Miracle-dz/UniFAR-FTUs huggingface dataset:
Assembly and Maintenance of Sarcomere Thin Filaments and Associated Diseases

Sarcomere assembly and maintenance are essential physiological processes required for cardiac and skeletal muscle function and organism mobility. Over decades of research, components of the sarcomere and factors involved in the formation and maintenance of this contractile unit have been identified. Although we have a general understanding of sarcomere assembly and maintenance, much less is known about the development of the thin filaments and associated factors within the sarcomere. In the last decade, advancements in medical intervention and genome sequencing have uncovered patients with novel mutations in sarcomere thin filaments. Pairing this sequencing with reverse genetics and the ability to generate patient avatars in model organisms has begun to deepen our understanding of sarcomere thin filament development. In this review, we provide a summary of recent findings regarding sarcomere assembly, maintenance, and disease with respect to thin filaments, building on the previous knowledge in the field. We highlight debated and unknown areas within these processes to clearly define open research questions.
Biomechanics of the Human Brain During Dynamic Rotation of the Head.

Traumatic brain injuries (TBI) are a substantial societal burden. The development of better technologies and systems to prevent and/or mitigate the severity of brain injury requires an improved understanding of the mechanisms of brain injury, and more specifically, how head impact exposure relates to brain deformation. Biomechanical investigations have used computational models to identify these relations, but more experimental brain deformation data is needed to validate these models and support their conclusions. The objective of this study was to generate a dataset describing in situ human brain motion under rotational loading at impact conditions considered injurious. Six head-neck human post-mortem specimens, unembalmed and never frozen, were instrumented with 24 sonomicrometry crystals embedded throughout the parenchyma that can directly measure dynamic brain motion. Dynamic brain displacement, relative to the skull, was measured for each specimen with four loading severities in the three directions of controlled rotation, for a total of twelve tests per specimen. All testing was completed 42-72 hours post-mortem for each specimen. The final dataset contains approximately 5,000 individual point displacement time-histories that can be used to validate computational brain models. Brain motion was direction-dependent, with axial rotation resulting in the largest magnitude of displacement. Displacements were largest in the mid-cerebrum, and the inferior regions of the brain - the cerebellum and brainstem - experienced relatively lower peak displacements. Brain motion was also found to be positively correlated to peak angular velocity, and negatively correlated with angular velocity duration, a finding that has implications related to brain injury risk assessment methods. This dataset of dynamic human brain motion will form the foundation for the continued development and refinement of computational models of the human brain for predicting traumatic brain injury.
Mitochondrial Quality Control: Role in Cardiac Models of Lethal Ischemia-Reperfusion Injury

The current standard of care for acute myocardial infarction or ‘heart attack’ is timely restoration of blood flow to the ischemic region of the heart. While reperfusion is essential for the salvage of ischemic myocardium, re-introduction of blood flow paradoxically kills (rather than rescues) a population of previously ischemic cardiomyocytes—a phenomenon referred to as ‘lethal myocardial ischemia-reperfusion (IR) injury’. There is long-standing and exhaustive evidence that mitochondria are at the nexus of lethal IR injury. However, during the past decade, the paradigm of mitochondria as mediators of IR-induced cardiomyocyte death has been expanded to include the highly orchestrated process of mitochondrial quality control. Our aims in this review are to: (1) briefly summarize the current understanding of the pathogenesis of IR injury, and (2) incorporating landmark data from a broad spectrum of models (including immortalized cells, primary cardiomyocytes and intact hearts), provide a critical discussion of the emerging concept that mitochondrial dynamics and mitophagy (the components of mitochondrial quality control) may contribute to the pathogenesis of cardiomyocyte death in the setting of ischemia-reperfusion.
Dementia detection with a combination of informant-based and performance-based measures in low-educated and illiterate elderly migrants

