Miracle-dz/UniFAR-FTUs huggingface dataset:
Atypical presentation of giant cell arteritis in a patient with vertebrobasilar stroke

Abstract Rationale: Giant cell arteritis (GCA) is known to present with typical manifestations like temporal headache and visual abnormalities. However, several cases with atypical manifestations were reported. Stroke occurs in 3% to 7% of patients with GCA. Patient concerns: A 67-year-old male patient with known hypertension presented with somnolence, disorientation and mild bilateral limb ataxia. The magnetic resonance imaging showed multiple acute infarctions in the territory of the vertebrobasilar system with occlusion of the left vertebral artery. Diagnosis: Ten months later, during a routine neurovascular follow-up, recanalization of the left vertebral artery was observed and a hypoechoic concentric “halo” sign around both vertebral arteries, mainly on the left side was evident. On further examination of the superficial temporal artery, a hypoechoic concentric “halo” sign was also found, which—along with increased inflammatory markers—raised suspicion about GCA. Classical GCA features like headache, temporal tenderness or amaurosis fugax were not present. Repeated in-depth diagnostic work-up including 48 hours Holter-ECG did not reveal another stroke etiology. Interventions: Intravenous Methylprednisolone 250 mg/d was immediately started and after 6 days the dose was tapered to 80 mg/d. The patient was discharged on a tapering scheme with the recommendation to start azathioprine. Additionally, we placed the patient on acetylsalicylic acid 100 mg/d and clopidogrel 75 mg/d. However, the patient was not compliant to treatment; he stopped prednisolone early and did not start azathioprine. Outcomes: The inflammatory markers were markedly reduced at the beginning of the treatment. After stopping the immunosuppressive medications, the inflammatory markers were once again increased. Three months later, the patient developed bilateral middle cerebral artery and right occipital lobe infarctions. Lessons: In patients with cryptogenic vertebrobasilar strokes, GCA may be considered in the differential diagnosis, especially if the inflammatory markers are increased.
YIPF5 Is Essential for Innate Immunity to DNA Virus and Facilitates COPII-Dependent STING Trafficking

Key Points YIPF5 positively regulates STING-mediated IFN production signaling. YIPF5 is essential for antiviral response against DNA viruses. YIPF5 facilitates STING trafficking by recruiting STING to COPII-coated vesicles. STING plays central roles in the innate immune response to pathogens that contain DNA. Sensing cytoplasmic DNA by cyclic GMP-AMP synthase produces cyclic GMP-AMP, which binds to and activates STING and induces STING translocation from the endoplasmic reticulum to the perinuclear microsome. However, this trafficking process has not been fully elucidated yet. In this study, we identified YIPF5 as a positive regulator of STING trafficking. YIPF5 is essential for DNA virus- or intracellular DNA-triggered production of type I IFNs. Consistently, knockdown of YIPF5 impairs cellular antiviral responses to DNA virus. Mechanistically, YIPF5 interacts with both STING and components of COPII, facilitating STING recruitment to COPII in the presence of cytoplasmic dsDNA. Furthermore, knockdown of components of COPII inhibits DNA virus-triggered production of type I IFNs, suggesting that COPII is involved in innate immune responses to DNA viruses. Collectively, our findings demonstrate that YIPF5 positively regulates STING-mediated innate immune responses by recruiting STING to COPII-coated vesicles and facilitating STING trafficking from the endoplasmic reticulum to Golgi, providing important insights into the molecular mechanisms of intracellular DNA-stimulated STING trafficking and activation.
Economic elasticities of input substitution using data envelopment analysis

