Miracle-dz/UniFAR-FTUs huggingface dataset:
Disease progression of spinocerebellar ataxia types 1, 2, 3 and 6 before and after ataxia onset

Our aim was to study the evolution of ataxia and neurological symptoms before and after ataxia onset in the most common spinocerebellar ataxias (SCAs), SCA1, SCA2, SCA3 and SCA6. We therefore jointly analysed the data of the EUROSCA and RISCA studies, which recruited ataxic and non‐ataxic mutation carriers.
For-Profit Businesses as Public Health Partners to Promote COVID-19 Vaccination

Health professionals employed by large businesses served as public health partners to encourage uptake of COVID-19 vaccines during the pandemic. Objective This study aimed to describe the actions used by health professionals employed by large, for-profit businesses to promote uptake of COVID-19 vaccines, and factors that facilitated and hindered coordination with local public health leaders. Methods In this qualitative multiple case study, we conducted telephone interviews with health professionals from businesses, health department leaders, and others who could provide information about local vaccination efforts (e.g., emergency managers, reporters). Results Businesses' self-interest (i.e., need to keep employees working), vaccine mandates, and characteristics of the businesses (e.g., ownership, expertise) facilitated leadership in COVID-19 vaccination efforts. Coordination with local health departments was influenced by the resources of the local health department and history of collaboration. Conclusions Health professionals employed by large businesses can serve as key public health partners, but their role is shaped by characteristics of the businesses and communities.
BRD4 PROTAC degrader MZ1 exhibits anti-B-cell acute lymphoblastic leukemia effects via targeting CCND3

ABSTRACT Introduction B-cell acute lymphoblastic leukemia (B-ALL) is the most prevalent malignant tumor affecting children. While the majority of B-ALL patients (90%) experience successful recovery, early relapse cases of B-ALL continue to exhibit high mortality rates. MZ1, a novel inhibitor of Bromodomains and extra-terminal (BET) proteins, has demonstrated potent antitumor activity against hematological malignancies. The objective of this study was to examine the role and therapeutic potential of MZ1 in the treatment of B-ALL. Methods In order to ascertain the fundamental mechanism of MZ1, a sequence of in vitro assays was conducted on B-ALL cell lines, encompassing Cell Counting Kit 8 (CCK8) assay, Propidium iodide (PI) staining, and Annexin V/PI staining. Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) were employed to examine protein and mRNA expression levels. Transcriptomic RNA sequencing (RNA-seq) was utilized to screen the target genes of MZ1, and lentiviral transfection was employed to establish stably-expressing/knockdown cell lines. Results MZ1 has been observed to induce the degradation of Bromodomain Containing 4 (BRD4), Bromodomain Containing 3 (BRD3), and Bromodomain Containing 2 (BRD2) in B-ALL cell strains, leading to inhibited cell growth and induction of cell apoptosis and cycle arrest in vitro. These findings suggest that MZ1 exhibits cytotoxic effects on two distinct molecular subtypes of B-ALL, namely 697 (TCF3/PBX1) and RS4;11 (MLL-AF4) B-ALL cell lines. Additionally, RNA-sequencing analysis revealed that MZ1 significantly downregulated the expression of Cyclin D3 (CCND3) gene in B-ALL cell lines, which in turn promoted cell apoptosis, blocked cell cycle, and caused cell proliferation inhibition. Conclusion Our results suggest that MZ1 has potential anti-B-ALL effects and might be a novel therapeutic target.
Age-specific sex ratios: Examining rural–urban variation within low- and middle-income countries

The balance of men and women in society, captured by sex ratios, determines key social and demographic phenomena. Previous research has explored sex ratios mainly at birth and up to age five at national level, whereas we address rural–urban gaps in sex ratios for all ages. Our measures are based on the United Nations data on rural and urban populations by age and sex for 112 low- and middle-income countries in 2015. We show that rural sex ratios are higher than urban sex ratios among children and older people, whereas at working ages, urban areas are dominated by males. Our analysis suggests that the urban transition itself is not driving the gap in rural–urban sex ratios. Rather, internal migration seems to be key in shaping rural–urban sex ratio divergence in sub-Saharan Africa, while both internal migration and mortality differentials appear to be the predominant mechanisms driving sex ratio gaps in Latin America.
Pulmonary pulse transit time as the first sign of pulmonary arterial hemodynamics alteration

