Despite several new developments in the treatment of multiple myeloma, all available therapies are only palliative without curative potential and all patients ultimately relapse. Thus, novel therapeutic options are urgently required to prolong survival of or to even cure myeloma. Here, we show that multiple myeloma cells express the potassium channel Kv1.3 in their mitochondria. The mitochondrial Kv1.3 inhibitors PAPTP and PCARBTP are efficient against two tested human multiple myeloma cell lines (L-363 and RPMI-8226) and against ex vivo cultured, patient-derived myeloma cells, while healthy bone marrow cells are spared from toxicity. Cell death after treatment with PAPTP and PCARBTP occurs via the mitochondrial apoptotic pathway. In addition, we identify up-regulation of the multidrug resistance pump MDR-1 as the main potential resistance mechanism. Combination with ABT-199 (venetoclax), an inhibitor of Bcl2, has a synergistic effect, suggesting that mitochondrial Kv1.3 inhibitors could potentially be used as combination partner to venetoclax, even in the treatment of t(11;14) negative multiple myeloma, which represent the major part of cases and are rather resistant to venetoclax alone. We thus identify mitochondrial Kv1.3 channels as druggable targets against multiple myeloma.

Research on intelligence and competence has developed widely independent of each other. The present paper aims at relating these traditions and at integrating the dominant models to fill gaps in the respective theories. We test the structural models derived from this integration in a series of confirmatory factor analyses and a latent moderated structural equations approach using teachers as an example. The data reveal that both fluid intelligence (gf) and domain-specific knowledge affect teachers’ ability to solve the domain-specific items. Teachers’ academic self-concept related to mathematics explains individual differences beyond gf. An interaction effect between gf and self-concept exists for teachers’ pedagogical content and general pedagogical knowledge, but not for their mathematics knowledge. This finding indicates that a positive self-concept cannot compensate for a lack of gf, but it supports the acquisition of domain-specific knowledge in case of high gf, probably because it facilitates overcoming challenges.

Trichinellosis and cysticercosis remain challenges to human health and animal productivity worldwide, especially in developing countries. While information on the occurrence of both diseases is infrequent, they are endemic in parts of Vietnam and mainly related to indigenous pigs kept by ethnic minorities. This study aimed to determine the seroprevalence and risk factors of both diseases in indigenous pigs and explore the perception and awareness of both human and pig trichinellosis and cysticercosis of pig farmers. A total of 352 pig sera samples from 131 holdings were collected and analyzed using ELISA antibody tests in six communes in the Da Bac districts of Hoa Binh province, Vietnam. A survey was conducted with representatives from these households to understand the knowledge and perspective on food-borne parasitic diseases. Overall, the seroprevalence of trichinellosis and T. solium cysticercosis was 13.6% (95% CI 10.2–17.7) and 1.7% (95% CI 0.6–3.7), respectively. The seroprevalence of trichinellosis was significantly higher in female and older pigs. Risk perception and knowledge of interviewed people on both human and pig trichinellosis and cysticercosis of pig farmers was poor. Risky practices, including free roaming of pigs and eating undercooked or fermented pork, were observed. Educational and awareness campaigns aligned with further research on feasible practice changes are critical to addressing these issues.

Equine arteritis virus (EAV), an enveloped positive-strand RNA virus, is an important pathogen of horses and the prototype member of the Arteiviridae family. Unlike many other enveloped viruses, which possess homotrimeric spikes, the spike responsible for cellular tropism in Arteriviruses is a heterotrimer composed of 3 glycoproteins: GP2, GP3, and GP4. Together with the hydrophobic protein E they are the minor components of virus particles. We describe the expression of all 3 minor glycoproteins, each equipped with a different tag, from a multi-cassette system in mammalian BHK-21 cells. Coprecipitation studies suggest that a rather small faction of GP2, GP3, and GP4 form dimeric or trimeric complexes. GP2, GP3, and GP4 co-localize with each other and also, albeit weaker, with the E-protein. The co-localization of GP3-HA and GP2-myc was tested with markers for ER, ERGIC, and cis-Golgi. The co-localization of GP3-HA was the same regardless of whether it was expressed alone or as a complex, whereas the transport of GP2-myc to cis-Golgi was higher when this protein was expressed as a complex. The glycosylation pattern was also independent of whether the proteins were expressed alone or together. The recombinant spike might be a tool for basic research but might also be used as a subunit vaccine for horses.