The use of elasticities of substitution between inputs is a standard method for addressing the effect of a change in the mix of inputs used for production from a technical or cost standpoint. Most estimation methods use parametric production or cost functions or frontiers to estimate these elasticities. A potentially useful nonparametric alternative is data envelopment analysis (DEA). The purpose of this paper is to derive elasticities of input substitution for both technical and cost frontiers using DEA, extending the use of this approach in the field of economics and associated fields. The paper provides derivations for both Hicksian (production and cost frontier) and Morishima (cost frontier) elasticities of input substitution, as well as a parsimonious method for estimating them using DEA. The derivations are presented using an agricultural example form Kansas, USA.
Bcl‐2/Bax ratio increase does not prevent apoptosis of glia and granular neurons in patients with temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is usually associated with hippocampal sclerosis (HS), characterized by gliosis and neuronal loss, mainly in the cornus ammonis (CA). Regardless the type of HS, gliosis is associated with neuronal loss. Indeed, glial reactivation seems to induce both neuronal and glial apoptosis. Anti‐apoptotic mechanisms are also activated in order to contain the cell death in chronic epilepsy. However, the role of the intrinsic apoptosis pathway in human TLE is unclear, mainly in relation to glial death. The purpose of this study was to evaluate the reactive gliosis areas in parallel with Bcl‐2/Bax ratio and active caspase 3 immunoreactivity in hippocampi of TLE patients in comparison with control hippocampi. We also sought to investigate whether the levels of these markers were correlated with TLE clinical parameters. Paraffin‐embedded sclerotic and control hippocampi were collected for immunohistochemical analyses of glial fibrillary acidic protein (GFAP), human leucocyte antigen DR (HLA‐DR), neuronal nuclei protein (NeuN), Bax, Bcl‐2 and active caspase 3. Sclerotic hippocampi presented higher immunoreactivity areas of GFAP and HLA‐DR than controls, with similar values in HS types 1 and 2. Bcl‐2 protein expression was increased in epileptic hippocampi, while Bax expression was similar to controls. Despite Bcl2/Bax ratio increase, granular neurons and glia exhibited active caspase 3 expression in TLE hippocampi, while controls did not show staining for the same marker. In conclusion, glial and neuronal death is increased in sclerotic hippocampi, independently of HS type, and co‐localized with gliosis. Furthermore, Bcl‐2/Bax ratio increase does not prevent expression of active caspase 3 by glia and granular neurons in TLE.
Multiple myeloma treatment patterns and clinical outcomes in the Latin America Haemato‐Oncology (HOLA) Observational Study, 2008–2016

Limited data are available regarding contemporary multiple myeloma (MM) treatment practices in Latin America. In this retrospective cohort study, medical records were reviewed for a multinational cohort of 1103 Latin American MM patients (median age, 61 years) diagnosed in 2008–2015 who initiated first‐line therapy (LOT1). Of these patients, 33·9% underwent autologous stem cell transplantation (ASCT). During follow‐up, 501 (45·4%) and 129 (11·7%) patients initiated second‐ (LOT2) and third‐line therapy (LOT3), respectively. In the LOT1 setting, from 2008 to 2015, there was a decrease in the use of thalidomide‐based therapy, from 66·7% to 42·6%, and chemotherapy from, 20·2% to 5·9%, whereas use of bortezomib‐based therapy or bortezomib + thalidomide increased from 10·7% to 45·5%. Bortezomib‐based therapy and bortezomib + thalidomide were more commonly used in ASCT patients and in private clinics. In non‐ASCT and ASCT patients, median progression‐free survival (PFS) was 15·0 and 31·1 months following LOT1 and 10·9 and 9·5 months following LOT2, respectively. PFS was generally longer in patients treated with bortezomib‐based or thalidomide‐based therapy versus chemotherapy. These data shed light on recent trends in the management of MM in Latin America. Slower uptake of newer therapies in public clinics and poor PFS among patients with relapsed MM point to areas of unmet therapeutic need in Latin America.
DNA probes that store mechanical information reveal transient piconewton forces applied by T cells

