Arabidopsis peroxin 16 trafficks through the ER and an intermediate compartment to pre-existing peroxisomes via overlapping molecular targeting signals.
Previously it has been shown that the endogenous Arabidopsis peroxin, AtPEX16, coexisted at steady state in membranes of the endoplasmic reticulum (ER) and peroxisomes. Herein, an ER-to-peroxisome trafficking pathway and the requisite molecular targeting signals for mycAtPEX16 transiently expressed in Arabidopsis and tobacco BY-2 suspension cells are described. Immunofluorescent mycAtPEX16 was observed initially in the cytosol (<2 h) and subsequently (2-4 h) in perinuclear/reticular ER and non-Golgi/non-peroxisome structures termed the ER-peroxisome intermediate compartment. After 4 h, all catalase- and ascorbate peroxidase-containing peroxisomes also possessed mycAtPEX16, indicative of mycAtPEX16 sorting to pre-existing peroxisomes. Incubations of bombarded cells at 15 degrees C, or in brefeldin A at 25 degrees C, resulted in accumulations of mycAtPEX16 within the ER. Following re-equilibration of cold-treated cells at 25 degrees C, or removal of brefeldin A, mycAtPEX16 was observed mainly in the ER-peroxisome intermediate compartment, and later within all of the peroxisomes in both species. Two internal membrane helices and the intervening sequence including the amino acid residues -VRS- were found necessary and sufficient for targeting AtPEX16 first to the ER and then to peroxisomes. Individual targeting signals for these organelles were indistinguishable, indicative of overlapping signal(s). In summary, the trafficking study of AtPEX16 revealed a dynamic link between the ER and pre-existing peroxisomes, which provided novel data in support of an upgraded semi-autonomous peroxisome model portraying participation of the ER in the sorting of certain peroxisome membrane proteins, such as AtPEX16, through an intermediate compartment to pre-existing plant peroxisomes.


Modulation of the binding affinity of myelopoietins for the interleukin-3 receptor by the granulocyte colony-stimulating factor receptor agonist.
Myelopoietins (MPOs) are a family of recombinant chimeric proteins that are both interleukin-3 (IL-3) receptor and granulocyte colony-stimulating factor (G-CSF) receptor agonists. In this study, MPO molecules containing one of three different IL-3 receptor agonists linked with a common G-CSF receptor agonist have been examined for their IL-3 receptor binding characteristics. Binding to the alpha-subunit of the IL-3 receptor revealed that the affinity of the MPO molecules was 1.7-3.4-fold less potent than those of their individual cognate IL-3 receptor agonists. The affinity decrease was reflected in the MPO chimeras having approximately 2-fold slower dissociation rates and 2.7-5.5-fold slower association rates than the corresponding specific IL-3 receptor agonists alone. The affinity of binding of the MPO molecules to the heteromultimeric alphabeta IL-3 receptor expressed on TF-1 cells was either 3-, 10-, or 42-fold less potent than that of the individual cognate IL-3 receptor agonist. Biophysical data from nuclear magnetic resonance, near-UV circular dichroism, dynamic light scattering, analytical ultracentrifugation, and size exclusion chromatography experiments determined that there were significant tertiary structural differences between the MPO molecules. These structural differences suggested that the IL-3 and G-CSF receptor agonist domains within the MPO chimera may perturb one another to varying degrees. Thus, the differential modulation of affinity observed in IL-3 receptor binding may be a direct result of the magnitude of these interdomain interactions.


RNA surveillance by the nuclear RNA exosome: mechanisms and significance.
The nuclear RNA exosome is an essential and versatile machinery that regulates maturation and degradation of a huge plethora of RNA species. The past two decades have witnessed remarkable progress in understanding the whole picture of its RNA substrates and the structural basis of its functions. In addition to the exosome itself, recent studies focusing on associated co-factors have been elucidating how the exosome is directed towards specific substrates. Moreover, it has been gradually realized that loss-of-function of exosome subunits affect multiple biological processes such as the DNA damage response, R-loop resolution, maintenance of genome integrity, RNA export, translation and cell differentiation. In this review, we summarize the current knowledge of the mechanisms of nuclear exosome-mediated RNA metabolism and discuss their physiological significance.


The presence of atrial natriuretic peptide in canine cerebrospinal fluid and its possible origin in the brain.
The presence of atrial natriuretic peptide (ANP) in canine cerebrospinal fluid (CSF) was clearly demonstrated and an attempt was made to determine its origin as either the brain or the atrium. The concentration of ANP in canine CSF was 0.78 +/- 0.37 pmol/l (n = 31) and showed no evident correlation with that in plasma (r = 0.12). Physiological doses of human alpha-ANP (alpha-hANP) were continuously infused intravenously into nine dogs, and ANP concentrations in CSF and plasma were examined six to eight times within a 120-min period following this. The ANP level in CSF was not influenced by the systemic administration of alpha-hANP up to 180 min. Only one low molecular weight peak corresponding to alpha-hANP could be obtained from the CSF samples, while both low and high molecular weight peaks were observed for plasma ANP by gel permeation chromatography. In the atrial and hypothalamic tissue extracts the same kinds of peaks were also evident. These results prove the presence of ANP in canine CSF and that it does not come from blood that has seeped across the blood-CSF barriers, but suggest that it may originate from the brain.


Congenital pulmonary airway malformation: A report of two cases.
Congenital pulmonary airway malformation (CPAM), previously known as congenital cystic adenomatoid malformation is a congenital disorder of the lung similar to bronchopulmonary sequestration. In CPAM, usually an entire lobe of lung is replaced by a non-working cystic piece of abnormal lung tissue. This abnormal tissue will never function as normal lung tissue. The underlying cause for CPAM is not known. It occurs in approximately 1 in every 30000 pregnancies. The association between CPAM and malignancy has been well documented. There is a small risk (0.7%) of malignant transformation within the cyst. So early diagnosis and surgical resection is important to prevent the grave complications. Herein, we are reporting two interesting cases of CPAM and one belonged to Type II and other belonged to Type III of Stocker's classification.


Randomized study of systemic chemotherapy following complete excision of nonosseous sarcomas.
Between June 1975 and April 1981, 61 of the 177 eligible patients whose nonosseous sarcomas of extremity or trunk origin had been completely excised primarily or after local recurrences agreed to participate in a randomized study of adjuvant chemotherapy. Dermatofibrosarcoma, lymphomas, myeloma, Kaposi's sarcoma, and embryonal rhabdomyosarcoma were excluded as were patients with significant second primary cancers and those who received either preoperative or postoperative radiation therapy. After stratification by anatomic status of disease, site of origin, and histologic grade, a random one half of the 61 participants began alternating courses of vincristine/cyclophosphamide/dactinomycin, and vincristine/doxorubicin/dacarbazine at six-week intervals for one year. The control group was evaluated at six-week intervals without adjuvant chemotherapy, but these patients were offered this chemotherapy later if they had progressive disease excised. Although 30% of the 61 patients experienced local recurrence of disease within the first five years after randomization, and only 54% were continuously disease free for five or more years, 82% were surviving at five years (Kaplan-Meier calculations) with a median follow-up of 64.3 months. Partial suppression of distant metastasis by adjuvant chemotherapy was apparent in the overall study, in the extremity tumor category, and in the subgroup of patients who had received limb-sparing surgery; however, no survival advantage for chemotherapy-treated patients was demonstrated. The 30 adjuvant chemotherapy-treated patients received a total of three thoracotomies as compared with 17 salvage thoracotomies for the 31 control patients; however, salvage surgery for local recurrences has been similar in the two groups. Recent improvement in the survival of patients with soft-tissue sarcomas is not necessarily a result of adjuvant chemotherapy or radiation therapy.


Central giant cell granuloma in a 4-year-old female child.
Central giant cell granulomas (CGCG) are reddish lesions of gingiva that account for an important number of disorders frequently diagnosed in the regular dental practice. Although the majority of the lesions are nonaggressive, asymptomatic, and slow-growing, about 30% show an aggressive, progressively destructive behavior, and a tendency to recur. We present a case of aggressive CGCG of the maxilla in a 4-year-old female child managed by surgical excision. To minimize the possible cost of esthetic, functional, and psychological problems, mainly in young patients, CGCG should be diagnosed and managed at the earliest.


Contribution of endogenous opioids to gonadal hormones-induced temporomandibular joint antinociception.
The authors have recently demonstrated that the high serum estradiol level during the proestrus phase of the estrous cycle and that the administration of estradiol or progesterone in ovariectomized female and of testosterone in orchiectomized male rats significantly decrease formalin-induced temporomandibular joint (TMJ) nociception. In this study, the authors investigate the contribution of endogenous opioids to this antinociceptive effect of gonadal hormones in the TMJ formalin test. The opioid receptor antagonist naloxone was administrated either in the surrounding of the trigeminal sensory complex or in the TMJ region. The antinociceptive effect induced by endogenous estradiol in proestrus females and by exogenous estradiol in ovariectomized females was blocked by the administration of naloxone in the surrounding of the trigeminal sensory complex, but not in the TMJ region. The antinociceptive effect induced by the administration of progesterone in ovariectomized females and of testosterone in orchiectomized males was blocked by the administration of naloxone either in the surrounding of the trigeminal sensory complex or in the TMJ region. The authors conclude that central and peripheral opioid mechanisms mediate the antinociceptive effect of progesterone and testosterone, and central opioid mechanisms mediate the antinociceptive effect of estradiol. These findings suggest that the enhanced pain perception during low gonadal hormone periods in women and animals may be mediated by a decrease in endogenous opioid activity. This suggestion helps explain the higher severity of some pain conditions, such as temporomandibular dysfunctions in women than in men, that have no hormonal fluctuations.


