Current neural induction protocols for human embryonic stem (hES) cells rely on embryoid body formation, stromal feeder co-culture or selective survival conditions. Each strategy has considerable ...drawbacks, such as poorly defined culture conditions, protracted differentiation and low yield. Here we report that the synergistic action of two inhibitors of SMAD signaling, Noggin and SB431542, is sufficient to induce rapid and complete neural conversion of >80% of hES cells under adherent culture conditions. Temporal fate analysis reveals the appearance of a transient FGF5+ epiblast-like stage followed by PAX6+ neural cells competent to form rosettes. Initial cell density determines the ratio of central nervous system and neural crest progeny. Directed differentiation of human induced pluripotent stem (hiPS) cells into midbrain dopamine and spinal motoneurons confirms the robustness and general applicability of the induction protocol. Noggin/SB431542-based neural induction should facilitate the use of hES and hiPS cells in regenerative medicine and disease modeling and obviate the need for protocols based on stromal feeders or embryoid bodies.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Many neurological and psychiatric disorders affect the cerebral cortex, and a clearer understanding of the molecular processes underlying human corticogenesis will provide greater insight into such ...pathologies. To date, knowledge of gene expression changes accompanying corticogenesis is largely based on murine data. Here we present a searchable, comprehensive, temporal gene expression data set encompassing cerebral cortical development from human embryonic stem cells (hESCs). Using a modified differentiation protocol that yields neurons suggestive of prefrontal cortex, we identified sets of genes and long noncoding RNAs that significantly change during corticogenesis and those enriched for disease-associations. Numerous alternatively spliced genes with varying temporal patterns of expression are revealed, including TGIF1, involved in holoprosencephaly, and MARK1, involved in autism. We have created a database (http://cortecon.neuralsci.org/) that provides online, query-based access to changes in RNA expression and alternatively spliced transcripts during human cortical development.
•Temporal RNA-seq resource of human cortical development from hESCs•Protocol resulting in enrichment for prefrontal cortical fates•Identified genes with temporally regulated splicing during corticogenesis•Online, searchable database of temporal profile and associated disease information
Using RNA-seq, van de Leemput and Boles et al. have established a resource profiling the transcriptional changes occurring during human cortical development using an in vitro model.
Tremor is one of the clinical manifestations of dystonia; however, there are no specific therapeutic trials evaluating the efficacy of treatments for dystonic tremor (DT), tremor associated with ...dystonia or primary writing tremor (PWT). We systematically reviewed the literature available up to July 2013 on the treatment of these tremors and retrieved the data of 487 patients published in 43 papers detailing the effects of given interventions on tremor severity. Treatment outcome was highly variable, depending on the specific type of intervention and tremor distribution. No specifically designed studies were available for the treatment of tremor associated with dystonia. As for the other tremors, drug efficacy was generally disappointing and a moderate effect was only found with anticholinergics, tetrabenazine, clonazepam, β-blockers and primidone; levodopa was only efficacious on tremor due to dopa-responsive dystonia. The largest amount of data was available for botulinum toxin injections, which provided a marked improvement, particularly for the management of axial tremors (head or vocal cords). In refractory DTs, deep brain stimulation of several targets was attempted. Deep brain stimulation of globus pallidus internus, thalamus or subthalamic area led to a marked improvement of dystonic axial or appendicular tremors in most cases refractory to other treatments. Few other non-invasive treatments, for example, orthotic device in PWT, have been used with anecdotal success. In conclusion, considering the lack of good-quality studies, future randomised controlled trials are needed. In absence of evidence-based guidelines, we propose an algorithm for the treatment of DT based on currently available data.
Background
Despite increased utilization of contralateral prophylactic mastectomy (CPM), there is insufficient evidence that it improves survival in average-risk women with unilateral breast cancer. ...CPM may be of heightened interest to patients with triple negative breast cancer (TNBC) because these patients are more likely to have BRCA1 mutation-associated disease and are not candidates for the chemoprevention benefits of adjuvant endocrine therapy.
Methods
Survival and recurrence outcomes were evaluated for all TNBC patients from a multi-institutional database (1999–2018) at two academic cancer programs in two metropolitan cities of the Northeast and Midwest. Median follow-up time was 3.7 years.
Results
Seven hundred and nighty six TNBC patients were evaluated and 15.45% underwent CPM. Women undergoing CPM were more likely to be white (
p
< 0.001), younger (
p
< 0.001), and underwent genetic testing (
p
< 0.001). A borderline survival benefit was observed for TNBC patients undergoing CPM (5-year overall survival 95.1% vs. 85.0%;
p
= 0.05). There was no difference in survival when BRCA mutation carriers were excluded (5-year overall survival 94.1% vs. 85.2%;
p
= 0.12). For BRCA mutation carriers, a numeric trend was observed for improved survival for patients undergoing CPM (5-year overall survival 97.2% vs. 84.1%;
p
= 0.35). Among patients not undergoing CPM, the rate of developing a new primary breast cancer was 2.2% (15/673). Among these 15 patients, 20% (3/15) were known BRCA mutation carriers.
