julilili42/papers huggingface dataset:
Mechanisms for the Formation of Acenes from α-Diketones by Bisdecarbonylation
2012-10-11

The bisdecarbonylation of bridged α-diketones has turned into an important reaction for the photochemical generation of higher acenes, in particular under matrix isolation conditions. Here, a computational mechanistic analysis of the bisdecarbonylation of dibenzobicyclo[2.2.2]octadienedione 2 to anthracene 1 is presented. The study employed the B3LYP functional in conjunction with the 6-311+G** basis set for geometry optimization on the S0, S1, and T1 potential energy surfaces as well as coupled cluster [CCSD(T)] and second-order multireference perturbation theory (MRMP2) with the cc-pVDZ basis set for evaluation of energies of intermediates and transition states. The first step of the most favorable pathway on the T1 surface has a barrier of 12 kcal mol(–1) with respect to the T1 minimum 2-3B1 and involves cleavage of the C–C bond between the bridgehead and one carbonyl atom, C(bridge)–C(O), yielding a biradical intermediate (INT1-T). On the S1 surface, the analogous step only has a barrier of less than 4 kcal mol(–1). A conical intersection of the S1 with the S0 surface exists after the transition state and provides a means for relaxation to a biradical intermediate (INT1-S) on the S0 surface. The concerted loss of two CO molecules from INT1-S has only a very small barrier. Similarly, consecutive loss of two CO molecules from the triplet state of this diradical (INT1-T) to give triplet anthracene is more favorable than ejection of triplet ethylenedione. Thus, the features identified computationally on the S0, S1, and T1 potential energy surface agree with earlier experimental observations of a fast photobisdecarbonylation within 7 ns from the triplet and singlet states of 2 and a lack of triplet ethylenedione formation.
Low-mass planets in nearly inviscid disks: numerical treatment
2012-10-11

\\n Context. Embedded planets disturb the density structure of the ambient disk, and gravitational back-reaction possibly will induce a change in the planet’s orbital elements. Low-mass planets only have a weak impact on the disk, so their wake’s torque can be treated in linear theory. Larger planets will begin to open up a gap in the disk through nonlinear interaction. Accurate determination of the forces acting on the planet requires careful numerical analysis. Recently, the validity of the often used fast orbital advection algorithm (FARGO) has been put into question, and special numerical resolution and stability requirements have been suggested. \\n Aims. We study the process of planet-disk interaction for low-mass planets of a few Earth masses, and reanalyze the numerical requirements to obtain converged and stable results. One focus lies on the applicability of the FARGO-algorithm. Additionally, we study the difference of two and three-dimensional simulations, compare global with local setups, as well as isothermal and adiabatic conditions. \\n Methods. We study the influence of the planet on the disk through two- and three-dimensional hydrodynamical simulations. To strengthen our conclusions we perform a detailed numerical comparison where several upwind and Riemann-solver based codes are used with and without the FARGO-algorithm. \\n Results. With respect to the wake structure and the torque density acting on the planet, we demonstrate that the FARGO-algorithm yields correct a correct and stable evolution for the planet-disk problem, and that at a fraction of the regular cpu-time. We find that the resolution requirements for achieving convergent results in unshocked regions are rather modest and depend on the pressure scale height H of the disk. By comparing the torque densities of two- and three-dimensional simulations we show that a suitable vertical averaging procedure for the force gives an excellent agreement between the two. We show that isothermal and adiabatic runs can differ considerably, even for adiabatic indices very close to unity.\\n
Cell‐intrinsic and ‐extrinsic control of Treg‐cell homeostasis and function revealed by induced CD28 deletion
2012-10-12

While the requirement for CD 28 and its ligands for the generation and function of “natural” (n) T reg cells is well established, it has not been possible yet to investigate cell‐intrinsic effects after interrupted CD 28 expression. Here, we demonstrate a selective loss of T reg cells after disruption of the CD28 gene. The decline in T reg‐cell number was accompanied by reduced homeostatic proliferation, probably due to lack of costimulation during self‐antigen recognition, and by impaired T reg‐cell function including downregulation of CTLA ‐4. The decline in T reg‐cell number was unaffected by thymectomy or by the presence of CD 28 expressing T cells within the same animal, indicating that impairment of peripheral homeostasis and function of n T reg cells by CD28 deletion is cell‐intrinsic. In contrast, downregulation of CD 25, the α chain of the IL ‐2 R , did not occur in the presence of WT T cells, indicating that its expression does not depend on CD 28 signals in cis .
The tyrosine‐sulfated peptide receptors PSKR1 and PSY1R modify the immunity of Arabidopsis to biotrophic and necrotrophic pathogens in an antagonistic manner
2012-10-13