Glyco-conjugation in 3-β-anhydroicaritine.
A convenient method has been developed for the glycol-conjugation in 3-position of β-anhydroicaritine in a reasonable yield. The structure of the 3-glycosylated β-anhydroicaritine derivatives was confirmed to be correct by 1H NMR, 13C NMR and HRMS spectrum. These compounds are less soluble than icaritin, but more soluble than icariside II in CCl4. The screening results showed that compounds 12h, 12i and 12j had higher cytotoxicity to HepG2 and MCF-7 at a concentration of 50 μM.


Treatment of primary biliary cirrhosis with ursodeoxycholic acid, budesonide and fibrates.
Long-term treatment with ursodeoxycholic acid (UDCA; 13-15 mg/kg/day) in patients with primary biliary cirrhosis (PBC) improves biochemical liver tests, delays histological progression and prolongs survival without liver transplantation. UDCA monotherapy appears sufficient for many patients as suggested by long-term observational data. However, the transplant-free survival rate of UDCA-treated patients remains significantly lower than that of an age- and sex-matched control population. Therefore, there is a continued need for new therapeutic options in PBC. In this article we review and discuss the following issues: the appropriate selection of patients requiring new therapeutic options, the role of budesonide in the management of these patients, and the emerging place of peroxisome proliferator-activated receptor-α ligands as anti-inflammatory and immunomodulating agents in PBC.


TfAP-2 is required for night sleep in Drosophila.
The AP-2 transcription factor APTF-1 is crucially required for developmentally controlled sleep behavior in Caenorhabditis elegans larvae. Its human ortholog, TFAP-2beta, causes Char disease and has also been linked to sleep disorders. These data suggest that AP-2 transcription factors may be highly conserved regulators of various types of sleep behavior. Here, we tested the idea that AP-2 controls adult sleep in Drosophila. Drosophila has one AP-2 ortholog called TfAP-2, which is essential for viability. To investigate its potential role in sleep behavior and neural development, we specifically downregulated TfAP-2 in the nervous system. We found that neuronal TfAP-2 knockdown almost completely abolished night sleep but did not affect day sleep. TfAP-2 insufficiency affected nervous system development. Conditional TfAP-2 knockdown in the adult also produced a modest sleep phenotype, suggesting that TfAP-2 acts both in larval as well as in differentiated neurons. Thus, our results show that AP-2 transcription factors are highly conserved regulators of development and sleep.


Epidemiology of falls in older adults in Texas.
The expected increase in the US older adult population implies an increased risk of fall-related injury among these individuals. We describe the epidemiology of fall morbidity among older adults in Texas, a large US state with a diverse population base. Texas Behavioral Risk Factor Surveillance System 2010 data were analyzed. The falls outcome was defined as falling: any fall in the past 3 months and a serious fall: a fall resulting in limited activities for at least 1 day or requiring medical attention. A total of 5996 subjects were included in this analysis; 17.6% (n = 1055) reported falling 1 to 5 times in the previous 3 months, and 361 (6%) experienced serious falls. Risk of falling had a significant positive association among respondents who rated their general health as fair to poor (relative risk [RR] 2.39, 95% confidence interval [CI] 1.55-3.68) and a negative association for those who reported regular physical activity (RR 0.59, 95% CI 0.42-0.82). A similar model examined the risk of serious falls and found statistically positive associations in respondents who reported fair or poor general health (RR 3.29, 95% CI 2.00-5.43). Negative associations were found for those who reported regular physical activity (RR 0.56, 95% CI 0.38-0.83) and for men (RR 0.62, 95% CI 0.39-0.98). No statistically significant correlations for either of the fall outcomes were found with residence, obesity, education, income, age, ethnicity, employment, marital status, diabetes mellitus, or cardiovascular disease. Interventions aimed at the prevention of falls should focus on maintaining and improving general health and promoting physical activity among older adults.


Major surgical postoperative complications and survival in breast cancer: Swedish population-based register study in 57 152 women.
Postoperative complications may activate prometastatic systemic pathways through tissue damage, wound healing, infection, and inflammation. Postoperative complications are associated with inferior survival in several types of cancer. The aim was to determine the association between postoperative complications and survival in breast cancer. This population-based cohort included women operated for T1-3 N0-3 M0 invasive breast cancer in Sweden from 2008 to 2017. Only major surgical postoperative complications leading to readmission and/or reoperation within 30 days were considered. Main outcomes were overall survival (OS) and breast cancer-specific survival (BCSS). Prospectively collected nationwide register data were used. Multivariable Cox models were adjusted for clinical and socioeconomic confounders and co-morbidity. Among 57 152 women, major surgical postoperative complications were registered for 1854 patients. Median follow-up was 6.22 (0.09-11.70) years. Overall, 9163 patients died, and 3472 died from breast cancer. Major surgical postoperative complications were more common after mastectomy with or without immediate reconstruction (7.3 and 4.3 per cent respectively) than after breast-conserving surgery (2.3 per cent). Unadjusted 5-year OS and BCSS rates were 82.6 (95 per cent c.i. 80.8 to 84.5) and 92.1 (90.8 to 93.5) per cent respectively for women with a major surgical postoperative complication, and 88.8 (88.6 to 89.1) and 95.0 (94.8 to 95.2) per cent for those without a complication (P < 0.001). After adjustment, all-cause and breast cancer mortality rates remained higher after a major surgical postoperative complication (OS: HR 1.32, 95 per cent c.i. 1.15 to 1.51; BCSS: HR 1.31, 1.04 to 1.65). After stratification for type of breast surgery, this association remained significant only for women who had mastectomy without reconstruction (OS: HR 1.41, 1.20 to 1.66; BCSS: HR 1.36, 1.03 to 1.79). Major surgical postoperative complications are associated with inferior survival, especially after mastectomy. These results underline the importance of surgical de-escalation.


Endovascular baroreflex amplification for resistant hypertension: what you need to know.
Endovascular baroreflex amplification is an alternative treatment strategy for patients with resistant hypertension. In endovascular baroreflex, the carotid baroreflex is activated by a MobiusHD® device (MD) which has been implanted in the internal carotid artery. This review will discuss the MD technology and mechanism of action and promising results in the first-in-human prospective study involving the use of the MD in patients with resistant hypertension.


Analysis of developmental preformation in the alpine herb Caltha leptosepala (Ranunculaceae).
Developmental preformation is ubiquitous among alpine and arctic tundra plant species and may cause a delay in plant morphological responses to environmental variation. The duration of preformation and seasonal pattern of development were examined in Caltha leptosepala to identify characteristics of architecture and development that may influence the timing of plant responses to environmental cues, both within a single growing season and between years. All structures in C. leptosepala are preformed: leaves are initiated one or two growing seasons before they mature and flowers are initiated one growing season before maturation. Features of development and architecture in C. leptosepala, however, appear to differ from the determinate growth patterns of other exclusively preforming species, and may allow within-season variability in the seasonal development and maturation of structures. Cohorts of leaves initiated are asynchronous with maturation cohorts, and each year the number of leaf primordia per plant at snowmelt exceeds the number to mature aboveground. Therefore, some flexibility in whether leaves complete a 2-yr or 3-yr developmental trajectory might occur. Plasticity in reproductive phenotype might also occur via the process of floral abortion. Despite developmental characteristics that might facilitate the expression of phenotypic plasticity, only slight variability was observed in the duration of preformation or in the seasonal pattern of initiation and emergence of structures. Growth patterns of C. leptosepala thus appear to be fundamentally constrained, and limitations to annual growth may assure that sufficient preformed primordia remain belowground at the end of each growing season for maturation of a full cohort during the subsequent season.


[A Case in Which a Laparotomy Transition, in a Patient with Sigmoid Colon Cancer, Prevented Peritoneal Metastasis from Being Missed].
We report a case of laparoscopic sigmoidectomy for sigmoid colon cancer where a laparotomy transition prevented peritoneal metastasis from being missed. Case: A 64-year-old woman was diagnosed with sigmoid colon cancer. Computed tomography revealed a large bowel obstruction and a 12 mm wide basal bulge in the gallbladder. A laparoscopic sigmoidectomy( D3 dissection)was first performed, and intra-abdominal observation revealed no disseminated nodules. A laparoscopic cholecystectomy was performed continuously but, due to strong adhesions, a laparotomy was administered. Three disseminated nodules were observed in the omentum during the laparotomy and a postoperative pathological examination revealed pT4aN1b(2/23)M1c1(P2), pStage Ⅳc. Adjuvant chemotherapy of 8 courses of CAPOX was performed and there has been no recurrence 20 months after surgery.


