Miracle-dz/UniFAR-FTUs huggingface dataset:
Second-Site Suppressors of Rous Sarcoma Virus CA Mutations: Evidence for Interdomain Interactions

ABSTRACT The capsid (CA) protein, the major structural component of retroviruses, forms a shell that encases the ribonucleoprotein complex in the virion core. The most conserved region of CA, ∼20 amino acids of the major homology region (MHR), lies within the carboxy-terminal domain of the protein. Structural and sequence similarities among CA proteins of retroviruses and the CA-like proteins of hepatitis B virus and various retrotransposons suggest that the MHR is involved in an aspect of replication common to these reverse-transcribing elements. Conservative substitutions in this region of the Rous sarcoma virus protein were lethal due to a severe deficiency in reverse transcription, in spite of the presence of an intact genome and active reverse transcriptase in the particles. This finding suggests that the mutations interfered with normal interactions among these constituents. A total of four genetic suppressors of three lethal MHR mutations have now been identified. All four map to the sequence encoding the CA-spacer peptide (SP) region of Gag. The F167Y mutation in the MHR was fully suppressed by a single amino acid change in the alpha helix immediately downstream of the MHR, a region that forms the major dimer interface in human immunodeficiency virus CA. This finding suggests that the F167Y mutation indirectly interfered with dimerization. The F167Y defect could also be repaired by a second, independent suppressor in the C-terminal SP that was removed from CA during maturation. This single residue change, which increased the rate of SP cleavage, apparently corrected the F167Y defect by modifying the maturation pathway. More surprising was the isolation of suppressors of the R170Q and L171V MHR mutations, which mapped to the N-terminal domain of the CA protein. This finding suggests that the two domains, which in the monomeric protein are separated by a flexible linker, must communicate with each other at some unidentified point in the viral replication cycle.
Evidence from pyrosequencing indicates that natural variation in animal personality is associated with DRD4 DNA methylation

Personality traits are heritable and respond to natural selection, but are at the same time influenced by the ontogenetic environment. Epigenetic effects, such as DNA methylation, have been proposed as a key mechanism to control personality variation. However, to date little is known about the contribution of epigenetic effects to natural variation in behaviour. Here, we show that great tit (Parus major) lines artificially selected for divergent exploratory behaviour for four generations differ in their DNA methylation levels at the dopamine receptor D4 (DRD4) gene. This D4 receptor is statistically associated with personality traits in both humans and nonhuman animals, including the great tit. Previous work in this songbird failed to detect functional genetic polymorphisms within DRD4 that could account for the gene–trait association. However, our observation supports the idea that DRD4 is functionally involved in exploratory behaviour but that its effects are mediated by DNA methylation. While the exact mechanism underlying the transgenerational consistency of DRD4 methylation remains to be elucidated, this study shows that epigenetic mechanisms are involved in shaping natural variation in personality traits. We outline how this first finding provides a basis for investigating the epigenetic contribution to personality traits in natural systems and its subsequent role for understanding the ecology and evolution of behavioural consistency.
Spermatogenesis and spermiogenesis in Ascaris lumbricoides Var. suum

Reorganization of the prophase I nucleus marks the beginning of the first meiotic division. A pair of centrioles is present at each pole at metaphase I and mitochondria are not observed in the spindle area. A chromosomal pellicle, which resembles a kinetochore plate but has no apparent association with microtubules, surrounds each autosome at metaphase I and II. The sex body lags behind the autosomes at anaphase I and segregates differentially to one daughter cell. Mitochondria and a pair of centrioles are present in the spindle during the second meiotic division. Localized condensation of chromatin and fusion of the condensed chromatin of the secondary spermatocyte telophase nucleus results in a compact spermatid nucleus. Loss of spermatid cytoplasm is effected by the ejection of a cytophore vesicle.
Inhibition of bacterial motility with human antiflagellar monoclonal antibodies attenuates Pseudomonas aeruginosa-induced pneumonia in the immunocompetent rat

