Miracle-dz/UniFAR-FTUs huggingface dataset:
Innovative molecular-based fluorescent nanoparticles for multicolor single particle tracking in cells

Based on an original molecular-based design, we present bright and photostable fluorescent organic nanoparticles (FONs) showing excellent colloidal stability in various aqueous environments. Complementary near-infrared emitting and green emitting FONs were prepared using a simple, fast and robust protocol. Both types of FONs could be simultaneously imaged at the single-particle level in solution as well as in biological environments using a monochromatic excitation and a dual-color fluorescence microscope. No evidence of acute cytotoxicity was found upon incubation of live cells with mixed solutions of FONs, and both types of nanoparticles were found internalized in the cells where their motion could be simultaneously tracked at video-rate up to minutes. These fluorescent organic nanoparticles open a novel non-toxic alternative to existing nanoparticles for imaging biological structures, compatible with live-cell experiments and specially fitted for multicolor single particle tracking.
Prevalence and risk factors of delayed onset lactogenesis II in China: a systematic review and meta-analysis

Abstract Background In 2017, China proposed to achieve the goal that 50% of infants aged 0-6 months should be exclusively breastfed by 2025 proposed by the World Health Assembly in 2012. However, delayed onset lactogenesis II has adverse effects on breastfeeding and thus on neonatal health. There has been no meta-analysis of the prevalence and risk factors of delayed onset lactogenesis II among parturient women in China. To provide best practices, updated evidence-based evidence is needed to supplement reviews on this topic. Objective The purpose of this systematic review and meta-analysis was to quantitatively analyze the prevalence and risk factors of delayed onset lactogenesis II in China. Methods We identified relevant studies by searching literature published prior to October 2022 in PubMed, Web of Science, China National Knowledge Infrastructure, Wanfang, and VIP databases for all available observational studies. Stata 16.0 were used for performing the systematic review and meta-analysis. Results The researchers examined data from 14 observational studies involving 17610 females. The prevalence of delayed onset lactogenesis II from these studies was 31% (95% CI = 25.0%–38.0%, p < .001), and the prevalence showed a significant increasing trend in China over the past decade. The frequency of breastfeeding was >2 times per day at 24–48 h after delivery was one protective factor against delayed onset lactogenesis II (OR = 0.41). The significant risk factors for delayed onset lactogenesis II were breastfeeding initiation > 30min after birth (OR = 1.31), maternal age > 35 years (OR = 2.19), primiparous women (OR = 2.38), maternal overweight/obesity (OR = 2.22), cesarean section (OR = 1.33), anxiety (OR = 3.23), depression (OR = 3.21) and gestational hypertension (OR = 3.43). Conclusions There is a high incidence of delayed onset lactogenesis II in Chinese parturient women. We identified eight risk factors and one protective factor for DOL II. These findings suggest health care professionals should pay attention to these risk parturients so as to better provide early preventive interventions to increase the breastfeeding rate.
Sex- and Lifestyle-Related Factors are Associated with Altered Hepatic CYP Protein Levels in People Diagnosed with Mental Disorders

In this study, we used human postmortem tissue to investigate hepatic protein expression levels of cytochrome P450 (CYP) 1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 by LC–MS/MS in a population of people suffering from mental disorders (n = 171). We report hepatic protein levels of these six CYP isoforms in 171 individuals in total, and define a focused population dataset of 116 individuals after excluding 55 samples due to low microsomal protein per gram of liver (MPPGL) yield. Postmortem decay was most likely the reason for the low MPPGL yield in the 55 samples. In the focused population, we found women to have significantly higher protein levels of CYP3A4 than men in addition to decreased CYP3A4 protein levels among obese individuals. Furthermore, MPPGL was negatively correlated with body mass index (BMI). An increase in CYP1A2 protein levels was observed among smokers, and increased CYP2E1 protein levels were observed among individuals with a history of alcohol abuse. Finally, individuals who received phenobarbital (CYP3A4 inducer) had significantly higher CYP3A4 levels. In conclusion, lifestyle-related factors prevalent among people suffering from mental disorders are associated with altered CYP protein levels, which may alter drug metabolism and affect the efficacy of commonly prescribed drugs. Furthermore, this investigation demonstrates that postmortem hepatic tissue can be used to study how lifestyle and effectors affect hepatic CYP-levels in a large cohort of patients. SIGNIFICANCE STATEMENT Using a large number of postmortem hepatic tissue specimens (n=116) originating from the autopsy of individuals diagnosed with mental disorders, we were able to show that hepatic CYP-levels were affected by alcohol, smoking, BMI, and sex and that MPPGL was affected by BMI. These lifestyle-related changes may alter drug metabolism and affect the efficacy of commonly prescribed drugs. It is a novel approach to use a large postmortem cohort to investigate how lifestyle and effectors affect hepatic CYP-levels.
Il‐6 and UGT1A1 variations may related to furosemide resistance in heart failure patients

