Miracle-dz/UniFAR-FTUs huggingface dataset:
Apathy and noradrenaline: silent partners to mild cognitive impairment in Parkinson's disease?

PURPOSE OF REVIEW Mild cognitive impairment (MCI) is a comorbid factor in Parkinson's disease. The aim of this review is to examine the recent neuroimaging findings in the search for Parkinson's disease MCI (PD-MCI) biomarkers to gain insight on whether MCI and specific cognitive deficits in Parkinson's disease implicate striatal dopamine or another system. RECENT FINDINGS The evidence implicates a diffuse pathophysiology in PD-MCI rather than acute dopaminergic involvement. On the one hand, performance in specific cognitive domains, notably in set-shifting and learning, appears to vary with dopaminergic status. On the other hand, motivational states in Parkinson's disease along with their behavioral and physiological indices suggest a noradrenergic contribution to cognitive deficits in Parkinson's disease. Finally, Parkinson's disease's pattern of neurodegeneration offers an avenue for continued research in nigrostriatal dopamine's role in distinct behaviors, as well as the specification of dorsal and ventral striatal functions. SUMMARY The search for PD-MCI biomarkers has employed an array of neuroimaging techniques, but still yields divergent findings. This may be due in part to MCI's broad definition, encompassing heterogeneous cognitive domains, only some of which are affected in Parkinson's disease. Most domains falling under the MCI umbrella include fronto-dependent executive functions, whereas others, notably learning, rely on the basal ganglia. Given the deterioration of the nigrostriatal dopaminergic system in Parkinson's disease, it has been the prime target of PD-MCI investigation. By testing well defined cognitive deficits in Parkinson's disease, distinct functions can be attributed to specific neural systems, overcoming conflicting results on PD-MCI. Apart from dopamine, other systems such as the neurovascular or noradrenergic systems are affected in Parkinson's disease. These factors may be at the basis of specific facets of PD-MCI for which dopaminergic involvement has not been conclusive. Finally, the impact of both dopaminergic and noradrenergic deficiency on motivational states in Parkinson's disease is examined in light of a plausible link between apathy and cognitive deficits.
Functional analysis of CTRP3/cartducin in Meckel’s cartilage and developing condylar cartilage in the fetal mouse mandible

CTRP3/cartducin, a novel C1q family protein, is expressed in proliferating chondrocytes in the growth plate and has an important role in regulating the growth of both chondrogenic precursors and chondrocytes in vitro. We examined the expression of CTRP3/cartducin mRNA in Meckel’s cartilage and in condylar cartilage of the fetal mouse mandible. Based on in situ hybridization studies, CTRP3/cartducin mRNA was not expressed in the anlagen of Meckel’s cartilage at embryonic day (E)11.5, but it was strongly expressed in Meckel’s cartilage at E14.0, and then reduced in the hypertrophic chondrocytes at E16.0. CTRP3/cartducin mRNA was not expressed in the condylar anlagen at E14.0, but was expressed in the upper part of newly formed condylar cartilage at E15.0. At E16.0, CTRP3/cartducin mRNA was expressed from the polymorphic cell zone to the upper part of the hypertrophic cell zone, but was reduced in the lower part of the hypertrophic cell zone. CTRP3/cartducin‐antisense oligodeoxynucleotide (AS‐ODN) treatment of Meckel’s cartilage and condylar anlagen from E14.0 using an organ culture system indicated that, after 4‐day culture, CTRP3/cartducin abrogation induced curvature deformation of Meckel’s cartilage with loss of the perichondrium and new cartilage formation. Aggrecan, type I collagen, and tenascin‐C were simultaneously immunostained in this newly formed cartilage, indicating possible transformation from the perichondrium into cartilage. Further, addition of recombinant mouse CTRP3/cartducin protein to the organ culture medium with AS‐ODN tended to reverse the deformation. These results suggest a novel function for CTRP3/cartducin in maintaining the perichondrium. Moreover, AS‐ODN induced a deformation of the shape, loss of the perichondrium/fibrous cell zone, and disorder of the distinct architecture of zones in the mandibular condylar cartilage. Additionally, AS‐ODN‐treated condylar cartilage showed reduced levels of mRNA expression of aggrecan, collagen types I and X, and reduced BrdU‐incorporation. These results suggest that CTRP3/cartducin is not only involved in the proliferation and differentiation of chondrocytes, but also contributes to the regulation of mandibular condylar cartilage.
Collagen-Based Medical Device as a Stem Cell Carrier for Regenerative Medicine