Two human monoclonal antibodies, directed against the type a and type b flagellar proteins of Pseudomonas aeruginosa, inhibited bacterial motility in vitro specifically and in a concentration-dependent manner. In order to determine if this decreased bacterial motility was associated with a decreased pathogenicity, the ability of these human antiflagellar monoclonal antibodies to attenuate P. aeruginosa-induced pneumonia in the rat was assessed. Incubation of P. aeruginosa with a 1:1 mixture of the human antiflagellar monoclonal antibodies prior to pulmonary instillation significantly (P < 0.05) ameliorated the bacterium-induced decrease in arterial blood oxygen pressure, blunted the increase in respiratory rate, and markedly reduced the area of pulmonary inflammation. Similarly, intravenous administration of the human antiflagellar monoclonal antibodies 1 h after pulmonary instillation of the bacteria also reduced the in vivo pathogenicity of P. aeruginosa. Therefore, human antiflagellar monoclonal antibodies can decrease the in vitro motility of P. aeruginosa and can reduce its in vivo pathogenicity when administered either before or after bacterial challenge.
Comparison of the Furlow Double‐Opposing Z‐Palatoplasty with the Wardill‐Kilner Procedure for Isolated Clefts of the Soft Palate

This retrospective investigation compared the operative experience speech results of 21 patients who underwent a Furlow double-opposing Z-palatoplasty with those of 10 patients who underwent a modified Wardill-Kilner procedure. The modification consisted of not incising the nasal mucosa. All patients presented with an isolated cleft of the soft palate and were operated on by a single surgeon. The choice of operative technique was based solely on the fact that the surgeon developed an increasing preference for the Furlow procedure over time. The mean age at surgery was 1.3 and 1.5 years for the Furlow group and the Wardill-Kilner group, respectively. The average postoperative follow-up was 2.5 and 3.1 years, respectively. The mean operative times and hospital stay were the same for both groups. Postoperative speech assessments involved equal-appearing interval scale ratings of hypernasality and nasal emission, as well as pressure-flow testing and perceptual judgments of overall velopharyngeal adequacy. Analysis failed to reveal any statistically or clinically significant differences between the two groups. (Plast. Reconstr. Surg. 95: 969, 1995.)
The interaction of carcinogenic hydrocarbons with tissue constituents. IV. A quantitative study of the binding to skin proteins of several C14-labeled hydrocarbons.

Summary 1.The quantity of radioactivity bound to the particulate and soluble proteins of skin has been determined at various times after single applications of eight C14-labeled hydrocarbons. 2.An excellent correlation between protein binding and carcinogenic activity was obtained with phenanthrene, 1,2-benzanthracene, 2′,6-dimethyl-1,2-benzanthracene, 1,2,5,6-dibenzanthracene, 3,4-benzpyrene, 20-methylcholanthrene and 9, 10-dimethyl-1,2-benzanthracene. 1,2,3,4-Dibenzanthracene, which is not carcinogenic, was extensively bound. 3.Cantharidin, maleic anhydride, and heptaldehyde, inhibitors of carcinogenesis, inhibited the protein binding of benzpyrene and 1,2,5,6-dibenzanthracene, whereas BAL, which is not inhibitory, did not affect the hydrocarbon binding. 4.Evidence has been obtained to suggest that the noncarcinogenic 1,2,3,4-dibenzanthracene is bound to sites different from those for the carcinogenic, 1,2,5,6-dibenzanthracene. 5.The bulk of the evidence strongly favors the obligatory association of protein binding and carcinogenesis, and this matter has been discussed.
Patterns and incidence of sinonasal malignancy with orbital invasion.

BACKGROUND Sinonasal malignancy with orbital invasion is rare. The objective of the current study was to evaluate the clinical and pathological features, treatment outcomes and survival rates for these malignancies. METHODS Ninety-three patients who were treated between 1997 and 2007 were retrospectively reviewed. Age, life style, symptoms, location of lesions, previous occurrences, histological subtypes, and treatment modalities were analyzed. RESULTS Ninety-three patients were evaluated, including 51 men and 42 women: the gender ratio was 1.2 men to 1.0 women. The median age was 40.5 years old. The nasal cavity (34.4%), the maxillary sinus (29.0%) and the ethmoid sinus (19.4%) were the most common primary malignant tumor sites. Almost half of the patients, 44.1% had squamous cell carcinoma, 13.9% had neuroectodermal carcinoma, 11.7% had rhabdomyosarcoma, 9% had adenocarcinoma and salivary gland-type carcinoma, and 11% had other malignancy. The majority of patients presented with T3/T4 (99%), N0 (93.1%), M0 (98%) disease. The distant metastasis rate was 20.9%. The overall survival and disease-free survival rates were 68.1% and 40.9% at three years, respectively. When the overall survival rate was computed according to the epicenter of the original malignant tumor, patients with nasal cavity malignancy and maxillary sinus had the best survival, and patients with ethmoid sinus malignancy had the worse survival (P = 0.03). According to their pathology classification, patients with rhabdomyosarcoma had worse overall survival than those with squamous cell carcinoma, or neuroendocrine carcinoma (P < 0.001). Squamous cell carcinoma and rhabdomyosarcoma invaded the orbit more often and malignancy of the nasal cavity invaded the orbit more than malignancy of the nasal sinus. CONCLUSIONS For nasal orbital tumors early diagnosis is crucial. Orbital exenteration and postoperative rehabilitation should be carefully considered. The current data suggest that surgical resection with postoperative radiation therapy may offer durable local control.
Computer Evaluation of Kinematics of Anterior Cruciate Ligament Reconstructions