Furosemide is a diuretic and is used for the treatment of patients with heart failure (HF). It has been found that in some HF patients, the drug does not treat patients efficiently. This condition is named as furosemide resistance. In this study, it is aimed to investigate the relationship between UDP‐glucuronosyltransferase 1 (UGT1A1) and interleukine‐6 (IL‐6) variations with furosemide resistance in HF patients. Sixty HF patients using furosemide (patient group) and 30 healthy individuals (control group) were enrolled in this study. Patients were divided into two subgroups as non‐responders (furosemide resistant) group (n = 30) and the responders (non‐resistant) group (n = 30) according to the presence of furosemide resistance (n = 30). Variations in the first exon of UGT1A1 and rs1800795 and rs1800796 variations in IL‐6 were analyzed by direct sequencing and real‐time polymerase chain reaction (RT‐PCR), respectively. The effects of newly detected mutations on 3‐D protein structure were analyzed by in silico analysis. At the end of the study, 11 variations were detected in UGT1A1, of which nine of them are novel and eight of them cause amino acid change. Also, rs1800795 and rs1800796 variations were detected in all the groups. When patient and control groups were compared with each other, rs1800796 mutation in IL‐6 was found statistically high in the patient group (p = 0.027). When the three groups were compared with each other, similarly, rs1800796 mutation in IL‐6 was found statistically high in the non‐responders group (p = 0.043). When allele distributions were compared between the patient and control groups, the C allele of rs1800795 mutation in IL‐6 was found statistically high in the patient group (p = 0.032). When allele distributions were compared between the three groups, 55T‐insertion in UGT1A1 was found statistically high in the non‐responders group (p = 0.017). According to in silico analysis results, two variations were found deleterious and six variations were detected as probably damaging to protein functions. Our study may contribute to the elucidation of pharmacogenetic features (drug response–gene relationship) and the development of individual‐specific treatment strategies in HF patients using furosemide.
Now that the door is open: an update on ischemic stroke pharmacotherapeutics for the neurointerventionalist

The last 10 years have seen a major shift in management of large vessel ischemic stroke with changes towards ever-expanding use of reperfusion therapies (intravenous thrombolysis and mechanical thrombectomy). These strategies ‘open the door’ to acute therapeutics for ischemic tissue, and we should investigate novel therapeutic approaches to enhance survival of recently reperfused brain. Key insights into new approaches have been provided through translational research models and preclinical paradigms, and through detailed research on ischemic mechanisms. Additional recent clinical trials offer exciting salvos into this new strategy of pairing reperfusion with neuroprotective therapy. This pairing strategy can be employed using drugs that have shown neuroprotective efficacy; neurointerventionalists can administer these during or immediately after reperfusion therapy. This represents a crucial moment when we emphasize reperfusion, and have the technological capability along with the clinical trial experience to lead the way in multiprong approaches to stroke treatment.
Puits multiples en limite semi-classique. II. Interaction moléculaire. Symétries. Perturbation

