We used transneuronal transport of neurotropic viruses to examine the topographic organization of circuits linking the cerebellar cortex with the arm area of the primary motor cortex (M1) and with ...area 46 in dorsolateral prefrontal cortex of monkeys. Retrograde transneuronal transport of the CVS-11 (challenge virus strain 11) strain of rabies virus in cerebello-thalamocortical pathways revealed that the arm area of M1 receives input from Purkinje cells located primarily in lobules IV-VI of the cerebellar cortex. In contrast, transneuronal transport of rabies from area 46 revealed that it receives input from Purkinje cells located primarily in Crus II of the ansiform lobule. Thus, both M1 and area 46 are the targets of output from the cerebellar cortex. However, the output to each area of the cerebral cortex originates from Purkinje cells in different regions of the cerebellar cortex. Anterograde transneuronal transport of the H129 strain of herpes simplex virus type 1 (HSV1) revealed that neurons in the arm area of M1 project via the pons to granule cells primarily in lobules IV-VI, whereas neurons in area 46 project to granule cells primarily in Crus II. Together, the findings from rabies and HSV1 experiments indicate that the regions of the cerebellar cortex that receive input from M1 are the same as those that project to M1. Similarly, the regions of the cerebellar cortex that receive input from area 46 are the same as those that project to area 46. Thus, our observations suggest that multiple closed-loop circuits represent a fundamental architectural feature of cerebrocerebellar interactions.
Vacuolar protein sorting 35 (VPS35) is a core component of the retromer complex, crucial to endosomal protein sorting and intracellular trafficking. We recently linked a mutation in VPS35 (p.D620N) ...to familial parkinsonism. Here, we characterize human VPS35 and retromer function in mature murine neuronal cultures and investigate neuron-specific consequences of the p.D620N mutation. We find VPS35 localizes to dendritic spines and is involved in the trafficking of excitatory AMPA-type glutamate receptors (AMPARs). Fundamental neuronal processes, including excitatory synaptic transmission, AMPAR surface expression and synaptic recycling are altered by VPS35 overexpression. VPS35 p.D620N acts as a loss-of-function mutation with respect to VPS35 activity regulating synaptic transmission and AMPAR recycling in mouse cortical neurons and dopamine neuron-like cells produced from induced pluripotent stem cells of human p.D620N carriers. Such perturbations to synaptic function likely produce chronic pathophysiological stress upon neuronal circuits that may contribute to neurodegeneration in this, and other, forms of parkinsonism.
Immune cells display a high degree of phenotypic plasticity, which may facilitate their participation in both the progression and resolution of injury-induced inflammation. The purpose of this study ...was to investigate the temporal expression of genes associated with classical and alternative polarization phenotypes described for macrophages and to identify related cell populations in the brain following neonatal hypoxia-ischemia (HI). HI was induced in 9-day old mice and brain tissue was collected up to 7 days post-insult to investigate expression of genes associated with macrophage activation. Using cell-markers, CD86 (classic activation) and CD206 (alternative activation), we assessed temporal changes of CD11b
cell populations in the brain and studied the protein expression of the immunomodulatory factor galectin-3 in these cells. HI induced a rapid regulation (6 h) of genes associated with both classical and alternative polarization phenotypes in the injured hemisphere. FACS analysis showed a marked increase in the number of CD11b
CD86
cells at 24 h after HI (+3667%), which was coupled with a relative suppression of CD11b
CD206
cells and cells that did not express neither CD86 nor CD206. The CD11b
CD206
population was mixed with some cells also expressing CD86. Confocal microscopy confirmed that a subset of cells expressed both CD86 and CD206, particularly in injured gray and white matter. Protein concentration of galectin-3 was markedly increased mainly in the cell population lacking CD86 or CD206 in the injured hemisphere. These cells were predominantly resident microglia as very few galectin-3 positive cells co-localized with infiltrating myeloid cells in
-EGFP-
mice after HI. In summary, HI was characterized by an early mixed gene response, but with a large expansion of mainly the CD86 positive population during the first day. However, the injured hemisphere also contained a subset of cells expressing both CD86 and CD206 and a large population that expressed neither activation marker CD86 nor CD206. Interestingly, these cells expressed the highest levels of galectin-3 and were found to be predominantly resident microglia. Galectin-3 is a protein involved in chemotaxis and macrophage polarization suggesting a novel role in cell infiltration and immunomodulation for this cell population after neonatal injury.