Pulse wave transit time is the duration of the pulse wave to travel from one artery to another; it is a standard, well-known measurement in an arterial segment of the systemic arterial circulation. However, in the last years, it was proven to have the same role in the pulmonary circulation in pulmonary disease as pulmonary hypertension, pulmonary fibrosis, or inflammatory systemic diseases associated with pulmonary hypertension as systemic sclerosis. 1 Pulmonary pulse transit time (PPTT) was defined as the time it takes the pulse wave to travel from the right ventricle (RV) through the pulmonary artery (PA) to the left ventricle through the right superior pulmonary vein. Pulse wave velocity (PWV) is the speed at which the pulse wave travels along an arterial vascular tree; it is inversely correlated with arterial compliance. Therefore, while arterial compliance decreases, the value of PWV increases and that of the pulse transit time shortens. Both, pulse transit time and PWV are clinical surrogates for arterial hemodynamics abnormalities assessment. 1 In addition, in clinical practice, both parameters could be assessed accurately and easily by noninvasive imaging techniques such as transthoracic echocardiography. 1 Arterial stiffness (modified by arteriosclerosis) increases with age while pulse transit time, as well as pulmonary vascular and left ventricular compliance, decreases with age. It is an echocardiographic parameter, which is assessed in pulsed Doppler as the interval between the peak of the S wave of the right superior pulmonary veins flow and the R wave on the electrocardiogram. Almost
Unravelling the internal architecture of the Alnö alkaline and carbonatite complex (central Sweden) using 3D models of gravity and magnetic data

Abstract. The Alno complex in central Sweden is one of the largest alkaline and carbonatite ring-shaped intrusions in the world. Presented here is the 3D inversion of ground gravity and aeromagnetic data that confirms some of the previous ideas about the 3D geometry of the complex but also suggests that the complex may continue laterally further to north than earlier expected. The gravity and aeromagnetic data show the complex as (i) a strong positiver Bouguer anomaly, around 20 mGal, one of the strongest gravity gradients observed in Sweden, and (ii) a strong positive magnetic anomaly, exceeding 2000 nT. Magnetic structures are clearly discernible within the complex and surrounding area. Petrophysical measurements (density, bulk magnetic susceptibility, and magnetic remanence) were used to constrain the 3D inversion. Both gravity and magnetic inversion models suggest that dense (> 2850 kg/m3) and magnetic (> 0.05 SI) rocks extend down to about 3.5–4 km depth. Previous studies have suggested a solidified magma reservoir at this approximate depth. The inversion models further suggest that two apparently separate regions within the intrusion with gravity and magnetic highs are likely connected at depth, starting from 800–1000 m, implying a common source for the rocks observed in these two regions. The modelling of the aeromagnetic data indicates that a more than 3 km wide ring-shaped magnetic high in the bay that can be a hidden part of the complex, linking a satellite intrusion in Soraker on the northern side of the bay to the main intrusion on the Alno Island. While the rim of the ring must consist of highly susceptible rocks to support the magnetic anomaly, the centre has a relatively low magnetisation and is probably made up of low-susceptible wall-rocks or metasomatised wall-rocks down to about 2 km. Below this depth the 3D susceptibility model shows higher magnetic susceptibility values. From these observations the solidified magma chamber is interpreted to extend further to north than has previously been suggested.
Nitrogen Subsidies in Glacial Meltwater: Implications for High Elevation Aquatic Chains

In certain alpine systems, glacially‐fed lakes and streams have nitrate concentrations one to two orders of magnitude higher than lakes and streams fed by snowmelt alone. To better understand how nitrogen subsidies from glacial meltwater propagate down a chain of lakes and streams we assessed the effects of these subsidies in a set of aquatic chains in the central U.S. Rocky Mountains. Algal biomass, algal community assemblage, and nutrient limitation were measured in a chain of lakes and streams fed by glacial meltwater (GSF) and a chain fed by snowmelt alone (SF). Nitrate ( NO3– ) concentrations in the GSF chain ranged from 228 to 70 μg L−1 declining from the top of the chain to the bottom, while NO3– concentrations in the SF chain were consistently low, < 9 μg L−1. In the glacial chain, both lakes were phosphorus‐limited; the strength of this limitation signal weakened down the chain, with the lake at the bottom showing secondary nitrogen and phosphorus colimitation. In the snowmelt chain, lakes were colimited with no change in strength down the chain. Algal biomass averaged 2.6 μg L−1 and 7.3 μg m−2 in SF lakes and streams and 5.4 μg L−1 and 9.2 μg m−2 in GSF lakes and streams. Phytoplankton and periphyton communities in the GSF chain were more homogeneous compared to the SF chain. Our results indicate nutrient subsidies in glacial meltwaters can propagate down aquatic chains and alter nutrient limitation patterns and algal communities compared to SF systems, creating heterogeneous patterns across the landscape.
The koala (Phascolarctos cinereus) prostate: a comprehensive histological and immunohistochemical investigation