Maintenance of mesenchymal stem cells (MSCs) requires a tissue-specific microenvironment (i.e., niche), which is poorly represented by the typical plastic substrate used for two-dimensional growth of MSCs in a tissue culture flask. The objective of this study was to address the potential use of collagen-based medical devices (HEMOCOLLAGENE®, Saint-Maur-des-Fossés, France) as mimetic niche for MSCs with the ability to preserve human MSC stemness in vitro. With a chemical composition similar to type I collagen, HEMOCOLLAGENE® foam presented a porous and interconnected structure (>90%) and a relative low elastic modulus of around 60 kPa. Biological studies revealed an apparently inert microenvironment of HEMOCOLLAGENE® foam, where 80% of cultured human MSCs remained viable, adopted a flattened morphology, and maintained their undifferentiated state with basal secretory activity. Thus, three-dimensional HEMOCOLLAGENE® foams present an in vitro model that mimics the MSC niche with the capacity to support viable and quiescent MSCs within a low stiffness collagen I scaffold simulating Wharton’s jelly. These results suggest that haemostatic foam may be a useful and versatile carrier for MSC transplantation for regenerative medicine applications.
Down regulation of epidermal growth factor receptors: direct demonstration of receptor degradation in human fibroblasts

The metabolism of the receptor for epidermal growth factor (EGF) has been measured by labeling the receptor in vivo with radioactive amino acid precursors and then determining, by immunoprecipitation with specific anti-EGF receptor antisera, the rate of degradation of the receptor when the cells are placed in a nonradioactive medium. In human fibroblasts the rate of EGF receptor degradation (t1/2 = 10.1 h) was faster than the rate of degradation of total cell protein. When EGF was added to the nonradioactive medium, the half-life of prelabeled receptor was decreased to 1.2 h in human fibroblasts. These data demonstrate by direct analysis of receptor protein that during "down regulation" the EGF receptor is rapidly degraded. Enhanced receptor degradation was observed 5-10 min after the addition of EGF. The EGF- induced degradation of the receptor was blocked by methylamine, chloroquine, iodoacetate, or incubation at 25 degrees C. We have also shown that EGF-induced down regulation in human fibroblasts results in a decrease in the total amount of EGF receptor protein present. The amount of EGF receptor protein has been quantitated by radiolabeling cellular protein and immunoprecipitation of the receptor. The EGF receptor constitutes approximately 0.0035% of the cellular protein in human fibroblasts.
Elevated O-GlcNAc levels activate epigenetically repressed genes and delay mouse ES cell differentiation without affecting naive to primed cell transition

The differentiation of mouse embryonic stem cells (ESCs) is controlled by the interaction of multiple signaling pathways, typically mediated by post-translational protein modiﬁcations. The addition of O -linked N -acetylglucosamine ( O -GlcNAc) to serine and threonine residues of nuclear and cytoplasmic proteins is one such modiﬁcation ( O -GlcNAcylation), whose function in ESCs is only now beginning to be elucidated. Here, we demonstrate that the speciﬁc inhibition of O -GlcNAc hydrolase (Oga) causes increased levels of protein O -GlcNAcylation and impairs differentiation of mouse ESCs both in serum-free monolayer and in embryoid bodies (EBs). Use of reporter cell lines demonstrates that Oga inhibition leads to a reduction in the number of Sox1-expressing neural progenitors generated following induction of neural differentiation as well as maintained expression of the ESC marker Oct4 (Pou5f1). In EBs, expression of mesodermal and endodermal markers is also delayed. However, the transition of na € ıve cells to primed pluripotency indicated by Rex1 (Zfp42), Nanog, Esrrb, and Dppa3 downregulation and Fgf5 upregulation remains unchanged. Finally, we demonstrate that increased O -GlcNAcylation results in upregulation of genes normally
Immediate Loading of a Single Implant in the Esthetic Zone