In recent years, the number of approved and investigational agents that can be safely administered for the treatment of lymphoma patients for a prolonged period of time has substantially increased. ...Many of these novel agents are evaluated in early-phase clinical trials in patients with a wide range of malignancies, including solid tumors and lymphoma. Furthermore, with the advances in genome sequencing, new “basket” clinical trial designs have emerged that select patients based on the presence of specific genetic alterations across different types of solid tumors and lymphoma. The standard response criteria currently in use for lymphoma are the Lugano Criteria which are based on 18F2-fluoro-2-deoxy-D-glucose positron emission tomography or bidimensional tumor measurements on computerized tomography scans. These differ from the RECIST criteria used in solid tumors, which use unidimensional measurements. The RECIL group hypothesized that single-dimension measurement could be used to assess response to therapy in lymphoma patients, producing results similar to the standard criteria. We tested this hypothesis by analyzing 47 828 imaging measurements from 2983 individual adult and pediatric lymphoma patients enrolled on 10 multicenter clinical trials and developed new lymphoma response criteria (RECIL 2017). We demonstrate that assessment of tumor burden in lymphoma clinical trials can use the sum of longest diameters of a maximum of three target lesions. Furthermore, we introduced a new provisional category of a minor response. We also clarified response assessment in patients receiving novel immune therapy and targeted agents that generate unique imaging situations.
The intestinal microbiota protect the host against enteric pathogens through a defense mechanism termed colonization resistance. Antibiotics excreted into the intestinal tract may disrupt ...colonization resistance and alter normal metabolic functions of the microbiota. We used a mouse model to test the hypothesis that alterations in levels of bacterial metabolites in fecal specimens could provide useful biomarkers indicating disrupted or intact colonization resistance after antibiotic treatment.
To assess in vivo colonization resistance, mice were challenged with oral vancomycin-resistant Enterococcus or Clostridium difficile spores at varying time points after treatment with the lincosamide antibiotic clindamycin. For concurrent groups of antibiotic-treated mice, stool samples were analyzed using quantitative real-time polymerase chain reaction to assess changes in the microbiota and using non-targeted metabolic profiling. To assess whether the findings were applicable to another antibiotic class that suppresses intestinal anaerobes, similar experiments were conducted with piperacillin/tazobactam.
Colonization resistance began to recover within 5 days and was intact by 12 days after clindamycin treatment, coinciding with the recovery bacteria from the families Lachnospiraceae and Ruminococcaceae, both part of the phylum Firmicutes. Clindamycin treatment caused marked changes in metabolites present in fecal specimens. Of 484 compounds analyzed, 146 (30%) exhibited a significant increase or decrease in concentration during clindamycin treatment followed by recovery to baseline that coincided with restoration of in vivo colonization resistance. Identified as potential biomarkers of colonization resistance, these compounds included intermediates in carbohydrate or protein metabolism that increased (pentitols, gamma-glutamyl amino acids and inositol metabolites) or decreased (pentoses, dipeptides) with clindamycin treatment. Piperacillin/tazobactam treatment caused similar alterations in the intestinal microbiota and fecal metabolites.
Recovery of colonization resistance after antibiotic treatment coincided with restoration of several fecal bacterial metabolites. These metabolites could provide useful biomarkers indicating intact or disrupted colonization resistance during and after antibiotic treatment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
ABSTRACT We give an overview of the Grism Lens Amplified Survey from Space (GLASS), a large Hubble Space Telescope program aimed at obtaining grism spectroscopy of the fields of 10 massive clusters ...of galaxies at redshift z = 0.308-0.686, including the Hubble Frontier Fields (HFF). The Wide Field Camera 3 (WFC3) yields near-infrared spectra of the cluster cores covering the wavelength range 0.81-1.69 m through grisms G102 and G141, while the Advanced Camera for Surveys in parallel mode provides G800L spectra of the infall regions of the clusters. The WFC3 spectra are taken at two almost orthogonal position angles in order to minimize the effects of confusion. After summarizing the scientific drivers of GLASS, we describe the sample selection as well as the observing strategy and data processing pipeline. We then utilize MACS J0717.5+3745, a HFF cluster and the first one observed by GLASS, to illustrate the data quality and the high-level data products. Each spectrum brighter than is visually inspected by at least two co-authors and a redshift is measured when sufficient information is present in the spectra. Furthermore, we conducted a thorough search for emission lines through all of the GLASS WFC3 spectra with the aim of measuring redshifts for sources with continuum fainter than We provide a catalog of 139 emission-line-based spectroscopic redshifts for extragalactic sources, including three new redshifts of multiple image systems (one probable, two tentative). In addition to the data itself, we also release software tools that are helpful to navigate the data.
