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Dopamine (DA) neurons in the substantia nigra (SN) control several essential functions, including the voluntary movement, learning and motivated behavior. Healthy DA SN neurons show diverse firing patterns in vivo, ranging from slow pacemaker-like activity (1-10 Hz) to transient high frequency bursts (<100 Hz), interspersed with pauses that can last hundreds of milliseconds. Recent in vivo patch experiments have started to reveal the subthreshold mechanisms underlying this physiological diversity, but the impact of challenges like cell loss on the in vivo activity of adult DA SN neurons, and how these may relate to behavioral disturbances, are still largely unknown. We investigated the in vivo electrophysiological properties of surviving SN DA neurons after partial unilateral 6-OHDA lesions, a single-hit, non-progressive model of neuronal cell loss. We show that mice subjected to this model have an initial motor impairment, measured by asymmetrical rotations in the open field test, which recovered over time. At 3 weeks post-lesion, when open field locomotion was strongly impaired, surviving DA SN neurons showed a compressed in vivo dynamic firing range, characterized by a 10-fold reduction of in vivo burst firing compared to controls. This in vivo phenotype was accompanied by pronounced in vitro pacemaker instability. In contrast, in the chronic post-lesion phase (>2 months), where turning symmetry in open field locomotion had recovered, surviving SN DA neurons displayed the full dynamic range of in vivo firing, including in vivo bursting, similar to controls. The normalized in vivo firing pattern was associated with a 2-fold acceleration of stable in vitro pacemaking, mediated by Kv4.3 potassium channel downregulation. Our findings demonstrate the existence of a homeostatic pacemaker plasticity mechanism in surviving DA SN neurons after pronounced cell loss.
Marine stratocumuli are the most dominant cloud type by area coverage in the Southern Ocean (SO). They can be divided into different self-organized cellular morphological regimes known as open and closed mesoscale-cellular convective (MCC) clouds. Open and closed cells are the two most frequent types of organizational regimes in the SO. Using the liDAR-raDAR (DARDAR) version 2 retrievals, we quantify 59 % of all MCC clouds in this region as mixed-phase clouds (MPCs) during a 4-year time period from 2007 to 2010. The net radiative effect of SO MCC clouds is governed by changes in cloud albedo. Both cloud morphology and phase have previously been shown to impact cloud albedo individually, but their interactions and their combined impact on cloud albedo remain unclear.
Here, we investigate the relationships between cloud phase, organizational patterns, and their differences regarding their cloud radiative properties in the SO. The mixed-phase fraction, which is defined as the number of MPCs divided by the sum of MPC and supercooled liquid cloud (SLC) pixels, of all MCC clouds at a given cloud-top temperature (CTT) varies considerably between austral summer and winter. We further find that seasonal changes in cloud phase at a given CTT across all latitudes are largely independent of cloud morphology and are thus seemingly constrained by other external factors. Overall, our results show a stronger dependence of cloud phase on cloud-top height (CTH) than CTT for clouds below 2.5 km in altitude.
Preconditioning through ice-phase processes in MPCs has been observed to accelerate individual closed-to-open cell transitions in extratropical stratocumuli. The hypothesis of preconditioning has been further substantiated in large-eddy simulations of open and closed MPCs. In this study, we do not find preconditioning to primarily impact climatological cloud morphology statistics in the SO. Meanwhile, in-cloud albedo analysis reveals stronger changes in open and closed cell albedo in SLCs than in MPCs. In particular, few optically thick (cloud optical thickness >10) open cell stratocumuli are characterized as ice-free SLCs. These differences in in-cloud albedo are found to alter the cloud radiative effect in the SO by 21 to 39 W m−2 depending on season and cloud phase.
Acute myeloid leukemia (AML) is a heterogeneous malignancy characterized by the accumulation of undifferentiated white blood cells (blasts) in the bone marrow. Valosin-containing protein (VCP) is an abundant molecular chaperone that extracts ubiquitylated substrates from protein complexes and cellular compartments prior to their degradation by the proteasome. We found that treatment of AML cell lines with the VCP inhibitor CB-5083 leads to an accumulation of ubiquitylated proteins, activation of unfolded protein response (UPR) and apoptosis. Using quantitative mass spectrometry-based proteomics we assessed the effects of VCP inhibition on the cellular ubiquitin-modified proteome. We could further show that CB-5083 decreases the survival of the AML cell lines THP-1 and MV4-11 in a concentration-dependent manner, and acts synergistically with the antimetabolite cytarabine and the BH3-mimetic venetoclax. Finally, we showed that prolonged treatment of AML cells with CB-5083 leads to development of resistance mediated by mutations in VCP. Taken together, inhibition of VCP leads to a lethal unfolded protein response in AML cells and might be a relevant therapeutic strategy for treatment of AML, particularly when combined with other drugs. The toxicity and development of resistance possibly limit the utility of VCP inhibitors and have to be further explored in animal models and clinical trials.
