Miracle-dz/UniFAR-FTUs huggingface dataset:
Role of Ndt80, Sum1, and Swe1 as Targets of the Meiotic Recombination Checkpoint That Control Exit from Pachytene and Spore Formation in Saccharomyces cerevisiae

ABSTRACT The meiotic recombination checkpoint, which is triggered by defects in recombination or chromosome synapsis, arrests sporulating cells of Saccharomyces cerevisiae at pachytene by preventing accumulation of active Clb-Cdc28. We compared the effects of manipulating the three known targets of the meiotic recombination checkpoint, NDT80, SWE1, and SUM1, in dmc1-arrested cells. Ndt80 is an activator of a set of middle sporulation-specific genes (MSGs), which includes CLB genes and genes involved in spore wall formation; Swe1 inhibits Clb-Cdc28 activity; and Sum1 is a repressor of NDT80 and some MSGs. Activation of the checkpoint leads to inhibition of Ndt80 activity and to stabilization of Swe1 and Sum1. Thus, dmc1-arrested cells fail to express MSGs, arrest at pachytene, and do not form spores. Our study shows that dmc1/dmc1 sum1/sum1 cells expressed MSGs prematurely and at high levels, entered the meiotic divisions efficiently, and in some cases formed asci containing mature spores. In contrast, dmc1/dmc1 swe1/swe1 cells expressed MSGs at a very low level, were inefficient and delayed in entry into the meiotic divisions, and never formed mature spores. We found that cells of dmc1/dmc1 sum1/sum1 ndt80/ndt80 and dmc1/dmc1 swe1/swe1 ndt80/ndt80 strains arrested at pachytene and that dmc1/dmc1 or dmc1/dmc1 swe1/swe1 cells overexpressing NDT80 were less efficient in bypassing checkpoint-mediated arrest than dmc1/dmc1 sum1/sum1 cells. Our results are consistent with previous suggestions that increased Clb-Cdc28 activity, caused by mutation of SWE1 or by an NDT80-dependent increase in CLB expression, allows dmc1/dmc1 cells to exit pachytene and that subsequent upregulation of Ndt80 activity by a feedback mechanism promotes entry into the meiotic divisions. Spore morphogenesis, however, requires efficient and timely activation of MSGs, which we speculate was achieved in dmc1/dmc1 sum1/sum1 cells by premature expression of NDT80.
Neurophysiologic studies of patients with Crohn's disease on long-term treatment with metronidazole.

Fifty-three patients with Crohn's disease were chosen for this study. They were divided into three groups: the first group (19 patients) was treated with metronidazole and had been receiving the drug for at least 1 year; the second group (13 patients) had previously had the same type of long-term treatment but had been off the drug for at least 3 months before entering the study; the third group (21 patients) had never received treatment with metronidazole. The maximum daily dose of metronidazole used was 800 mg. All patients were examined with a broad set of neurophysiologic investigations devised to reveal signs of peripheral neuropathy. No significant difference was found between the three groups. The conclusion was that a daily dose of metronidazole not exceeding 800 mg is well tolerated by patients with Crohn's disease with regard to objective signs of neurotoxicity. A few patients from all three groups showed a raised perception threshold for changes of temperature in the feet (as compared with the department's normal standard). The results of the test were almost identical in the three groups and thus not connected with the metronidazole treatment. During the study, patients were asked about subjective neurologic symptoms such as tingling and numbness. A few patients from all three groups reported such paresthesias from time to time, but they were of a transient nature, not perpetual, and, in patients taking metronidazole, not aggravated despite continuing treatment with unchanged dose. (ABSTRACT TRUNCATED AT 250 WORDS)
Identification of Neuronal Nuclei (NeuN) as Fox-3, a New Member of the Fox-1 Gene Family of Splicing Factors*

