The ability to chronically monitor neuronal activity in the living brain is essential for understanding the organization and function of the nervous system. The genetically encoded green fluorescent ...protein-based calcium sensor GCaMP provides a powerful tool for detecting calcium transients in neuronal somata, processes, and synapses that are triggered by neuronal activities. Here we report the generation and characterization of transgenic mice that express improved GCaMPs in various neuronal subpopulations under the control of the Thy1 promoter. In vitro and in vivo studies show that calcium transients induced by spontaneous and stimulus-evoked neuronal activities can be readily detected at the level of individual cells and synapses in acute brain slices, as well as chronically in awake, behaving animals. These GCaMP transgenic mice allow investigation of activity patterns in defined neuronal populations in the living brain and will greatly facilitate dissecting complex structural and functional relationships of neural networks.
► Thy1-GCaMP2.2c and Thy1-GCaMP3 transgenic lines were generated ► Spontaneous and evoked calcium transients can be detected in acute brain slices ► Calcium transients can be detected in dendrites and spines in vivo ► Calcium transients can be detected in neuronal populations in vivo
Chen et al. generate transgenic mice expressing genetically encoded calcium sensors and demonstrate the utility of these mice in optically monitoring neuronal activity in vivo.
Calcium/calmodulin-dependent kinase II (CaMKII) plays a central part in long-term potentiation (LTP), which underlies some forms of learning and memory. Here we monitored the spatiotemporal dynamics ...of CaMKII activation in individual dendritic spines during LTP using two-photon fluorescence lifetime imaging microscopy, in combination with two-photon glutamate uncaging. Induction of LTP and associated spine enlargement in single spines triggered transient ( approximately 1 min) CaMKII activation restricted to the stimulated spines. CaMKII in spines was specifically activated by NMDA receptors and L-type voltage-sensitive calcium channels, presumably by nanodomain Ca(2+) near the channels, in response to glutamate uncaging and depolarization, respectively. The high degree of compartmentalization and channel specificity of CaMKII signalling allow stimuli-specific spatiotemporal patterns of CaMKII signalling and may be important for synapse-specificity of synaptic plasticity.
The differential code bias (DCB) of global navigation satellite systems (GNSSs) affects precise ionospheric modeling and applications. In this paper, daily DCBs of the BeiDou Navigation Satellite ...System (BDS) are estimated and investigated from 2-year multi-GNSS network observations (2013–2014) based on global ionospheric maps (GIMs) from the Center for Orbit Determination in Europe (CODE), which are compared with Global Positioning System (GPS) results. The DCB of BDS satellites is a little less stable than GPS solutions, especially for geostationary Earth orbit (GEO) satellites. The BDS GEO observations decrease the precision of inclined geosynchronous satellite orbit (IGSO) and medium Earth orbit (MEO) DCB estimations. The RMS of BDS satellites DCB decreases to about 0.2 ns when we remove BDS GEO observations. Zero-mean condition effects are not the dominant factor for the higher RMS of BDS satellites DCB. Although there are no obvious secular variations in the DCB time series, sub-nanosecond variations are visible for both BDS and GPS satellites DCBs during 2013–2014. For satellites in the same orbital plane, their DCB variations have similar characteristics. In addition, variations in receivers DCB in the same region are found with a similar pattern between BDS and GPS. These variations in both GPS and BDS DCBs are mainly related to the estimated error from ionospheric variability, while the BDS DCB intrinsic variation is in sub-nanoseconds.
To examine barriers to initiation and continuation of mental health treatment among individuals with common mental disorders.
Data were from the World Health Organization (WHO) World Mental Health ...(WMH) surveys. Representative household samples were interviewed face to face in 24 countries. Reasons to initiate and continue treatment were examined in a subsample (n = 63,678) and analyzed at different levels of clinical severity.
Among those with a DSM-IV disorder in the past 12 months, low perceived need was the most common reason for not initiating treatment and more common among moderate and mild than severe cases. Women and younger people with disorders were more likely to recognize a need for treatment. A desire to handle the problem on one's own was the most common barrier among respondents with a disorder who perceived a need for treatment (63.8%). Attitudinal barriers were much more important than structural barriers to both initiating and continuing treatment. However, attitudinal barriers dominated for mild-moderate cases and structural barriers for severe cases. Perceived ineffectiveness of treatment was the most commonly reported reason for treatment drop-out (39.3%), followed by negative experiences with treatment providers (26.9% of respondents with severe disorders).
