Top-down modulation of sensory processing allows the animal to select inputs most relevant to current tasks. We found that the cingulate (Cg) region of the mouse frontal cortex powerfully influences ...sensory processing in the primary visual cortex (V1) through long-range projections that activate local γ-aminobutyric acid–ergic (GABAergic) circuits. Optogenetic activation of Cg neurons enhanced V1 neuron responses and improved visual discrimination. Focal activation of Cg axons in V1 caused a response increase at the activation site but a decrease at nearby locations (center-surround modulation). Whereas somatostatin-positive GABAergic interneurons contributed preferentially to surround suppression, vasoactive intestinal peptide-positive interneurons were crucial for center facilitation. Long-range corticocortical projections thus act through local microcircuits to exert spatially specific top-down modulation of sensory processing.
Invasive procedures including loop electrosurgical excision, cervical conization, and endometrial sampling are often recommended when atypical glandular cells (AGC) are detected on Pap smear with ...unsatisfactory colposcopy. These invasive procedures may result in patient anxiety, increased medical expense, and increasing the risk of preterm delivery in subsequent pregnancies. This study was performed to assess methylation biomarkers in the triage of AGC on Pap smear for invasive procedures.
We conducted a multicenter study in 13 medical centers in Taiwan from May 2012 to May 2014. A total of 55 samples diagnosed "AGC not otherwise specified" (AGC-NOS) were included. All patients with AGC underwent colposcopy, cervical biopsy, endometrial sampling, and conization if indicated. Multiplex quantitative methylation-specific polymerase chain reaction (QMSPCR) was performed. Sensitivity, specificity, and accuracy were calculated for detecting CIN3+ and endometrial complex hyperplasia.
In 55 patients with AGC, the sensitivity for methylated (m) SOX1m, PAX1 m, ZNF582m,PTPRRm, AJAP1m, HS3ST2m, and POU4F3m for detecting CIN3+ and endometrial complex hyperplasia lesions was 100, 86, 71, 86, 86, 57, and 100%; specificity was 67, 79, 85, 50, 52, 96, and 52%, respectively. Testing for high risk-HPV had a sensitivity of 57% and specificity of 75% for CIN3+ and endometrial complex hyperplasia lesions.
Methylated (m) SOX1m and POU4F3m could be new methylation biomarkers for detection of CIN3+ and endometrial complex hyperplasia in AGC. Women with AGC and positive SOX1m / POU4F3m, colposcopy, cervical conization or endometrial sampling should be considered.
The ryanodine receptors (RyRs) are high-conductance intracellular Ca(2+) channels that play a pivotal role in the excitation-contraction coupling of skeletal and cardiac muscles. RyRs are the largest ...known ion channels, with a homotetrameric organization and approximately 5,000 residues in each protomer. Here we report the structure of the rabbit RyR1 in complex with its modulator FKBP12 at an overall resolution of 3.8 Å, determined by single-particle electron cryomicroscopy. Three previously uncharacterized domains, named central, handle and helical domains, display the armadillo repeat fold. These domains, together with the amino-terminal domain, constitute a network of superhelical scaffold for binding and propagation of conformational changes. The channel domain exhibits the voltage-gated ion channel superfamily fold with distinct features. A negative-charge-enriched hairpin loop connecting S5 and the pore helix is positioned above the entrance to the selectivity-filter vestibule. The four elongated S6 segments form a right-handed helical bundle that closes the pore at the cytoplasmic border of the membrane. Allosteric regulation of the pore by the cytoplasmic domains is mediated through extensive interactions between the central domains and the channel domain. These structural features explain high ion conductance by RyRs and the long-range allosteric regulation of channel activities.
Computing-in-memory (CIM) based on embedded nonvolatile memory is a promising candidate for energy-efficient multiply-and-accumulate (MAC) operations in artificial intelligence (AI) edge devices. ...However, circuit design for NVM-based CIM (nvCIM) imposes a number of challenges, including an arealatency-energy tradeoff for multibit MAC operations, patterndependent degradation in signal margin, and small read margin. To overcome these challenges, this article proposes the following: 1) a serial-input non-weighted product (SINWP) structure; 2) a down-scaling weighted current translator (DSWCT) and positive-negative current-subtractor (PN-ISUB); 3) a currentaware bitline clamper (CABLC) scheme; and 4) a triple-margin small-offset current-mode sense amplifier (TMCSA). A 55-nm 1-Mb ReRAM-CIM macro was fabricated to demonstrate the MAC operation of 2-b-input, 3-b-weight with 4-b-out. This nvCIM macro achieved T MAC = 14.6 ns at 4-b-out with peak energy efficiency of 53.17 TOPS/W.