NeuN (neuronal nuclei) is a neuron-specific nuclear protein which is identified by immunoreactivity with a monoclonal antibody, anti-NeuN. Anti-NeuN has been used widely as a reliable tool to detect most postmitotic neuronal cell types in neuroscience, developmental biology, and stem cell research fields as well as diagnostic histopathology. To date, however, the identity of its antigen, NeuN itself, has been unknown. Here, we identify NeuN as the Fox-3 gene product by providing the following evidence: 1) Mass spectrometry analysis of anti-NeuN immunoreactive protein yields the Fox-3 amino acid sequence. 2) Recombinant Fox-3 is recognized by anti-NeuN. 3) Short hairpin RNAs targeting Fox-3 mRNA down-regulate NeuN expression. 4) Fox-3 expression is restricted to neural tissues. 5) Anti-Fox-3 immunostaining and anti-NeuN immunostaining overlap completely in neuronal nuclei. We also show that a protein cross-reactive with anti-NeuN is the synaptic vesicle protein, synapsin I. Anti-NeuN recognizes synapsin I in immunoblots with one order of magnitude lower affinity than Fox-3, and does not recognize synapsin I using immunohistology. Fox-3 (also called hexaribonucleotide-binding protein 3 and D11Bwg0517e) contains an RNA recognition motif and is classified as a member of the Fox-1 gene family that binds specifically to an RNA element, UGCAUG. We demonstrate that Fox-3 functions as a splicing regulator using neural cell-specific alternative splicing of the non-muscle myosin heavy chain II-B pre-mRNA as a model. Identification of NeuN as Fox-3 clarifies an important element of neurobiology research.
Ethnic Identity, Bicultural Identity Integration, and Psychological Well-Being Among Transracial Adoptees: A Longitudinal Study.

The ethnic identity development plays a crucial role in adolescence and emerging adulthood and may be more complex for adoptees who do not share their ethnic identity with their adoptive families. Evidence from the studies was mixed, with strong ethnic identity not always found to be indicative of improved psychological adjustment. Recently research carried out on ethnic minorities has highlighted that the relation between ethnic identity and well-being could be influenced by Bicultural Identity Integration (BII) (Benet-Martínez et al., 2002): It reflects how individuals who experience more than one culture organize and combine their dual cultural backgrounds. These results are consistent also among adoptees (Manzi, Ferrari, Rosnati, & Benet-Martínez, 2013) but need to be further explored. A longitudinal study was conducted to investigate whether and the extent to which ethnic identity, national identity, and BII are protective factors for adoptees' psychological well-being. A self-report questionnaire was administered to 79 Italian transracial adoptees, aged between 15 and 25, at two time points, one year apart. In line with predictions, longitudinal analyses showed the crucial role of BII that turned out to increase higher levels of well-being one year later. Results are discussed in relation to implications for intervention with adoptive parents and children.
Growth factor delivery vehicles for tendon injuries: Mesenchymal stem cells and Platelet Rich Plasma.

BACKGROUND tendon tissue shows limited regeneration potential with formation of scar tissue and inferior mechanical properties. The capacity of several growth factors to improve the healing response and decrease scar formation is described in different preclinical studies. Besides the application of isolated growth factors, current research focuses on two further strategies to improve the healing response in tendon injuries: platelet rich plasma (PRP) and mesenchymal stem cells (MSCs). OBJECTIVE the present review focuses on these two options and describes their potential to improve tendon healing. RESULTS in vitro experiments and animal studies showed promising results for the use of PRP, however clinical controlled studies have shown a tendency of reduced pain related symptoms but no significant differences in overall clinical scores. On the other hand MSCs are not totally arrived in clinical use so that there is still a lack of randomized controlled trials. In basic research experiments they show an extraordinary paracrine activity, anti-inflammatory effect and the possibility to differentiate in tenocytes when different activating-factors are added. CONCLUSION preclinical studies have shown promising results in improving tendon remodeling but the comparability of current literature is difficult due to different compositions. PRP and MSCs can act as efficient growth factor vehicles, however further studies should be performed in order to adequate investigate their clinical benefits in different tendon pathologies.
Sulfation of acetaminophen by the perfused rat liver: The effect of red blood cell carriage

Acetaminophen uptake and conversion in the perfused rat liver to acetaminophen sulfate was studied with the multiple indicator dilution technique (MID). Because acetaminophen is avidly bound to red blood cells and not albumin, a pre‐equilibrated MID dose containing the noneliminated references (51Cr‐labeled red blood cells [RBC, a vascular reference], [58Co]EDTA [a small molecular weight interstitial reference that does not enter cells], and D2O [a cellular reference]) and [<3>H]‐acetaminophen was introduced into the portal vein of the single‐pass perfused rat liver (1 mg/L acetaminophen) under varying conditions of hematocrit, with observation of timed outflow profiles in the hepatic venous blood. The [<3>H] acetaminophen curve exhibited an early high peak, paralleling that for red cells and varying with hematocrit, followed by a prolonged decline, with the late appearance of acetaminophen sulfate product; the early peak disappeared when red cells were absent from the dose and perfusate. Analysis demonstrated a slow release of acetaminophen from the red blood cells and rapid liver cell entry, so that red cell binding was displayed as a red cell carriage effect that reduced the rate of liver cell entry and hence of sulfation of [<3>H]‐acetaminophen. The liver cells exhibited a concomitant very low permeability to product acetaminophen sulfate, leading to protracted product outflow curves. An inferred slow efflux‐mediated storage phenomenon for product was found to evolve as a result. (HEPATOLOGY 1995; 22:267–282.)
Spontaneous regression of lymphoproliferative disorders in patients treated with methotrexate for rheumatoid arthritis and other rheumatic diseases.

