Miracle-dz/UniFAR-FTUs huggingface dataset:
Goblet cell interactions reorient bundled mucus strands for efficient airway clearance

Abstract The respiratory tract of larger animals is cleared by sweeping bundled strands along the airway surface. These bundled strands can be millimetric in length and consist of MUC5B mucin. They are produced by submucosal glands, and upon emerging from these glands, the long axis of the bundled strands is oriented along the cilia-mediated flow toward the oral cavity. However, after release, the bundled strands are found to have turned orthogonal to the flow, which maximizes their clearance potential. How this unexpected reorientation is accomplished is presently not well understood. Recent experiments suggest that the reorientation process involves bundled strands sticking to MUC5AC mucus threads, which are tethered to the goblet cells. Such goblet cells are present in small numbers throughout the airway epithelium. Here, we develop a minimal model for reorientation of bundled mucus strands through adhesive interactions with surface goblet cells. Our simulations reveal that goblet cell interactions can reorient the bundled strands within 10 mm of release—making reorientation on the length scale of the tracheal tube feasible—and can stabilize the orthogonal orientation. Our model also reproduces other experimental observations such as strong velocity fluctuations and significant slow-down of the bundled strand with respect to the cilia-mediated flow. We further provide insight into the strand turning mechanism by examining the effect of strand shape on the impulse exerted by a single goblet cell. We conclude that goblet cell–mediated reorientation is a viable route for bundled strand reorientation, which should be further validated in future experiment.
Diagnostic accuracy of the 5.07 monofilament test for diabetes polyneuropathy: influence of age, sex, neuropathic pain and neuropathy severity

Introduction There is a need for simple and cheap diagnostic tools for diabetic polyneuropathy (DPN). We aimed to assess the diagnostic accuracy of the 5.07/10 g monofilament test in patients referred to polyneuropathy assessments, as well as to examine how disease severity, age, sex and neuropathic pain (NP) impact diagnostic accuracy. Research design and methods Five Norwegian university hospitals recruited patients with diabetes aged 18–70 referred to neurological outpatient clinics for polyneuropathy assessments. The 5.07/10 g Semmes-Weinstein monofilament examination (SWME) was validated against the Toronto consensus for diagnosing diabetic neuropathies; the results were stratified by age, sex and NP. Disease severity was graded by a combined nerve conduction study (NCS) Z-score, and logistic regression was applied to assess whether disease severity was a predictor of diagnostic accuracy. Results In total, 506 patients were included in the study. Global sensitivity was 0.60 (95% CI 0.55, 0.66), specificity 0.82 (95% CI 0.75, 0.87), positive and negative predictive values were 0.86 (95% CI 0.81, 0.90) and 0.52 (95% CI 0.46, 0.58), respectively, positive and negative likelihood ratios were 3.28 (95% CI 2.37, 4.53) and 0.49 (95% CI 0.42, 0.57), respectively. The SWME was less sensitive in females (0.43), had lower specificity in patients with NP (0.56), and performed worse in patients ≥50 years. NCS-based disease severity did not affect diagnostic accuracy (OR 1.15, 95% CI 0.95, 1.40). Conclusions This multicenter study demonstrates poor diagnostic performance for the 5.07/10 g SWME in patients with diabetes referred to polyneuropathy assessments; it is particularly unsuited for female patients and those with NP. The diagnostic accuracy of the SWME was not influenced by NCS-based disease severity, demonstrating that it does not perform better in patients with later stages of DPN. We do not recommend the use of the 5.07/10 g monofilament in the evaluation of patients with diabetes referred to polyneuropathy assessments.
A Swiss digital Delphi study on patient-reported outcomes.