Summary The tyrosine‐sulfated peptides PSK α and PSY 1 bind to specific leucine‐rich repeat surface receptor kinases and control cell proliferation in plants. In a reverse genetic screen, we identified the phytosulfokine ( PSK ) receptor PSKR 1 as an important component of plant defense. Multiple independent loss‐of‐function mutants in PSKR 1 are more resistant to biotrophic bacteria, show enhanced pathogen‐associated molecular pattern responses and less lesion formation after infection with the bacterial pathogen Pseudomonas syringae pv. tomato DC 3000. By contrast, pskr1 mutants are more susceptible to necrotrophic fungal infection with Alternaria brassicicola , show more lesion formation and fungal growth which is not observed on wild‐type plants. The antagonistic effect on biotrophic and necrotrophic pathogen resistance is reflected by enhanced salicylate and reduced jasmonate responses in the mutants, suggesting that PSKR 1 suppresses salicylate‐dependent defense responses. Detailed analysis of single and multiple mutations in the three paralogous genes PSKR 1 , ‐ 2 and PSY 1‐receptor ( PSY 1R ) determined that PSKR 1 and PSY 1R, but not PSKR 2, have a partially redundant effect on plant immunity. In animals and plants, peptide sulfation is catalyzed by a tyrosylprotein sulfotransferase ( TPST ). Mutants lacking TPST show increased resistance to bacterial infection and increased susceptibility to fungal infection, mimicking the triple receptor mutant phenotypes. Feeding experiments with PSK α in tpst‐1 mutants partially restore the defense‐related phenotypes, indicating that perception of the PSK α peptide has a direct effect on plant defense. These results suggest that the PSKR subfamily integrates growth‐promoting and defense signals mediated by sulfated peptides and modulates cellular plasticity to allow flexible adjustment to environmental changes.
Gene expression analysis of mTOR pathway: association with human longevity
2012-10-13

Summary mTOR signalling is implicated in the development of disease and in lifespan extension in model organisms. This pathway has been associated with human diseases such as diabetes and cancer, but has not been investigated for its impact on longevity per se . Here, we investigated whether transcriptional variation within the mTOR pathway is associated with human longevity using whole‐blood samples from the Leiden Longevity Study. This is a unique cohort of Dutch families with extended survival across generations, decreased morbidity and beneficial metabolic profiles in middle‐age. By comparing mRNA levels of nonagenarians and middle‐aged controls, the mTOR signalling gene set was found to associate with old age ( P = 4.6 × 10 −7 ). Single gene analysis showed that seven of 40 mTOR pathway genes had a significant differential expression of at least 5%. Of these, the RPTOR (Raptor) gene was found to be differentially expressed also when the offspring of nonagenarians was compared with their spouses, indicating association with familial longevity in middle‐age. This association was not explained by variation between the groups in the prevalence of type 2 diabetes and cancer or glucose levels. Thus, the mTOR pathway not only plays a role in the regulation of disease and aging in animal models, but also in human health and longevity.
Microglial repopulation model reveals a robust homeostatic process for replacing CNS myeloid cells
2012-10-15

Under most physiological circumstances, monocytes are excluded from parenchymal CNS tissues. When widespread monocyte entry occurs, their numbers decrease shortly after engraftment in the presence of microglia. However, some disease processes lead to focal and selective loss, or dysfunction, of microglia, and microglial senescence typifies the aged brain. In this regard, the long-term engraftment of monocytes in the microglia-depleted brain remains unknown. Here, we report a model in which a niche for myeloid cells was created through microglia depletion. We show that microglia-depleted brain regions of CD11b-HSVTK transgenic mice are repopulated with new Iba-1-positive cells within 2 wk. The engrafted cells expressed high levels of CD45 and CCR2 and appeared in a wave-like pattern frequently associated with blood vessels, suggesting the engrafted cells were peripheral monocytes. Although two times more numerous and morphologically distinct from resident microglia up to 27 wk after initial engraftment, the overall distribution of the engrafted cells was remarkably similar to that of microglia. Two-photon in vivo imaging revealed that the engrafted myeloid cells extended their processes toward an ATP source and displayed intracellular calcium transients. Moreover, the engrafted cells migrated toward areas of kainic acid-induced neuronal death. These data provide evidence that circulating monocytes have the potential to occupy the adult CNS myeloid niche normally inhabited by microglia and identify a strong homeostatic drive to maintain the myeloid component in the mature brain.
Sensitive Troponins – Which Suits Better for Hemodialysis Patients? Associated Factors and Prediction of Mortality
2012-10-15