PURPOSE To determine the clinicopathologic features of lymphoproliferative disorders (LPD) that occur in the setting of methotrexate (MTX) therapy for rheumatic diseases (RD) and to define the relationship between the presence of Epstein-Barr virus (EBV) in tumor cells and the response of LPD to MTX withdrawal. PATIENTS AND METHODS In addition to nine new cases, we analyzed 28 cases previously reported in the literature of LPD in patients receiving MTX for RD. In addition to MTX, immunosuppressive therapy included corticosteroids in 19 patients, azathioprine in three, and cyclosporine in one. Extranodal disease was identified in 16 patients, but none had CNS involvement. Pathologic findings included five cases of Hodgkin's disease and seven low-grade lymphomas. The remaining patients had intermediate or aggressive lymphomas. In situ hybridization studies (ISHS) for EBV-RNA transcripts were positive in 12 of 27 patients (44%). RESULTS Among 37 patients, 16 were initially observed after MTX withdrawal without additional antitumor therapy. Six achieved a spontaneous complete remission (CR), three had a partial response (PR), one had a minimal response, and six had no response to MTX withdrawal. Of 10 responding patients, EBV was detected by ISHS (n = 6) or polymerase chain reaction (PCR) (n = 2); one patient had a CR despite the absence of EBV by PCR and one had a CR but did not have viral assays performed. Only one of six patients with negative EBV by ISHS or PCR responded to MTX withdrawal. CONCLUSION MTX withdrawal and observation for a short period should be considered in the initial management of patients who develop LPD while on MTX therapy. Responses were consistently observed, but not limited to patients in whom EBV was detected by ISHS or PCR. Further studies are required to confirm these findings and to evaluate the role for EBV in LPD that occur in patients receiving MTX.
A Mean-Variance Benchmark for Household Portfolios over the Life Cycle

We embed human capital as an innate, illiquid asset in Markowitz' one-period mean-variance framework. By solving the Markowitz problem for different values of the ratio of human capital to financial wealth, we emulate life-cycle effects in household portfolio decisions. The portfolio derived with this approach is very similar to the optimal portfolio derived in the much more complicated dynamic life-cycle models. An application of our simple method illustrates that young households may optimally refrain from stock investments because a house investment combined with a mortgage is more attractive from a pure investment perspective. Another application establishes some theoretical support for the growth/value tilts in households' portfolios found empirically.
Development of visual cortical axons: Layer‐specific effects of extrinsic influences and activity blockade

During normal cortical development, individual pyramidal neurons form intracortical axonal arbors that are specific for particular cortical layers. Pyramidal neurons within layer 6 are able to develop layer‐specific projections in cultured slices of ferret visual cortex, indicating that extrinsic influences, including patterned visual activity, are not required (Dantzker and Callaway [1998] J Neurosci 18:4145–4154). However, when spontaneous activity is blocked in cultures with tetrodotoxin, layer 6 pyramidal neurons fail to preferentially target their axons to layer 4. To determine whether mechanisms that regulate the development of layer 6 pyramidal neuron arbors can be generalized to pyramidal neurons in other layers, we examined the development of layer 5 and layer 2/3 pyramidal neurons in cultured slices of ferret visual cortex prepared on postnatal day 14 or 15. Layer 5 pyramidal neurons developed layer‐specific axonal arbors during 5–7 days in vitro. However, unlike layer 6 pyramidal neurons, layer 5 pyramidal neurons formed layer‐specific axonal arbors in the presence of tetrodotoxin. In contrast to layer 5 and layer 6 pyramidal neurons, layer 2/3 pyramidal neurons did not form appropriate layer‐specific projections during 5–7 days in vitro. Taken together, these data suggest that the development of layer‐specific axons is regulated by different mechanisms for neurons in different layers and cannot be categorically classified as either activity‐dependent or independent. Instead, the type of pyramidal neuron, the layers targeted, and the type of activity must be considered. J. Comp. Neurol. 430:321–331, 2001. © 2001 Wiley‐Liss, Inc.
Comorbid conditions and gender impact the primary survival of distal radio-cephalic arteriovenous fistula inpatients on long-term hemodialysis.