Abstract Objective Detecting dementia in people who are illiterate or have a low level of education is complicated because many cognitive screening tests are not suitable for these persons. Caregiver or informant-based judgment of cognitive status may aid diagnosis. Our goal was to investigate the diagnostic accuracy of the Informant Questionnaire for Cognitive Decline in the Elderly (IQCODE) in a population of elderly non-Western migrants with a high illiteracy rate. Second, we wanted to investigate the diagnostic accuracy of IQCODE and Rowland Universal Dementia Screening (RUDAS) combined. Method 109 geriatric outpatients and 20 community controls were included. Geriatricians provided a research diagnosis of intact cognition (n = 27), mild cognitive impairment (MCI; n = 33) or dementia (n = 49). Diagnostic accuracy was calculated for the clinical sample (n = 109). ROC curves for prediction of group status for IQCODE, RUDAS and the combination of both were created. Results Predictive validity was high for both IQCODE and RUDAS and was highest for the combination (Area Under the Curve .91). Sensitivity, specificity, Youden index, predictive value, and likelihood ratio for IQCODE and RUDAS are reported. Conclusions In this study in non-Western elderly migrants, half of whom were illiterate, the IQCODE proved to be a valid instrument for dementia detection, and adding the RUDAS increased accuracy. Combining performance-based and informant-based data is recommended to enhance diagnostic precision.
IGF2 drives formation of ileal neuroendocrine tumors in patients and mice.

By the strictest of definitions, a genetic driver of tumorigenesis should fulfill two criteria: it should be altered in a high percentage of patient tumors, and it should also be able to cause the same type of tumor to form in mice. No gene that fits either of these criteria has ever been found for ileal neuroendocrine tumors (I-NETs), which in humans are known for an unusual lack of recurrently mutated genes, and which have never been detected in mice. In the following report, we show that I-NETs can be generated by transgenic RT2 mice, which is a classic model for a genetically unrelated disease, pancreatic neuroendocrine tumors (PNETs). The ability of RT2 mice to generate I-NETs depended upon genetic background. I-NETs appeared in a B6AF1 genetic background, but not in a B6 background nor even in an AB6F1 background. AB6F1 and B6AF1 have identical nuclear DNA but can potentially express different allelic forms of imprinted genes. This led us to test human I-NETs for loss of imprinting, and we discovered that the IGF2 gene showed loss of imprinting and increased expression in the I-NETs of 57% of patients. By increasing IGF2 activity genetically, I-NETs could be produced by RT2 mice in a B6 genetic background, which otherwise never developed I-NETs. The facts that IGF2 is altered in a high percentage of patients with I-NETs, and that I-NETs can form in mice that have elevated IGF2 activity, define IGF2 as the first genetic driver of ileal neuroendocrine tumorigenesis.
Neuroendoscopy in the Treatment of Hydrocephalus and Arachnoid Cysts

Objective To discuss the effect of neuroendoscopy in the treatment of hydrocephalus and a- rachnoid cysts.Methods 82 cases with hydrocephalus and arachnoid cysts were treated with the third ven- tricucilostomy,dilatation of ventricular aqueduct and cysto-ventricucilostomy by neuroendoscope.Results 55 cases(67%)showed significant effects,21 cases(25.6%)improvement and 6 cases(7.4%)no effect.The total effective rate was 92.5%. Conclusions Neuroendoscopy is an effective method to treat hydrocephalus and arachnoid cysts with simple operation,satisfactory curative effect and less complications.
Heat Shock Protein 90 Chaperone Regulates the E3 Ubiquitin-Ligase Hakai Protein Stability