Inhibition of pancreatic secretory and trophic response to caerulein by the H2-receptor antagonist ranitidine in the rat.
The effect of ranitidine (20 mg . kg-1) and cimetidine (50 mg . kg-1) on pancreatic secretory and trophic responses to caerulein (1 microgram . kg-1) was studied in the rat. Ranitidine or cimetidine were administered alone or combined with caerulein twice a day for 7 days. Saline-treated rats were used as controls. At the end of treatment animals were anesthetized and pancreatic juice was collected for 1 h after intravenous secretin plus CCK-PZ (8 U . kg-1). Afterwards rats were sacrificed and growth and composition of pancreatic tissue were determined. Compared with control (saline) values, volume of pancreatic juice and output of trypsin and amylase were increased by treatment with caerulein. Ranitidine, when given combined with caerulein, completely abolished the secretory response induced by the peptide, whereas it was totally ineffective when given alone. Cimetidine (alone or combined with caerulein) was always ineffective. Caerulein increased pancreatic weight, total pancreatic trypsin, amylase and RNA content. Here again ranitidine, combined with caerulein, abolished almost completely the trophic effect of caerulein on the pancreas, but when given alone it did not influence pancreatic growth and composition. Also in this case, cimetidine was completely inactive. These results suggest that ranitidine affects exocrine pancreas with an action independent of the H2-receptor blockade.


Feasibility and effect of para-right bundle branch pacing in patients with atrial fibrillation and complete atrioventricular block.
Chronic right ventricular apex (RVA) pacing can induce negative clinical effects. The aim of the present study was to compare RVA pacing with para-right bundle branch (para-RBB) pacing in terms of electrocardiogram (ECG) and echocardiographic (ECHO) features. Forty-one consecutive persistent atrial fibrillation patients with an indication for permanent pacing treatment due to complete atrioventricular block were randomly assigned to receive a screw-in lead either in the RVA (n = 22) or at the para-RBB (n = 19). Para-RBB pacing leads were located according to the RBB potential recorded by electrophysiology catheter. ECG was recorded before and after implantation. All patients underwent the pacemaker programming at 1 day, 6 months, 12 months and 24 months after implantation. ECHO examination was performed during follow-up at 6, 12 and 24 months after implantation to assess the heart function and synchronism. There was no significant difference in pacing lead parameters between para-RBB pacing group and RVA pacing group. Compared with RVA pacing group, the para-RBB pacing group obtained a narrower QRS complex, more synchronic ventricular systole, and less negative effect on heart function (p < 0.05). Para-RBB pacing has potential clinical benefits and may be a physiological pacing site.


Yttrium oxide nanoparticle loaded scaffolds with enhanced cell adhesion and vascularization for tissue engineering applications.
In situ tissue engineering is emerging as a novel approach in tissue engineering to repair damaged tissues by boosting the natural ability of the body to heal itself. This can be achieved by providing suitable signals and scaffolds that can augment cell migration, cell adhesion on the scaffolds and proliferation of endogenous cells that facilitate the repair. Lack of appropriate cell proliferation and angiogenesis are among the major issues associated with the limited success of in situ tissue engineering during in vivo studies. Exploitation of metal oxide nanoparticles such as yttrium oxide (Y2O3) nanoparticles may open new horizons in in situ tissue engineering by providing cues that facilitate cell proliferation and angiogenesis in the scaffolds. In this context, Y2O3 nanoparticles were synthesized and incorporated in polycaprolactone (PCL) scaffolds to enhance the cell proliferation and angiogenic properties. An optimum amount of Y2O3-containing scaffolds (1% w/w) promoted the proliferation of fibroblasts (L-929) and osteoblast-like cells (UMR-106). Results of chorioallantoic membrane (CAM) assay and the subcutaneous implantation studies in rats demonstrated the angiogenic potential of the scaffolds loaded with Y2O3 nanoparticles. Gene expression study demonstrated that the presence of Y2O3 in the scaffolds can upregulate the expression of cell proliferation and angiogenesis related biomolecules such as VEGF and EGFR. Obtained results demonstrated that Y2O3 nanoparticles can perform a vital role in tissue engineering scaffolds to promote cell proliferation and angiogenesis.


Double-Negative T Cells Attenuate Cisplatin-Induced Acute Kidney Injury via Upregulating IL-10/AT2R Axis.
Our previous research showed that TCR+CD4-CD8-double-negative (DN) T cells protect renal epithelial cells from cisplatin-induced acute kidney injury (AKI). Therefore, this study is aimed at investigating the mechanism underlying the effect of DN T cells against Cis-induced AKI. HK-2 cells cultured alone or with DN T cells were treated with or without Cis. After treatment, the cell viability and death were analyzed by a CCK-8 kit and flow cytometric assay with Annexin V/PI staining, respectively. The expressions of inflammatory factors in HK-2 and DN T cells were analyzed using qPCR. The expression levels of nephrotoxicity-associated biomarkers (KIM, calbindin, and TIMP-1), Bcl-2, and angiotensin AT2 receptor (AT2R) were determined by Western blot and qPCR. The administration of cisplatin significantly decreased the cell viability and AT2R expression, and increased cell death, inflammatory factors, and nephrotoxicity-associated biomarkers of HK-2 cells, while these effects were partly attenuated when cocultured with DN T cells. IL-10 expression was significantly increased in DN T cells after coculture, and cisplatin treatment aggravated this elevation. IL-10 supplementation exhibited a similar effect to coculture, whereas anti-IL-10 antibody reversed the effect of coculture on cisplatin-treated HK-2 cells. Finally, PD123319, an AT2R antagonist, also reversed the effect of IL-10 and coculture on the cell viability, death, and the expression of KIM, calbindin, TIMP-1, and Bcl-2 of cisplatin-treated HK-2 cells. DN T cells protected HK-2 cells from cisplatin-induced injury through IL-10/AT2R axis, which may act as a potential target for the treatment of cisplatin-induced AKI.


Potential predictors of bleeding risk in inherited factorVII deficiency. Clinical, biological and molecular criteria.
Due to the wide molecular and clinical heterogeneities of inherited factor VII (FVII) deficiency, consensus guidelines for management of this coagulation disorder are not currently well established. Therefore, potential clinical, plasmatic or genetic criteria, that could be predictive for bleeding tendency in this condition, have been evaluated. Genotypic criteria including FVII genotypes and thrombophilic mutations are of particular interest to better understand some of the variations observed in bleeding phenotypes but they are still poorly informative for the management of surgery in FVII-deficient patients. Up to now, no plasma parameters have been found to be reliable predictors of bleeding risk. Nevertheless, tissue factor and platelet pathways remain to be explored. Finally, clinical history appears to be the best predictor of bleeding risk after haemostatic challenges in inherited FVII deficiencies. Furthermore, the absence of history of bleeding or mild bleeding phenotypes including menorrhagia, bruises and epistaxis (not inducing iron deficiency anaemia or requiring blood substitutive treatment) could enable minor surgery to be performed in FVII-deficient patients without blood replacement therapy.


Proteomic analysis of sperm regions that mediate sperm-egg interactions.
The sperm interacts with three oocyte-associated structures during fertilization: the cumulus cell layer surrounding the oocyte, the egg extracellular matrix (the zona pellucida), and the oocyte plasma membrane. Each of these interactions is mediated by the sperm head, probably through proteins both on the sperm surface and within the acrosome, a specialized secretory granule. In this study, we have used subcellular fractionation in order to generate a proteome of the sperm head subcellular compartments that interact with oocytes. Of the proteins we identified for which a gene knockout has been tested, a third have been shown to be essential for efficient reproduction in vivo. Many of the other presently untested proteins are likely to have a similarly important role. Twenty-five percent of the cell surface fraction proteins are previously uncharacterized. We have shown that at least two of these novel proteins are localized to the sperm head. In summary, we have identified over 100 proteins that are expressed on mature sperm at the site of sperm-oocyte interactions.


School nursing in a Health Action Zone: how the service needs to change.
This article summarises the findings of a qualitative study carried out between January and July 2000. The aims were to examine the public health role of school nurses and to find out the views of young people, other agencies and school nurses on the school nursing service and how they want it to develop. The study was funded by the national Health Action Zone Fellowship Programme. Six recommendations to improve the school nursing service are made, based on issues raised during focus groups with young people aged 13-14 years, semi-structured interviews with stakeholders, and a workshop for school nurses. The recommendations are further supported by the findings of a literature review.


Nickel allergy and orthodontic treatment.
Nickel is the most common contact allergen affecting females in Europe and the USA. Nickel-containing metal alloys are extensively used for dental prostheses and orthodontic appliances. The aim of this study was to elucidate whether nickel sensitive persons are at greater risk of developing discomfort in the oral cavity during orthodontic treatment. Data from 1085 consecutive girls in active orthodontic treatment or in retention were collected by means of a questionnaire. No nickel allergic reaction on the oral mucosa was found. The majority of the girls with unspecific mucosal reactions and skin lesions were atopics with a chronic dermatitis. The findings do not indicate that nickel sensitive persons are at greater risk of developing discomfort in the oral cavity when wearing an intraoral orthodontic appliance.