We continue the study of [11] of the «splitting» of the eigenvalues of a semi-classical Schrodinger operator: P=−h 2 Δ+V(x)−E 0 , (h→0) in the case of several potential wells. The basic idea of the method is the same as in [11]: For each potential well, we consider as a reference problem, the operator P with Dirichlet boundary conditions in a large domain which contains the given well, but not the other. The eigenvalues of P in a given can be described by eigenvalues for the reference problems with certain exponentially small corrections due to the interaction between the wells. We improve the remainder estimates in such a way that also the case of «molecular interaction» can be treated. We also study the case when V is invariant under a finite group of isometries, as well as the effect of small perturbations on the potential. Several examples and applications are given On poursuit l'etude de [11] du «splitting» des valeurs propres de l'operateur de Schrodinger semi-classique: P=−h 2 Δ+V−E 0 (h→0) dans le cas de plusieurs puits de potentiel. L'idee de base est la meme que dans [11]. Pour chaque puits de potentiel on considere comme probleme de reference, l'operateur P avec condition de Dirichlet dans un grand domaine qui contient le puits donne mais pas les autres. Les valeurs propres de P dans un intervalle d'energie: I(h)=[E 0 +o(1), E 0 +o(1)], sont donnees par des valeurs propres des problemes de reference avec certaines corrections exponentiellement petites, dues a l'interaction entre les puits. On ameliore l'estimation de l'erreur de facon a pouvoir traiter aussi des cas d'interaction «moleculaire». On etudie egalement le cas ou V est invariant par un groupe fini d'isometries, ainsi que l'effet des petites perturbations de V. On donne plusieurs exemples et applications
Incidence of hypertension in people with HIV infection: a longitudinal observational study

Objective: Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality in people with HIV (PWH). Although hypertension is a well-known risk factor for CVD, studies investigating incident hypertension in PWH and its risk factors are scarce. In the present study, we set out to investigate incident hypertension and its predictors in the context of well-treated HIV infection. Methods: We included 532 PWH from the Copenhagen Comorbidity in HIV (COCOMO study). All included individuals took part in both baseline and 2.5 years follow-up examinations. Linear and Poisson regression were used to test our hypotheses, both before and after adjusting for confounders. Results: One hundred and five (19.7%) cases of incident hypertension occurred during 1217 person-years of follow-up (PYFU), corresponding to 8.5 cases per 100 PYFU. Waist-hip-ratio (relative risk (RR) 1.61 [1.34–1.94] and adjusted RR (aRR) 1.54 [1.24–1.91]) and central obesity (RR 2.41 [1.61–3.61] and aRR 2.29 [1.49, 3.52]) were significantly associated with this condition. No HIV-specific factors were found to be associated with incident hypertension. Conclusions: In the present study, the incidence rate of hypertension in well-treated PWH was comparable to that of the general population from similar socio-economic settings. Traditional risk factors, in particular age and indices of adipose tissue accumulation, were associated with incident hypertension. Our results may further underline the pivotal importance of focusing on lifestyle changes and weight loss, rather than on HIV-specific factors, in order to prevent incident hypertension in well-treated PWH.
Quantum Optimal Control Problems with a Sparsity Cost Functional

ABSTRACT In this article, the investigation of a class of quantum optimal control problems with L1 sparsity cost functionals is presented. The focus is on quantum systems modeled by Schrödinger-type equations with a bilinear control structure as it appears in many applications in nuclear magnetic resonance spectroscopy, quantum imaging, quantum computing, and in chemical and photochemical processes. In these problems, the choice of L1 control spaces promotes sparse optimal control functions that are conveniently produced by laboratory pulse shapers. The characterization of L1 quantum optimal controls and an efficient numerical semi-smooth Newton solution procedure are discussed.
Remodeling male coercion and the evolution of sexual autonomy by mate choice

Abstract Models of sexual conflict over mating, including conflict over indirect benefits of mate choice, have generally presumed that female resistance to male coercion must involve direct confrontation, which can lead to sexually antagonistic coevolutionary arms-races. We built a quantitative model examining the largely ignored possibility that females may evolve new, additional mate preferences for new male traits that undermine male capacity to coerce. Thus, females may “remodel” the coercive capacity of the male phenotype in order to enhance their own sexual autonomy—a novel alternative mechanism by which females may avoid arms-races. We demonstrate that evolutionary “remodeling” is possible, in spite of costs to males, because females that prefer males with protective, autonomy-enhancing traits (traits correlated with lower coercion effectiveness) are likelier to gain indirect benefits of having attractive mates. Our analysis reveals new possibilities for the evolution of systems of sexual conflict over indirect benefits, showing that autonomy-enhancing male traits can act as a “public good,” benefiting all females regardless of mating preferences, leading to oscillatory dynamics; and that preferences for more protective male traits will often be favored relative to preferences for less protective traits, potentially leading to an evolutionary “snowball” of expanding sexual autonomy.
RESEARCH NOTE ON THE RELATION BETWEEN SUMMATION AND FACILITATION