The COVID-19 pandemic may have caused people to feel isolated, left out, and in need of companionship. Effective strategies to cope with such unrelenting feelings of loneliness are needed. In times of COVID-19, we conducted a smartphone-based ecological momentary assessment (EMA) study with 280 lonely participants in Germany over 7 months, where a long and hard second national lockdown was in place. Each participant reported their daily loneliness and coping strategies for loneliness once in the evening for 7 consecutive days. We found that managing emotions and social relationships were associated with decreased feelings of loneliness, while using a problem-focused coping strategy was associated with increased feelings of loneliness amid COVID-19. Interestingly, managing emotions was particularly effective for easing loneliness during the second lockdown. Females tend to use more emotion-focused coping strategies to overcome their loneliness compared to males. Our study highlights the importance of managing emotions against loneliness throughout the COVID-19 pandemic in Germany. Designing technology that provides emotional support to people may be one of the keys to easing loneliness and promoting well-being.

Background: Overseas Filipino workers (OFWs) is one of the largest communities of international migrant workers. They face systemic barriers to fulfilling their health needs. The COVID-19 pandemic worsened this condition and provided a context to evaluate the utility of a digital mental health intervention delivered within a stepped-care model to address OFW mental health. Using an implementation science framework, this study aimed to evaluate stakeholders’ perspectives on the implementation of Kumusta Kabayan, a mobile phone-based mental health app, for OFWs in Macao.

Methods: A mixed-methods convergent design was used by conducting two parallel steps, including quantitative and qualitative measures. The quantitative data was collected from Filipino team members and local non-governmental organization (NGO) staff members (N = 12). The qualitative data were gathered from interviews with OFWs in Macao who used the app (N = 25; 80% females, 76% domestic workers).

Results: From the online survey, the staff members of the local partner NGO and the Filipino team members strongly perceived that their organization could adapt Kumusta Kabayan to their program and generally evaluated that Kumusta Kabayan achieved its goal and was received well by OFWs. In the interviews, the OFW app users shared their experiences in using Kumusta Kabayan, which was thematically organized into six aspects of the participants’ experience: (1) promotional channel and expectation; (2) when to use the app and in what language; (3) lessons learnt; (4) memorable aspects; (5) key facilitators and barriers; and (6) suggestions.

Conclusion: Kumusta Kabayan was well accepted and shows potential to be integrated into the existing support services for OFWs in Macao. This app has the promise of being scaled-up for OFWs in other countries by collaborating with local and overseas stakeholders. Lessons learnt from this evaluation could also be implemented in wider digital mental health services in different settings.

Whether TERT promoter mutation is related to more aggressive clinicopathologic features and worse outcomes in papillary thyroid carcinoma patients (PTCs) is still variable and controversial. Our intention was to investigate the risk or prognostic factors that may additionally predict the TERT promoter mutation doable of these lesions and new prevention techniques in PTCs. A total of 2,539 PTC patients with 11.50% TERT mutation have been analyzed using Revman 5.3 software in this study. The PubMed and Embase databases were systematically searched for works published until November 9, 2021. The following variables had been associated with an extended chance of TERT promoter mutation in PTC patients: age < 45 years (MD = 10.93, 95%CI = 7.25-14.61); gender = male (pooled OR = 1.63, 95%CI = 1.17-2.28); tumor size > 1 cm (MD = 0.56, 95%CI = 0.34-0.77); lymph node metastasis (pooled OR = 1.29, 95%CI = 0.93-1.79); vascular invasion (pooled OR=1.78, 95%CI = 0.83-3.84); extrathyroidal extension (pooled OR = 2.00, 95%CI = 1.32-3.02); distant metastasis (pooled OR = 1.46, 95%CI = 1.04-2.04); advanced TNM stage (pooled OR = 3.19, 95%CI = 2.28-4.45). In addition, multifocality (pooled OR = 0.67, 95%CI = 0.14-3.24) had no affiliation with TERT promoter mutation in PTC patients. Our finding showed that age < 45 years, male, tumor size > 1 cm, lymph node metastasis, vascular invasion, and superior/advanced TNM stage were dangerous elements for TERT promoter mutation of worse effect in PTCs while that multifocality was once negatively correlated. TERT promoter mutation is drastically associated with recurrence and PTC-related mortality.