Assessment of effectiveness of different dosage regimens of pantoprazole in controlling symptoms and healing esophageal lesions of patients with mild erosive esophagitis.
Gastroesophageal reflux disease is a very common affection, and esophageal involvement is particularly frequent. The means to effectively control symptoms and improve esophageal inflammation in these patients is to reduce esophageal acid exposure. For this purpose, we use gastric proton pump inhibitor, that can suppress gastric acid secretion. To compare the effectiveness of two different pantoprazole dosage regimens (20 and 40 mg/day), in controlling symptoms and healing esophageal lesions of patients with mild erosive esophagitis. Fifty-seven patients with endoscopically confirmed mild erosive esophagitis characterized as non-confluent erosions in the distal esophagus, were randomly to be treated either with pantoprazole 20 mg/day (group I, 28 patients) or 40 mg/day (group II, 29 patients) over a period of 4 weeks. After treatment completion, the patients were assessed for clinical and endoscopic outcome, i.e., absence of erosions in distal esophagus and improvement of gastroesophageal reflux symptoms. At the end of the treatment, 73.1% of the patients in group I and 85.7% of the patients in group II had endoscopic improvement. We also observed, that 88.5% of the patients in group I and 92.9% of the patients in group II had complete elimination of heartburn and regurgitation. Pantoprazole dosage regimens of 20 mg/day and 40 mg/day provide equivalent effectiveness in controlling symptoms and healing esophageal lesions of mild esophagitis.


[Peripartum cardiomyopathy].
Peripartum cardiomyopathy (PP-CMP) or Meadows' syndrom, is a dilated cardiomyopathy which occurs during or following pregnancy. It is characterized by heart failure with a systolic left ventricle ejection fraction of less than 45%. It is rare and its pathophysiologic mechanism is poorly elucidated. From a clinical point of view, it is characterized by unespected heart failure with rapid onset of symptoms, unpredictable evolution and risk of refractory cardiogenic shock, justifying patient's management in Cardiovascular Unit. PP-CMP requires no specific treatment compared to other causes of heart failure. We here report the case of a 29-year old primip at 32 weeks of amenorrhea presenting with congestive heart failure associated with peripartum cardiomyopathy. The aim of this study was to highlight the features of this heart disease which, despite its rarity, should not be disregarded by obstetricians.


Tapping spin glasses and ferromagnets on random graphs.
We consider a tapping dynamics, analogous to that in experiments on granular media, on spin glasses and ferromagnets on random thin graphs. Between taps, zero temperature single spin flip dynamics takes the system to a metastable state. Tapping corresponds to flipping simultaneously any spin with probability p. This dynamics leads to a stationary regime with a steady state energy E(p). We analytically solve this dynamics for the one-dimensional ferromagnet and +/-J spin glass. Numerical simulations for spin glasses and ferromagnets of higher connectivity are carried out; in particular, we find a novel first order transition for the ferromagnetic systems.


Evidence for unlinked rrn operons in the Planctomycete Pirellula marina.
Southern hybridization of rRNAs to chromosomal BamHI-digested DNA of the eubacterium Pirellula marina revealed the presence of two sets of 16S and 23S rRNA genes. The two copies of the 23S rRNA genes, located on 11- and about 13-kilobase (kb) inserts, were isolated from a lambda bacteriophage Charon 35 library. The 11-kb fragment was cloned directly into pBR322, while a 5.4-kb BamHI-PstI rDNA subfragment of the approximately 13-kb insert was cloned into pUC18. Both recombinant plasmids, pPI1100 and pPI540, were characterized by restriction enzyme mapping and Southern hybridization with the large rRNA species. Restriction fragments from both inserts were subcloned into phage M13 mp18 and mp19. Correlation of genomic hybridization data with physical characterization of recombinant plasmids showed that, in contrast to the general organization of rrn operons in eubacteria, the 16S rRNA genes of P. marina are separated by at least 8.5 (pPI540) and 4.4 (pPI1100) kb, respectively, from the closely linked 23S-5S rRNA genes. Comparison of the flanking regions from both 23S-5S rRNA genes with published consensus sequences of structural elements indicates the presence of putative transcription signals, i.e., a single Pribnow box, discriminator, antitermination boxes A, B, and C, and a Rho-independent terminator.


Pharmacokinetics of intranasal mometasone in the fixed-dose combination GSP301 versus two monotherapy intranasal mometasone formulations.
GSP301 is a fixed-dose combination (FDC) of the antihistamine olopatadine hydrochloride and the corticosteroid mometasone furoate developed as a single nasal spray (NS). To assess the relative bioavailability of mometasone administered as GSP301 FDC versus two mometasone monotherapy NS formulations. In this single-dose, open-label, crossover study, healthy adults (age range, 18-65 years) were randomized equally to one of six treatment sequences for three 72-hour treatment periods with GSP301 (olopatadine 665 μg-mometasone 50 μg), the mometasone furoate monotherapy component of GSP301 (MF-sponsor, 50 μg), and U.S. Food and Drug Administration-approved mometasone (MF, 50 μg); all the treatments were administered as two sprays per nostril. To evaluate the relative bioavailability of mometasone, pharmacokinetic (PK) estimates, the maximum plasma concentration (Cmax), the area under the plasma concentration time curve (AUC) from time 0 to the last time point with measurable concentration (AUC0-t), and AUC from time 0 to time infinity (AUC0-∞) were compared by analysis of variance. Safety and tolerability were also assessed. A total of 30 healthy subjects were randomized. Most subjects were white men who were not obese, mean age of ∼43 years. The geometric mean ratios for natural log transformed Cmax, AUC0-t, and AUC0-∞ of mometasone in GSP301 to MF-sponsor were 113.83, 118.36, and 118.50, respectively. For GSP301 and MF, geometric mean ratios for Cmax, AUC0-t, and AUC0-∞ were 141.84, 109.92, and 115.14, respectively. The percentages of subjects who reported treatment-emergent adverse events (TEAE) were 10.0%, 13.3%, and 10.3% for GSP301, MF-sponsor, and MF treatments, respectively. All TEAEs were mild, and none resulted in discontinuation. Mometasone bioavailability with GSP301 was comparable with MF-sponsor and MF monotherapies. A slightly higher Cmax was observed with GSP301 than with MF, but AUC was comparable. The addition of olopatadine to mometasone in GSP301 did not considerably affect the PK of mometasone. GSP301 was well tolerated, with only mild adverse events reported.


Improving the detection of transmembrane β-barrel chains with N-to-1 extreme learning machines.
Transmembrane β-barrels (TMBBs) are extremely important proteins that play key roles in several cell functions. They cross the lipid bilayer with β-barrel structures. TMBBs are presently found in the outer membranes of Gram-negative bacteria and of mitochondria and chloroplasts. Loop exposure outside the bacterial cell membranes makes TMBBs important targets for vaccine or drug therapies. In genomes, they are not highly represented and are difficult to identify with experimental approaches. Several computational methods have been developed to discriminate TMBBs from other types of proteins. However, the best performing approaches have a high fraction of false positive predictions. In this article, we introduce a new machine learning approach for TMBB detection based on N-to-1 Extreme Learning Machines that significantly outperforms previous methods achieving a Matthews correlation coefficient of 0.82, a probability of correct prediction of 0.92 and a sensitivity of 0.73.


Enzymatic properties of a member (AKR1C20) of the aldo-keto reductase family.
AKR1C20, a member of the aldo-keto reductase (AKR) superfamily, found by mouse genomic analysis, exhibits the highest sequence identity (89%) with mouse liver 17beta-hydroxysteroid dehydrogenase (HSD) type 5, but its function remains unknown. In this report, we have expressed the recombinant AKR1C20 from its cDNA, and examined its properties. The purified enzyme was a 36-kDa monomer, and showed both 17beta-HSD and 3alpha-HSD activities in the presence of NADP(H) as the coenzymes. While the Km values for testosterone and 5alpha-dihydrotestosterone were high (>0.2 mM), those for 3alpha-hydroxy- and 3-keto-steroids were low (0.3-5 microM), resulting in high catalytic efficiency for the substrates. Although no significant dehydrogenase activity towards non-steroidal alcohols was observed, the enzyme highly reduced alpha-dicarbonyl compounds such as 16-ketoestrone, 9,10-phenanthrenequinone, acenaphthenequinone, 1-phenylisatin and camphorquinone. The pH optima of the dehydrogenase and reductase activities were 10.5 and 6.5-7.5, respectively. The enzyme was inhibited by sulfobromophthalein, hexestrol, indomethacin and flufenamic acid. The properties of AKR1C20 are distinct from those of previously known mouse 17beta-HSD type 5 (AKR1C6), 3alpha-HSD (AKR1C14) and other members of the AKR1C subfamily. Thus, AKR1C20 is a novel 3alpha(17beta)-HSD, which may also function as a reductase for xenobiotic alpha-dicarbonyl compounds.