AIMS OF THE STUDY Health-related quality of life (HRQoL) indicators are patient-reported outcomes (PROs). PROs are defined as any report of the status of a patient's health condition or health behaviour that comes directly from the patient, without interpretation of the patient's response by a clinician or anyone else. Despite Swiss national bodies (FOPH, FMH) recognising the potential of PRO measures (PROMs) for improving the health system, no consensus has yet emerged regarding a generic PROM framework or specific domains for practical uptake. The aim of the present digital Delphi study was to generate a consensual Swiss expert opinion on a generic PROM framework, measurement domains and items from a validated instrument (PROMIS [Patient-Reported Outcome Measurement Information System]) as well as on the role and implementation of PROs in the Swiss healthcare system via PRO consensus statements. METHODS A 4-round digital Delphi study was conducted among Swiss PRO stakeholders. A total of n = 21 Swiss PROM stakeholders completed round 1 surveys on the PROM framework. During the stakeholder meeting, n = 11 stakeholders completed round 2 and round 3 surveys pertaining to measurement domains and items, respectively. In-meeting key questions and discussion items were extracted, consolidated into statements and subjected to consensus voting in a round 4, post-meeting survey. Consensus was defined as ≥70% agreement. RESULTS Pre-meeting, agreement was reached for the tripartite framework of physical, mental and social health (95-100%). During the meeting, agreement was reached on all seven measurement domains of a generic PROM (PROMIS-29), ranging from 80% (Anxiety, Sleep Disturbance) to 100% (Pain Interference, Depression, Ability to Participate in Social Roles). Consensus was also reached for all PROMIS-29 items, with average domain consensus ranging from 83% (Sleep Disturbance, Ability to Participate in Social Roles) to 100% (Depression). Finally, four post-meeting consensus statements regarding PROs in Switzerland reached agreement. CONCLUSIONS A Delphi method can help identify areas of need regarding PROMs in Switzerland. The current study identified a generic PROM as a missing quality indicator for the Swiss national health system's value. A pre-meeting informational briefing, expert presentations and moderation supported three voting rounds to help identify PROMIS-29 as a PROM framework (round 1), measurement domains (round 2) and items (round 3) as a basis for further validation research. The empirical agreement among diverse stakeholders supports broad consensus towards preliminary feasibility of integrating generic PROMs into the Swiss health system based on content relevance.
The copenhagen cross-linguistic naming test (C-CLNT): Development and validation in a multicultural memory clinic population

Abstract Objective: Despite recent advances in cross-cultural neuropsychological test development, suitable tests for cross-linguistic assessment of language functions are not widely available. The aims of this study were to develop and validate a brief naming test, the Copenhagen Cross-Linguistic Naming Test (C-CLNT), for the assessment of culturally, linguistically, and educationally diverse older adult populations in Europe. Method: The C-CLNT was based on a set of standardized color drawings. Items for the C-CLNT were selected by considering name agreement and frequency across five European and two non-European languages. Ambiguities in some of the selected items and scoring criteria were resolved after pilot testing in 10 memory clinic patients. The final 30-item C-CLNT was validated by verifying its psychometric properties in 24 controls and 162 diverse memory clinic patients with affective disorder, mild cognitive impairment, and with dementia. Results: The C-CLNT had acceptable scale reliability (coefficient alpha = .67) and good construct validity, with moderate to strong correlations with traditional language tests (r = .42– .75). Diagnostic accuracy for dementia was good and significantly better than that of the Boston Naming Test (areas under the curve of .80 vs .64, p < .001), but was poor for mild cognitive impairment. Only 3% of the variance in C-CLNT test scores was explained by immigrant background, while 6% was explained by age and years of education. In comparison, these proportions were 34 and 22% for the BNT. Conclusions: The C-CLNT has promising clinical utility for cross-linguistic assessment of naming impairment in culturally, linguistically, and educationally diverse older adults.
Psychopharmakotherapie mit dem MAO-Hemmer Tranylcypromin Schwerpunkte und Trends aus Theorie und Praxis

Zusammenfassung Der irreversible Monoaminoxidase-Hemmer Tranylcypromin ist seit mehr als 60 Jahren als Antidepressivum bekannt. Ziel dieses Übersichtsartikels ist die Bestimmung des Standes der Wissenschaft und Therapie von Tranylcypromin. Dafür wird die aktuelle Fachliteratur ausgewertet und hinsichtlich gegenwärtiger Schwerpunkte und allgemeiner Trends der praktischen Psychopharmakotherapie eingeordnet. Im Ergebnis kann Tranylcypromin heute durch neue Metaanalysen kontrollierter Studien als gut etabliert für die Behandlung der therapieresistenten Depression gelten. Die Dosierung (Maximaldosis, Erhaltungsdosis) wird zunehmend für Anforderungen der therapieresistenten Depression angepasst. Die Monoaminoxidase ist nicht nur primäre pharmakologische Zielstruktur von Tranylcypromin sondern bestimmt zu Therapiebeginn als arzneistoffmetabolisierendes Enzym enantioselektiv auch die Pharmakokinetik des Monoaminoxidase-Hemmers. Mit zunehmender Diversität der antidepressiven Pharmakotherapie ist eine fortwährende Zuordnung von Tranylcypromin als therapeutische „ultima ratio“ bei Depression überdenkenswert. Es wird geschlussfolgert, dass Tranylcypromin als Mittel der zweiten Wahl eine wertvolle Option der antidepressiven Therapie bleibt. Die Kriterien für eine Umstellung von anderen Antidepressiva auf den Monoaminoxidase-Hemmer müssen noch besser definiert werden.
Perceptual control or action-selection? Comment on: a perceptual control theory of emotional action