Low perceived need and attitudinal barriers are the major barriers to seeking and staying in treatment among individuals with common mental disorders worldwide. Apart from targeting structural barriers, mainly in countries with poor resources, increasing population mental health literacy is an important endeavor worldwide.
The aim was to examine barriers to initiation and continuation of treatment among individuals with common mental disorders in the US general population.
Respondents in the National Comorbidity Survey ...Replication with common 12-month DSM-IV mood, anxiety, substance, impulse control and childhood disorders were asked about perceived need for treatment, structural barriers and attitudinal/evaluative barriers to initiation and continuation of treatment.
Low perceived need was reported by 44.8% of respondents with a disorder who did not seek treatment. Desire to handle the problem on one's own was the most common reason among respondents with perceived need both for not seeking treatment (72.6%) and for dropping out of treatment (42.2%). Attitudinal/evaluative factors were much more important than structural barriers both to initiating (97.4% v. 22.2%) and to continuing (81.9% v. 31.8%) of treatment. Reasons for not seeking treatment varied with illness severity. Low perceived need was a more common reason for not seeking treatment among individuals with mild (57.0%) than moderate (39.3%) or severe (25.9%) disorders, whereas structural and attitudinal/evaluative barriers were more common among respondents with more severe conditions.
Low perceived need and attitudinal/evaluative barriers are the major barriers to treatment seeking and staying in treatment among individuals with common mental disorders. Efforts to increase treatment seeking and reduce treatment drop-out need to take these barriers into consideration as well as to recognize that barriers differ as a function of sociodemographic and clinical characteristics.
From the 1920s to the eve of the Pacific War in 1941, more than 50,000 young second-generation Japanese Americans (Nisei) embarked on transpacific journeys to the Japanese Empire, putting an ocean ...between themselves and pervasive anti-Asian racism in the American West. Born U.S. citizens but treated as unwelcome aliens, this contingent of Japanese Americans-one in four U.S.-born Nisei-came in search of better lives but instead encountered a world shaped by increasingly volatile relations between the U.S. and Japan. Based on transnational and bilingual research in the United States and Japan, Michael R. Jin recuperates the stories of this unique group of American emigrants at the crossroads of U.S. and Japanese empire. From the Jim Crow American West to the Japanese colonial frontiers in Asia, and from internment camps in America to Hiroshima on the eve of the atomic bombing, these individuals redefined ideas about home, identity, citizenship, and belonging as they encountered multiple social realities on both sides of the Pacific. Citizens, Immigrants, and the Stateless examines the deeply intertwined histories of Asian exclusion in the United States, Japanese colonialism in Asia, and volatile geopolitical changes in the Pacific world that converged in the lives of Japanese American migrants.
CaMKII plays a critical role in decoding calcium (Ca2+) signals to initiate long-lasting synaptic plasticity. However, the properties of CaMKII that mediate Ca2+ signals in spines remain elusive. ...Here, we measured CaMKII activity in spines using fast-framing two-photon fluorescence lifetime imaging. Following each pulse during repetitive Ca2+ elevations, CaMKII activity increased in a stepwise manner. Thr286 phosphorylation slows the decay of CaMKII and thus lowers the frequency required to induce spine plasticity by several fold. In the absence of Thr286 phosphorylation, increasing the stimulation frequency results in high peak mutant CaMKIIT286A activity that is sufficient for inducing plasticity. Our findings demonstrate that Thr286 phosphorylation plays an important role in induction of LTP by integrating Ca2+ signals, and it greatly promotes, but is dispensable for, the activation of CaMKII and LTP.
•CaMKII acts as a leaky integrator of Ca2+ pulses in dendritic spines•Phosphorylation at T286 is necessary for optimal integration of Ca2+ pulses•Phosphorylation at T286 is dispensable for the maintenance of LTP
Chang et al. showed that CaMKII activation acts as a leaky integrator of Ca2+ pulses in dendritic spines, and demonstrated that phosphorylation of T286 is necessary for optimal integration of Ca2+ pulses during the induction of LTP but dispensable for the maintenance of LTP.