Severe developmental defects in Dictyostelium null mutants for actin-binding proteins.
The actin cytoskeleton is implicated in many cellular processes, such as cell adhesion, locomotion, contraction and cytokinesis, which are central to any development. The extent of polymerization, cross-linking, and bundling of actin is regulated by several actin-binding proteins. Knock-out mutations in these proteins have revealed in many cases only subtle, if any, defects in development, suggesting that the actin system is redundant, with multiple proteins sharing overlapping functions. The apparent redundancy may, however, reflect limitations of available laboratory assays in assessing the developmental role of a given protein. By using a novel assay, which reproduces conditions closer to the natural ones, we have re-examined the effects of disruption of many actin-binding proteins, and show here that deletion of alpha-actinin, interaptin, synexin, 34-kDa actin-bundling protein, and gelation factor affect to varying degrees the efficiency of Dictyostelium cells to complete development and form viable spores. No phenotypic defects were found in hisactophilin or comitin null mutants.


Changes in cytosolic and nuclear progesterone receptors during pregnancy in rat placenta.
These studies examine changes in placental growth and the abundance of progesterone receptors (Rp) in whole placentas between Days 9 and 22 of pregnancy. In addition, some placentas were dissected into decidual basalis, junctional zone, and labyrinth zone before assay of Rp. High affinity binding of 3H-progesterone to Rp was detected at all stages of pregnancy in whole placentas and in decidua basalis and the junctional zone of the placenta. Cytosolic and nuclear receptors exhibited similar affinity for progesterone in both tissues (Kd = 3.1 +/- 0.3 and 4.4 +/- 0.7 nM, respectively). Receptor binding in whole placentas increased from Day 9 to Day 12 (p less than 0.05), declined markedly at Day 16 (p less than 0.05), and returned to former levels on Days 19 and 22 (p less than 0.05). Decidua basalis contained 84% of total Rp on Day 14, which declined to 67% on Day 17 (p less than 0.05). The junctional zone contained 16% of total Rp on Day 14 and 33% on Day 17. After Day 17, junctional zone was the only source of Rp. The decline in Rp on Day 16 followed regression of decidua basalis; recovery of Rp thereafter was due to growth of the junctional zone. The labyrinth zone did not express significant amounts of Rp at any stage despite a 4-fold increase in growth in late pregnancy. Although the biologic role of the Rp in maintenance of pregnancy is poorly understood, these studies suggest that the maternal decidua basalis and fetal junctional zone are targets of progesterone action.


Adult langerhans cell histiocytosis with hepatic and pulmonary involvement.
Langerhans cell histiocytosis (LCH) is a rare proliferative disorder of Langerhans cells of unknown etiology. It can involve multiple organ systems with different clinical presentation, which complicates the diagnosis. It can range from isolated to multisystem disease with different prognosis. Although common among children, liver involvement is relatively rare in adults and frequently overlooked. Natural history of liver LCH fits into two stages: an early stage with infiltration by histiocytes and a late stage with sclerosis of the biliary tree. Pulmonary findings are more common and include multiple nodules in different stages of cavitation, predominantly in the upper lobes. We present a case of adult LCH with pulmonary and biopsy proven liver involvement with resolution of the hepatic findings after treatment.


Efficacy of coblation annuloplasty in discogenic low back pain: a prospective observational study.
In degenerative disc, the innervated outer annulus is confirmed to the major origin resulted in discogenic pain. To alleviate the discogenic pain, annuloplasty with electrothermal technology was proved to be effective, which mainly involves the thermal heating of the annulus to denature collagen fibers and denervate posterior annular nerve fibers. However, little is known that efficacy of annuloplasty with coblation technology in treating discogenic pain through directly interrupting nerves in outer annulus.The purpose of this study was to evaluate the clinical outcomes of coblation annuloplasty for the treatment of discogenic low back pain.In a clinical prospective observational study, 17 consecutive patients with discogenic low back pain underwent coblation annuloplasty under local anesthesia. Pain visual analogue scale (VAS) scores, patient responses stating significant (≥50%) pain relief, and modified MacNab criteria were adopted to evaluate the pain intensity, degree of pain relief, and functional status after 6 months of follow-up.The preoperative pain VAS score was 6.5 ± 0.8(95% confidence interval [CI] 6.1-6.9) and the pain VAS score decreased to 2.9 ± 1.6 (95% CI 2.1-3.8), 2.9 ± 1.7 (95% CI 2.1-3.8), 3.2 ± 1.6 (95% CI 2.4-4.1), 3.2 ± 1.7 (95% CI 2.4-4.2) at 1 week and 1, 3 and 6 month postoperatively, respectively. 12 (70.6%), 11 (64.7%), 10 (58.8%) and 10 (58.8%) of patients reported significant pain relief at 1 week and 1, 3 and 6 months postoperatively. At 1, 3, and 6 months postoperatively, the numbers of patients with "excellent" or "good" ratings were 13 (76.5%), 11 (64.7%), and 10 (58.8%) according to the modified MacNab criteria. No serious complications were observed.The finds show that coblation annuloplasty is an effective, safe, and less uncomfortable procedure in managing discogenic low back pain.


The hydration of actin.
The hydration of actin was studied by differential scanning calorimetry between -30 degrees C and 30 degrees C and by thermogravimetric analysis. The differential scanning calorimetry provided the freezable water content of G- and F-actin as a function of concentration, and the thermogravimetric analysis measured the total water content. The difference between the two yielded the nonfreezable water content (bound water) as a function of concentration. The nonfreezable water content of G-actin was higher than the F-actin over the whole concentration range from 1-40% actin.


Bilingual language lateralization: a meta-analytic tale of two hemispheres.
Two meta-analyses of 66 behavioral studies examined variables influencing functional cerebral lateralization of each language of brain-intact bilingual adults. Functional lateralization was found to be primarily influenced by age of onset of bilingualism: bilinguals who acquired both languages by 6 years of age showed bilateral hemispheric involvement for both languages, whereas those who acquired their second language after age 6 showed left hemisphere dominance for both languages. Moreover, among late bilinguals, left hemisphere involvement was found to be greater for those less proficient in their second language, those whose second language was English, and for studies involving dichotic listening paradigms; early bilinguals instead showed bilateral involvement in every condition. Implications of the observed differences in lateralization between early and late bilinguals are explored for existing theories of bilingualism and for neurocognitive models of brain functional organization of language.


Reconstruction of Achilles tendon defect with a free quadriceps bone-tendon graft without anastamosis.
We report a method of Achilles tendon reconstruction using a free quadriceps bone-tendon graft. The patient had a prior repair of a re-ruptured Achilles tendon, following which he developed massive necrosis of his skin and Achilles tendon leaving a 10 cm defect. First stage reconstruction consisted of soft tissue coverage of the skin defect with a sural fasciocutaneous flap. Reconstruction of the Achilles tendon followed, with the patellar bone block fixed to the calcaneus and the quadriceps tendon sutured proximally.


The integration of MRI in radiation therapy: collaboration of radiographers and radiation therapists.
The increased utilisation of magnetic resonance imaging (MRI) in radiation therapy (RT) has led to the implementation of MRI simulators for RT treatment planning and influenced the development of MRI-guided treatment systems. There is extensive literature on the advantages of MRI for tumour volume and organ-at-risk delineation compared to computed tomography. MRI provides both anatomical and functional information for RT treatment planning (RTP) as well as quantitative information to assess tumour response for adaptive treatment. Despite many advantages of MRI in RT, introducing an MRI simulator into a RT department is a challenge. Collaboration between radiographers and radiation therapists is paramount in making the best use of this technology. The cross-disciplinary training of radiographers and radiation therapists alike is an area rarely discussed; however, it is becoming an important requirement due to detailed imaging needs for advanced RT treatment techniques and with the emergence of hybrid treatment systems. This article will discuss the initial experiences of a radiation oncology department in implementing a dedicated MRI simulator for RTP, with a focus on the training required for both radiographer and RT staff. It will also address the future of MRI in RT and the implementation of MRI-guided treatment systems, such as MRI-Linacs, and the role of both radiation therapists and radiographers in this technology.


Chemistry and genotoxicity of caramelized sucrose.
Caramelization of a 1% sucrose solution at 180 degrees C accompanied characteristic changes in pH, Mr, UV-absorbance, and fluorescence values as well as increased reducing power activity after 40-60 min. Similar changes occurred to sucrose heated at 150 degrees C, after 150-240 min. Bioactivity of caramelized sucrose samples was tested for mutagenic activity, using Salmonella typhimurium strains TA-98 and TA-100, respectively, as well as the Saccharomyces D7 yeast strain for mitotic recombination and Chinese hamster ovary cells (CHO) to assess clastogenicity. Caramelized sucrose expressed no mutagenicity in the TA-98 strain, but gave positive (p < 0.05) results with the TA-100, base-pair substitution strain. Similarly, mitotic recombination in the Saccharomyces D7 yeast strain and clastogenic activity in CHO cells were induced when exposed to caramelized sucrose. In the all cases, preincubation with S-9 reduced (p < 0.05) the mutagenic activities of caramelized sucrose. Fractionation of the caramelized sucrose into volatile and nonvolatile compounds was performed and tested for clastogenicity using CHO cells. Volatile components contributed approximately 10% to total clastogenicity, which was enhanced by the presence of S-9. Nonvolatile components recovered, consisting of relatively lower Mr, gave highest (p < 0.05) clastogenic activity, denoting that higher Mr caramel colors are relatively free of this property.