ABSTRACT The Perceptual Control Theory of Emotional Action provides a compelling view of the synergy between action and perception in the context of emotion. In this invited response, we outline three suggestions to further clarify and concretesise the theory in the hope that it can provide a solid basis for the theoretical, empirical, and clinical fields of emotion and emotion regulation. First, we emphasise the importance of concretesising these ideas in a way that is biologically plausible and testable in terms of its neuronal implementation, which has not been addressed in the main manuscript. Secondly, we highlight the challenges for this account to effectively describe core symptoms in emotional disorders, an essential step if the theory aims to foster the development of better-tuned neurocognitively grounded interventions. Finally, we take a leap on what action-oriented accounts of emotion can mean for the field of emotion regulation.
Prolonged water limitation shifts the soil microbiome from copiotrophic to oligotrophic lifestyles in Scots pine mesocosms

Abstract Reductions in soil moisture due to prolonged episodes of drought can potentially affect whole forest ecosystems, including soil microorganisms and their functions. We investigated how the composition of soil microbial communities is affected by prolonged episodes of water limitation. In a mesocosm experiment with Scots pine saplings and natural forest soil maintained at different levels of soil water content over 2 years, we assessed shifts in prokaryotic and fungal communities and related these to changes in plant development and soil properties. Prolonged water limitation induced progressive changes in soil microbial community composition. The dissimilarity between prokaryotic communities at different levels of water limitation increased over time regardless of the recurrent seasons, while fungal communities were less affected by prolonged water limitation. Under low soil water contents, desiccation‐tolerant groups outcompeted less adapted, and the lifestyle of prokaryotic taxa shifted from copiotrophic to oligotrophic. While the abundance of saprotrophic and ligninolytic groups increased alongside an accumulation of dead plant material, the abundance of symbiotic and nutrient‐cycling taxa decreased, likely impairing the development of the trees. Overall, prolonged episodes of drought appeared to continuously alter the structure of microbial communities, pointing to a potential loss of critical functions provided by the soil microbiome.
Acute stress symptoms in general population during the first wave of COVID lockdown in Italy: Results from the COMET trial

The coronavirus disease of 2019 (COVID‐19) pandemic is an unprecedented traumatic event that has severely impacted social, economic, and health well‐being worldwide. The COvid Mental hEalth Trial was specifically designed to evaluate the impact of the COVID‐19 pandemic and its containment measures on the mental health of the Italian general population in terms of COVID‐19‐related acute stress disorder (ASD) symptoms.
Recent progress in understanding the cellular and genetic basis of plant responses to low oxygen holds promise for developing flood-resilient crops

Abstract With recent progress in active research on flooding and hypoxia/anoxia tolerance in native and agricultural crop plants, vast knowledge has been gained on both individual tolerance mechanisms and the general mechanisms of flooding tolerance in plants. Research on carbohydrate consumption, ethanolic and lactic acid fermentation, and their regulation under stress conditions has been accompanied by investigations on aerenchyma development and the emergence of the radial oxygen loss barrier in some plant species under flooded conditions. The discovery of the oxygen-sensing mechanism in plants and unravelling the intricacies of this mechanism have boosted this very international research effort. Recent studies have highlighted the importance of oxygen availability as a signalling component during plant development. The latest developments in determining actual oxygen concentrations using minute probes and molecular sensors in tissues and even within cells have provided new insights into the intracellular effects of flooding. The information amassed during recent years has been used in the breeding of new flood-tolerant crop cultivars. With the wealth of metabolic, anatomical, and genetic information, novel holistic approaches can be used to enhance crop species and their productivity under increasing stress conditions due to climate change and the subsequent changes in the environment.
AEP-cleaved DDX3X induces alternative RNA splicing events to mediate cancer cell adaptation in harsh microenvironments