The E3 ubiquitin-ligase Hakai binds to several tyrosine-phosphorylated Src substrates, including the hallmark of the epithelial-to-mesenchymal transition E-cadherin, and signals for degradation of its specific targets. Hakai is highly expressed in several human cancers, including colon cancer, and is considered as a drug target for cancer therapy. Here, we report a link between Hakai and the heat shock protein 90 (Hsp90) chaperone complex. Hsp90 participates in the correct folding of its client proteins, allowing them to maintain their stability and activity. Hsp90 inhibitors specifically interfere with the association with its Hsp90 client proteins, and exhibit potent anti-cancer properties. By immunoprecipitation, we present evidence that Hakai interacts with Hsp90 chaperone complex in several epithelial cells and demonstrate that is a novel Hsp90 client protein. Interestingly, by overexpressing and knocking-down experiments with Hakai, we identified Annexin A2 as a Hakai-regulated protein. Pharmacological inhibition of Hsp90 with geldanamycin results in the degradation of Hakai in a lysosome-dependent manner. Interestingly, geldanamycin-induced Hakai degradation is accompanied by an increased expression of E-cadherin and Annexin A2. We also show that geldanamycin suppresses cell motility at least in part through its action on Hakai expression. Taken together, our results identify Hakai as a novel Hsp90 client protein and shed light on the regulation of Hakai stability. Our results open the possibility to the potential use of Hsp90 inhibitors for colorectal cancer therapy through its action on Hakai client protein of Hsp90.
Riboflavin Plays a Pivotal Role in the UVA-Induced Cytotoxicity of Fibroblasts as a Key Molecule in the Production of H2O2 by UVA Radiation in Collaboration with Amino Acids and Vitamins

To investigate environmental factors that contribute to ultraviolet A (UVA)-induced oxidative stress, which accelerates the senescence and toxicity of skin cells, we irradiated human fibroblasts cultured in commonly used essential media with UVA and evaluated their viability and production of reactive oxygen species. The viability of fibroblasts exposed to a single dose of 3.6 J/cm2 UVA was not reduced when cultured in Hanks balanced salt solution, but it was significantly decreased when cultured in Dulbecco’s modified Eagle’s medium (DMEM), which contains various amino acids and vitamins. Furthermore, cell viability was not reduced when fibroblasts were cultured in DMEM and treated with a hydrogen peroxide (H2O2) scavenger such as glutathione or catalase added after UVA irradiation. In addition, we confirmed that the production of H2O2 was dramatically increased by UVA photosensitization when riboflavin (R) coexisted with amino acids such as tryptophan (T), and found that R with folic acid (F) produced high levels of H2O2 after UVA irradiation. Furthermore, we noticed that R and F or R and T have different photosensitization mechanisms since NaN3, which is a singlet oxygen quencher, suppressed only R and T photosensitization. Lastly, we examined the effects of antioxidants (L-ascorbic acid, trolox, L-cysteine, and L-histidine), which are singlet oxygen or superoxide or H2O2 scavengers, on R and F or on R and T photosensitization, and found that 1 mM ascorbic acid, Trolox, and L-histidine were strongly photosensitized with R, and produced significant levels of H2O2 during UVA exposure. However, 1 mM L-cysteine dramatically suppressed H2O2 production by UVA photosensitization. These data suggest that a low concentration of R-derived photosensitization is elicited by different mechanisms depending on the coexisting vitamins and amino acids, and regulates cellular oxidative stress by producing H2O2 during UVA exposure.
Molecular and Regulatory Mechanisms of Desensitization and Resensitization of GABAA Receptors with a Special Reference to Propofol/Barbiturate