Hospitals preparing future attack response.
As recovery efforts continue following the attacks on New York and Washington, hospitals have been looking beyond the short-term crises of emergency supply readiness and alternatives to air transport. They are trying to prepare for future emergencies in the face of warnings about additional terrorist attacks.


Hemispheric white matter lesions in the elderly prone to falling.
Brain computed tomography studies of two groups of elderly (mean age 83.3 years, SE 1.7) with no neurologic diagnoses were compared. Sixteen of the subjects were non-fallers and the remaining 17 had frequent unexplained falls. The group of fallers had a significantly greater degree of white-matter hypodensity of the elderly (Student's t-test = 2.7, p less than 0.01).


Granule cells control recovery from classical conditioned fear responses in the zebrafish cerebellum.
Although previous studies show that the cerebellum is involved in classical fear conditioning, it is not clear which components in the cerebellum control it or how. We addressed this issue using a delayed fear-conditioning paradigm with late-stage zebrafish larvae, with the light extinguishment as the conditioned stimulus (CS) and an electric shock as the unconditioned stimulus (US). The US induced bradycardia in the restrained larvae. After paired-associate conditioning with the CS and US, a substantial population of the larvae displayed CS-evoked bradycardia responses. To investigate the roles of the zebrafish cerebellum in classical fear conditioning, we expressed botulinum toxin or the Ca2+ indicator GCaMP7a in cerebellar neurons. The botulinum-toxin-dependent inhibition of granule-cell transmissions in the corpus cerebelli (CCe, the medial lobe) did not suppress the CS-evoked bradycardia response, but rather prolonged the response. We identified cerebellar neurons with elevated CS-evoked activity after the conditioning. The CS-evoked activity of these neurons was progressively upregulated during the conditioning and was downregulated with repetition of the unpaired CS. Some of these neurons were activated immediately upon the CS presentation, whereas others were activated after a delay. Our findings indicate that granule cells control the recovery from conditioned fear responses in zebrafish.


[Monoinfection of human Metapneumovirus in Cordoba: first clinical and epidemiological research in children with respiratory infection in 2011].
Human metapneumovirus (hMPV) RNA virus discovered in 2001, is a pathogen associated with acute respiratory infection (ARI) in children under 5 years; its prevalence ranges from 5-15%. In Córdoba, it is not integrated into the viral research in patients with low IRA (LARI). Detect hMPV in children under 5 years hospitalized for LARI in the Children's Hospital "Santísima Trinidad" of Cordoba (HNC) in 2011 and describe the clinical and epidemiological characteristics of monoinfecciones without comorbidity. Prospective, observational study. It includes (informed consent) children under 5 years with LARI of HNC from January to December 2011. The viral detection was performed using immunofluorescence of nasopharyngeal aspirate secretions. Demographic, epidemiological and clinical data of positive cases were recorded. Of 223 patients enrolled, respiratory viruses were detected in 74 (33.2%). HMPV prevalence was 4.04% (9/223), representing the 2nd place with Parainfluenza 3 (4.04%) after RSV (19.73%). Season from July to December. The average age for hMPV was 7.4 ± 6.8 months (0-60 months), 4/9 males. The average hospital stay in days was 5.6 ± 0.5 and prodrome days: 1.9 days ± 0.6. All patients require oxygen therapy (3.9 ± 1.3 days) without mechanical ventilation. Diagnosis of bronchiolitis cases occurred in 5/9 and 4/9 pneumonia. No complications at discharge. First report to document the presence of hMPV in child population of Cordoba. Its prevalence in 2011 was 4, 04%. Among monoinfecciones no fatalities or complications at discharge were recorded.


In silico assessment of collateral eddy current heating in biocompatible implants subjected to magnetic hyperthermia treatments.
Purpose: Bearing partially or fully metallic passive implants represents an exclusion criterion for patients undergoing a magnetic hyperthermia procedure, but there are no specific studies backing this restrictive decision. This work assesses how the secondary magnetic field generated at the surface of two common types of prostheses affects the safety and efficiency of magnetic hyperthermia treatments of localized tumors. The paper also proposes the combination of a multi-criteria decision analysis and a graphical representation of calculated data as an initial screening during the preclinical risk assessment for each patient.Materials and methods: Heating of a hip joint and a dental implant during the treatment of prostate, colorectal and head and neck tumors have been assessed considering different external field conditions and exposure times. The Maxwell equations including the secondary field produced by metallic prostheses have been solved numerically in a discretized computable human model. The heat exchange problem has been solved through a modified version of the Pennes' bioheat equation assuming a temperature dependency of blood perfusion and metabolic heat, i.e. thermorregulation. The degree of risk has been assessed using a risk index with parameters coming from custom graphs plotting the specific absorption rate (SAR) vs temperature increase, and coefficients derived from a multi-criteria decision analysis performed following the MACBETH approach.Results: The comparison of two common biomaterials for passive implants - Ti6Al4V and CoCrMo - shows that both specific absorption rate (SAR) and local temperature increase are found to be higher for the hip prosthesis made by Ti6Al4V despite its lower electrical and thermal conductivity. By tracking the time evolution of temperature upon field application, it has been established that there is a 30 s delay between the time point for which the thermal equilibrium is reached at prostheses and tissues. Likewise, damage may appear in those tissues adjacent to the prostheses at initial stages of treatment, since recommended thermal thresholds are soon surpassed for higher field intensities. However, it has also been found that under some operational conditions the typical safety rule of staying below or attain a maximum temperature increase or SAR value is met.Conclusion: The current exclusion criterion for implant-bearing patients in magnetic hyperthermia should be revised, since it may be too restrictive for a range of the typical field conditions used. Systematic in silico treatment planning using the proposed methodology after a well-focused diagnostic procedure can aid the clinical staff to find the appropriate limits for a safe treatment window.


[Availability of inputs for reproductive planning in three cycles of the Program for Improvement of Access and Quality in Basic Healthcare: 2012, 2014, and 2018].
The objective was to assess the availability of inputs for reproductive planning in basic healthcare units (UBS in Portuguese) that participated in the National Program for Improvement of Access and Quality of Basic Care (PMAQ-AB) and their distribution according to contextual factors. A comparative study was conducted of the three cycles of the PMAQ-AB (2012, 2014, and 2018). The study assessed the availability in the UBS of ethynyl-estradiol + levonorgestrel, norethisterone, norethisterone + estradiol, levonorgestrel, medroxyprogesterone, male and female condoms, IUDs, and rapid pregnancy tests. The study considered the availability and presence of all the inputs. Availability was assessed according to contextual factors in the city where the UBS was located. Availability of total inputs increased from 1.5% to 10.9%. In all the cycles, ethynyl-estradiol + levonorgestrel and male condoms showed the highest availability, and IUDs the lowest. Individual input´s availability also increased, with the highest increase of 36p.p. for female condoms, rapid pregnancy tests, and norethisterone + estradiol and the lowest of 15p.p. for ethynyl-estradiol + levonorgestrel, norethisterone, and IUDs. The North of Brazil showed the worst results. The largest increases were in the UBS in the municipalities with the lowest HDI and in those that participated in all the cycles of the PMAQ. Condoms are the only widely available inputs, and it is important to expand the availability of the other inputs, mainly IUDs and rapid pregnancy tests. The period under study experienced the promotion of equity, but regional inequalities need to be overcome. It is essential to monitor the inputs´ availability in order to improve reproductive planning.


Analysis of the water state and microfractal dimension of tilapia fillets during freezing and thawing.
To study the effects of freezing and thawing times and freezing temperatures on the water state and microstructure of tilapia fillets, experiments on tilapia fillets were carried out at -4 and -18°C with one to four freezing and thawing cycles (FTCs). Low-field nuclear magnetic resonance (LF-NMR) and nuclear magnetic resonance imaging were used to observe the water state after different treatments, and scanning electron microscopy (SEM) and frozen sections were used to observe the microstructure changes. Fractal dimension (FD) was used to quantitatively characterize the microstructure of the fish tissue, and the correlation between FD and fish fillet quality parameters was studied by principal component analysis (PCA). The findings showed that with the increase of FTCs, the thawing loss increased, and the water holding capacity (WHC) fell. FTCs cause a decrease in immobilized water and an increase in free water in the fillet. This indicates the migration of immobilized water to free water. SEM and frozen slice images showed that the growth of ice crystals led to the destruction of myogenic fibers. A decrease in freezing temperature inhibited ice crystal growth. The FD value dropped in accordance with an increase in FTCs. PCA demonstrated that the WHC, NMR data, and FD value had a strong correlation with the quality changes in the tilapia fillets. Therefore, FD and water state can reflect the quality characteristics of tilapia fillets. PRACTICAL APPLICATION: The water migration in tilapia fillets is detected with LF-NMR, and the microscopic image may be quantified using the FD value. Both approaches can offer fresh perspectives on how to assess the quality of tilapia fillets and reflect changes in their quality.


