Miracle-dz/UniFAR-FTUs huggingface dataset:
Low prevalence of diagnosed asthma in Greenland – a call for increased focus on diagnosing

ABSTRACT The aim of this study was to estimate prevalence of patients with asthma in Greenland according to age, gender and residence and to investigate the associated quality of care. The study was performed as a cross-sectional study with data extracted from the Greenlandic electronical medical record. A total of 870 patients aged 12 years or above were diagnosed with asthma at the end of 2022, corresponding to a prevalence of 1.9%. In 2020, the total prevalence was 0.2%. The prevalence of patients aged 12 years or above with asthma was highest among patients in Nuuk (3.3%) compared with patients in the remaining parts of Greenland (1.1%). More women than men were diagnosed with asthma, and the prevalence increased with age from 20 to 59 years. The prevalence of current smokers was high among the asthma population. The quality of care was significantly higher among patients living in Nuuk for all process indicators compared with patients from the remaining parts of Greenland. The prevalence of asthma in Greenland is low compared to other comparable populations and might be underestimated. Initiatives supporting increased focus on diagnosing asthma are thus warranted.
Optical spectroscopy of a complete sample of southern 2-Jy radio sources

We present optical spectra for a complete sample of radio galaxies and quasars comprising all sources from the Wall & Peacock 2.7-GHz sample with redshifts z<0.7 and declinations δ<+10°; this sample is complete down to a flux density of 2 Jy. Although not all of the 2-Jy sources have spectroscopic redshifts, we argue that most of the unidentified objects are at high redshifts and that our z<0.7 sample is largely complete. The optical data will be analysed in a future paper
Multi‐Targeting DKK1 and LRP6 Prevents Bone Loss and Improves Fracture Resistance in Multiple Myeloma

An imbalance between bone resorption and bone formation underlies the devastating osteolytic lesions and subsequent fractures seen in more than 90% of multiple myeloma (MM) patients. Currently, Wnt‐targeted therapeutic agents that prevent soluble antagonists of the Wnt signaling pathway, sclerostin (SOST) and dickkopf‐1 (DKK1), have been shown to prevent bone loss and improve bone strength in preclinical models of MM. In this study, we show increasing Wnt signaling via a novel anti–low‐density lipoprotein receptor‐related protein 6 (LRP6) antibody, which potentiates Wnt1‐class ligand signaling through binding the Wnt receptor LRP6, prevented the development of myeloma‐induced bone loss primarily through preventing bone resorption. When combined with an agent targeting the soluble Wnt antagonist DKK1, we showed more robust improvements in bone structure than anti‐LRP6 treatment alone. Micro–computed tomography (μCT) analysis demonstrated substantial increases in trabecular bone volume in naïve mice given the anti‐LRP6/DKK1 combination treatment strategy compared to control agents. Mice injected with 5TGM1eGFP murine myeloma cells had significant reductions in trabecular bone volume compared to naïve controls. The anti‐LRP6/DKK1 combination strategy significantly improved bone volume in 5TGM1‐bearing mice by 111%, which was also superior to anti‐LRP6 single treatment; with similar bone structural changes observed within L4 lumbar vertebrae. Consequently, this combination strategy significantly improved resistance to fracture in lumbar vertebrae in 5TGM1‐bearing mice compared to their controls, providing greater protection against fracture compared to anti‐LRP6 antibody alone. Interestingly, these improvements in bone volume were primarily due to reduced bone resorption, with significant reductions in osteoclast numbers and osteoclast surface per bone surface demonstrated in 5TGM1‐bearing mice treated with the anti‐LRP6/DKK1 combination strategy. Importantly, Wnt stimulation with either single or combined Wnt‐targeted agents did not exacerbate tumor activity. This work provides a novel approach of targeting both membrane‐bound and soluble Wnt pathway components to provide superior skeletal outcomes in patients with multiple myeloma and other bone destructive cancers. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
A Qualitative Analysis of Hospitalist Perceptions of Self-Directed Discharge Among Inpatients with Opioid Use Disorder