Oxygen and nutrient deprivation are common features of solid tumors. Although abnormal alternative splicing (AS) has been found to be an important driving force in tumor pathogenesis and progression, the regulatory mechanisms of AS that underly the adaptation of cancer cells to harsh microenvironments remain unclear. Here, we found that hypoxia- and nutrient deprivation–induced asparagine endopeptidase (AEP) specifically cleaved DDX3X in a HIF1A-dependent manner. This cleavage yields truncated carboxyl-terminal DDX3X (tDDX3X-C), which translocates and aggregates in the nucleus. Unlike intact DDX3X, nuclear tDDX3X-C complexes with an array of splicing factors and induces AS events of many pre-mRNAs; for example, enhanced exon skipping (ES) in exon 2 of the classic tumor suppressor PRDM2 leads to a frameshift mutation of PRDM2. Intriguingly, the isoform ARRB1-Δexon 13 binds to glycolytic enzymes and regulates glycolysis. By utilizing in vitro assays, glioblastoma organoids, and animal models, we revealed that AEP/tDDX3X-C promoted tumor malignancy via these isoforms. More importantly, high AEP/tDDX3X-C/ARRB1-Δexon 13 in cancerous tissues was tightly associated with poor patient prognosis. Overall, our discovery of the effect of AEP-cleaved DDX3X switching on alternative RNA splicing events identifies a mechanism in which cancer cells adapt to oxygen and nutrient shortages and provides potential diagnostic and/or therapeutic targets.
Overcoming the congenitally disadvantageous mutation through adaptation to environmental UV exposure in land snails

Congenital fitness-disadvantageous mutations are not maintained in the population; they are purged from the population through processes such as purifying selection. However, these mutations could persist in the population as polymorphisms when it is advantageous for the individuals carrying them in adapting to a specific external environment. We tested this hypothesis using the dimorphic land snail Euhadra peliomphala simodae in Japan; these snails have dark or bright coloured shells. The survival rate of dark snails at hatching was lower than that of the bright ones, as observed in the F1 progenies produced through crossing. Dark snails have a congenital fitness-disadvantageous mutation; however, they also have protection against ultraviolet radiation. They have a higher survival rate than the bright snails in a UV environment, as observed using the UV exposure experiments and UV transmittance measurements. This is a good example of a congenitally disadvantageous mutation that is advantageous for adapting to the external environment. These results explain the maintenance of polymorphism and highlight the genotypic and phenotypic diversity in the wild population.
Interaction of species A rotavirus VP4 with the cellular proteins vimentin and actin related protein 2 discovered by a proximity interactome assay

ABSTRACT Rotavirus (RV) is one of the most significant pathogens in humans and animals with diarrhea worldwide. Cell entry is the first step in viral infection, and the outer capsid protein VP4 is crucial for RV attachment and internalization. In order to discover novel candidate host factors involved in RV cell entry, a proximity labeling method was applied to systematically investigate the VP4 and host protein interactions. A total of 174 high-confidence host proteins were identified using proximity labeling. Further analysis showed that 88 proteins were located in the cytoskeleton, plasma membrane, and extracellular region, which could be involved in RV entry. Importantly, vimentin (VIM) and actin-related protein 2 (ACTR2) were identified to promote RV infection at an early step. The results of co-immunoprecipitation assay showed that VIM or ACTR2 physically interacted with VP4. Blocking VIM or ACTR2 function by silencing with small interfering RNA or inhibition by specific antibodies significantly restricted RV infection. Furthermore, increasing the amounts of VIM or ACTR2 by overexpression from transfected recombinant proteins or incubation with recombinant proteins promoted RV infection. Collectively, this study revealed that RV VP4 interacted with host proteins and demonstrated that interaction with VIM and ACTR2 promoted RV replication, providing valuable resources and potential drug targets for better understanding and treating this disease. IMPORTANCE Rotavirus (RV) is an important zoonosis virus, which can cause severe diarrhea and extra-intestinal infection. To date, some proteins or carbohydrates have been shown to participate in the attachment or internalization of RV, including HGBAs, Hsc70, and integrins. This study attempted to indicate whether there were other proteins that would participate in the entry of RV; thus, the RV VP4-interacting proteins were identified by proximity labeling. After analysis and verification, it was found that VIM and ACTR2 could significantly promote the proliferation of RV in intestinal cells. Through further viral binding assays after knockdown, antibody blocking, and recombinant protein overexpression, it was revealed that both VIM and ACTR2 could promote RV replication. Rotavirus (RV) is an important zoonosis virus, which can cause severe diarrhea and extra-intestinal infection. To date, some proteins or carbohydrates have been shown to participate in the attachment or internalization of RV, including HGBAs, Hsc70, and integrins. This study attempted to indicate whether there were other proteins that would participate in the entry of RV; thus, the RV VP4-interacting proteins were identified by proximity labeling. After analysis and verification, it was found that VIM and ACTR2 could significantly promote the proliferation of RV in intestinal cells. Through further viral binding assays after knockdown, antibody blocking, and recombinant protein overexpression, it was revealed that both VIM and ACTR2 could promote RV replication.
Evolution of the Hidaka metamorphic belt, northern Japan

