizing ranking lists of the most severe stressors. We synthesized the results of 42 prospective cross-sectional observational studies from different international regions. All investigations had assessed patient ratings. Thirteen studies also measured HCP ratings, and four studies included ratings of relatives. Data indicated that patients rate the severity of stressors lower than HCPs and relatives do. Out of all ranking lists, we extracted 137 stressor items that were most frequently ranked among the most severe stressors. After allocation to four domains, a group of clinical ICU experts sorted these stressors with good to excellent agreement according to their stress levels. Our results may contribute to improve HCPs’ and relatives’ understanding of patients’ perceptions of stressors in the ICU. The synthesized stressor rankings can be used for the development of new assessment instruments of stressors.

Additional file 2: Figure S1. Gene expression patterns for all clock genes quantified in septic shock patients. The lines are colored according to the classification of rhythmicity in Fig. 2. The empty boxes represent clock genes that did not pass the inclusion criteria for the analysis.

In 1965 Dr. Harry Angelman reported a neurodevelopmental disorder affecting three unrelated children who had similar symptoms: brachycephaly, mental retardation, ataxia, seizures, protruding tongues, and remarkable paroxysms of laughter. Over the past 50 years, the disorder became Angelman’s namesake and symptomology was expanded to include hyper-activity, stereotypies, and severe sleep disturbances. The sleep disorders in many Angelman syndrome (AS) patients are broadly characterized by difficulty falling and staying asleep at night. Some of these patients sleep less than 4 hours a night and, in most cases, do not make up this lost-sleep during the day—leading to the speculation that AS patients may “need” less sleep. Most AS patients also have severely reduced levels of melatonin, a hormone produced by the pineal gland exclusively at night. This nightly pattern of melatonin production is thought to help synchronize internal circadian rhythms and promote nighttime sleep in humans and other diurnal species. It has been proposed that reduced melatonin levels contribute to the sleep problems in AS patients. Indeed, emerging evidence suggests melatonin replacement therapy can improve sleep in many AS patients. However, AS mice show sleep problems that are arguably similar to those in humans despite being on genetic backgrounds that do not make melatonin. This suggests the hypothesis that the change in nighttime melatonin may be a secondary factor rather than the root cause of the sleeping disorder. The goals of this review article are to revisit the sleep and melatonin findings in both AS patients and animal models of AS and discuss what AS may tell us about the underlying mechanisms of, and interplay between, melatonin and sleep.

Circadian clocks enable organisms to predict and align their behaviors and physiologies to constant daily day-night environmental cycle. Because the ubiquitin ligase Siah2 has been identified as a potential regulator of circadian clock function in cultured cells, we have used Siah2-deficient mice to examine its function in vivo. Our experiments demonstrate a striking and unexpected sexually dimorphic effect of Siah2 deficiency on the regulation of rhythmically expressed genes. The absence of Siah2 in females, but not in males, altered the expression of core circadian clock genes and drastically remodeled the rhythmic hepatic transcriptome. Siah2 loss, only in females, increased the expression of 100’s of genes selectively at mid-day, resulting in a ∼70% increase in the number of rhythmically expressed genes, and shifted the expression of 100’s of other genes from a mid-night peak, to a mid-day peak. The combined result is a near inversion of overall rhythmicity in gene expression selectively in Siah2-deficient females. This dramatic reorganization created a substantial misalignment between rhythmic liver functions and feeding/behavioral rhythms, and consequently impaired daily patterns of lipid/lipoprotein metabolism and metabolic responses to high-fat diet. Collectively, our results suggest that Siah2 is part of a female-specific circadian mechanism important for maintaining metabolic homeostasis and may play a key role in the establishing sexual dimorphisms in metabolism. Signficance statement Circadian clocks drive daily rhythms in many aspects of our physiology, optimally aligning functions across the day-night cycle. How circadian clocks drives these rhythms is thought to be due to largely similar transcriptional pathways and mechanisms in males and females, although some rhythms are modulated by sex and growth hormones. In this study, we present data that uncover the surprising existence of a female-specific transcriptional mechanism that is essential for the proper rhythmic control of gene expression in the liver. Disrupting this mechanism substantially impairs the circadian regulation of lipid and cholesterol metabolism selectively in females, impairing their resistance to diet-induced obesity. These results reveal that circadian clocks may be broadly coupled to physiological rhythms using unexpected sex-specific mechanisms.

We present laser-induced photothermal synthesis of atomically precise graphene nanoribbons (GNRs). The kinetics of photothermal bottom-up GNR growth are unravelled by in situ Raman spectroscopy carried out in ultrahigh vacuum. We photothermally drive the reaction steps by short periods of laser irradiation and subsequently analyze the Raman spectra of the reactants in the irradiated area. Growth kinetics of chevron GNRs (CGNRs) and seven atoms wide armchair GNRs (7-AGNRs) is investigated. The reaction rate constants for polymerization, cyclodehydrogenation, and interribbon fusion are experimentally determined. We find that the limiting rate constants for CGNR growth are several hundred times smaller than for 7-AGNR growth and that interribbon fusion is an important elementary reaction occurring during 7-AGNR growth. Our work highlights that photothermal synthesis and in situ Raman spectroscopy are a powerful tandem for the investigation of on-surface reactions.

Age-related macular degeneration (AMD) is the most common cause of central vision loss among elderly populations in industrialized countries. Genome-wide association studies have consistently associated two genomic loci with progression to late-stage AMD: the complement factor H (CFH) locus on chromosome 1q31 and the age-related maculopathy susceptibility 2-HtrA serine peptidase 1 (ARMS2-HTRA1) locus on chromosome 10q26. While the CFH risk variant has been shown to alter complement activity, the ARMS2-HTRA1 risk haplotype remains enigmatic due to high linkage disequilibrium and inconsistent functional findings spanning two genes that are plausibly causative for AMD risk. In this review, we detail the genetic and functional evidence used to support either ARMS2 or HTRA1 as the causal gene for AMD risk, emphasizing both the historical development and the current understanding of the ARMS2-HTRA1 locus in AMD pathogenesis. We conclude by summarizing the evidence in favor of HTRA1 and present our hypothesis whereby HTRA1-derived ECM fragments mediate AMD pathogenesis.

Der Inhalt des philosophische Systems Simon L. Franks lasst sich mit dem Begriff WIR zusammenfassen. Als Grundbegriff der Sozialphilosophie untersucht Frank das Wir in seinem Werk Die geistigen Grundlagen der Gesellschaft, veroffentlicht 1930 in Paris in russischer Sprache. Auch seine Werke zur Religionsphilosophie und zur Metaphysik – Das Unergrundliche und Die Realitat und der Mensch – , gleichfalls in der Emigration in Paris veroffentlicht, haben unter je anderer Rucksicht die Einheit des Wir zum Thema.