Aims
To examine determinants of intention to leave a nursing position in rural and remote areas within the next year, for Registered Nurses or Nurse Practitioners (RNs/NPs) and Licensed Practical ...Nurses (LPNs).
Design
A pan‐Canadian cross‐sectional survey.
Methods
The Nursing Practice in Rural and Remote Canada II survey (2014–2015) used stratified, systematic sampling and obtained two samples of questionnaire responses on intent to leave from 1,932 RNs/NPs and 1,133 LPNs. Separate logistic regression analyses were conducted for RNs/NPs and LPNs.
Results
For RNs/NPs, 19.8% of the variance on intent to leave was explained by 11 variables; and for LPNs, 16.9% of the variance was explained by seven variables. Organizational commitment was the only variable associated with intent to leave for both RNs/NPs and LPNs.
Conclusions
Enhancement of organizational commitment is important in reducing intent to leave and turnover. Since most variables associated with intent to leave differ between RNs/NPs and LPNs, the distinction of nurse type is critical for the development of rural‐specific turnover reduction strategies. Comparison of determinants of intent to leave in the current RNs/NPs analysis with the first pan‐Canadian study of rural and remote nurses (2001–2002) showed similarity of issues for RNs/NPs over time, suggesting that some issues addressing turnover remain unresolved.
Impact
The geographic maldistribution of nurses requires focused attention on nurses' intent to leave. This research shows that healthcare organizations would do well to develop policies targeting specific variables associated with intent to leave for each type of nurse in the rural and remote context. Practical strategies could include specific continuing education initiatives, tailored mentoring programs, and the creation of career pathways for nurses in rural and remote settings. They would also include place‐based actions designed to enhance nurses' integration with their communities and which would be planned together with communities and nurses themselves.
摘要
目的
探讨注册护士或执业护士(RNs/NPs)和持证护士(LPNs)在未来一年内辞去农村和偏远地区护理职务的决定因素。
设计
泛加拿大横断面调查。
方法
加拿大农村和边远地区护理实践II调查(2014‐2015)过程中,采用分层、系统抽样的方法,对1932名注册护士/执业护士和1133名持证护士进行问卷调查,调查样本显示,共两名有意离职。分别对注册护士/执业护士和持证护士进行逻辑回归分析。
结果
19.8%注册护士或执业护士的离职意愿与11个变量相关,而16.9%持证护士的离职意愿与7个变量相关;组织承诺是唯一与注册护士/执业护士和持证护士离职意愿都相关的变量。
结论
强化组织承诺可以降低离职意愿和离职率,这一点至关重要。由于注册护士/执业护士和持证护士的离职意愿相关变量大多不同,护士类型的区分对于农村地区离职率降低策略的制定至关重要。将当前注册护士/执业护士分析中的离职意愿决定因素与首次泛加拿大农村和远程护士研究(2001‐2002年)进行比较,比较结果表明,随着时间的推移,注册护士/执业护士的问题趋同,表明部分离职相关问题仍未解决。
影响
当前,护士地理分布不均,因此需要关注护士的离职意愿。研究表明,医疗单位应该针对与农村和偏远地区不同类型护士离职意愿相关的特定变量制定政策。实际策略包括制定具体的继续教育计划,因地制宜编制指导计划,以及为农村和偏远地区的护士确定职业发展道路。此外,包括地方行动,旨在加强护士与社区的融合,同时为社区和护士作出规划。
Microlenses with typical stellar masses (a few M⊙) have traditionally been disregarded as potential sources of gravitational lensing effects at LIGO/Virgo frequencies, since the time delays are often ...much smaller than the inverse of the frequencies probed by LIGO/Virgo, resulting in negligible interference effects at LIGO/Virgo frequencies. While this is true for isolated microlenses in this mass regime, we show how, under certain circumstances and for realistic scenarios, a population of microlenses (for instance stars and remnants from a galaxy halo or from the intracluster medium) embedded in a macromodel potential (galaxy or cluster) can conspire together to produce time delays of order one millisecond, which would produce significant interference distortions in the observed strains. At sufficiently large magnification factors (of several hundred), microlensing effects should be common in gravitationally lensed gravitational waves. We explored the regime where the predicted signal falls in the frequency range probed by LIGO/Virgo. We find that stellar mass microlenses, permeating the lens plane, and near critical curves, can introduce interference distortions in strongly lensed gravitational waves. Lensed events with negative parity, or saddle points (which have never before been studied in the context of gravitational waves), and that take place near caustics of macromodels, are more likely to produce measurable interference effects at LIGO/Virgo frequencies. This is the first study that explores the effect of a realistic population of microlenses, including a macromodel, on strongly lensed gravitational waves.
PDF