BACKGROUND Vascular access failure complicates the clinical picture of patients on long-term hemodialysis, increasing the number of hospitalizations and the respective costs. In these patients we analyzed the possible meaningful relationship between comorbidities and primary survival of the autologous distal radio-cephalic arteriovenous fistula (dAVF), pointing out the influence of other variables on that relationship. METHODS We evaluated the dAVF placed in our unit between January 1, 1995, and December 31, 2003, on 105 patients (55 males) 63.8 +/- 14.1 (average +/- SD) years old. The dAVF creation date was the starting point while the dAVF failures due to either thrombosis or malfunction (KT/V < 1.2) were the study end-point. Death, conversion to peritoneal dialysis, transfer to other units and renal transplantation were assumed as censure criteria. ICED score, single comorbidities, use of temporary catheter at the hemodialysis initiation, serum lipids and CRP levels, hematocrit, blood platelet count and coagulative parameters (at the time of the dAVF creation) were considered as covariates. The Kaplan-Meier method and Cox's proportional hazards regression were used in the dAVF survival analysis. RESULTS During the study we recorded 38 dAVF failures (median primary survival of the dAVF 487.3 days, with a failure rate of 0.645 per patient-year). Age, lab variables, single comorbidities, and use of temporary catheters did not impact the dAVF primary survival. Conversely ICED score > 1 (P = 0.014; hazard ratio = 1.648; 95% CI = 1.106-2.454) as well as feminine gender (P = 0.018; hazard ratio = 1.640; 95% CI = 1.024-2.256) increased the risk of dAVF failure. CONCLUSIONS In our cohort of patients on long-term hemodialysis neither the single comorbidities nor the temporary catheterization influence the lifespan of the vascular access. However our data demonstrated the meaningful inverse relationship between dAVF primary survival and a composite comorbidity index reflecting not only the type of the diseases but also their associations and severities. This relationship was not influenced by other covariates although the feminine gender was significantly associated with worse survival of the vascular access.
Anchor Or Fiction? the Role of Adding Exchange to Charity

Anchor or Fiction? The Role of Adding Exchange to CharityBarbara Briers, Mario Pandelaere and Luk WarlopKatholieke Universiteit Leuven AbstractCharities often bundle donation requests with the offering of a near-worthless token, like a postcard. Little research has examined whether this raises more money than merely asking to donate. Our studies suggest that in mere donation settings people may have difficulties to estimate a socially acceptable donation amount and therefore prefer opportunities that provide them with a fixed price, an anchor. When the suggested reference price is low enough, exchange requests lead to more compliance than mere donation requests. Moreover, we show that, when accompanied by specified amounts, mere donation requests result in even better compliance rates than exchange requests.
Role of obinutuzumab in the treatment of chronic lymphocytic leukemia.

PURPOSE The pharmacology, pharmacokinetics, safety and efficacy, and place in therapy of obinutuzumab in the treatment of chronic lymphocytic leukemia (CLL) are reviewed. SUMMARY Obinutuzumab, a fully humanized monoclonal antibody that targets the CD20 receptor on mature B cells, was recently approved for use in combination with chlorambucil in patients with previously untreated CLL. In a Phase III clinical trial including 671 patients with CLL and significant comorbidities, patients who received obinutuzumab-chlorambucil combination therapy had longer median progression-free survival than those who received rituximab plus chlorambucil (26.7 months versus 15.2 months, p < 0.001) or chlorambucil alone (11.1 months, p < 0.001). Overall survival was also improved with the use of obinutuzumab-chlorambucil versus chlorambucil alone (hazard ratio for death, 0.41, p = 0.002) and similar to survival with the use of rituximab plus chlorambucil. The main type of adverse effect reported in association with obinutuzumab use is infusion-related reactions (IRRs), which occurred in 66% of patients in the Phase III trial, with 20% of reactions categorized as grade 3 or 4; IRR risk can be reduced with appropriate dosing, premedication, patient monitoring, and immediate treatment of IRRs. Ongoing clinical trials are evaluating the effects of obinutuzumab in patients with newly diagnosed and relapsed or treatment-refractory CLL. CONCLUSION In patients who are elderly or who have multiple comorbidities, the use of obinutuzumab, a CD20 monoclonal antibody, in combination with chlorambucil is an efficacious regimen for treatment-naive patients with symptomatic CLL.
Blockage of Epidermal Growth Factor Receptor-Phosphatidylinositol 3-Kinase-AKT Signaling Increases Radiosensitivity of K-RAS Mutated Human Tumor Cells In vitro by Affecting DNA Repair