Implementation and evaluation of a Tele-OSCE in oral and maxillofacial surgery – a pilot report
(2022)
Background: The ongoing changes in learning and education towards digitalisation have been rapidly accelerated by the COVID-19 pandemic. Especially in dental education where contact to the oral cavity is an integral part of training the chosen digital examination methods and training formats must undergo high requirements to full fill the goal of a real alternative to face-to-face exams. Therefore, this study compared student performance in a newly developed Tele-OSCE with a prior OSCE examinations in presence within an oral- and maxillofacial surgery curriculum.
Methods: Study participants were fourth-year (in a five year curriculum) dental students and board certified maxillofacial surgeons (examiners) that took part in a newly developed Tele-OSCE that comprised three five-minute stations (structured facial examination, management mandibular fracture and squamous cell carcinoma) using the zoom® software. Student performance was measured using validated OSCE-Checklists and compared to a previous OSCE examination from the winter term 2019 with the same OSCE stations that was conducted in presence. Significant differences were tested using the Mann-Whitney U test. Furthermore, the new Tele-OSCE was evaluated by students and examiners using previously developed questionnaires.
Results: Sixty-six dental students (study group: n=34, summer term 2021, control group: n=32 winter term 2019) and nine examiners participated in the study. Compared to previous non-pandemic OSCEs, there were no significant (p=0.53) differences in overall student performance. Evaluation of the Tele-OSCE showed that the demonstration and rating of practical skills was limited due to missing standard patients or phantoms, however, students did not fear to be misjudged. The demonstration and rating of anamnestic and consultation competencies was seen as unproblematic by students and examiners.
Discussion: This pilot-study showed the feasibility of a Tele-OSCE as a formative examination in dental education. However, both students and examiners felt that the demonstration and assessment of practical skills was limited due the new examination format. Nevertheless, Tele-OSCEs might offer an alternative to enable students to complete their dental training.
Seismic arrays provide tools for the localization of events without clear phases or events outside the network, where the station coverage prohibits classical localization techniques. Beam forming allows the determination of the direction (back azimuth) and horizontal (apparent) velocity of an incoming wavefront. Here we combine multiple arrays to retrieve event epicentres from the area of intersecting beams without the need to specify a velocity model. The analysis is performed in the time domain, which allows selecting a relatively narrow time window around the phase of interest while preserving frequency bandwidth. This technique is applied to earthquakes and hybrid events in the region of Fogo and Brava, two islands of the southern chain of the Cape Verde archipelago. The results show that the earthquakes mainly originate near Brava, whereas the hybrid events are located on Fogo. By multiple-event beam stacking we are able to further constrain the epicentral locations of the hybrid events in the northwestern part of the collapse scar of Fogo. In previous studies, these events were attributed to shallow hydrothermal processes. However, we obtain relatively high apparent velocities at the arrays, pointing to either deeper sources or complex ray paths. For a better understanding of possible errors of the multi-array analysis, we also compare slowness values obtained from the array analysis with those derived from earthquake locations from classical (local network) localizations. In general, the results agree well. Nevertheless, some systematic deviations of the array-derived back-azimuth and slowness values occur that can be quantified for certain event locations.
Seismic arrays provide tools for the localization of events without clear phases or events outside the network, where the station coverage prohibits classical localization techniques. Beam forming allows the determination of the direction (back azimuth) and horizontal (apparent) velocity of an incoming wavefront. Here we combine multiple arrays to retrieve event epicentres from the area of intersecting beams without the need to specify a velocity model. The analysis is performed in the time domain, which allows selecting a relatively narrow time window around the phase of interest while preserving frequency bandwidth. This technique is applied to earthquakes and hybrid events in the region of Fogo and Brava, two islands of the southern chain of the Cape Verde archipelago. The results show that the earthquakes mainly originate near Brava, whereas the hybrid events are located on Fogo. By multiple-event beam stacking we are able to further constrain the epicentral locations of the hybrid events in the northwestern part of the collapse scar of Fogo. In previous studies, these events were attributed to shallow hydrothermal processes. However, we obtain relatively high apparent velocities at the arrays, pointing to either deeper sources or complex ray paths. For a better understanding of possible errors of the multi-array analysis, we also compare slowness values obtained from the array analysis with those derived from earthquake locations from classical (local network) localizations. In general, the results agree well. Nevertheless, some systematic deviations of the array-derived back-azimuth and slowness values occur that can be quantified for certain event locations.