Association of osteoarthritis with serum levels of the environmental contaminants perfluorooctanoate and perfluorooctane sulfonate in a large Appalachian population.
Perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) are persistent environmental contaminants that affect metabolic regulation, inflammation, and other factors implicated in the pathogenesis of osteoarthritis (OA). However, the link between these compounds and OA remains unknown. In this study, the authors investigated the association of OA with PFOA and PFOS in a population of 49,432 adults from 6 PFOA-contaminated water districts in the mid-Ohio Valley (2005-2006). Participants completed a comprehensive health survey; serum levels of PFOA, PFOS, and a range of other blood markers were also measured. Medical history, including physician diagnosis of osteoarthritis, was assessed via self-report. Analyses included adjustment for demographic and lifestyle characteristics, body mass index, and other potential confounders. Reported OA showed a significant positive association with PFOA serum levels (for highest quartile of PFOA vs. lowest, adjusted odds ratio = 1.3, 95% confidence interval: 1.2, 1.5; P-trend = 0.00001) and a significant inverse association with PFOS (for highest quartile vs. lowest, adjusted odds ratio = 0.8, 95% confidence interval: 0.7, 0.9; P-trend = 0.00005). The relation between PFOA and OA was significantly stronger in younger and nonobese adults. Although the cross-sectional nature of this large, population-based study limits causal inference, the observed strong, divergent associations of reported OA with PFOA and PFOS may have important public health and etiologic implications and warrant further investigation.


Regulation of immunoglobulin promoter activity by TFII-I class transcription factors.
The restriction of immunoglobulin variable region promoter activity to B lymphocytes is a well known paradigm of promoter specificity. Recently, a cis-element, located downstream of the transcription initiation site of murine heavy chain variable promoters, was shown to be critical for B cell activity and specificity. Here we show that mutation of this element, termed DICE (Downstream Immunoglobulin Control Element), reduces in vivo activity in B cells. Gel mobility shift assays show that DICE forms B cell-specific complexes that were also sensitive to DICE mutation. DICE mutation strongly reduces the ability of a distal immunoglobulin heavy chain intronic enhancer to stimulate transcription. We also identify a DICE-interacting factor: a TFII-I-related protein known as BEN (also termed Mus-TRD1 and WBSCR11). Dominant-negative and RNAi-mediated knockdown experiments indicate that BEN can both positively and negatively regulate IgH promoter activity, depending on the cell line.


Interpersonal sensitivity is correlated with sociotropy but not with autonomy in healthy subjects.
Interpersonal sensitivity is a depression-prone personality trait closely related to anxious attachment, whereas sociotropy and autonomy are personality vulnerability factors in the cognitive theory of depression. In the present study, the relationships of interpersonal sensitivity with sociotropy and autonomy were studied in 362 healthy subjects. Interpersonal sensitivity was assessed using the Interpersonal Sensitivity Measure (IPSM), whereas sociotropy and autonomy were evaluated using the Sociotropy and Autonomy subscales, respectively, of the Sociotropy-Autonomy Scale. The IPSM was significantly correlated with the Sociotropy subscale (β = 0.61, p < 0.001) but not with the Autonomy subscale. All subscales of the IPSM correlated significantly with the Sociotropy subscale, and the correlation for the Separation Anxiety subscale (β = 0.56, p < 0.001) was strongest. The present study suggests that interpersonal sensitivity is correlated with sociotropy but not with autonomy in healthy subjects.


Three-dimensional functional images of myocardial oxygen consumption from positron tomography.
Images from positron emission tomography (PET) are usually presented as transaxial slices portraying tissue radioactivity. Studies can be difficult to interpret from transaxial images, and the temporal changes in tissue tracer concentrations which permit quantitative determinations of metabolism and perfusion are not displayed. We have developed a method to give quantitatively accurate three-dimensional images of myocardial oxygen consumption from serial images of the myocardial washout of carbon-11-acetate. Following i.v. bolus injection, data are collected for 20-30 min. The time-activity curves for each pixel in the transaxial slices are fit to a monoexponential function to determine the washout rate, which is directly related to the rate of myocardial oxygen utilization. Thus, functional images of myocardial oxygen consumption are produced for all seven slices of PET data. A previously developed method is then used to generate realistic and quantitatively accurate three-dimensional images.


Recent advances in shell-sheddable nanoparticles for cancer therapy.
Cancer remains one of the most incurable diseases associated with high mortality and morbidity. Although extensive studies have been carried out for cancer therapy, there are still no gold standards available for treatment. Spurred by advances in biomaterial sciences, recent efforts have focused on the development of polymeric nanoparticles for site-specific delivery of anticancer drugs. Such nanoparticles have distinct characteristics, including high thermodynamic stability, good biocompatibility, and prolonged circulation in the bloodstream. Owing to these unique features, systemically administered nanoparticles can passively accumulate at tumor tissue with leaky vasculature and poor lymphatic drainage system, which is called the enhanced permeation and retention (EPR) effect. However, the site-specific accumulation of nanoparticles does not guarantee high antitumor efficacy because the conventional nanoparticles release the drugs in a sustained manner via the passive diffusion mechanism, which may not endow tumor tissue with cytotoxic local concentrations of the drugs. To surmount this limitation, nanoparticles that can rapidly release the drug at the tumor site need to be developed. In recent years, it has been demonstrated that shell-sheddable nanoparticles have an ability to rapidly release the drug by recognizing the specific environments of the tumor tissue. After systemic administration, shell-sheddable nanoparticles reach tumor sites via the EPR effect, followed by exposure to tumor microenvironment-specific stimuli which cause a burst release of the drug. Representative stimuli, used to design shell-sheddable nanparticles, include pH, redox, enzymes, temperature, ultraviolet, and ultrasound. In this review, we discuss the recent advances in tumor-specific, shell-sheddable nanoparticles for drug delivery.


Polarimetric Thomson scattering measurements in Joint European Torus high temperature plasmas.
Thomson scattered light is polarized in the same orientation as the incident laser beam at low electron temperatures (Te). At high Te, part of the spectrum begins to become randomly polarized due to relativistic reasons. First measurements of the depolarized Thomson scattering spectrum were obtained from Joint European Torus (JET) pulses in 2016. This paper builds upon these initial measurements with the data obtained during 2021. These new measurements improve upon first results, in particular, by obtaining spectral measurements of the depolarized spectrum. The recent JET campaign was well suited to these measurements with long and hot plasmas. The resulting data are averaged over many plasmas and laser pulses to obtain a measurement of the amount of "p" and "s" scattered light as a function of Te. This experimentally obtained d(p/s)/dTe is then fitted and found to show reasonable agreement with the theoretically predicted depolarized fraction. Error estimates on the measured "p/s" have been obtained and show that the measurements are meaningful. This is good news for ITER for which the intention is to use this measurement as a check on Te determined by the core plasma Thomson scattering diagnostic by using conventional spectral measurement techniques.


Ferroptosis: roles and molecular mechanisms in diabetic cardiomyopathy.
Diabetic cardiomyopathy (DCM) is a serious complication of type 1 and type 2 diabetes, which leads to the aggravation of myocardial fibrosis, disorders involving systolic and diastolic functions, and increased mortality of patients with diabetes through mechanisms such as glycolipid toxicity, inflammatory response, and oxidative stress. Ferroptosis is a form of iron-dependent regulatory cell death that is attributed to the accumulation of lipid peroxides and an imbalance in redox regulation. Increased production of lipid reactive oxygen species (ROS) during ferroptosis promotes oxidative stress and damages myocardial cells, leading to myocardial systolic and diastolic dysfunction. Overproduction of ROS is an important bridge between ferroptosis and DCM, and ferroptosis inhibitors may provide new targets for the treatment of patients with DCM.


Healed meniscal tears in unstable knees. A long-term followup of seven years.
Peripheral vertical ruptures of the medial (N = 24) and the lateral (N = 4) meniscus were repaired in 28 patients (mean age, 27 years). They all had an ACL lesion, combined in 26 cases with a MCL tear. These injuries were reconstructed or sutured during the same session as the meniscus repairs. Approximately 1 year later, meniscal healing was proven arthroscopically in 20 and the other 8 had no clinical signs of meniscal rerupture. All patients were reexamined between 6 to 8 years after the initial repair. Instrumented stability testing, the Lysholm knee function score and an activity score (Tegner) were used. The patients' subjective evaluations were also recorded. In spite of the previous reconstruction, all knees were quite unstable (mean +5 mm increased laxity compared with the uninjured side). At followup, 3 of the 28 repaired menisci (11%) had reruptured in connection with a minor trauma during sports or daily activity. The knee function score averaged 88 points, the activity level dropped 2 steps compared with activities before injury (from 7 to 5). Twenty patients were satisfied with the results, 5 partly satisfied, and 3 not satisfied. A healed meniscal tear has a good chance of survival in an unstable knee. The most critical period of meniscal repair probably lies in the healing period just after surgery.


Nitric Oxide Acts as an Inhibitor of Postharvest Senescence in Horticultural Products.
Horticultural products display fast senescence after harvest at ambient temperatures, resulting in decreased quality and shorter shelf life. As a gaseous signal molecule, nitric oxide (NO) has an important physiological effect on plants. Specifically, in the area of NO and its regulation of postharvest senescence, tremendous progress has been made. This review summarizes NO synthesis; the effect of NO in alleviating postharvest senescence; the mechanism of NO-alleviated senescence; and its interactions with other signaling molecules, such as ethylene (ETH), abscisic acid (ABA), melatonin (MT), hydrogen sulfide (H2S), hydrogen gas (H2), hydrogen peroxide (H2O2), and calcium ions (Ca2+). The aim of this review is to provide theoretical references for the application of NO in postharvest senescence in horticultural products.