In hemodialysis patients, elevations of plasma troponin concentrations are explained by cardiac function and dialysis-related parameters, which contribute to cardiac strain. Both are highly predictive of increased risk of death.
Endoscopic Inguinofemoral Lymphadenectomy—Extended Follow-up
2012-10-15

O-IFLA and E-IFLA are efficient with respect to oncologic safety. E-IFLA is technically more challenging. E-IFLA can avoid secondary wound healing and lymphatic complications. E-IFLA is a safe procedure while a reduction of CO2 pressures optimizes the safety profile. Because cancer control rates remained equivalent during an extended follow-up, oncologic durability could be confirmed.
Rod and Cone Function in Patients with KCNV2 Retinopathy
2012-10-15

A specific genotype-phenotype correlation in retinal function could not be demonstrated. KCNV2 mutations cause a unique form of retinal disorder illustrating the importance of K(+)-channels for the resting potential, activation and deactivation of photoreceptors, while phototransduction remains unchanged. The reduced oscillatory potentials further suggest an altered function of the inner retina. Besides the characteristically steep amplitude-versus-intensity relationship, flicker responses at intermediate frequencies (5-15 Hz) are significantly reduced and shifted in phase.
Synthesis of Atorvastatin Lactone Linker Constructs for Target Fishing
2012-10-15

Abstract With the aim of connecting atorvastatin lactone 9 to a linker for affinity‐based target fishing, a concise route to the pyrrolecarboxylic acid 8 was developed. Key features of the synthesis of the diol‐containing side‐chain were a catalytic enantioselective vinylogous aldol reaction resulting in 5‐hydroxy‐enoate 14 (88 % ee ). Subsequent intramolecular oxa‐Michael addition and amide reduction furnished key building block 5 . As we have described previously, Paal–Knorr reaction of amine 5 with diketone 6 led to pyrrole 7 , which – after carboxylation – provided acid 8 . Since atorvastatin lactone is an aniline derivative of acid 7 , we prepared two linkers having an aniline terminus. For this purpose ethylene glycol based allyl ethers 20 and 27 were combined with nitrostyrene 22 by cross‐metathesis. After hydrogenation of the nitro group and the double bond, anilines 25 and 29 , respectively, were obtained. The anilines were condensed with carboxylic acid 8 to afford the corresponding amides 30 and 35 . Elaboration of the side‐chain then provided atorvastatin lactone linker constructs 34 and 39 , respectively.
Correction: Characterization and Therapeutic Potential of Induced Pluripotent Stem Cell-Derived Cardiovascular Progenitor Cells
2012-10-15

Background: Cardiovascular progenitor cells (CPCs) have been identified within the developing mouse heart and differentiating pluripotent stem cells by intracellular transcription factors Nkx2.5 and Islet 1 (Isl1).Study of endogenous and induced pluripotent stem cell (iPSC)-derived CPCs has been limited due to the lack of specific cell surface markers to isolate them and conditions for their in vitro expansion that maintain their multipotency.Methodology/Principal Findings: We sought to identify specific cell surface markers that label endogenous embryonic CPCs and validated these markers in iPSC-derived Isl1 + /Nkx2.5 + CPCs.We developed conditions that allow propagation and characterization of endogenous and iPSC-derived Isl1 + /Nkx2.5 + CPCs and protocols for their clonal expansion in vitro and transplantation in vivo.Transcriptome analysis of CPCs from differentiating mouse embryonic stem cells identified a panel of surface markers.Comparison of these markers as well as previously described surface markers revealed the combination of Flt1 + /Flt4 + best identified and facilitated enrichment for Isl1 + /Nkx2.5 + CPCs from embryonic hearts and differentiating iPSCs.Endogenous mouse and iPSC-derived Flt1 + /Flt4 + CPCs differentiated into all three cardiovascular lineages in vitro.Flt1 + /Flt4 + CPCs transplanted into left ventricles demonstrated robust engraftment and differentiation into mature cardiomyocytes (CMs). Conclusion/Significance:The cell surface marker combination of Flt1 and Flt4 specifically identify and enrich for an endogenous and iPSC-derived Isl1 + /Nkx2.5 + CPC with trilineage cardiovascular potential in vitro and robust ability for engraftment and differentiation into morphologically and electrophysiologically mature adult CMs in vivo post transplantation into adult hearts.
VPA response in SMA is suppressed by the fatty acid translocase CD36
2012-10-16