Fluorescent nanodiamonds (FNDs) are nontoxic and photostable nanomaterials, ideal for long‐term in vivo imaging applications. This paper reports that FNDs with a size of ≈140 nm can be covalently ...conjugated with folic acid (FA) for receptor‐mediated targeting of cancer cells at the single‐particle level. The conjugation is made by using biocompatible polymers, such as polyethylene glycol, as crosslinked buffer layers. Ensemble‐averaged measurements with flow cytometry indicate that more than 50% of the FA‐conjugated FND particles can be internalized by the cells (such as HeLa cells) through receptor‐mediated endocytosis, as confirmed by competitive inhibition assays. Confocal fluorescence microscopy reveals that these FND particles accumulate in the perinuclear region. The absolute number of FNDs internalized by HeLa cells after 3 h of incubation at a particle concentration of 10 µg mL−1 is in the range of 100 particles per cell. The receptor‐mediated uptake process is further elucidated by single‐particle tracking of 35‐nm FNDs in three dimensions and real time during the endocytosis.
Flow cytometry and fluorescence microscopy analyses of HeLa cells incubated with folate‐conjugated fluorescent nanodiamonds (FNDs), with or without free ligands, in the media show that the FND bioconjugates are internalized by the cells (see image) through receptor‐mediated endocytosis and that they can be used as agents for targeted cellular imaging.
Although nude mice are an ideal photoaging research model, skin biopsies result in inflammation and are rarely performed at baseline. Meanwhile, studies on antiphotoaging antioxidants or rejuvenation ...techniques often neglect the spontaneous reversal capacity. Full-field optical coherence tomography (FFOCT) can acquire cellular details noninvasively. This study aimed to establish a photoaging and sequential function reversal nude mice model assisted by an in vivo cellular resolution FFOCT system. We investigated whether a picosecond alexandrite laser (PAL) with a diffractive lens array (DLA) accelerated the reversal. In the sequential noninvasive assessment using FFOCT, a spectrophotometer, and DermaLab Combo®, the photodamage percentage recovery plot demonstrated the spontaneous recovery capacity of the affected skin by UVB-induced transepidermal water loss and UVA-induced epidermis thickening. A PAL with DLA not only accelerated skin barrier regeneration with epidermal polarity, but also increased dermal neocollagenesis, whereas the nonlasered group still had >60% collagen intensity loss and 40% erythema from photodamage. Our study demonstrated that FFOCT images accurately resemble the living tissue. The photoaging and sequential function reversal model provides a reference to assess the spontaneous recovery capacity of nude mice from photodamage. This model can be utilized to evaluate the sequential noninvasive photodamage and reversal effects after other interventions.
Accessible Summary
What is known on the subject?
Individuals diagnosed with substance use disorders may perceive stigma and suffer from mental health problems.
Perceived stigma is related to poor ...mental health among individuals diagnosed with substance use disorders.
The social support deterioration deterrence model proposes that stressors (e.g. perceived stigma) negatively affect mental health via reduced perceived social support. To the best of the present authors’ knowledge, the model has never been tested in the context of perceived stigma among individuals diagnosed with substance use disorders.
What the paper adds to existing knowledge?
The paper used structural equation modelling to show that the social support deterioration deterrence model could explain the relationship between perceived stigma and depression among individuals diagnosed with substance use disorders.
Perceived support from family and perceived support from friends are mediators in the association between perceived stigma and depression among individuals diagnosed with substance use disorders.
What are the implications for practice?
Psychosocial interventions to increase perceived support from family and friends would be helpful in addressing perceived stigma effects on mental health.
Introduction
Although the relationship between perceived stigma and mental health outcomes is documented in the existing literature, very few studies have investigated the mechanism linking perceived stigma and mental health outcomes among individuals diagnosed with substance use disorders. To the best of the present authors’ knowledge, the social support deterioration deterrence model has never been tested in the context of perceived stigma among individuals diagnosed with substance use disorders.
Aim/Question
Guided by the social support deterioration deterrence model, the present study investigated the mediating role of perceived support from three types of social network members (i.e. significant others, family members, and friends) in the association between perceived stigma and depression in individuals diagnosed with substance use disorders.
Method
The study employed a cross‐sectional survey design comprising 300 participants diagnosed with substance use disorders in Taiwan.
Results
Results of a structural equation modelling analysis indicated that perceived stigma was significantly associated with depression. The relationship between perceived stigma and depression was partially mediated by perceived family support and perceived friend support.
Discussion
Consistent with the prediction of the social support deterioration deterrence model, the negative effect of perceived stigma on depression for individuals diagnosed with substance use disorders is through the mediating effect of social support.
Implications for practices
Based on the present study's results, psychosocial interventions to increase perceived support from family and friends would be helpful in addressing negative effects of perceived stigma on mental health among individuals diagnosed with substance use disorders.