The Hidaka metamorphic belt is a tilted island-arc assembly of crustal layers developed during early to middle Tertiary age. The P-T estimates of metamorphic rocks in the amphibolite and granulite facies reveal a relatively high geothermal gradient (40°C km−1), possibly caused by the large amount of gabbroic intrusions, at an early evolutional stage of the crust. The crust was subsequently displaced subhorizontally from north to south, giving rise to detachment of lower to upper crustal layers from the lowest crust, and to the formation of a duplex of crustal metamorphic layers. This was followed by dextral transpression in which the crustal layers were uplifted and tilted steeply eastward. Geological setting In Hokkaido, northern Japan, there are two Cretaceous arc-trench systems; one occupies the western part of Hokkaido and the other occupies the eastern part (Fig. 1). The western system consists of the Oshima granitic-volcanic terrane and the Sorachi-Yezo subduction-accretionary terrane on the eastern side where the Kamuikotan serpentinite melange with high-P/T schists occurs. Westward subduction occurred during early to late Cretaceous time (Okada 1982, Kiminami & Kontani 1983, Ishizuka et al. 1983). The eastern system is composed of the Tokoro subduction-accretion terrane which is situated on the western side of the Nemuro volcanic terrane. This northeast-ward subduction was active in the late Cretaceous (Sakakibara 1986, Sakakibara et al. 1986). Late Cretaceous accretionary complexes of both arc-trench systems are juxtaposed in the central part of Hokkaido where the Hidaka metamorphic belt occurs (Fig. 1). A collision between the two arc-trench
Pressure Regime in the Upper Cretaceous Shales and Sandstones in the Washakie Basin, Wyoming

Abstract The Upper Cretaceous shales in the Washakie Basin below a depth of 9000 ± 1000 feet typically are overpressured. The change of pressure regime from normally pressured to overpressured coincides with marked changes in the geochemical and geophysical properties of the Upper Cretaceous rock/fluid system, as reflected in increases in acoustic transit time, hydrocarbon production index, vitrinite reflectance, aromaticity of kerogen, progressive clay diagenesis, displacement pressure, and sealing capacity of the fine-grained rocks. The Upper Cretaceous shale section in the Washakie Basin below 9000 ± 1000 feet is overpressured on a basinwide scale. The driving mechanism of the pressure compartmentalization is the generation and storage of liquid hydrocarbons that subsequently react to gas, converting the fluid-flow system to a multiphase regime in which capillarity controls permeability. Sandstone bodies within the overpressured shale section are subdivided stratigraphically and diagenetically into relatively small, isolated, gas saturated, anomalously pressured compartments. The major difference between pressure compartmentalization in the Upper Cretaceous shale and the sandstone bodies is one of scale. In both cases, the major driving mechanism of compartmentalization is hydrocarbon generation, storage, and subsequent reaction. In the Washakie Basin, the abnormally pressured sandstones are gas saturated. The most significant aspect of developing prospects in the gas saturated portion of the basin is the delineation of gas storage capacity and deliverability in the potential reservoir target.