Functional loss of SMN1 causes proximal spinal muscular atrophy (SMA), the most common genetic condition accounting for infant lethality. Hence, the hypomorphic copy gene SMN2 is the only resource of functional SMN protein in SMA patients and influences SMA severity in a dose-dependent manner. Consequently, current therapeutic approaches focus on SMN2. Histone deacetylase inhibitors (HDACi), such as the short chain fatty acid VPA (valproic acid), ameliorate the SMA phenotype by activating the SMN2 expression. By analyzing blood SMN2 expression in 16 VPA-treated SMA patients, about one-third of individuals were identified as positive responders presenting increased SMN2 transcript levels. In 66% of enrolled patients, a concordant response was detected in the respective fibroblasts. Most importantly, by taking the detour of reprograming SMA patients' fibroblasts, we showed that the VPA response was maintained even in GABAergic neurons derived from induced pluripotent stem cells (iPS) cells. Differential expression microarray analysis revealed a complete lack of response to VPA in non-responders, which was associated with an increased expression of the fatty acid translocase CD36. The pivotal role of CD36 as the cause of non-responsiveness was proven in various in vitro approaches. Most importantly, knockdown of CD36 in SMA fibroblasts converted non- into pos-responders. In summary, the concordant response from blood to the central nervous system (CNS) to VPA may allow selection of pos-responders prior to therapy. Increased CD36 expression accounts for VPA non-responsiveness. These findings may be essential not only for SMA but also for other diseases such as epilepsy or migraine frequently treated with VPA.
NMDA receptor blockade by memantine does not prevent adaptation to recurrent hypoglycaemia in healthy men
2012-10-16

Abstract Aims Recurrent hypoglycaemia leads to an attenuation of hypoglycaemic symptoms and hormonal counterregulatory responses. This phenomenon poses a severe problem in the treatment of patients with diabetes mellitus, but the underlying neuroendocrine mechanisms are unclear. On the basis of animal experimental findings, we hypothesized that counterregulatory attenuation represents a basic adaptive learning process relying on synaptic long‐term potentiation or depression. If so, attenuation should be prevented by blocking glutamatergic N ‐methyl‐ d ‐aspartate ( NMDA ) receptors. Methods Sixteen healthy young men participated in two conditions, separated by 4 weeks. Participants received the NMDA antagonist memantine over 5 days (15 mg/day) in one condition and placebo in the other one. After 3 days of drug administration, participants underwent two hypoglycaemic clamps on day 4 and another one on day 5. We assessed blood concentrations of counterregulatory hormones (cortisol, ACTH , epinephrine, norepinephrine, growth hormone and glucagon) as well as subjective symptoms of hypoglycaemia and word‐list recall as an indicator of short‐term memory. Results Counterregulatory responses of all hormones as well as neuroglycopenic and autonomic symptom ratings showed robust attenuation following the third as compared to the first hypoglycaemia (p &lt; 0.05). NMDA receptor antagonization by memantine impaired memory function but did not alter any neuroendocrine measure of counterregulatory attenuation (p &gt; 0.17). Conclusions Attenuation of the endocrine as well as symptomatic counterregulatory response to recurrent hypoglycaemia is not prevented by the NMDA receptor blocker memantine. Our results do not support the view that adaptation to repeated hypoglycaemia relies on NMDA receptor‐mediated plastic processes involving long‐term potentiation or depression.
Label-Free Imaging of Cerebral β-Amyloidosis with Extended-Focus Optical Coherence Microscopy
2012-10-17