Implant dentistry has been a challenging field over the past decades with the introduction of multiple systems. The successful treatment outcomes of the dental implant were mainly due to the strict treatment protocols. However, the long waiting period between visits was challenging to the clinicians. In addition to other patient related issues. Immediate loading implant was introduced to overcome these problems. Nevertheless, several factors contribute to the success of immediate implant loading, which is advisable to be considered and assessed properly before the procedure, especially when replacing a missing tooth in the anterior zone of the maxilla with an immediate loaded implant. and demands to restore esthetic appearance as soon as possible is necessary. Patient satisfaction with an immediate loading can be obtained due to multiple reasons; the low cost of the treatment because of less surgical steps, the shorten length of the overall treatment and less surgical trauma to the pre-implant soft tissue that will help in the pleasant soft tissue profile appearance (Table 1) [5-8].
Improving the Modeling of Disease Data from the Government Surveillance System: A Case Study on Malaria in the Brazilian Amazon

The study of the effect of large-scale drivers (e.g., climate) of human diseases typically relies on aggregate disease data collected by the government surveillance network. The usual approach to analyze these data, however, often ignores a) changes in the total number of individuals examined, b) the bias towards symptomatic individuals in routine government surveillance, and; c) the influence that observations can have on disease dynamics. Here, we highlight the consequences of ignoring the problems listed above and develop a novel modeling framework to circumvent them, which is illustrated using simulations and real malaria data. Our simulations reveal that trends in the number of disease cases do not necessarily imply similar trends in infection prevalence or incidence, due to the strong influence of concurrent changes in sampling effort. We also show that ignoring decreases in the pool of infected individuals due to the treatment of part of these individuals can hamper reliable inference on infection incidence. We propose a model that avoids these problems, being a compromise between phenomenological statistical models and mechanistic disease dynamics models; in particular, a cross-validation exercise reveals that it has better out-of-sample predictive performance than both of these alternative models. Our case study in the Brazilian Amazon reveals that infection prevalence was high in 2004–2008 (prevalence of 4% with 95% CI of 3–5%), with outbreaks (prevalence up to 18%) occurring during the dry season of the year. After this period, infection prevalence decreased substantially (0.9% with 95% CI of 0.8–1.1%), which is due to a large reduction in infection incidence (i.e., incidence in 2008–2010 was approximately one fifth of the incidence in 2004–2008). We believe that our approach to modeling government surveillance disease data will be useful to advance current understanding of large-scale drivers of several diseases.
Mouse Macrophage Paraoxonase 2 Activity Is Increased Whereas Cellular Paraoxonase 3 Activity Is Decreased Under Oxidative Stress

Objective—To determine whether paraoxonases (PONs) are expressed in macrophages and to analyze the oxidative stress effect on their expression and activities. Methods and Results—We demonstrated the presence (mRNA, protein, activity) of PON2 and PON3 but not PON1 in murine macrophages, whereas in human macrophages, only PON2 was expressed. Under oxidative stress as present in mouse peritoneal macrophages (MPMs) from apoE-deficient (E0) mice as well as in C57BL6 mice, MPMs that were incubated with buthionine sulfoximine, with angiotensin II, with 7-ketocholesterol, or with oxidized phosphatidylcholine, PON2 mRNA levels and lactonase activity toward dihydrocoumarin significantly increased (by 50% to 130%). In contrast, PON3 lactonase activity toward lovastatin was markedly reduced (by 29% to 57%) compared with control cells. The supplementation of E0 mice with dietary antioxidants (vitamin E, pomegranate juice) significantly increased macrophage PON3 activity (by 23% to 40%), suggesting that oxidative stress was the cause for the reduced macrophage PON3 activity. Incubation of purified PON2 or PON3 with E0 mice MPMs resulted in reduced cellular lipid peroxides content by 14% to 19% and inhibition of cell-mediated LDL oxidation by 32% to 39%. Conclusions—Increased macrophage PON2 expression under oxidative stress could represent a selective cellular response to reduce oxidative burden, which may lead to attenuation of macrophage foam cell formation.
Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death.