The semi-arid steppe and forest-steppe regions of southern Siberia have a long history of human occupation. During the Bronze and Iron Ages, the area became home to a number of archaeological cultures that greatly influenced the cultural and technological development and exchange processes in the middle latitudes of Eurasia and left a rich archaeological record. One of the lesser-known Iron Age archaeological cultures is the Tashtyk culture, which flourished in the Minusinsk Basin in the upper reaches of the Yenisei during the 1st to 7th centuries CE. Using an extensive set of radiocarbon dates and identifications of plant and animal remains from the best-preserved and most spectacular Grave 4 of the Oglakhty burial ground, our study aims to improve the age determination of the examined grave and to better understand the natural environments and way of life of the local population in this remote region of Central Asia during the early 1st millennium CE. Our dating approach could narrow down the probabilistic age range of the time at which Grave 4 was constructed and used to ca. 250–300 CE. The inferred age together with polychrome jin silks documented in Grave 4 suggests a connection between the local populations and silk producing centres in eastern China via either oases-states in the Tarim and Turfan basins or via the Mongolian steppes. The records of zooarchaeological remains and artefacts approve that the local Tashtyk people were skilful craftsmen and had a complex subsistence economy mainly based on animal husbandry, which was supplemented by hunting-gathering and small-scale agriculture. The available evidence on the use of sheep indicates that they played an important role in the local economy, although other domesticated animals (such as goats, cattle, horses) were bred as well. Whether reindeer were present locally (i.e. domesticated) or their skins were obtained through hunting or more distant exchange requires further investigation. Also, the role of agriculture and millet cultivation (mentioned in the reports of the first archaeological excavations) remains an important topic for upcoming research. The available, albeit still rare, palaeoenvironmental records from the region suggest drier conditions during the 4th to 1st centuries BCE, partly corresponding to a colder and dryer phase in the North Atlantic region. The regional pollen and isotope records demonstrate a weak trend towards wetter and warmer climate during the following five centuries representing the Tashtyk culture.

Rapidly evolving floods are rare but powerful drivers of landscape reorganisation that have severe and long-lasting impacts on both the functions of a landscape’s subsystems and the affected society. The July 2021 flood that particularly hit several river catchments of the Eifel region in western Germany and Belgium was a drastic example. While media and scientists highlighted the meteorological and hydrological aspects of this flood, it was not just the rising water levels in the main valleys that posed a hazard, caused damage, and drove environmental reorganisation. Instead, the concurrent coupling of landscape elements and the wood, sediment, and debris carried by the fast-flowing water made this flood so devastating and difficult to predict. Because more intense floods are able to interact with more landscape components, they at times reveal rare non-linear feedbacks, which may be hidden during smaller events due to their high thresholds of initiation. Here, we briefly review the boundary conditions of the 14–15 July 2021 flood and discuss the emerging features that made this event different from previous floods. We identify hillslope processes, aspects of debris mobilisation, the legacy of sustained human land use, and emerging process connections and feedbacks as critical non-hydrological dimensions of the flood. With this landscape scale perspective, we develop requirements for improved future event anticipation, mitigation, and fundamental system understanding.

Pulmonary hemorrhage (P-Hem) occurs among multiple species and can have various causes. Cytology of bronchoalveolar lavage fluid (BALF) using a 5-tier scoring system of alveolar macrophages based on their hemosiderin content is considered the most sensitive diagnostic method. We introduce a novel, fully annotated multi-species P-Hem dataset, which consists of 74 cytology whole slide images (WSIs) with equine, feline and human samples. To create this high-quality and high-quantity dataset, we developed an annotation pipeline combining human expertise with deep learning and data visualisation techniques. We applied a deep learning-based object detection approach trained on 17 expertly annotated equine WSIs, to the remaining 39 equine, 12 human and 7 feline WSIs. The resulting annotations were semi-automatically screened for errors on multiple types of specialised annotation maps and finally reviewed by a trained pathologist. Our dataset contains a total of 297,383 hemosiderophages classified into five grades. It is one of the largest publicly available WSIs datasets with respect to the number of annotations, the scanned area and the number of species covered.

Biological invasions may result from multiple introductions, which might compensate for reduced gene pools caused by bottleneck events, but could also dilute adaptive processes. A previous common-garden experiment showed heritable latitudinal clines in fitness-related traits in the invasive goldenrod Solidago canadensis in Central Europe. These latitudinal clines remained stable even in plants chemically treated with zebularine to reduce epigenetic variation. However, despite the heritability of traits investigated, genetic isolation-by-distance was non-significant. Utilizing the same specimens, we applied a molecular analysis of (epi)genetic differentiation with standard and methylation-sensitive (MSAP) AFLPs. We tested whether this variation was spatially structured among populations and whether zebularine had altered epigenetic variation. Additionally, we used genome scans to mine for putative outlier loci susceptible to selection processes in the invaded range. Despite the absence of isolation-by-distance, we found spatial genetic neighborhoods among populations and two AFLP clusters differentiating northern and southern Solidago populations. Genetic and epigenetic diversity were significantly correlated, but not linked to phenotypic variation. Hence, no spatial epigenetic patterns were detected along the latitudinal gradient sampled. Applying genome-scan approaches (BAYESCAN, BAYESCENV, RDA, and LFMM), we found 51 genetic and epigenetic loci putatively responding to selection. One of these genetic loci was significantly more frequent in populations at the northern range. Also, one epigenetic locus was more frequent in populations in the southern range, but this pattern was lost under zebularine treatment. Our results point to some genetic, but not epigenetic adaptation processes along a large-scale latitudinal gradient of S. canadensis in its invasive range.