S runnrurion refers to the small reduction of threshold contrast as a signal is extended in space or time, or when multiple signals are presented simultaneously. Facifirotion refers to the large reduction in the threshold contrast increment when it is superimposed on a near-threshold pedestal contrast. Separate hypotheses relate each of these effects to distinct measures of the log-log steepness of the psychometric function. This note shows that for Zaltemative forced-choice (2afc) proportion correct, the Weibull function P(c) = l-(1-y)exp(-(c/a)p) and the d' power law d'(c) = (c/c,,&~ are practically indistinguishable. Furthermore, their steepness parameters are proportional to each other, B = 1.247 b. This implies a simple relation between 2afc summation and facilitation which can be tested without measuring the psychometric function.
Conformational flexibility of β‐arrestins – How these scaffolding proteins guide and transform the functionality of GPCRs

G protein‐coupled receptors (GPCRs) constitute the largest family of transmembrane proteins and play a crucial role in regulating diverse cellular functions. They transmit their signaling via binding to intracellular signal transducers and effectors, such as G proteins, GPCR kinases, and β‐arrestins. To influence specific GPCR signaling behaviors, β‐arrestins recruit effectors to form larger signaling complexes. Intriguingly, they facilitate divergent functions for the binding to different receptors. Recent studies relying on advanced structural approaches, novel biosensors and interactome analyses bring us closer to understanding how this specificity is achieved. In this article, we share our hypothesis of how active GPCRs induce specific conformational rearrangements within β‐arrestins to reveal distinct binding interfaces, enabling the recruitment of a subset of effectors to foster specialized signaling complexes. Furthermore, we discuss methods of how to comprehensively assess β‐arrestin conformational states and present the current state of research regarding the functionality of these multifaceted scaffolding proteins.
Seismic evidence for global basalt accumulation in the mantle transition zone

The mantle’s compositional structure reflects the thermochemical evolution of Earth. Yet, even the radial average composition of the mantle remains debated. Here, we analyze a global dataset of shear and compressional waves reflecting off the 410- and 660-km discontinuities that is 10 times larger than any previous studies. Our array analysis retrieves globally averaged amplitude-distance trends in SS and PP precursor reflectivity from which we infer relative wavespeed and density contrasts and associated mantle composition. Our results are best matched by a basalt-enriched mantle transition zone, with higher basalt fractions near 660 (~40%) than 410 (~18–31%). These are consistent with mantle-convection/plate-recycling simulations, which predict that basaltic crust accumulates in the mantle transition zone, with basalt fractions peaking near the 660. Basalt segregation in the mantle transition zone also implies that the overall mantle is more silica enriched than the often-assumed pyrolitic mantle reference composition.
Effectiveness, safety and quality of life of trifluridine/tipiracil in pretreated patients with metastatic colorectal cancer: Real‐world data from the noninterventional TACTIC study in Germany