It is known that desensitization of GABAA receptor (GABAAR)-mediated currents is paradoxically correlated with the slowdown of their deactivation, i.e., resensitization. It has been shown that an upregulation of calcineurin enhances the desensitization of GABAAR-mediated currents but paradoxically prolongs the decay phase of inhibitory postsynaptic currents/potentials without appreciable diminution of their amplitudes. The paradoxical correlation between desensitization and resensitization of GABAAR-mediated currents can be more clearly seen in response to a prolonged application of GABA to allow more desensitization, instead of brief pulse used in previous studies. Indeed, hump-like GABAAR currents were produced after a strong desensitization at the offset of a prolonged puff application of GABA in pyramidal cells of the barrel cortex, in which calcineurin activity was enhanced by deleting phospholipase C-related catalytically inactive proteins to enhance the desensitization/resensitization of GABAAR-mediated currents. Hump-like GABAAR currents were also evoked at the offset of propofol or barbiturate applications in hippocampal or sensory neurons, but not GABA applications. Propofol and barbiturate are useful to treat benzodiazepine/alcohol withdrawal syndrome, suggesting that regulatory mechanisms of desensitization/resensitization of GABAAR-mediated currents are important in understanding benzodiazepine/alcohol withdrawal syndrome. In this review, we will discuss the molecular and regulatory mechanisms underlying the desensitization and resensitization of GABAAR-mediated currents and their functional significances.
Role of JAK/STAT3 Signaling in the Regulation of Metastasis, the Transition of Cancer Stem Cells, and Chemoresistance of Cancer by Epithelial–Mesenchymal Transition

The JAK/STAT3 signaling pathway plays an essential role in various types of cancers. Activation of this pathway leads to increased tumorigenic and metastatic ability, the transition of cancer stem cells (CSCs), and chemoresistance in cancer via enhancing the epithelial–mesenchymal transition (EMT). EMT acts as a critical regulator in the progression of cancer and is involved in regulating invasion, spread, and survival. Furthermore, accumulating evidence indicates the failure of conventional therapies due to the acquisition of CSC properties. In this review, we summarize the effects of JAK/STAT3 activation on EMT and the generation of CSCs. Moreover, we discuss cutting-edge data on the link between EMT and CSCs in the tumor microenvironment that involves a previously unknown function of miRNAs, and also discuss new regulators of the JAK/STAT3 signaling pathway.
Pediatric Pulmonology

Division of Pediatrics, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile Department of Pediatric Pulmonology and Cardiology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts Department of Medicine, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts Department of Pediatric Infectious Diseases and Immunology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile Millennium Institute on Immunology and Immunotherapy, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
Long-Term Effects of Air Pollutants on Mortality Risk in Patients with End-Stage Renal Disease

Long-term exposure to air pollutants significantly increases the morbidity and mortality associated with various diseases. However, little is known about the relationship between air pollutants and end-stage renal disease (ESRD)-related mortality. A total of 5041 patients who started dialysis between 2008 and 2015 were prospectively enrolled in the Clinical Research Center for End-Stage Renal Disease (CRC-ESRD) cohort study. We assigned a daily mean concentration of air pollutants (PM10, NO2, and SO2) to each participant. Time-varying Cox models were used to investigate the relationship between air pollutants and mortality in ESRD patients. During the follow-up period (mean 4.18 years), 1475 deaths occurred among 5041 participants. We found a significant long-term relationship between mortality risk and PM10 (HR 1.33, CI 1.13–1.58), NO2 (HR 1.46, CI 1.10–1.95), and SO2 (HR 1.07, CI 1.03–1.11). Elderly patients and patients who lived in metropolitan areas had an increased risk associated with PM10. Elderly patients also had increased risks associated NO2 and SO2. Long-term exposure to air pollutants had negative effects on mortality in ESRD patients. These effects were prominent in elderly patients who lived in metropolitan areas, suggesting that ambient air pollution, in addition to traditional risk factors, is important for the survival of these patients.
A Stacked Back Side-Illuminated Voltage Domain Global Shutter CMOS Image Sensor with a 4.0 μm Multiple Gain Readout Pixel †