Abstract The prostate of the koala (Phascolarctos cinereus), and of marsupials more generally, is the primary contributor of seminal fluid, yet comparatively little is known about its microanatomy or biochemistry. This study explored evidence of parenchymal segmentation of the koala prostate. The prostate of three sexually mature koalas were processed for histopathology, histochemistry (Masson's trichrome, Alcian Blue, periodic acid Schiff staining), and immunohistochemistry using basal (tumor protein 63, cytokeratin 14) and luminal (cytokeratin 8/18, prostate specific antigen, androgen receptor) markers. Results confirmed clear segmentation of the koala prostate into three zones, anterior, central, and posterior, characterized by differences in the proportion of glandular tissue, as well as the thickness of collagen fibers; there were also distinct differences in the secretions produced in each zone. Based on immunohistochemistry, the koala prostate showed evidence of both basal proliferative and luminal secretory cells. The ratio of cell types varied across the three segments, with the central segment housing the highest density of basal cells. Globular bodies produced in the anterior zone were shown to possess the same markers as those described for human prostasomes. This study is the first to comprehensively document the marsupial prostate in terms of microanatomy and corresponding immunohistochemistry. While further biochemical analysis, such as proteomics of each segment will better define the relative functions of each tissue, the data presented here are consistent with the hypothesis that the koala prostate potentially represents an example of an ontological stage in the evolutionary differentiation of male eutherian accessory glands. Summary Sentence This is the first study to comprehensively document a marsupial prostate in terms of microanatomy and corresponding immunohistochemistry. Graphical Abstract
Mirikizumab-Induced Transcriptome Changes in Ulcerative Colitis Patient Biopsies at Week 12 Are Maintained Through Week 52

INTRODUCTION: Mirikizumab, an anti-interleukin-23p19 monoclonal antibody, demonstrated efficacy in phase 2 and 3 randomized clinical trials of patients with moderate-to-severe ulcerative colitis (UC). Previous results have shown that 12 weeks of mirikizumab treatment downregulated transcripts associated with UC disease activity and tumor necrosis factor inhibitor resistance. We assessed week-52 gene expression from week-12 responders receiving mirikizumab or placebo. METHODS: In the phase 2 AMAC study (NCT02589665), mirikizumab-treated patients achieving week-12 clinical response were rerandomized to mirikizumab 200 mg subcutaneous every 4 or 12 weeks through week 52 (N = 31). Week-12 placebo responders continued placebo through week 52 (N = 7). The limma R package clustered transcript changes in colonic mucosa biopsies from baseline to week 12 into differentially expressed genes (DEGs). Among DEGs, similarly expressed genes (DEGSEGs) maintaining week-12 expression through week 52 were identified. RESULTS: Of 89 DEGSEGs, 63 (70.8%) were present only in mirikizumab induction responders, 5 (5.6%) in placebo responders, and 21 (23.6%) in both. Week-12 magnitudes and week-52 consistency of transcript changes were greater in mirikizumab than in placebo responders (log2FC > 1). DEGSEG clusters (from 84 DEGSEGs identified in mirikizumab and mirikizumab/placebo responders) correlated to modified Mayo score (26/84 with Pearson correlation coefficient [PCC] >0.5) and Robarts Histopathology Index (55/84 with PCC >0.5), sustained through week 52. DISCUSSION: Mirikizumab responders had broader, more sustained transcriptional changes of greater magnitudes at week 52 vs placebo. Mirikizumab responder DEGSEGs suggest a distinct molecular healing pathway associated with mirikizumab interleukin-23 inhibition. The cluster's correlation with disease activity illustrates relationships between clinical, endoscopic, and molecular healing in UC.
Quadriceps and gluteus medius activity during stable and unstable loading exercises in athletes. A cross‐sectional study