This is a retrospective cohort study by analyzing a multi‐institutional electronic medical records database in Taiwan to compare long‐term effectiveness and risk of major adverse cardiac events ...(MACE) in chemotherapy‐naïve metastatic castration‐resistant prostate cancer (mCRPC) patients treated with enzalutamide (ENZ) or abiraterone (AA). Patients aged 20 years and older and newly receiving androgen receptor targeted therapies ENZ or AA from September 2016 to December 2019 were included. We followed patients from initiation of therapies to the occurrence of outcomes (prostate‐specific antigen (PSA) response rate, PSA progression free survival (PFS), overall survival (OS), and MACE), death, the last clinical visit, or December 31, 2020. We performed multivariable Cox proportional hazard models to compare ENZ and AA groups for the measured outcomes. A total of 363 patients treated with either ENZ (n = 157) or AA (n = 206) were identified. The analysis found a significantly higher proportion of patients with a PSA response rate higher than 50% among those receiving ENZ than among those receiving AA (ENZ vs AA: 75.80% vs 63.59%, P = .01). However, there was no significant difference in PSA PFS (adjusted hazard ratio: 0.86; 95% CI 0.63‐1.17) and OS (0.68: 0.41‐1.14) between the use of ENZ and AA in chemotherapy‐naïve mCRPC patients. Regarding the cardiovascular (CV) safety outcome, there was a significantly lower risk of MACE in patients receiving ENZ, compared to patients receiving AA (0.20: 0.07‐0.55). The findings suggest that enzalutamide may be more efficacious for PSA response and suitable for chemotherapy‐naïve mCRPC patients with high CV risk profile.
What's new?
While second generation androgen receptor (AR)‐targeted therapies are promising for the treatment of chemotherapy‐naïve metastatic castration‐resistant prostate cancer (mCRPC), data on survival benefit and cardiovascular safety are lacking. Here, using a multi‐institutional electronic health records database, the authors investigated the effectiveness, long‐term outcome, and cardiovascular safety of the AR‐targeted mCRPC therapies enzalutamide and abiraterone. Compared to abiraterone, enzalutamide is more efficacious in terms of prostate‐specific antigen response and carries a lower risk of major adverse cardiac events. The findings are relevant for treatment decisions regarding AR‐targeted therapies for chemotherapy‐naïve mCRPC patients with high risk of adverse cardiovascular events.
Background
Dynamic in vivo changes in melanin in melasma lesions after exposure to ultraviolet (UV) irradiation have not been described.
Objectives
To determine whether melasma lesions and nearby ...perilesions demonstrated different adaptive responses to UV irradiation and whether the tanning responses were different among different locations on face.
Methods
We collected sequential images from real‐time cellular resolution full‐field optical coherence tomography (CRFF‐OCT) at melasma lesions and perilesions among 20 Asian patients. Quantitative and layer distribution analyses for melanin were performed using a computer‐aided detection (CADe) system that utilizes spatial compounding‐based denoising convolutional neural networks.
Results
The detected melanin (D) is melanin with a diameter >0.5 µm, among which confetti melanin (C) has a diameter of >3.3 µm and corresponds to a melanosome‐rich package. The calculated C/D ratio is proportional to active melanin transportation. Before UV exposure, melasma lesions had more detected melanin (p = 0.0271), confetti melanin (p = 0.0163), and increased C/D ratio (p = 0.0152) in the basal layer compared to those of perilesions. After exposure to UV irradiation, perilesions have both increased confetti melanin (p = 0.0452) and the C/D ratio (p = 0.0369) in basal layer, and this effect was most prominent in right cheek (p = 0.030). There were however no significant differences in the detected, confetti, or granular melanin areas before and after exposure to UV irradiation in melasma lesions in all the skin layers.
Conclusions
Hyperactive melanocytes with a higher baseline C/D ratio were noted in the melasma lesions. They were “fixed” on the plateau and were not responsive to UV irradiation regardless of the location on face. Perilesions retained adaptability with a dynamic response to UV irradiation, in which more confetti melanin was shed, mainly in the basal layer. Therefore, aggravating effect of UV on melasma was mainly due to UV‐responsive perilesions rather than lesions.
In this paper, we conduct mathematical and numerical analyses for COVID-19. To predict the trend of COVID-19, we propose a time-dependent SIR model that tracks the transmission and recovering rate at ...time t. Using the data provided by China authority, we show our one-day prediction errors are almost less than 3%. The turning point and the total number of confirmed cases in China are predicted under our model. To analyze the impact of the undetectable infections on the spread of disease, we extend our model by considering two types of infected persons: detectable and undetectable infected persons. Whether there is an outbreak is characterized by the spectral radius of a 2 X 2 matrix. If R 0 > 1, then the spectral radius of that matrix is greater than 1, and there is an outbreak. We plot the phase transition diagram of an outbreak and show that there are several countries on the verge of COVID-19 outbreaks on Mar. 2, 2020. To illustrate the effectiveness of social distancing, we analyze the independent cascade model for disease propagation in a configuration random network. We show two approaches of social distancing that can lead to a reduction of the effective reproduction number R e .
PDF