Abstract Background: People with opioid use disorder (OUD) have high rates of hospital admissions and high rates of patient-directed discharge, leading to significant morbidity and mortality. In this study, we aimed to understand hospitalist attitudes toward patients with OUD leaving before treatment completion and their willingness to collaborate with patients in future initiatives focused on improving the experience of hospital-based care for patients with OUD. Methods: We conducted semi-structured interviews with hospitalists at two hospitals in Philadelphia, PA to explore their perspectives on social and structural factors that contribute to patients with OUD leaving the hospital before treatment completion. Interviews were recorded, transcribed, and coded with NVivo using conventional content analysis. Results: Twenty-two hospitalists (64% female, 72.7% White, mean age 37) were interviewed between February and April 2021. Hospitalists listed the following as reasons for patients with OUD leaving before treatment completion: untimely and inadequate pain/withdrawal treatment, limited prescribing options in medications for OUD, restrictive visitor and smoking policies, and patient social and other obligations. Twenty out of 22 hospitalists were willing to engage in collaborative patient-centered care but noted institutional barriers. Conclusion: Hospitalists stated willingness to collaborate with patients on identifying and developing systems-level solutions that would allow for patient-centered care. In-hospital access to addiction consult service, staff with lived experience, and other culturally competent resources are key to reducing self-directed discharge, as is training to address stigma and reframe perceptions of appropriate dosing for pain and withdrawal. Hospitalists note a need for transitions to outpatient care after hospital discharge.
Detrimental effects of sickle cell disease and hydroxycarbamide on ovarian reserve but uncertain impact on fertility

We read with interest the recent report by Pecker et al. 1 Concomitantly with their work, we studied the ovarian reserve in women with severe sickle cell disease. Our objective was to characterize the impact of sickle cell disease and its treatments on the ovarian reserve and fertility in this context. Our ﬁ ndings were generally in line with those of Pecker et al but extended the latter ’ s conclusions and shed new light on the physiopathology of diminished ovarian reserve in sickle cell disease
Phenotypic and transcriptomic impact of expressing mammalian TET2 in the Drosophila melanogaster model

ABSTRACT Ten-Eleven Translocation (TET) proteins have recently come to light as important epigenetic regulators conserved in multicellular organisms. TET knockdown studies in rodents have highlighted the critical role of these proteins for proper brain development and function. Mutations in mammalian mTET proteins and mTET2 specifically are frequent and deregulated in leukaemia and glioma respectively. Accordingly, we examined the role of mTET2 in tumorigenesis in larval haemocytes and adult heads in Drosophila melanogaster. Our findings showed that expression of mutant and wild type mTET2 resulted in general phenotypic defects in adult flies and accumulation of abdominal melanotic masses. Notably, flies with mTET2-R43G mutation at the N-terminus of mTET2 exhibited locomotor and circadian behavioural deficits, as well as reduced lifespan. Flies with mTET2-R1261C mutation in the catalytic domain, a common mutation in acute myeloid leukaemia (AML), displayed alterations affecting haemocyte haemostasis. Using transcriptomic approach, we identified upregulated immune genes in fly heads that were not exclusive to TET2 mutants but also found in wild type mTET2 flies. Furthermore, inhibiting expression of genes that were found to be deregulated in mTET2 mutants, such as those involved in immune pathways, autophagy, and transcriptional regulation, led to a rescue in fly survival, behaviour, and hemocyte number. This study identifies the transcriptomic profile of wild type mTET2 versus mTET2 mutants (catalytic versus non-catalytic) with indications of TET2 role in normal central nervous system (CNS) function and innate immunity.
The influence of maxillary incisor angles on the stress distributions of temporomandibular joints under incisal biting

The incisal biting was one of the most regular jaw activities. The direction of bite force on the incisor tip and the mandible position were relevant to the incisor angle as biting. This study was carried out to explore the influence on the temporomandibular joint (TMJ) caused by the incisor angle.
Cholinergic depolarization recruits a persistent Ca2+ current in Aplysia bag cell neurons.