Conclusions
Our data demonstrate no survival benefit for TNBC patients without BRCA1/2 mutations undergoing CPM.
Punding is a stereotyped behavior characterized by an intense fascination with a complex, excessive, nongoal oriented, repetitive activity. Men tend to repetitively tinker with technical equipment ...such as radio sets, clocks, watches and car engines, the parts of which may be analyzed, arranged, sorted and cataloged but rarely put back together. Women, in contrast, incessantly sort through their handbags, tidy continuously, brush their hair or polish their nails. Punders are normally aware of the inapposite and obtuse nature of the behavior; however, despite the consequent self-injury, they do not stop such behavior. The most common causes of punding are dopaminergic replacement therapy in patients affected by Parkinson's disease (PD) and cocaine and amphetamine use in addicts. The vast majority of information about punding comes from PD cases. A critical review of these cases shows that almost all afflicted patients (90%) were on treatment with drugs acting mainly on dopamine receptors D1 and D2, whereas only three cases were reported in association with selective D2 and D3 agonists. Epidemiological considerations and available data from animal models suggest that punding, drug-induced stereotypies, addiction and dyskinesias all share a common pathophysiological process. Punding may be related to plastic changes in the ventral and dorsal striatal structures, including the nucleus accumbens, and linked to psychomotor stimulation and reward mechanisms. Possible management guidelines are proposed.
Abstract Background Deep Brain Stimulation of the Subthalamic Nucleus (STN-DBS) is an effective treatment for Parkinson's disease (PD), but only few studies investigated its long-term efficacy. ...Furthermore, little is known about the role of PD-subtype on STN-DBS long-term outcome. Objective To report the results of a long-term follow-up (mean 11 years, range 10–13) on 26 patients bilaterally implanted in two centres. Methods Patients were assessed preoperatively and 1, 5 and 11 years after the implant by the Unified Parkinson's Disease Rating Scale (UPDRS) and a battery of neuropsychological tests. Stimulation parameters, drugs dosages, non-motor symptoms and adverse events were also recorded. Results At 11 years, stimulation significantly improved the motor symptoms by 35.8%, as compared to the preoperative off-state. Motor complications were well controlled, with a 84.6% improvement of dyskinesias and a 65.8% improvement of motor fluctuations. Despite this, the UPDRS-II-on score worsened by 88.5%, mainly for the worsening of poorly levodopa-responsive symptoms. More than 70% of the patients performed in the normal range in most of the neuropsychological tests, despite the development of dementia in 22.7%. Age at disease onset, axial subscore in off-condition and presence of REM behaviour disorder at baseline were found to be associated with a higher risk of developing disability over time. Conclusions Our study confirms the long-term safety and efficacy of STN-DBS in PD. Nevertheless, the functionality of patients worsens over time, mainly for the onset and progression of levodopa-resistant and non-motor symptoms. The role of PD-subtype seems to be relevant in the long-term outcome.
EARLY DETECTION CD can manifest with a previously unsuspected range of clinical presentations, including the typical malabsorption syndrome (chronic diarrhoea, weight loss, abdominal distension) and ...a spectrum of symptoms potentially affecting any organ or body system. 4- 6 As CD is often atypical or even clinically silent, the vast majority of cases remain undiagnosed for many years and exposed to the risk of long term complications. 7 PREVALENCE Analysis of the world codistribution of the two key components (HLA genes and grains) involved in CD pathogenesis 2 would predict a wide distribution of the disease, both in regions where CD is described as a frequent disorder (that is, Europe) 6 and in areas where the disease has been historically considered rare (that is, the USA).
This paper presents fiber Bragg grating (FBG) inscription with a pulsed 248 nm UV KrF laser in polymer optical fibers (POFs) made of different polymers, namely polymethyl methacrylate (PMMA), ...cyclic-olefin polymer and co-polymer, and Polycarbonate. The inscribed gratings and the corresponding inscription parameters are compared with grating inscribed in POFs made of the aforementioned materials but with the hitherto most used laser for inscription, which is a continuous wave 325 nm UV HeCd laser. Results show a reduction of the inscription time of at least 16 times. The maximum time reduction is more than 130 times. In addition, a reflectivity and a bandwidth close to or higher than the ones with the 325 nm laser were obtained. The polymer optical fiber Bragg gratings (POFBGs) inscribed with the 248 nm laser setup present high stability with small variations in their central wavelength, bandwidth, and reflectivity after 40 days.
We report the design, fabrication, and testing of lumped element kinetic inductance detectors (LEKID) showing performance in line with the requirements of the next generation space telescopes ...operating in the spectral range from 80 GHz to 600 GHz. This range is of particular interest for cosmic microwave background studies. For this purpose we designed and fabricated 100 pixel arrays covering five distinct bands. These wafers were measured via multiplexing, in which a full array is read out using a single pair of lines. We adopted a custom cold black body installed in front of the detectors and regulated at temperatures between 1 K and 20 K. In this paper, we describe in the main design considerations, fabrication processes, testing and data analysis.
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