Prominent excursions in the number of cosmogenic nuclides (e.g., 10Be) around 774 CE/775 document the most severe solar proton event (SPE) throughout the Holocene. Its manifestation in ice cores is valuable for geochronology, but also for solar-terrestrial physics and climate modeling. Using the ECHAM/MESSy Atmospheric Chemistry (EMAC) climate model in combination with the Warning System for Aviation Exposure to SEP (WASAVIES), we investigate the transport, mixing, and deposition of the cosmogenic nuclide 10Be produced by the 774 CE/775 SPE. By comparing the model results to the reconstructed 10Be time series from four ice core records, we study the atmospheric pathways of 10Be from its stratospheric source to its sink at Earth's surface. The reconstructed post-SPE evolution of the 10Be surface fluxes at the ice core sites is well captured by the model. The downward transport of the 10Be atoms is controlled by the Brewer-Dobson circulation in the stratosphere and cross-tropopause transport via tropopause folds or large-scale sinking. Clear hemispheric differences in the transport and deposition processes are identified. In both polar regions the 10Be surface fluxes peak in summertime, with a larger influence of wet deposition on the seasonal 10Be surface flux in Greenland than in Antarctica. Differences in the peak 10Be surface flux following the 774 CE/775 SPE at the drilling sites are explained by specific meteorological conditions depending on the geographic locations of the sites.

Many exposed high-pressure meta-serpentinites comprise a channelized network of olivine-rich veins that formed during dehydration at depth and allowed the fluid to escape from the dehydrating rock. While previous studies have shown that chemical heterogeneities in rocks can control the formation of olivine-enriched vein-like interconnected porosity networks on the sub-millimeter scale, it is still unclear how these networks evolve toward larger scales and develop nearly pure olivine veins. To explore this, we study the effect of reactive fluid flow on a dehydrating serpentinite. We use thermodynamic equilibrium calculations to investigate the effect of variations in the bulk silica content in serpentinites on the dehydration reaction of antigorite + brucite = olivine + fluid and the silica content of this fluid phase. Further, we develop a numerical model that combines the effects of intrinsic chemical heterogeneities with reactive transport with dissolved silica as metasomatic agent. Our model shows how reactive transport can lead to vein widening and olivine enrichment within a vein in an antigorite-rich matrix, such as observed in the veins of the Erro Tobbio meta-serpentinites. This is a critical step in the evolution toward larger-scale vein systems and in the evolution of dynamic porosity, as this step helps account for the chemical feedback between the dehydrating rock and the liberated fluid.

Background: Acetylsalicylic acid (ASA) may cause difficult-to-treat symptoms of the airways, skin, or gastrointestinal tract in hypersensitive patients. Due to the chemical relationship between salicylic acid and ASA, a role of a low-salicylate diet has been discussed.

Methods: This review evaluates whether low salicylate diets are meaningful from an allergological or nutritional–physiological perspective.

Results: The body’s arachidonic acid metabolism plays a crucial role in the pathogenesis of ASA intolerance. Despite their chemical affinity, ASA and salicylic acid affect the arachidonic pathway differently. The intake of salicylic acid with food is low compared to therapeutic doses of ASA. There is increasing evidence that protective effects of a high fruit and vegetables diet is related in part to the intake of salicylates. In salicylatelow diets, fruit and vegetables are reduced, harboring the risk of an insufficient diet and malnutrition.

Conclusion: Dietary therapy in ASA-intolerant patients is not recommended.