Many behaviors and types of information storage are mediated by lengthy changes in neuronal activity. In bag cell neurons of the hermaphroditic sea snail, Aplysia californica, a transient cholinergic synaptic input triggers an ~30 min afterdischarge. This causes these neuroendocrine cells to release egg laying hormone and elicit reproductive behavior. When acetylcholine is pressure-ejected onto a current-clamped bag cell neuron, the evoked depolarization is far longer than the current evoked by acetylcholine under voltage-clamp, suggesting recruitment of another conductance. Our earlier studies found bag cell neurons to display a voltage-dependent persistent Ca2+ current. Hence, we hypothesized that this current is activated by the acetylcholine-induced depolarization, and sought a selective Ca2+ current blocker. Rapid Ca2+ current evoked by 200-ms depolarizing steps in voltage-clamped, cultured bag cell neurons demonstrated a concentration-dependent sensitivity to Ni2+, Co2+, Zn2+, and verapamil but not Cd2+ or -conotoxin GIVa. Leak subtraction of Ca2+ current evoked by 10-s depolarizing steps using the IC100 of Ni2+, Co2+, Zn2+, or verapamil revealed persistent Ca2+ current, demonstrating persistent current block. Only Co2+ and Zn2+ did not suppress the acetylcholine-induced current, although Zn2+ appeared to impact additional channels. When Co2+ was applied during an acetylcholine-induced depolarization, the amplitude was reduced; furthermore, protein kinase C activation, previously established to enhance the persistent Ca2+ current, extended the depolarization. Therefore, the persistent Ca2+ current sustains the acetylcholine-induced depolarization and may translate brief cholinergic input into afterdischarge initiation. This could be a general mechanism of triggering long-term change in activity using a short-lived input.
A One Health review of aerodigestive disease in dogs

Abstract This review article seeks to define and describe aerodigestive disease in dogs, and review current and emerging methods of diagnostic evaluation. Aspiration of gastric contents into the respiratory tract is associated with the development and progression of numerous respiratory diseases in humans. In veterinary medicine the term “aspiration” is considered synonymous with “aspiration pneumonia” which, while frequently encountered, does not accurately reflect the breadth of aspiration associated respiratory syndromes (AARS). In the clinical veterinary literature, the effect of alimentary dysfunction on respiratory disease and vice versa (aerodigestive disease) is rarely investigated despite evidence in the human literature, animal models, and some studies and case reports linking alimentary and respiratory disease in small animals. Current methods of investigating aerodigestive diseases in veterinary patients are limited by inadeqate sensitivity or specificity, potential for bias, cost, and availability. This necessitates investigations into advanced diagnostics to identify potentially underrecognized animals with AARS. Additionally, similarities in anatomy, physiology, and several disorders between dogs and humans, make experimental and naturally occurring canine models of AARS integral to translational research. Thus, evaluating dogs with aerodigestive disease might represent an area of substantial clinical relevance in human as well as veterinary medicine.
On the origins of sleep disordered breathing, cardiorespiratory and metabolic dysfunction: which came first, the chicken or the egg?

Sleep disordered breathing (SDB) is a complex, sex specific and highly heterogeneous group of respiratory disorders. Nevertheless, sleep fragmentation and repeated fluctuations of arterial blood gases for several hours per night are at the core of the problem; together, they impose significant stress to the organism with deleterious consequences on physical and mental health. SDB increases the risk of obesity, diabetes, depression and anxiety disorders; however, the same health issues are risk factors for SDB. So, which came first, the chicken or the egg? What causes the appearance of the first significant apnoeic events during sleep? These are important questions because although moderate to severe SDB affects ∼500 million adults globally, we still have a poor understanding of the origins of the disease, and the main treatments (and animal models) focus on the symptoms rather than the cause. Because obesity, metabolic dysfunction and stress‐related neurological disorders generally appear progressively, we discuss how the development of these diseases can lead to specific anatomical and non‐anatomical traits of SDB in males and females while considering the impacts of sex steroids. In light of the growing evidence indicating that the carotid bodies are important sensors of key metabolic and endocrine signals associated with stress and dysmetabolism, we propose that these organs play a key role in the process.
The Arp2/3 complex enhances cell migration on elastic substrates