Significance To defend against cancer and viral infections, the T cell receptor (TCR) must recognize antigens on the surface of target cells. TCR antigen recognition involves the transmission of forces which are often weak, infrequent, and short lived, and hence difficult to study. We solve this challenge by developing molecular probes that store mechanical information. This approach reveals the TCR forces when encountering different antigens, and this mechanical sampling is correlated with antigen potency. Since coreceptors are heavily involved in tuning immune function, we investigate the programmed cell death receptor 1 (PD1) and show that T cells transmit forces to this coinhibitory receptor, thus suggesting that mechanics may play a role in this important checkpoint pathway. The advent of molecular tension probes for real-time mapping of piconewton forces in living systems has had a major impact on mechanobiology. For example, DNA-based tension probes have revealed roles for mechanics in platelet, B cell, T cell, and fibroblast function. Nonetheless, imaging short-lived forces transmitted by low-abundance receptors remains a challenge. This is a particular problem for mechanoimmunology where ligand–receptor bindings are short lived, and a few antigens are sufficient for cell triggering. Herein, we present a mechanoselection strategy that uses locking oligonucleotides to preferentially and irreversibly bind DNA probes that are mechanically strained over probes at rest. Thus, infrequent and short-lived mechanical events are tagged. This strategy allows for integration and storage of mechanical information into a map of molecular tension history. Upon addition of unlocking oligonucleotides that drive toehold-mediated strand displacement, the probes reset to the real-time state, thereby erasing stored mechanical information. As a proof of concept, we applied this strategy to study OT-1 T cells, revealing that the T cell receptor (TCR) mechanically samples antigens carrying single amino acid mutations. Such events are not detectable using conventional tension probes. Each mutant peptide ligand displayed a different level of mechanical sampling and spatial scanning by the TCR that strongly correlated with its functional potency. Finally, we show evidence that T cells transmit pN forces through the programmed cell death receptor-1 (PD1), a major target in cancer immunotherapy. We anticipate that mechanical information storage will be broadly useful in studying the mechanobiology of the immune system.
Angiotensin Receptor Blockers Effect on Serum Uric Acid—A Class Effect?

Purpose: To provide a comprehensive review to determine whether there is a class effect among angiotensin receptor blockers (ARBs) in relation to serum uric acid. Summary: A literature search was conducted and 8 articles were identified for inclusion in this review. In the studies reviewed, candesartan and valsartan were shown to have either a neutral or negative effect on serum uric acid. Azilsartan was shown to have a negative impact on serum uric acid while eprosartan appeared to have no impact on serum uric acid levels. Irbesartan demonstrated either a neutral or positive effect on serum uric acid while losartan exhibited a positive effect. Conclusion: The available data indicate that the reduction of serum uric acid is not a class effect of ARBs. Of the available agents, only losartan has clear evidence of its ability to lower serum uric acid. For patients with high blood pressure and elevated serum uric acid, losartan should be considered as a first-line agent with irbesartan as an alternative when appropriate.
In Vitro Digestion of Human Milk: Influence of the Lactation Stage on the Micellar Carotenoids Content

Human milk is a complex fluid with nutritive and non-nutritive functions specifically structured to cover the needs of the newborn. The present study started with the study of carotenoid composition during progress of lactation (colostrum, collected at 3–5 d postpartum; mature milk, collected at 30 d postpartum) with samples donated from full-term lactating mothers (women with no chronic diseases, nonsmokers on a regular diet without supplements, n = 30). Subsequently, we applied an in vitro protocol to determine the micellarization efficiency of the carotenoids, which were separated by HPLC and quantified by the external standard method. That in vitro protocol is tailored for the biochemistry of the digestive tract of a newborn. To the best of our knowledge, the present study is the first report of carotenoids micellar contents, obtained in vitro. This study reveals, from the in vitro perspective, that colostrum and mature milk produce significant micellar contents of carotenoids despite lipids in milk are within highly complex structures. Indeed, the lactation period develops some influence on the micellarization efficiency, influence that might be attributed to the dynamics of the milk fat globule membrane (MFGM) during the progress of lactation.
Combover interacts with the axonemal component Rsp3 and is required for Drosophila sperm individualization