We demonstrate label-free imaging of cerebral β-amyloidosis ex vivo and in a living mouse model of Alzheimer's disease using extended-focus Fourier domain optical coherence microscopy (xfOCM). xfOCM provides 3D, high-resolution images of individual β-amyloid plaques in the brain parenchyma and vasculature and requires no staining of the Alzheimeric sample under investigation. xfOCM also opens the possibility to perform minimally invasive studies of β-amyloid pathology in vivo , without the use of labeling methods, which potentially confound experimental findings.
A Comprehensive Small Interfering RNA Screen Identifies Signaling Pathways Required for Gephyrin Clustering
2012-10-17

The postsynaptic scaffold protein gephyrin is clustered at inhibitory synapses and serves for the stabilization of GABA A receptors. Here, a comprehensive kinome-wide siRNA screen in a human HeLa cell-based model for gephyrin clustering was used to identify candidate protein kinases implicated in the stabilization of gephyrin clusters. As a result, 12 hits were identified including FGFR1 (FGF receptor 1), TrkB, and TrkC as well as components of the MAPK and mammalian target of rapamycin (mTOR) pathways. For confirmation, the impact of these hits on gephyrin clustering was analyzed in rat primary hippocampal neurons. We found that brain-derived neurotrophic factor (BDNF) acts on gephyrin clustering through MAPK signaling, and this process may be controlled by the MAPK signaling antagonist sprouty2. BDNF signaling through phosphatidylinositol 3-kinase (PI3K)–Akt also activates mTOR and represses GSK3β, which was previously shown to reduce gephyrin clustering. Gephyrin is associated with inactive mTOR and becomes released upon BDNF-dependent mTOR activation. In primary neurons, a reduction in the number of gephyrin clusters due to manipulation of the BDNF–mTOR signaling is associated with reduced GABA A receptor clustering, suggesting functional impairment of GABA signaling. Accordingly, application of the mTOR antagonist rapamycin leads to disinhibition of neuronal networks as measured on microelectrode arrays. In conclusion, we provide evidence that BDNF regulates gephyrin clustering via MAPK as well as PI3K–Akt–mTOR signaling.
The Novel Cis-Encoded Small RNA h2cR Is a Negative Regulator of hfq2 in Burkholderia cenocepacia
2012-10-17

Small non-coding regulatory RNAs (sRNAs) post-transcriptionally affect multiple phenotypes in prokaryotes and eukaryotes, yet most of the underlying regulatory mechanisms and the nature of the target mRNAs remain unclear. Here we report the identification and functional analysis of the novel cis-encoded sRNA h2cR, from the human opportunistic pathogen Burkholderia cenocepacia J2315. The sRNA was found to negatively regulate the hfq2 mRNA, through binding to part of the 5'-UTR region of the hfq2 mRNA, resulting in accelerated hfq2 mRNA decay and reduced protein levels in exponentially growing cells. Both the h2cR transcript and the hfq2 mRNA are stabilized by the other B. cenocepacia RNA chaperone, Hfq. Infection experiments using the nematode Caenorhabditis elegans revealed that down-regulation of Hfq2 by h2cR decreases the B. cenocepacia ability to colonize and persist within the nematode, suggesting a role for h2cR on bacterial persistence in the host.
Allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia and pulmonary mucormycosis
2012-10-17

Abstract Mucormycosis is a serious invasive fungal infection in immunocompromised patients. Patients undergoing treatment for hematologic malignancies are predominantly prone to the pulmonary manifestation of mucormycosis. Historically, allogeneic hematopoietic cell transplantation ( HCT ) in patients suffering from pulmonary mucormycosis ( PM ) was considered contraindicated owing to mortality rates up to 90%. We present 3 patients with acute myeloid leukemia and PM who were treated with radical surgical debridement combined with high‐dose liposomal amphotericin B ( LAB ), and subsequently underwent successful allogeneic HCT . To date, all 3 patients are in complete remission and show no signs of mucormycosis. Allogeneic HCT in patients with PM seems feasible provided that the infectious focus is completely removed surgically and adequate antifungal pharmacotherapy, such as high‐dose LAB or posaconazole, is established.
Faculty Opinions recommendation of Meta-analysis: effect of preoperative infliximab use on early postoperative complications in patients with ulcerative colitis undergoing abdominal surgery.
2012-10-17

Read the full review for this Faculty Opinions recommended article: Meta-analysis: effect of preoperative infliximab use on early postoperative complications in patients with ulcerative colitis undergoing abdominal surgery.