A backside-illuminated complementary metal-oxide-semiconductor (CMOS) image sensor with 4.0 μm voltage domain global shutter (GS) pixels has been fabricated in a 45 nm/65 nm stacked CMOS process as a proof-of-concept vehicle. The pixel components for the photon-to-voltage conversion are formed on the top substrate (the first layer). Each voltage signal from the first layer pixel is stored in the sample-and-hold capacitors on the bottom substrate (the second layer) via micro-bump interconnection to achieve a voltage domain GS function. The two sets of voltage domain storage capacitor per pixel enable a multiple gain readout to realize single exposure high dynamic range (SEHDR) in the GS operation. As a result, an 80dB SEHDR GS operation without rolling shutter distortions and motion artifacts has been achieved. Additionally, less than −140dB parasitic light sensitivity, small noise floor, high sensitivity and good angular response have been achieved.
Anti-Bacterial and Anti-Inflammatory Effects of Toothpaste with Swiss Medicinal Herbs towards Patients Suffering from Gingivitis and Initial Stage of Periodontitis: From Clinical Efficacy to Mechanisms

Objective: To distinguish clinical effects and mechanisms of sodium monofluorophosphate plus xylitol and herbal extracts of Swiss medicinal plants (Chamomilla recutita, Arnica montana, Echinacea purpurea, and Salvia officinalis). Materials and Methods: A 2-month-long comparative clinical study of toothpaste containing 1450 ppm sodium monofluorophosphate and xylitol (control, 15 patients) and toothpaste additionally containing extracts of the medicinal herbs (experiment, 35 patients) was performed on patients with gingivitis and the initial stage of periodontitis. Clinical indices of gingivitis/periodontitis were quantified by Loe & Silness’s, CPITN, OHI-S, and PMA indexes. The pro-inflammatory and anti-inflammatory interleukins, nitrites/nitrates, total antioxidant activity, and bacterial pattern characteristic for gingivitis and periodontitis were quantified in the gingival crevicular fluid and plaque. In the in vitro tests, direct anti-bacterial effects, inhibition of catalase induction in Staphylococcus aureus, in response to oxidative burst of phagocytes, and intracellular bacterial killing were determined for the toothpastes, individual plant extracts, and their mixture. Results: Experimental toothpaste was more efficient clinically and in the diminishing of bacterial load specific for gingivitis/periodontitis. Although the control toothpaste exerted a direct moderate anti-bacterial effect, herbal extracts provided anti-inflammatory, anti-oxidant, direct, and indirect anti-bacterial actions through inhibition of bacterial defence against phagocytes. Conclusions: Chemical and plant-derived anti-bacterials to treat gingivitis and periodontitis at the initial stage should be used in combination amid their different mechanisms of action. Plant-derived actives for oral care could substitute toxic chemicals due to multiple modes of positive effects.
Clustered DNA Double-Strand Breaks: Biological Effects and Relevance to Cancer Radiotherapy

Cells manage to survive, thrive, and divide with high accuracy despite the constant threat of DNA damage. Cells have evolved with several systems that efficiently repair spontaneous, isolated DNA lesions with a high degree of accuracy. Ionizing radiation and a few radiomimetic chemicals can produce clustered DNA damage comprising complex arrangements of single-strand damage and DNA double-strand breaks (DSBs). There is substantial evidence that clustered DNA damage is more mutagenic and cytotoxic than isolated damage. Radiation-induced clustered DNA damage has proven difficult to study because the spectrum of induced lesions is very complex, and lesions are randomly distributed throughout the genome. Nonetheless, it is fairly well-established that radiation-induced clustered DNA damage, including non-DSB and DSB clustered lesions, are poorly repaired or fail to repair, accounting for the greater mutagenic and cytotoxic effects of clustered lesions compared to isolated lesions. High linear energy transfer (LET) charged particle radiation is more cytotoxic per unit dose than low LET radiation because high LET radiation produces more clustered DNA damage. Studies with I-SceI nuclease demonstrate that nuclease-induced DSB clusters are also cytotoxic, indicating that this cytotoxicity is independent of radiogenic lesions, including single-strand lesions and chemically “dirty” DSB ends. The poor repair of clustered DSBs at least in part reflects inhibition of canonical NHEJ by short DNA fragments. This shifts repair toward HR and perhaps alternative NHEJ, and can result in chromothripsis-mediated genome instability or cell death. These principals are important for cancer treatment by low and high LET radiation.