ABSTRACT Gamete formation is key to survival of higher organisms. In male animals, spermatogenesis gives rise to interconnected spermatids that differentiate and individualize into mature sperm, each tightly enclosed by a plasma membrane. In Drosophila melanogaster, individualization of sister spermatids requires the formation of specialized actin cones that synchronously move along the sperm tails, removing inter-spermatid bridges and most of the cytoplasm. Here, we show that Combover (Cmb), originally identified as an effector of planar cell polarity (PCP) under control of Rho kinase, is essential for sperm individualization. cmb mutants are male sterile, with actin cones that fail to move in a synchronized manner along the flagella, despite being correctly formed and polarized initially. These defects are germline autonomous, independent of PCP genes, and can be rescued by wild-type Cmb, but not by a version of Cmb in which known Rho kinase phosphorylation sites are mutated. Furthermore, Cmb binds to the axonemal component Radial spoke protein 3, knockdown of which causes similar individualization defects, suggesting that Cmb coordinates the individualization machinery with the microtubular axonemes. Summary: The PCP effector Combover is required for the process of separation and ensheathment of interconnected spermatids, likely by coordinating the actin-based individualization machinery with the axonemes.
The interaction between suction feeding performance and prey escape response determines feeding success in larval fish

ABSTRACT The survival of larval marine fishes during early development depends on their ability to feed before depleting their yolk reserves. Most larval fish capture prey by expanding their mouth, generating a ‘suction flow’ that draws the prey into it. These larvae dwell in a hydrodynamic environment that impedes their ability to capture even non-evasive prey; however, the marine environment is characterized by an abundance of evasive prey, predominantly copepods. Copepods sense the hydrodynamic disturbance created by approaching predators and perform high-acceleration escape maneuvers. Using a 3D high-speed video system, we characterized the interaction between Sparus aurata larvae and prey from a natural zooplankton assemblage that contained evasive prey, and assessed the factors that determine the outcome of these interactions. At 8–33 days post hatching, larvae preferentially attacked large prey that was moving prior to the initialization of the strike; however, feeding success was lower for larger, more evasive prey. Thus, larvae were challenged in capturing their preferred prey. Larval feeding success increased with increasing Reynolds numbers, but decreased sharply when the prey performed an escape maneuver. The kinematics of successful strikes resulted in a shorter response time but higher hydrodynamic signature available for the prey, suggesting that strike success in our experiments was determined by brevity rather than stealth: executing a fast strike eliminated a potential escape response by the prey. Our observations of prey selectivity reveal that larval performance, rather than preferences, determines their diet during early development. Summary: Larval fish preferentially target large moving prey, but have a hard time capturing this preferred prey because their suction flows are often too weak to counter the prey's escape response.
Risk Factors for Major Amputation in the Japanese Population　- How Can We Predict and Prevent Lower Limb Loss in Patients With Peripheral Arterial Disease?