Treatment of relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT) remains a great challenge. Aiming to evaluate the combination of venetoclax and hypomethylating agents (HMAClax) for the treatment of relapse of myeloid malignancies after alloHSCT, we retrospectively collected data from 32 patients treated at 11 German centers. Venetoclax was applied with azacitidine (n = 13) or decitabine (n = 19); 11 patients received DLI in addition. HMAClax was the first salvage therapy in 8 patients. The median number of cycles per patient was 2 (1–19). All but 1 patient had grade 3/4 neutropenia. Hospital admission for grade 3/4 infections was necessary in 23 patients (72%); 5 of these were fatal. In 30 evaluable patients, overall response rate (ORR) was 47% (14/30, 3 CR MRDneg, 5 CR, 2 CRi, 1 MLFS, 3 PR). ORR was 86% in first salvage patients versus 35% in later salvage patients (p = 0.03). In 6 patients with molecular relapse (MR), ORR was 67% versus 42% in patients with hematological relapse (HR) (n = 24, p = n.s.). After a median follow-up of 8.4 months, 25 patients (78%) had died and 7 were alive. Estimated median overall survival was 3.7 months. Median survival of patients with HMAClax for first versus later salvage therapy was 5.7 and 3.4 months (p = n.s.) and for patients with MR (not reached) compared to HR (3.4 months, p = 0.024). This retrospective case series shows that venetoclax is utilized in various different combinations, schedules, and doses. Toxicity is substantial and patients who receive venetoclax/HMA combinations for MR or as first salvage therapy derive the greatest benefit.
The present study examined the impact of the COVID-19 pandemic on the emotional quality of dreams, the incorporation of pandemic-related themes, and the occurrence of lucid dreaming. Dream reports and lucidity ratings of psychiatric outpatients (n = 30) and healthy controls (n = 81) during two lockdowns in Germany were compared to those of healthy controls (n = 33) before the pandemic. Results confirmed previous reports that pandemic-specific themes were incorporated into dreams. Overall, however, incorporation into dreams was rare. Contrary to expectations, psychiatric outpatients did not differ from controls in the frequency of dream incorporation of pandemic-related content. Moreover, incorporation was independent of psychiatric symptoms and loneliness. Loneliness was, however, associated with threat-related content, suggesting that it represents a risk for bad dreams but not for crisis-specific dream incorporation. Regarding lucid dreaming, both groups had similar scores for its underlying core dimensions, i.e., insight, control, and dissociation, during the two lockdowns. Scores for control and dissociation but not insight were lower compared to the pre-pandemic sample. Our working hypothesis is that REM sleep during lockdowns intensified as a means of increased emotional consolidation, rendering the associated mental state less hybrid and thereby less lucid.
Researchers have suggested that the recognition memory effects resulting from two separate attentional manipulations—attentional boost and perceptual degradation—may share a common cause; namely a transient up-regulation of attention at the time of encoding that leads to enhanced memory performance at the time of retrieval. Prior research has demonstrated that inducing two similar transient shifts of attention simultaneously produces redundant performance in memory. In the present study, we sought to evaluate the combined influence of the attentional boost and perceptual degradation on recognition memory. If these two effects share a common cause, then we ought to observe a redundancy in memory performance, such that these two factors interact. Yet, across four experiments we fail to observe such a redundancy in recognition memory. We evaluate these results using the limited resource model of attention and speculate on how combining transient shifts of attention may produce redundant memory performance in the one case, but non-redundant performance in the other case.
We show a shift in the prevalence of respiratory viral pathogens in community-acquired pneumonia patients during the COVID-19 pandemic. Our data support the efficiency of non-pharmaceutical interventions on virus circulation except for rhinoviruses. The consequences of an altered circulation on subsequent winter seasons remain unclear and support the importance of systematic virological surveillance.