The aim of this study was to evaluate the muscle activation of the vastus medialis, vastus lateralis, and gluteus medius during different strength and stability exercises with a water tank compared with a sandbag. A cross‐sectional study was conducted in the Functional Anatomy Laboratory, and the sample consisted of 28 athletes. The main outcome measures were surface electromyography (dependent variable), water tank and sandbag, and exercise type (independent variables): Isometric Single Leg Stance (ISLS), One Leg Deadlift (OLDL), Front Rack Forward Lunge (FRFL), and Lateral Lunge (LL). Repeated measures analysis of variance (ANOVA) revealed a significant Group × Time interaction in gluteus medius root mean square (RMS) (F = 14.198, p < 0.001, ŋ2 = 0.35), vastus lateralis RMS (F = 24.374, p < 0.001, ŋ2 = 0.47), and vastus medialis RMS (F = 27.261, p < 0.001, ŋ2 = 0.50). In the between‐group analysis, statistically significant differences were observed in gluteus medius RMS in the ISLS: 28.5 ± 15.8 water tank and 20.8 ± 12.6 sandbag (p < 0.001, ŋ2 = 0.08) and OLDL: 29.7 ± 13.3 water tank and 26.5 ± 13.1 sandbag (p < 0.001, ŋ2 = 0.01). In vastus lateralis in ISLS: 30.4 ± 37.6 water tank and 19.0 ± 26.7 sandbag (p < 0.001, ŋ2 = 0.03). In vastus medialis in ISLS: 14.2 ± 13.0 water tank and 7.0 ± 5.6 sandbag (p < 0.001, ŋ2 = 0.12), OLDL: 21.5 ± 16.9 water tank and 15.5 ± 10.7 sandbag (p = 0.002, ŋ2 = 0.04), and LL: 51.8 ± 29.6 water tank and 54.3 ± 29.3 sandbag (p = 0.017, ŋ2 = 0.00). These results confirm significantly greater activation of the gluteus medius and vastus medialis in the ISLS and OLDL exercises, and of the vastus lateralis in the water tank ISLS exercise. However, the vastus medialis shows greater activation in the LL exercise.
Respiratory Interoception and Pathological Illness Anxiety: Disentangling Bias

ABSTRACT Objective Biased interoception decoupled from physiology might be relevant in the etiology of pathological illness anxiety (PIA). Empirical evidence for interoceptive deviations in illness anxiety is scarce but potentially informative to optimize treatments. We hypothesized that persons with PIA differ fundamentally in the classification of bodily sensations from those without PIA. Methods In a respiratory categorization task, participants breathed into a pulmonary training device. Inspiration effort was varied by eight resistive loads. The lower/higher four loads were introduced as belonging to arbitrary categories “A”/”B,” respectively. Participants memorized respiratory sensations in a first experimental block and were asked to label the resistances in a second block. We calculated the sensitivity of resistance classification according to category and response bias in terms of categorical misclassification. Data of 39 participants with PIA and 35 controls were compared with regard to sensitivity and response bias by group, resistive load, and their interaction in a multiple regression. Results With similar sensitivity, patients more often labeled loads above the categorical border erroneously as belonging to category A, thus underestimating their resistance (β = −0.06, p = .001; η2 = 0.02). Conclusions Individuals with PIA showed a systematic “wait and see” approach. Altered respiroception in PIA might stem from biased perception during training phase, the recognition phase, biased memory, or a combination of these. Its exact characteristics remain unknown, and future research must address the challenge of developing reliable and valid paradigms accounting for the variability of interoceptive biases. Registration This work was preregistered on OSF (https://osf.io/9shcw).
Test–retest reliability of eye tracking measures in a computerized Trail Making Test