BACKGROUND In November 2001, the Food and Drug Administration (FDA) approved drotrecogin alfa (activated) (DrotAA) for adults who had severe sepsis and a high risk of death. The FDA required a study to evaluate the efficacy of DrotAA for adults who had severe sepsis and a low risk of death. METHODS We randomly assigned adult patients with severe sepsis and a low risk of death (defined by an Acute Physiology and Chronic Health Evaluation [APACHE II] score <25 or single-organ failure) to receive an intravenous infusion of placebo or DrotAA (24 microg per kilogram of body weight per hour) for 96 hours in a double-blind, placebo-controlled, multicenter trial. The prospectively defined primary end point was death from any cause and was assessed 28 days after the start of the infusion. In-hospital mortality within 90 days after the start of the infusion was measured, and safety information was collected. RESULTS Enrollment in the trial was terminated early because of a low likelihood of meeting the prospectively defined objective of demonstrating a significant reduction in the 28-day mortality rate with the use of DrotAA. The study enrolled 2640 patients and collected data on 2613 (1297 in the placebo group and 1316 in the DrotAA group) at the 28-day follow-up. There were no statistically significant differences between the placebo group and the DrotAA group in 28-day mortality (17.0 percent in the placebo group vs. 18.5 percent in the DrotAA group; P=0.34; relative risk, 1.08; 95 percent confidence interval, 0.92 to 1.28) or in in-hospital mortality (20.5 percent vs. 20.6 percent; P=0.98; relative risk, 1.00; 95 percent confidence interval, 0.86 to 1.16). The rate of serious bleeding was greater in the DrotAA group than in the placebo group during both the infusion (2.4 percent vs. 1.2 percent, P=0.02) and the 28-day study period (3.9 percent vs. 2.2 percent, P=0.01). CONCLUSIONS The absence of a beneficial treatment effect, coupled with an increased incidence of serious bleeding complications, indicates that DrotAA should not be used in patients with severe sepsis who are at low risk for death, such as those with single-organ failure or an APACHE II score less than 25.
Dietary Content and Gastrointestinal Function of Soybean Oligosaccharides in Monogastric Animals

Soybean is a major ingredient in non-ruminant animal diets throughout the world. There is an extensive body of information suggesting that soybean is an excellent source of high quality protein, whereas less attention has been paid to soybean oligosaccharides. Soybean oligosaccharides, also referred to as ┙-galacto-oligosaccharides, oligosaccharides of the raffinose family or simply ┙-galactosides, are water-soluble, low-molecular weight carbohydrates raffinose, stachyose and verbascose. In maturing seeds, oligosaccharides are formed by successive addition of galactosyl moieties to a sucrose primer. Alpha-galactosides are characterized by the presence of ┙(1→6) linkages between galactose moieties which are bonded via ┙(1→3) to terminal sucrose. Unlike other oligosaccharides, soybean ┙galactosides can be extracted directly from the raw material and do not require enzymatic manufacturing processes. Soybean oligosaccharides comprise approximately 4% of the soybean dry matter (DM) and during processing in the preparation of soybean meal (SBM) they are not removed or destroyed. Therefore, in SBM, ┙-galactosides represent approximately 5-6% but could be as high as 8% DM. Other processed soybean products, however, may contain significantly less oligosaccharides than SBM. The oligosaccharide content of soy protein concentrates (SPC) is as low as 3% DM while soy protein isolates (SPI) contain only trace amounts of oligosaccharides. Soybean oligosaccharides appear to be indigestible in the upper intestinal tract of monogastric animals due to the absence of ┙-galactosidase enzyme. However, they are easily fermented by the lower gut microflora, resulting in the production of various gases and short-chain fatty acids. Studies have shown considerable microbial fermentation of ┙galactosides in the small intestine with some authors referring to soybean oligosaccharides as bifidogenic factors which stimulate the growth of beneficial bacteria and others claiming that increased consumption of oligosaccharides may lead to negative effects in the large intestine of mammals, such as flatulence, diarrhea, and excessive dietary protein decay.
Multipathing with MPTCP and OpenFlow