with non-diabetic patients, PAD in diabetic patients is accompanied by neuropathy, occurs in younger individuals with less sex differences, has increased below-the-knee stenotic/occluded arterial lesions (there are relatively few lesions in the aorto-iliac arteries) and increased multi-level arterial lesions, and has reduced intermittent claudication symptoms because of the narrower range of activity. Higashi et al1 report that the lower limb amputation event rate of diabetic patients with PAD was 4.43-fold higher than that of patients with PAD alone (i.e., without DM). C urrently, there is a rise in ischemic foot ulcer/necrosis lesions because of peripheral arterial disease (PAD), and this is further increasing with the rapid increase in diabetic and dialysis patients and population aging. Lower extremity amputation significantly reduces patients’ activities of daily life and quality of life, leading to shortened life prognosis and increased treatment cost. The burden on both patients and society is high. However, awareness of PAD and foot lesions in primary care is somewhat lacking. The need to predict and prevent leg amputation is an urgent global issue that includes Japan. In this issue of the Journal, Higashi and colleagues1 report their retrospective analysis of a 2-year observational prospective cohort study (4,016 eligible patients at 1,745 clinics in Japan) that evaluated predictors of amputation in diabetic patients undergoing antiplatelet therapy for PAD. Amputation risk was predicted at baseline by a history of lower extremity revascularization (LER)/amputation, chronic kidney disease (CKD), and comorbid cerebrovascular disease (CVD) and coronary artery disease (CAD). In patients with PAD and diabetes (DM), the amputation event rate was highest for those with ankle-brachial pressure index (ABI) <0.40 and progressively decreased at higher ABI cutoffs. The authors’ findings from this large cohort are valuable because they are likely to be representative of patients with PAD and DM who receive antiplatelet therapy in real-world clinical practice in Japan. In addition, they contribute to early detection and preventive risk factor management for ischemic foot lesions and limb amputation (Figure). DM is the strongest risk factor for PAD development and its prevalence in PAD patients in Japan is reported to be 41.2%. 2 Furthermore, 70% of patients with severe lower extremity ischemia in Japan undergoing peripheral revascularization suffer from DM, and half account for dialysis.3 In diabetic patients, typical symptoms of PAD such as intermittent claudication are not always obvious, 75% are asymptomatic, and some are diagnosed only when there is pain at rest and gangrene appears. This results in a high risk of leg amputation. This is because, compared Article p 1929
Serum interleukin‐33 as a novel marker for long‐term prognosis and recurrence in acute ischemic stroke patients

Interleukin‐33, a newly identified member of interleukin‐1 family, had been confirmed to play a crucial role in regulating inflammatory responses in various disease. However, the exact role of interleukin‐33 in the disease process of acute ischemic stroke still remains unclear. This study aims to demonstrate the relationship between interleukin‐33 levels and long‐term functional outcome as well as ischemic stroke recurrence.
Brain–computer interfaces and personhood: interdisciplinary deliberations on neural technology

Objective. Scientists, engineers, and healthcare professionals are currently developing a variety of new devices under the category of brain–computer interfaces (BCIs). Current and future applications are both medical/assistive (e.g. for communication) and non-medical (e.g. for gaming). This array of possibilities has been met with both enthusiasm and ethical concern in various media, with no clear resolution of these conflicting sentiments. Approach. To better understand how BCIs may either harm or help the user, and to investigate whether ethical guidance is required, a meeting entitled ‘BCIs and Personhood: A Deliberative Workshop’ was held in May 2018. Main results. We argue that the hopes and fears associated with BCIs can be productively understood in terms of personhood, specifically the impact of BCIs on what it means to be a person and to be recognized as such by others. Significance. Our findings suggest that the development of neural technologies raises important questions about the concept of personhood and its role in society. Accordingly, we propose recommendations for BCI development and governance.
Stress and the brain: Perceived stress mediates the impact of the superior frontal gyrus spontaneous activity on depressive symptoms in late adolescence

Identifying factors for the prediction of depression is a long‐standing research topic in psychiatry and psychology. Perceived stress, which reflects the tendency to appraise one's life situations as stressful and overwhelming, has emerged as a stable predictor for depressive symptoms. However, the neurobiological bases of perceived stress and how perceived stress influences depressive symptoms in the healthy brain remain largely unknown. Here, we investigated these issues in 217 healthy adolescents by estimating the fractional amplitude of low‐frequency fluctuations (fALFFs) via resting‐state functional magnetic resonance imaging. A whole‐brain correlation analysis showed that higher levels of perceived stress were associated with greater fALFF in the left superior frontal gyrus (SFG), which is a core brain region for cognitive control and emotion regulation‐related processes. Mediation analysis further indicated that perceived stress mediated the link between the fALFF in the left SFG and depressive symptoms. Importantly, our results remained significant even when excluding the influences of head motion, anxiety, SFG gray matter structure, and school environment. Altogether, our findings suggested that the fALFF in the left SFG is a neurofunctional marker of perceived stress in adolescents and revealed a potential indirect effect of perceived stress on the association between the SFG spontaneous activity and depressive symptoms.