The seamless phase Ⅱ/Ⅲ design integrates independent phase Ⅱ and phase Ⅲ clinical trials into a continuous, phased adaptive clinical trial design. Compared with traditional independent phase Ⅱ and ...phase Ⅲ clinical trials, the seamless design offers significant advantages in accelerating drug or vaccine development and improving clinical trial efficiency. Currently, the application of this design in anti-tumor drug research is becoming increasingly mature, and it is gradually expanding to clinical trials of vaccines, including the 9-valent human papillomavirus vaccine, sabin strain inactivated polio vaccine, and others. This paper aims to clarify the seamless phase Ⅱ/Ⅲ design concept and offer valuable insights into its implementation. It accomplishes this by presenting a clinical trial example featuring a phase Ⅱ/Ⅲ seamless design for a 9-valent human papillomavirus vaccine. The article delves into the specific considerations and potential challenges related to implementing the seamless design, aiming to prov
Androgen receptor splicing variants (ARVs) that lack the ligand-binding domain (LBD) are associated with the development of castration-resistant prostate cancer (CRPC), including resistance to the ...new generation of high-affinity anti-androgens. However, the mechanism by which ARV expression is regulated is not fully understood. In this study, we show that the activation of classical nuclear factor-kappa B (NF-κB) signaling increases the expression of ARVs in prostate cancer (PCa) cells and converts androgen-sensitive PCa cells to become androgen-insensitive, whereas downregulation of NF-κB signaling inhibits ARV expression and restores responsiveness of CRPC to anti-androgen therapy. In addition, we demonstrated that combination of anti-androgen with NF-κB-targeted therapy inhibits efficiently tumor growth of human CRPC xenografts. These results indicate that induction of ARVs by activated NF-κB signaling in PCa cells is a critical mechanism by which the PCa progresses to CRPC. This has important implications as it can prolong the survival of CRPC patients by restoring the tumors to once again respond to conventional androgen-deprivation therapy (ADT).
Hypervirulent (hypermucoviscous) Klebsiella pneumoniae strains constitute an increasing proportion of the K. pneumoniae strains isolated from patients in China. Disturbingly, the frequency of ...antimicrobial-resistant strains identified among these isolates has increased in recent years.
Background.
New hypervirulent variants of Klebsiella pneumoniae (hvKP) are emerging globally, most of which exhibit antimicrobial susceptibility.
Methods.
A retrospective study was conducted in 88 patients with cultures positive for K. pneumoniae hospitalized in the Beijing You'an Hospital from April 2010 to June 2012. The clinical and molecular data of the hvKP isolates (defined as string test positive) were compared with those of the classic K. pneumoniae (cKP) isolates.
Results.
Overall, 33.0% (29/88) of K. pneumoniae isolates were hvKP. Univariate analysis revealed the following risk factors for hvKP: virulence gene rmpA (odds ratio OR, 16.92 95% confidence interval {CI}, 4.842–59.145), capsule antigens K1 (OR, 3.355 95% CI, 1.153–9.768) and K2 (OR, 9.280 95% CI, 0.987–87.250), alcoholic hepatitis (OR, 7.435 95% CI, 1.397–39.572), liver abscess (OR, 9.068 95% CI, 1.747–47.061), metastatic infection (OR, 2.752 95% CI, 1.100–6.886), community-acquired infection (OR, 10.432 95% CI, 3.623–30.033), sputum isolation (OR, 0.312 95% CI, .095–1.021), and HIV infection (<0.001 not applicable). Multivariate analysis implicated rmpA (OR, 17.398 95% CI, 4.224–71.668) and community-acquired infection (OR, 6.844 95% CI, 1.905–24.585) as independent risk factors. The proportion of hvKP isolates increased from April to December 2010, January to September 2011, and October 2011 to June 2012 (to 25.5%, 26.7%, and 54.5%, respectively). Resistance to 14 of 19 tested antimicrobials was found to be significantly greater in cKP compared to hvKP. Importantly, resistance to all the tested antimicrobials, except carbapenems and amikacin, was observed in a proportion of hvKP strains, 17% (5/29) of which expressed extended-spectrum β-lactamase. Furthermore, antimicrobial resistance in hvKP strains increased over time.
Conclusions.
HvKP strains are being isolated from patients in China with increasing frequency and constitute an increasing proportion of K. pneumoniae strains, indicating an increasing propensity for the acquisition of antimicrobial resistance.
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