Current clinical and instrumented outcome measurements of knee instability lack accuracy, especially when multiplanar instability is considered. The aim of our cadaveric study was to describe the kinematics in the intact, double bundle, and anteromedial bundle reconstructed anterior cruciate ligament knee by applying a protocol for computer-assisted evaluation of knee kinematics. An optical navigation system was used to acquire knee motion (n = 5) during clinical evaluations by tracking markers rigidly attached to the bones. The protocol included acquisition of anteroposterior translations and internal-external rotations and evaluation of three clinical knee laxity tests (anterior drawer, manual, and instrumented Lachman). Our anteroposterior translation data showed the double-bundle technique and anteromedial bundle technique could restore anteroposterior stability comparable to the intact state. For internal-external laxity, the double-bundle technique demonstrated overcorrection at 15°, 60°, 75°, and 90°. The anterior drawer and manual Lachman knee laxity tests showed improved stability for the double-bundle compared to the anteromedial bundle technique. This pilot study suggests the computation of knee laxity with a high precision method might be a step toward a more precise kinematic test of knee stability for evaluating different reconstruction methods.Level of Evidence: Level II, prognostic study. See the Guidelines for Authors for a complete description of levels of evidence.
NPPB is a novel candidate biomarker expressed by cancer‐associated fibroblasts in epithelial ovarian cancer

Most solid tumors contain cancer‐associated fibroblasts (CAFs) that support tumorigenesis and malignant progression. However, the cellular origins of CAFs in epithelial ovarian cancers (EOCs) remain poorly understood, and their utility as a source of clinical biomarkers for cancer diagnosis has not been explored in great depth. Here, we report establishing in vitro and in vivo models of CAFs in ovarian cancer development. Normal ovarian fibroblasts and mesenchymal stem cells cultured in the presence of EOC cells acquired a CAF‐like phenotype, and promoted EOC cell migration in vitro. CAFs also promoted ovarian cancer growth in vivo in both subcutaneous and intraperitoneal murine xenograft assays. Molecular profiling of CAFs identified gene expression signatures that were highly enriched for extracellular and secreted proteins. We identified novel candidate CAF‐specific biomarkers for ovarian cancer including NPPB, which was expressed in the stroma of 60% primary ovarian cancer tissues (n = 145) but not in the stroma of normal ovaries (n = 4). NPPB is a secreted protein that was also elevated in the blood of 50% of women with ovarian cancer (n = 8). Taken together, these data suggest that the tumor stroma is a novel source of biomarkers, including NPPB, that may be of clinical utility for detection of EOC.
Blood Transfusion: Quality and Safety Issues in Thalassemia, Basic Requirements and New Trends

Guidelines for minimizing risks from alloimmunization, other transfusion reactions, and infection risks are presented based on the Thalassemia International Federation (TIF) guidelines. Future developments including pretreatment of the red cell product that may reduce infection risks are discussed. The rationale for guidelines about the transfusion regime that optimizes the balance between over- and undertransfusing patients is discussed. The optimal approach is still debated and may vary with the patient population in question. Because of changes in the preparation of red cell products in recent years, there is variability in iron content of a ‘unit’ of blood. It is recommended that each center involved in the treatment of thalassemia knows the average hematocrit and volume of the blood product that they are using, as this impacts on response to chelation therapy.
Pulsatile systems for colon targeting of budesonide: In vitro and in vivo evaluation