Data sets in e-science are increasing exponentially in size. To transfer these huge data sets we need to make efficient use of all available network capacity. This means using multiple paths when available. In this paper a prototype of such a multipath network is presented. Several emerging network technologies are integrated to achieve the goal of efficient high end-to-end throughput. Multipath TCP is used by the end hosts to distribute the traffic across multiple paths and OpenFlow is used within the network to do the wide area traffic engineering. Extensive monitoring is part of the demonstration. A website will show the actual topology (including link outages), the paths provisioned through the network and traffic statistics on all links and the end-to-end aggregate throughput.
Rescaled Multimode Fibers for Mode-Division Multiplexing

Graded-index-core multimode fibers can be appropriately rescaled in diameters and adjusted in alphas to exhibit low differential mode group delays for 15, 21, and 28 spatial modes (five-, six-, and seven-mode groups, respectively). The fibers are actually designed to support six-, seven-, and eight-mode groups but their last mode group is neglected, which reduces the impact of cladding and the sensitivity to process variability, and, thus, allows to dramatically decrease the differential mode group delays. An eight-mode-group rescaled multimode fiber is fabricated. Differential-mode-group delays <90 ps/km are obtained for the first seven mode groups (28 spatial modes), which is equivalent to those of ten-spatial-mode fibers.
Courts, scheduled damages, and medical malpractice insurance

We study how the functioning of the judicial system affects the availability and affordability of medical liability insurance, as proxied by the number of insurers and the premiums paid. We use two unique datasets collected in Italy from 2000 to 2010. Using the first dataset—insurance contracts for hospitals—we estimate the average treatment effect of schedules on insurers and premiums paid, conditional on judicial efficiency and proxied by different measures. Our identification rests on the partial overlap between healthcare districts and judicial districts, meaning that the caseload of a court and malpractice events at the healthcare provider level are not perfectly correlated. On average, the adoption of schedules does not produce any significant effect on insurers or on premiums paid. However, adopting schedules has a robust and significant effect on the number of insurers, but only in inefficient courts. We further investigate these findings using a second dataset comprising 17,578 malpractice insurance claims. We find evidence of a composition effect among claims that is triggered by higher levels of judicial inefficiency: As a court’s inefficiency increases, the likelihood for a case to not be decided on the merits decreases and the levels of reserve and recovery per claim decrease.
Modes of Overinitiation, dnaA Gene Expression, and Inhibition of Cell Division in a Novel Cold-Sensitive hda Mutant of Escherichia coli

ABSTRACT The chromosomal replication cycle is strictly coordinated with cell cycle progression in Escherichia coli. ATP-DnaA initiates replication, leading to loading of the DNA polymerase III holoenzyme. The DNA-loaded form of the β clamp subunit of the polymerase binds the Hda protein, which promotes ATP-DnaA hydrolysis, yielding inactive ADP-DnaA. This regulation is required to repress overinitiation. In this study, we have isolated a novel cold-sensitive hda mutant, the hda-185 mutant. The hda-185 mutant caused overinitiation of chromosomal replication at 25°C, which most likely led to blockage of replication fork progress. Consistently, the inhibition of colony formation at 25°C was suppressed by disruption of the diaA gene, an initiation stimulator. Disruption of the seqA gene, an initiation inhibitor, showed synthetic lethality with hda-185 even at 42°C. The cellular ATP-DnaA level was increased in an hda-185-dependent manner. The cellular concentrations of DnaA protein and dnaA mRNA were comparable at 25°C to those in a wild-type hda strain. We also found that multiple copies of the ribonucleotide reductase genes (nrdAB or nrdEF) or dnaB gene repressed overinitiation. The cellular levels of dATP and dCTP were elevated in cells bearing multiple copies of nrdAB. The catalytic site within NrdA was required for multicopy suppression, suggesting the importance of an active form of NrdA or elevated levels of deoxyribonucleotides in inhibition of overinitiation in the hda-185 cells. Cell division in the hda-185 mutant was inhibited at 25°C in a LexA regulon-independent manner, suggesting that overinitiation in the hda-185 mutant induced a unique division inhibition pathway.