The prospective, multicenter, noninterventional TACTIC study assessed effectiveness and safety of trifluridine/tipiracil (FTD/TPI) in patients with metastatic colorectal cancer (mCRC) in a real‐world setting in Germany, thus evaluating the external validity of the findings from the pivotal RECOURSE trial. Primary endpoint was overall survival (OS). Secondary objectives included progression‐free survival (PFS), safety, and quality of life (QoL). Subgroups comprised patients with good (<3 metastatic sites at inclusion, ≥18 months from diagnosis of first metastasis to inclusion) or poor (remaining patients) prognostic characteristics (GPC/PPC). GPC without liver metastases was considered best prognostic characteristics (BPC). In total, 307 eligible patients (pretreated or not suitable for other available therapies) were treated with FTD/TPI. Overall, median [95%‐CI] OS was 7.4 months [6.4‐8.6], median PFS was 2.9 months [2.8‐3.3]. In BPC (n = 65) and GPC (n = 176) compared to PPC (n = 124) subgroup, median OS (13.3 [9.1‐17.6] vs 8.9 [7.6‐9.8] vs 5.1 [4.4‐7.0] months) and median PFS (4.0 [3.3‐5.3] vs 3.4 [3.0‐3.7] vs 2.6 [2.4‐2.8] months) were longer. Patient‐reported QoL, assessed by validated questionnaires (EQ‐5D‐5L, PRO‐CTCAE), was stable throughout FTD/TPI treatment. Predominant FTD/TPI‐related adverse events of grades 3 or 4 were neutropenia (13.0%), leukopenia (7.5%), and anemia (5.2%). Altogether, palliative FTD/TPI therapy in patients with pretreated mCRC was associated with prolonged survival, delayed progression, maintained health‐related QoL, and manageable toxicity. Low metastatic burden and indolent disease were favorable prognostic factors for survival. TACTIC confirms the effectiveness and safety of FTD/TPI, highlighting its value in routine clinical practice.
Needs and limiting factors for high power low frequency projectors

The advances in the acoustic quieting of submarines will necessitate the use of active sonar as on adjunct as a means of dedecting submarines, bring about a deep research in high power,low frequency projectors The needs and limiting factors for high power, low frequency are discussed and different type projectors of high power and low frequency are compared
Cryo-EM visualization of DNA-PKcs structural intermediates in NHEJ

DNA double-strand breaks (DSBs), one of the most cytotoxic forms of DNA damage, can be repaired by the tightly regulated nonhomologous end joining (NHEJ) machinery (Stinson and Loparo and Zhao et al.). Core NHEJ factors form an initial long-range (LR) synaptic complex that transitions into a DNA-PKcs (DNA-dependent protein kinase, catalytic subunit)–free, short-range state to align the DSB ends (Chen et al.). Using single-particle cryo–electron microscopy, we have visualized three additional key NHEJ complexes representing different transition states, with DNA-PKcs adopting distinct dimeric conformations within each of them. Upon DNA-PKcs autophosphorylation, the LR complex undergoes a substantial conformational change, with both Ku and DNA-PKcs rotating outward to promote DNA break exposure and DNA-PKcs dissociation. We also captured a dimeric state of catalytically inactive DNA-PKcs, which resembles structures of other PIKK (Phosphatidylinositol 3-kinase-related kinase) family kinases, revealing a model of the full regulatory cycle of DNA-PKcs during NHEJ.
Intensive Blood Pressure Lowering Improves Left Ventricular Hypertrophy in Older Patients with Hypertension: The STEP Trial

BACKGROUND: Intensive systolic blood pressure (SBP) lowering has been increasingly used; however, its effect on cardiac remodeling remains not fully understood. This secondary analysis of the Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients trial aims to determine the changes in left ventricular hypertrophy (LVH) that occur in the context of intensive SBP lowering. METHODS: A total of 7141 older patients with hypertension were randomly assigned to intensive treatment (SBP target, 110–130 mm Hg) or standard treatment (130–150 mm Hg). LVH was defined according to the Peguero-Lo Presti criteria on a standard 12-lead echocardiogram. RESULTS: At baseline, the prevalence of LVH (16.6% versus 16.5%) and the mean Peguero-Lo Presti value (1811 versus 1808 μV) were comparable between the treatment groups. During a median follow-up of 3.24 years, intensive SBP lowering was associated with a significantly lower risk of new LVH occurrence (hazard ratio, 0.76 [95% CI, 0.66–0.89]; P=0.001) and slower progression of the mean Peguero-Lo Presti index value by −23.47 μV/y (95% CI, −34.93 to −12.01; P=0.000). However, the rates of regression of baseline LVH did not differ significantly. Notably, the beneficial effect of intensive SBP lowering in terms of cardiovascular events (hazard ratio, 0.75 [95% CI, 0.59–0.97]) was not markedly attenuated after adjusting for LVH as a time-varying covariate (hazard ratio, 0.76 [95% CI, 0.59–0.97]). CONCLUSIONS: Intensive SBP lowering protects against LVH development in older hypertensive patients, however, this favorable effect could not explain most of the reduction in cardiovascular events associated with intensive SBP lowering.