The purpose of this study is to increase the lag time and prevent release of budesonide, a corticosteroid drug used in Crohn’s disease for the first 5 h and efficiently deliver it to the colon. Eudragit S100 spray-coated capsules and pulsatile systems using tablet plugs of cellulose acetate butyrate (CAB), HPMC K4M, guar gum, and pectin were prepared. Eudragit S100-coated capsules released 80.62% after 5 h. In pulsatile systems, decreasing the ratio of the polymer significantly increased the rate and extent of drug release. Spray-coating with EUD S100 decreased the extent of drug release to 48.41%, 69.94%, 80.58%, and 45.23% in CAB, HPMC K4M, pectin, and guar gum, respectively; however, the entire amount was released in the target area. In the presence of bacterial enzymes, selected formulas showed nearly 100% release. X-ray imaging performed to monitor the capsules throughout the GIT in human volunteers of the capsules and spray-coated pulsatile systems with 25% guar gum in the plug showed bursting in the transverse and ascending colon, respectively. Both formulations showed marked reduction in induced rabbit colitis model.
Induction of nitric oxide synthase during Japanese encephalitis virus infection: evidence of protective role.

The ability of Japanese encephalitis virus (JEV) and JEV-induced macrophage-derived factor (MDF) to modulate nitric oxide synthase (NOS) activity in brain and tumor necrosis factor-alpha (TNF-alpha) and the possible antiviral role of NOS during JEV infection were investigated. NOS activity and particularly that of the inducible form of NOS (iNOS) was significantly enhanced in JEV or JEV-induced MDF-treated mice. Following JEV infection, total NOS activity in brain was gradually increased from Day 3 and reached a peak on Day 6. MDF-induced NOS activity and iNOS activity were dose dependent and maximum activity was observed at 1 h after treatment. The response was sensitive to anti-MDF antibody treatment and N(G)-monomethyl-L-arginine (L-NMMA), an inhibitor of NOS. Pretreatment of JEV-infected mice with L-NMMA increased the mortality as evident from reduced mean survival time (MST, 11.8 days) compared to placebo treated JEV-infected mice (MST, 17 days). The enhanced level of TNF-alpha observed in the early phase of JEV infection correlated well with the enhanced activity of iNOS. These observations thus provide evidence of the protective role of iNOS during JEV infection and indicate that iNOS may be a key mediator in host innate immune response to infection.
Self‐organization of neural tissue architectures from pluripotent stem cells

Despite being a subject of intensive research, the mechanisms underlying the formation of neural tissue architectures during development of the central nervous system remain largely enigmatic. So far, studies into neural pattern formation have been restricted mainly to animal experiments. With the advent of pluripotent stem cells it has become possible to explore early steps of nervous system development in vitro. These studies have unraveled a remarkable propensity of primitive neural cells to self‐organize into primitive patterns such as neural tube‐like rosettes in vitro. Data from more advanced 3D culture systems indicate that this intrinsic propensity for self‐organization can even extend to the formation of complex architectures such as a multilayered cortical neuroepithelium or an entire optic cup. These novel experimental paradigms not only demonstrate the enormous self‐organization capacity of neural stem cells, they also provide exciting prospects for studying the earliest steps of human neural tissue development and the pathogenesis of brain malformations in reductionist in vitro paradigms. J. Comp. Neurol. 522:2831–2844, 2014. © 2014 Wiley Periodicals, Inc.
The contribution of the external carotid artery to cerebral perfusion in carotid disease.