The Trail Making Test (TMT) is a frequently applied neuropsychological test that evaluates participants’ executive functions based on their time to connect a sequence of numbers (TMT-A) or alternating numbers and letters (TMT-B). Test performance is associated with various cognitive functions ranging from visuomotor speed to working memory capabilities. However, although the test can screen for impaired executive functioning in a variety of neuropsychiatric disorders, it provides only little information about which specific cognitive impairments underlie performance detriments. To resolve this lack of specificity, recent cognitive research combined the TMT with eye tracking so that eye movements could help uncover reasons for performance impairments. However, using eye-tracking-based test scores to examine differences between persons, and ultimately apply the scores for diagnostics, presupposes that the reliability of the scores is established. Therefore, we investigated the test–retest reliabilities of scores in an eye-tracking version of the TMT recently introduced by Recker et al. (2022). We examined two healthy samples performing an initial test and then a retest 3 days (n = 31) or 10 to 30 days (n = 34) later. Results reveal that, although reliabilities of classic completion times were overall good, comparable with earlier versions, reliabilities of eye-tracking-based scores ranged from excellent (e.g., durations of fixations) to poor (e.g., number of fixations guiding manual responses). These findings indicate that some eye-tracking measures offer a strong basis for assessing interindividual differences beyond classic behavioral measures when examining processes related to information accumulation processes but are less suitable to diagnose differences in eye–hand coordination.
Nineteen-year, real-world experience of first-line combination chemotherapy in patients with metastatic colorectal cancer: a propensity score analysis from southern Thailand

Objective Combination fluoropyrimidine-based chemotherapy is the standard first-line treatment for metastatic colorectal cancer (CRC). We performed a propensity score (PS)-based analysis to report our real-world experience with long-term follow-up of this regimen for metastatic CRC. Methods In this retrospective study, 170 patients with newly diagnosed metastatic CRC treated with first-line combination chemotherapy between January 2003 and March 2021 were identified. Cox proportional hazards regression analysis and PS-based approaches with the logistic regression model were adopted, and the results were compared. Results The hazard ratio for overall survival (OS) in the oxaliplatin- and irinotecan-based groups was 0.79 (95% confidence interval = 0.56–1.11), and the median OS times in these groups were 16.8 and 13.0 months, respectively. The median time to progression (TTP) for these regimens were 9.0 and 8.9 months, respectively. The objective response rates for the oxaliplatin- and irinotecan-based groups were 42.7% and 34.6%, respectively. OS and TTP did not differ between these regimens in all PS matching models. Conclusions First-line treatment using fluoropyrimidine-based chemotherapy regimens in combination with oxaliplatin or irinotecan in patients with metastatic CRC provided comparable efficacy and tolerable toxicity profiles in a real-world setting with long-term follow-up.
The Influence of Prestimulus 1/f-Like versus Alpha-Band Activity on Subjective Awareness of Auditory and Visual Stimuli

Alpha rhythmic activity is often suggested to exert an inhibitory influence on information processing. However, relatively little is known about how reported alpha-related effects are influenced by a potential confounding element of the neural signal, power-law scaling. In the current study, we systematically examine the effect of accounting for 1/f activity on the relation between prestimulus alpha power and human behavior during both auditory and visual detection (N = 27; 19 female, 6 male, 2 nonbinary). The results suggest that, at least in the scalp-recorded EEG signal, the difference in alpha power often reported before visual hits versus misses is probably best thought of as a combination of narrowband alpha and broadband shifts. That is, changes in broadband parameters (exponent and offset of 1/f-like activity) also appear to be strong predictors of the subsequent awareness of visual stimuli. Neither changes in posterior alpha power nor changes in 1/f-like activity reliably predicted detection of auditory stimuli. These results appear consistent with suggestions that broadband changes in the scalp-recorded EEG signal may account for a portion of prior results linking alpha band dynamics to visuospatial attention and behavior, and suggest that systematic re-examination of existing data may be warranted. Significance Statement Fluctuations in alpha band (∼8–12 Hz) activity systematically follow the allocation of attention across space and sensory modality. Increases in alpha amplitude, which often precede failures to report awareness of threshold visual stimuli, are suggested to exert an inhibitory influence on information processing. However, fluctuations in alpha activity are often confounded with changes in the broadband 1/f-like pattern of the neural signal. When both factors are considered, we find that changes in broadband activity are as effective as narrowband alpha activity as predictors of subsequent visual detection. These results are consistent with emerging understanding of the potential functional importance of broadband changes in the neural signal and may have significant consequences for our understanding of alpha rhythmic activity.