Cell migration on soft surfaces occurs in both physiological and pathological processes such as corticogenesis during embryonic development and cancer invasion and metastasis. The Arp2/3 complex in neural progenitor cells was previously demonstrated to be necessary for cell migration on soft elastic substrate but not on stiff surfaces, but the underlying mechanism was unclear. Here, we integrate computational and experimental approaches to elucidate how the Arp2/3 complex enables cell migration on soft surfaces. We found that lamellipodia comprised of a branched actin network nucleated by the Arp2/3 complex distribute forces over a wider area, thus decreasing stress in the substrate. Additionally, we found that interactions between parallel focal adhesions within lamellipodia prolong cell–substrate interactions by compensating for the failure of neighboring adhesions. Together with decreased substrate stress, this leads to the observed improvements in migratory ability on soft substrates in cells utilizing lamellipodia-dependent mesenchymal migration when compared with filopodia-based migration. These results show that the Arp2/3 complex–dependent lamellipodia provide multiple distinct mechanical advantages to gliomas migrating on soft 2D substrates, which can contribute to their invasive potential.
Gut bacteria influence Blastocystis sp. phenotypes and may trigger pathogenicity

Whilst the influence of intestinal microbiota has been shown in many diseases such as irritable bowel syndrome, colorectal cancer, and aging, investigations are still scarce on its role in altering the nature of other infective organisms. Here we studied the association and interaction of Blastocystis sp. and human intestinal microbiota. In this study, we investigated the gut microbiome of Blastocystis sp. -free and Blastocystis sp. ST3-infected individuals who are symptomatic and asymptomatic. We tested if the expression of phenotype and pathogenic characteristics of Blastocystis sp. ST3 was influenced by the alteration of its accompanying microbiota. Blastocystis sp. ST3 infection alters bacterial composition. Its presence in asymptomatic individuals showed a significant effect on microbial richness compared to symptomatic ones. Inferred metagenomic findings suggest that colonization of Blastocystis sp. ST3 could contribute to the alteration of microbial functions. For the first time, we demonstrate the influence of bacteria on Blastocystis sp. pathogenicity. When Blastocystis sp. isolated from a symptomatic individual was co-cultured with bacterial suspension of Blastocystis sp. from an asymptomatic individual, the parasite demonstrated increased growth and reduced potential pathogenic expressions. This study also reveals that Blastocystis sp. infection could influence microbial functions without much effect on the microbiota diversity itself. Our results also demonstrate evidence on the influential role of gut microbiota in altering the characteristics of the parasite, which becomes the basis for the contradictory findings on the parasite’s pathogenic role seen across different studies. Our study provides evidence that asymptomatic Blastocystis sp. in a human gut can be triggered to show pathogenic characteristics when influenced by the intestinal microbiota.
Baicalein suppresses HER2‐mediated malignant transformation of HER2‐overexpressing ovarian cancer cells by downregulating HER2 gene expression

The upregulation of the HER2 oncogene is associated with a variety of human cancers and is associated with poor prognosis. Baicalein is reported to have anti‐tumor activity, but the molecular mechanism of this effect in HER2‐positive cancer cells has not been studied. In this study, our data showed that baicalein can inhibit the proliferation and transformation potential of ovarian cancer cells overexpressing HER2. Baicalein treatment caused a dose‐dependent inhibition of HER2 gene expression at the transcriptional level. Baicalein acted on ovarian cancer cells overexpressing HER2 to downregulate the PI3K/Akt signaling pathway downstream of HER2 and inhibit the expression or activity of downstream targets, such as VEGF and cyclin D1 and MMP2. Oral administration of baicalein supplemented with a pharmaceutical excipient significantly inhibited the growth of HER2‐overexpressing ovarian SKOV‐3 cancer xenografts in mice. These results suggest that downregulation of HER2 gene expression by baicalein at the transcriptional level contributes to inhibit the in vitro and in vivo proliferation and HER2‐mediated malignant transformation of HER2‐overexpressing ovarian cancer cells.
The NK1 antagonist L-733,060 facilitates sequence learning