Purpose: It is known that blockage of epidermal growth factor receptor (EGFR)/phosphatidylinositol 3-kinase (PI3K) activity enhances radiation sensitivity of human tumor cells presenting a K-RAS mutation. In the present study, we investigated whether impaired repair of DNA double-strand breaks (DSB) is responsible for the radiosensitizing effect of EGFR and PI3K inhibition in K-RAS mutated (K-RASmt) cells. Experimental Design: The effect of the EGFR tyrosine kinase inhibitor BIBX1382BS (BIBX) on cellular radiosensitivity was determined in K-RASmt (A549) and K-RASwt (FaDu) cell lines by clonogenic survival assay. Radiation-induced phosphorylation of H2AX (Ser139), ATM (Ser1981), and DNA-dependent protein kinase catalytic subunit (DNA-PKcs; Thr2609) was analyzed by immunoblotting. Twenty-four hours after irradiation, residual DSBs were quantified by identification of γH2AX foci and frequency of micronuclei. Results: BIBX reduced clonogenic survival of K-RASmt-A549 cells, but not of K-RASwt-FaDu cells, after single-dose irradiation. Analysis of the radiation-induced H2AX phosphorylation revealed that BIBX, as well as the PI3K inhibitor LY294002, leads to a marked reduction of P-H2AX in K-RASmt-A549 and MDA-MB-231 cells, but not in K-RASwt-FaDu and HH4ded cells. Likewise, radiation-induced autophosphorylation of DNA-PKcs at Thr2609 was only blocked in A549 cells by these two inhibitors and AKT1 small interfering RNA transfection. However, neither in K-RASmt nor in K-RASwt cells the inhibitors did affect radiation-induced ATM phosphorylation. As a consequence of inhibitor treatment, a significant enhancement of both residual DSBs and frequency of micronuclei was apparent only in A549 but not in FaDu cells following radiation. Conclusion: Targeting of the EGFR-dependent PI3K-AKT pathway in K-RAS-mutated A549 cells significantly affects postradiation survival by affecting the activation of DNA-PKcs, resulting in a decreased DSB repair capacity.
EXOGENOUS CYTOCHROME C RESTORES MYOCARDIAL CYTOCHROME OXIDASE ACTIVITY INTO THE LATE PHASE OF SEPSIS

Mitochondrial dysfunction is thought to play a role in the pathogenesis of a variety of disease states, including sepsis. An acquired defect in oxidative phosphorylation potentially causes sepsis-induced organ dysfunction. Cytochrome oxidase (CcOX), the terminal oxidase of the respiratory chain, is competitively inhibited early in sepsis and progresses, becoming noncompetitive during the late phase. We have previously demonstrated that exogenous cytochrome c can overcome myocardial CcOX competitive inhibition and improve cardiac function during murine sepsis at the 24-h point. Here, we evaluate the effect of exogenous cytochrome c on CcOX activity and survival in mice at the later time points. Exogenous cytochrome c (800 μg) or saline was intravenously injected 24 h after cecal ligation and puncture (CLP) or sham operation. Steady-state mitochondrial cytochrome c levels and heme c content increased significantly 48 h post-CLP and remained elevated at 72 h in cytochrome c-injected mice compared with saline injection. Cecal ligation and puncture inhibited CcOX at 48 h in saline-injected mice. However, cytochrome c injection abrogated this inhibition and restored CcOX kinetic activity to sham values at 48 h. Survival after CLP to 96 h after cytochrome c injection approached 50% compared with only 15% after saline injection. Thus, a single injection of exogenous cytochrome c 24 h post-CLP repletes mitochondrial substrate levels for up to 72 h, restores myocardial COX activity, and significantly improves survival.