PURPOSE In the presence of carotid occlusion, the external carotid artery (ECA) becomes an important source of cerebral blood flow, especially if the circle of Willis is incomplete. The contribution of the ECA to hemispheric blood flow in patients with severe ipsilateral carotid stenosis has never been previously investigated. METHODS One hundred eight patients were monitored during sequential cross-clamping of the external (ECA) and then ipsilateral internal carotid artery (ICA) during carotid endarterectomy using transcranial Doppler sonography (TCD) (Neuroguard CDS, Los Angeles, Calif), to measure middle cerebral artery blood flow velocity, and near-infrared spectroscopy, to measure regional cerebral oxygen saturation (CsO(2)) (Invos 3100A; Somanetics, Troy, Mich). RESULTS On the ipsilateral ECA cross-clamp, the median fall in CsO(2) was 3% (interquartile range, 1%-4%; P <.0001). On addition of the ICA cross-clamp there was a further fall of 3% and a total fall of 6% (3%-9%; P <.0001). The median percentage fall in middle cerebral artery blood flow velocity on ECA clamping was 12% (4%-24%; P <.0001); on ICA clamping it was 48% (25%-74%; P <.0001). Falls in TCD on ECA clamping were greater with increasing severity of ipsilateral ICA stenosis. The correlation between CsO(2) and TCD on external clamping, although less strong than that on internal clamping, was statistically significant r = 0.32; P =. 01; Spearman rank correlation). CONCLUSIONS The falls in TCD and CsO(2) were of a similar order of magnitude and must therefore reflect a fall in cerebral perfusion. The ipsilateral ECA contributes significantly to intracranial blood flow and oxygen saturation in severe carotid stenosis.
Outcome of Hemiresurfacing in Osteonecrosis of the Femoral Head

Hemiresurfacing of the femoral head for treatment of osteonecrosis has been proposed as a reasonable alternative to total hip arthroplasty. The results of 59 patients with Ficat Stage III osteonecrosis done by a single surgeon are reviewed. At an average followup of 4.5 years, 16 patients were considered failures because of conversion to total hip arthroplasty or considerable groin pain requiring medication. Failure did not correlate with age, body mass index, preoperative length of symptoms, acetabular articular cartilage status at the time of surgery, or cause of the underlying disease. The only factor associated with failure was a lower preoperative Harris hip score. Conversion of the failed implants to total hip arthroplasty was straightforward, confirming the conservative nature of the procedure. However, pain relief and recovery after resurfacing are less reliable than that associated with total hip arthroplasty. This procedure may be appropriate for patients younger than 30 years, given the ease of conversion to THR if failure occurs. The patient should be counseled regarding expectations.
Genetic analysis of Nkx2.2 and Nkx2.9 transcription factors in mouse brain development: specific functions in the hindbrain

Die Homeobox-Transkriptionsfaktoren Nkx2.2 und Nkx2.9 zeigen ein zeitlich und raumlich uberlappendes Expressionsmuster in der ventralen Region des zentralen Nervensystems (ZNS). Beide Transkriptionsfaktoren spielen eine wichtige Rolle in der Spezifizierung von neuronalen Subtypen im ventralen Neuralrohr. In dieser Arbeit wurde die Bedeutung von Nkx2.2 und Nkx2.9 fur die Entwicklung von branchiovisceralen Motorneuronen im murinen Hinterhirn untersucht. Es zeigt sich, das beide Transkriptionsfaktoren eine redundante Funktion wahrend der Bildung von branchiovisceralen Vorlauferzellen ausuben. Der gleichzeitige Verlust von Nkx2.2 und Nkx2.9 fuhrt zur einer Transformation der Zellschicksale in den Rhombomeren 4 bis 7. In der Nkx2.2:Nkx2.9 Doppelmutante ist eine signifikante Verringerung von branchiovisceralen Motorneuronen zu beobachten, die mit einer gleichzeitigen Zunahme von somatischen Motorneuronen einhergeht. Die Reduktion von branchiovisceralen Motorneuronen ist am deutlichsten in caudalen Rhombomeren der Nkx2.2:Nkx2.9 Doppelmutante zu sehen. Wahrend in Nkx2.2:Nkx2.9 defizienten Embryonen alle caudalen branchiovisceralen Motorkerne des Nucleus ambiguus und des dmnX verloren gehen und der Motornukleus des Facialis deutlich reduziert ist, erscheint der anterior gelegene Trigeminus Motorkern in Abwesenheit von Nkx2.2 und Nkx2.9 unverandert. Die genetische Markierung der Nkx2.2 Zelllinie durch Cre-vermittelte Rekombination zeigt, dass die branchiovisceralen Motorneurone im Hinterhirn aus p3 Vorlauferzellen hervor gehen und in Nkx2.2:Nkx2.9 Doppelmutanten das Schicksal von somatischen Motorneuronen einschlagen. Zusammenfassend liefert meine Arbeit experimentelle Daten, die klar zeigen dass die Determinierung von branchiovisceralen Motorneuronen des Hinterhirns im Bereich der Rhombomere 4 bis 7 absolut von der Funktion der beiden Transkriptionsfaktoren Nkx2.2 und Nkx2.9 abhangig ist.