Throughout the last decades, integration programmes in Western Europe have centrally revolved around debates on Muslim populations and the institutionalization of Islam. The concept of integration has become a master paradigm with which to structure plurality of immigration societies across Western Europe. Critically reflecting this inflation, this article argues that the integration of Muslims is animated by a contingent liberal-secular matrix through which the sovereign state, in close connection with civil society, is enabled to decide what counts as proper and improper religion. Integration directed toward Muslims as a “religious minority” is therefore indicative of the very problems that it purports to resolve. In a genealogical vein, the article begins by suggesting that integration is a liberal “recursion” of earlier projects of minority management such as assimilation and conditional recognition within emerging nation-states. It argues that the epistemological ground which animated the assimilatory forces of the modern nation-state has been intimately bound by an imperial knowledge order which classifies and hierarchizes people along a race-religion nexus. The analysis continues by dwelling on contemporary examples of state organized dialog with Muslims, and more specifically the establishment of Islamic Theology Chairs at state universities. Through these examples the article shows that the institutionalization of Islam in Europe reconfigures a pattern which conditionally embraces religious difference, while at the same time continuing hierarchical rankings and by transforming it to make it fit for religion's legitimate place in public life. Finally, the article suggests that the somatic aspirations prevalent in assimilation projects and imperial race-religion constellations are both inscribed and concealed in the frequent invocation of Muslims to reveal their loyalty to the liberal-secular contract by bracketing their religious sensibilities for the sake of secular reason.

Recent progress in studies of holographic dualities, originally motivated by insights from string theory, has led to a confluence with concepts and techniques from quantum information theory. A particularly successful approach has involved capturing holographic properties by means of tensor networks which not only give rise to physically meaningful correlations of holographic boundary states, but also reproduce and refine features of quantum error correction in holography. This topical review provides an overview over recent successful realizations of such models. It does so by building on an introduction of the theoretical foundations of AdS/CFT and necessary quantum information concepts, many of which have themselves developed into independent, rapidly evolving research fields.

A new genus, Caucasoseris, is established to accommodate Prenanthes abietina, a species of hitherto uncertain systematic position distributed in the western Caucasus and northeasternmost Turkey in montane conifer and mixed forests. Agreement has existed that the species belongs somewhere in the Crepidinae or Lactucinae but its morphological features do not match any genus and previous molecular phylogenetic analyses could not establish its sister group. This study provides additional micro- and macromorphological, palynological and anatomical data, and used a molecular phylogenetic sampling designed to ascertain its relationship. A sister group relationship with the Chondrillinae is inferred from the phylogenetic tree based on nrITS. In the plastid DNA tree, where the Chondrillinae are resolved as a clade nested inside the Crepidinae, the species is resolved further remote from the Chondrillinae clade and in a rather early diverging position of the Crepidinae. In agreement also with the anatomical and micro- and macromorphological findings, it is considered an orphan lineage with affinities to the Chondrillinae, best treated as a genus of its own. A key to the genera of the Chondrillinae including Caucasoseris is provided.

Quality early childhood development (ECD) settings that address children's needs holistically provide safe and nurturing opportunities for children to thrive. We evaluated, through a quasi-experimental design, the impact of a social-emotional skills-building program (Pisotón) across ECD centers in Colombia. Developmental outcomes of children participating in Pisotón (n = 37) for 12 weeks were compared to those of children who did not participate in the program (n = 37) using the International Development and Early Learning Assessment (IDELA) measure and the Child Behavior Checklist (CBCL). The results show that participation in Pisotón significantly increased children's social-emotional development score by 0.37 standard deviation units as assessed by IDELA. Study implications are discussed.

In many songbird species, young birds learn their song from adult conspecifics. Like much animal communication, birdsong is multimodal: singing is accompanied by beak and body movements. We hypothesized that these visual cues could enhance vocal learning thus partly explaining the reduced learning from unimodal audio playbacks compared to multimodal live social tutoring observed in many birdsong studies. To test this, juvenile zebra finches, Taeniopygia guttata, were tutored in a yoked design where replicate tutoring groups of three male–female dyads were exposed to the same live tutor simultaneously in three different ways. (1) Tutees were housed with the tutor in a central compartment; hence they could hear, see and interact with their tutor (‘live’). (2) Tutees placed in one of two adjacent compartments could hear but not see the same tutor from behind a black loudspeaker cloth (‘audio-only’). (3) Tutees could likewise hear the tutor through loudspeaker cloth but could also see the tutor through a one-way mirror (‘audiovisual’). Comparisons of subadult and adult song showed more changes in the audio-only than in the audiovisual or live tutored tutees, suggesting the audio-only group's song development was delayed. According to (blinded) human observer similarity scoring, the audio-only tutees' singing was least similar and the live tutees' singing most similar to their tutor's singing, while the audiovisual tutees showed an intermediate level of similarity, but the between-treatment differences in similarity were not significant. Conversely, the audio-only group showed the highest similarity values with their father's song, which they only heard before the experimental tutoring. Given that the quantity and quality of the tutor song input were the same across treatments within tutoring groups, the results support the hypothesis that visual in addition to auditory exposure to a tutor can affect the timing and possibly also the amount of vocal learning.