Background: Although several brain regions and electrophysiological patterns have been related to sequence learning, less attention has been paid to the role that different neuromodulators play. Aims: Here we sought to investigate the role of substance P (SP) in sequence learning in an operant conditioning preparation, supported by a reinforcement learning model. Methods: Two experiments were performed to test the effects of an NK1 receptor (at which SP primarily acts) antagonist on learning and performing action sequences. In experiment 1, rats were trained to perform an action sequence until stable performance was achieved, and then, in phase 2, they were switched to perform the reverse sequence. In experiment 2, rats were trained to perform an action sequence, and in phase 2, they continued to do the same sequence. In both experiments in the first 3 days of phase 2, rats were injected with an NK1 receptor antagonist (L-733,060, i.p.) or with vehicle. Additionally, we developed a reinforcement learning model which allowed the in silico replication of our experimental tasks. Results: We found that administering an NK1 receptor antagonist weakened the stable retention of a well-learned sequence, allowing the faster acquisition of a new sequence, without impairing the continued performance of a crystallized sequence. Using our reinforcement learning model, we suggest that SP could be acting through the state value learning rate, modulating the effects of the reward prediction error. Conclusions: Our results suggest that SP could be involved in the consolidation of a sequence representation through a modulatory effect on the reward prediction error.
Biphasic reinforcement of nascent adhesions by vinculin

Vinculin is an integral component of integrin adhesions, where it functions as a molecular clutch coupling intracellular contraction to the extracellular matrix. Quantitating its contribution to the reinforcement of newly forming adhesions, however, requires ultrasensitive cell force assays covering short time and low force ranges. Here, we have combined atomic force microscopy‐based single‐cell force spectroscopy (SCFS) and optical tweezers force spectroscopy to investigate the role of vinculin in reinforcement of individual nascent adhesions during the first 5 min of cell contact with fibronectin or vitronectin. At minimal adhesion times (5‐10 s), mouse embryonic fibroblast (MEF) wildtype (wt) and vinculin knock‐out (vin(−/−)) cells develop comparable adhesion forces on the scale of several individual integrin‐ligand bonds, confirming that vinculin is dispensable for adhesion initiation. In contrast, after 60 to 120 s, adhesion strength and traction reinforce quickly in wt cells, while remaining low in vin(−/−) cells. Re‐expression of full‐length vinculin or a constitutively active vinculin mutant (vinT12) in MEF vin(−/−) cells restored adhesion and traction with the same efficiency, while vinculin with a mutated talin‐binding head region (vinA50I) or missing the actin‐binding tail‐domain (vin880) was ineffective. Integrating total internal reflection fluorescence imaging into the SCFS setup furthermore enabled us to correlate vinculin‐green fluorescent protein (GFP) recruitment to nascent adhesion sites with the built‐up of vinculin‐dependent adhesion forces directly. Vinculin recruitment and cell adhesion reinforcement followed synchronous biphasic patterns, suggesting vinculin recruitment, but not activation, as the rate‐limiting step for adhesion reinforcement. Combining sensitive SCFS with fluorescence microscopy thus provides insight into the temporal sequence of vinculin‐dependent mechanical reinforcement in nascent integrin adhesions.
Structural insights into constitutive activity of 5-HT6 receptor

Significance GPCR display agonist-independent signaling transduction that is known as constitutive activity. 5-HT6R has a high level of constitutive activity which is related to the therapy of neuropsychiatric disorders. However, the mechanism of constitutive activity is still poorly understood. Therefore, we report serotonin-bound 5-HT6R-Gs complex structure, and illuminate the two structural determinants required for constitutive 5-HT6R activity: 1) The interhelical hydrogen bond between T2806.47 and N3127.45 in 5-HT6R that abolished the negative allosteric modulator-Na+ and 2) a pair of equally charged amino acids (R3258.48 from the receptor/R389 from Gαs) that experienced a repulsive force to facilitate receptor activation. This structural information has enabled the design of a receptor-specific nanobody-NB6A1 that was found to reduce the receptor’s basal activity.