Novel Electrocardiographic Criteria for the Diagnosis of Left Ventricular Hypertrophy in the Japanese General Population.
Although there are several diagnostic criteria for left ventricular hypertrophy (LVH), their sensitivity remains low. A recent study reported that the sum of the amplitude of the deepest S wave in any lead (SD) and the S wave in lead V4 (SV4) (SD + SV4) improved sensitivity compared with commonly used criteria. To test whether this new formula improves sensitivity in the Japanese general population, we analyzed 12-lead electrocardiograms for Japanese residents participating in the Iwaki Health Promotion Project (n = 866). Left ventricular mass was calculated by echocardiography, indicating that 156 (18%) of the study population had LVH. In receiver operating characteristic analyses, the sum of the R wave in limb lead Ι (RLΙ) and the S wave in V4 (SV4) (RLΙ + SV4) showed a higher area under the curve (AUC = 0.76) than the Sokolow-Lyon voltage criteria (0.61) and the SD + SV4 criteria (0.63), and almost the same AUC as the Cornell voltage criteria (0.74) and the Cornell product criteria (0.76). The validation study also showed similar results. The cutoff values of RLΙ + SV4 criteria were ≥1.6 mV in men and ≥1.4 mV in women with a sensitivity of 39% and a specificity of 89%, whereas the sensitivity and specificity calculated based on SD + SV4 criteria were 21% and 94%, respectively. Thus, the diagnostic criterion of RLΙ + SV4 seems to be more useful than the previous criteria for diagnosing LVH in the Japanese general population.


Quantification and rapid metabolite identification in drug discovery using API time-of-flight LC/MS.
Liquid chromatography/mass spectrometry (LC/MS), utilizing a time-of-flight (TOF) mass analyzer, has been evaluated and applied to problems in bioanalysis for pharmacokinetics and drug metabolism. The data obtained by TOF MS differ from those obtained using quadrupole mass spectrometer instruments in that full-scan spectra can be routinely collected with greater sensitivity and speed. Both quantitative and qualitative information, including compound concentration in rat plasma and full-scan atmospheric pressure ionization mass spectra, are concurrently obtained. This approach has been used to characterize the disposition of several drug compounds that have been simultaneously dosed to rats in a cassette format. Quantitation limits in the 5-25 ng/mL range (approximately 20 nM) were obtained from nominal mass chromatograms (0.5 Da resolution). A reference lock mass was used to provide accurate mass measurement to reach third decimal place accuracy in the monoisotopic molecular weight. An improvement in quantitation limits was demonstrated after using accurate mass determinations. Several possible preliminary drug metabolites were confirmed or refuted, based on accurate mass. The trend of metabolite formation and clearance was qualitatively evaluated.


Factor XIII: a coagulation factor with multiple plasmatic and cellular functions.
Factor XIII (FXIII) is unique among clotting factors for a number of reasons: 1) it is a protransglutaminase, which becomes activated in the last stage of coagulation; 2) it works on an insoluble substrate; 3) its potentially active subunit is also present in the cytoplasm of platelets, monocytes, monocyte-derived macrophages, dendritic cells, chondrocytes, osteoblasts, and osteocytes; and 4) in addition to its contribution to hemostasis, it has multiple extra- and intracellular functions. This review gives a general overview on the structure and activation of FXIII as well as on the biochemical function and downregulation of activated FXIII with emphasis on new developments in the last decade. New aspects of the traditional functions of FXIII, stabilization of fibrin clot, and protection of fibrin against fibrinolysis are summarized. The role of FXIII in maintaining pregnancy, its contribution to the wound healing process, and its proangiogenic function are reviewed in details. Special attention is given to new, less explored, but promising fields of FXIII research that include inhibition of vascular permeability, cardioprotection, and its role in cartilage and bone development. FXIII is also considered as an intracellular enzyme; a separate section is devoted to its intracellular activation, intracellular action, and involvement in platelet, monocyte/macrophage, and dendritic cell functions.


Exposure-Efficacy Analysis of Antibody-Drug Conjugates Delivering an Excessive Level of Payload to Tissues.
Antibody-drug conjugates (ADCs) contain a disease-receptor antibody and a payload drug connected via a linker. The payload delivery depends on both tumor properties and ADC characteristics. In this study, we used different linkers, attachment sites, and doses to modulate payload delivery of several ADCs bearing maytansinoids (e.g., DM1), auristatins (e.g., MMAE), and DNA alkylating agents [e.g., pyrrolo[2,1-c][1,4]benzodiazepine-dimer (PBD)] as payloads in HER2- or CD22-expressing xenograft models. The tumor growth inhibition and ADC stability and exposure data were collected and analyzed from these dosed animals. The trend analysis suggests that intratumoral payload exposures that directly related the combination of conjugate linker and dose correlate with the corresponding efficacies of three payload types in two antigen-expressing xenograft models. These preliminary correlations also suggest that a minimal threshold concentration of intratumoral payload is required to support sustained efficacy. In addition, an ADC can deliver an excessive level of payload to tumors that does not enhance efficacy ("Plateau" effect). In contrast to tumor payload concentrations, the assessments of systemic exposures of total antibody (Tab) as well as the linker, dose, site of attachment, plasma stability, and drug-to-antibody ratio changes of these ADCs did not consistently rationalize the observed ADC efficacies. The requirement of a threshold payload concentration for efficacy is further supported by dose fractionation studies with DM1-, MMAE-, and PBD-containing ADCs, which demonstrated that single-dose regimens showed better efficacies than fractionated dosing. Overall, this study demonstrates that 1) the linker and dose together determine the tissue payload concentration that correlates with the antitumor efficacy of ADCs and 2) an ADC can deliver an unnecessary level of payload to tumors in xenograft models.


[Secular trends in diarrhea disease of childhood in the city of São Paulo, Brazil (1984-1996)].
Data from two consecutive household surveys undertaken in mid-80s and mid-90s allow to characterize and analyse secular trends in infant and child diarrhea in the city of S. Paulo, Brazil. The two surveys included random population samples aged from zero to 59 months of age (1,016 in the period of 1984-85 and 1,280 in 1995-96). In both surveys the instant prevalence of diarrhea (proportion of examined individuals reporting three or more episodes of liquid stools in 24 hours) and the annual incidence of hospitalizations due to the disease were calculated. These two indicators were estimated from household interviews conducted by pediatricians with the children's mothers. In both surveys the interviews were distributed throughout a period of almost 12 months to assure a uniform coverage of the various areas of the city during the four seasons. For each survey, the study of the social distribution of the disease took into account tertiles of the per capita family income. For the study of the determinants of secular trends, hierarchical causal models, multivariate regression analyses and calculations analogous to the ones used to assess population attributable risks were applied. In the time span from the first to the second survey, there was substantial reduction in both the prevalence of diarrhea (from 1.70% to 0.90%) and the hospitalizations due to the disease (from 2.21 to 0.79 hospitalizations per 100 children-year). A more significant reduction was observed among the third poorest families, narrowing the social gradient relative to the disease. An increase in family income and improvement in water supply could substantially explain part of the decline in the disease and, for children under two years of age, a discrete increase in breast-feeding may have also played a positive role.


Heterologous expression and identification of the genes involved in anaerobic degradation of 1,3-dihydroxybenzene (resorcinol) in Azoarcus anaerobius.
Azoarcus anaerobius, a strictly anaerobic, gram-negative bacterium, utilizes resorcinol as a sole carbon and energy source with nitrate as an electron acceptor. Previously, we showed that resorcinol degradation by this bacterium is initiated by two oxidative steps, both catalyzed by membrane-associated enzymes that lead to the formation of hydroxyhydroquinone (HHQ; 1,2,4-benzenetriol) and 2-hydroxy-1,4-benzoquinone (HBQ). This study presents evidence for the further degradation of HBQ in cell extracts to form acetic and malic acids. To identify the A. anaerobius genes required for anaerobic resorcinol catabolism, a cosmid library with genomic DNA was constructed and transformed into the phylogenetically related species Thauera aromatica, which cannot grow with resorcinol. By heterologous complementation, a transconjugant was identified that gained the ability to metabolize resorcinol. Its cosmid, designated R(+), carries a 29.88-kb chromosomal DNA fragment containing 22 putative genes. In cell extracts of T. aromatica transconjugants, resorcinol was degraded to HHQ, HBQ, and acetate, suggesting that cosmid R(+) carried all of the genes necessary for resorcinol degradation. On the basis of the physiological characterization of T. aromatica transconjugants carrying transposon insertions in different genes of cosmid R(+), eight open reading frames were found to be essential for resorcinol mineralization. Resorcinol hydroxylase-encoding genes were assigned on the basis of sequence analysis and enzyme assays with two mutants. Putative genes for hydroxyhydroquinone dehydrogenase and enzymes involved in ring fission have also been proposed. This work provides the first example of the identification of genes involved in the anaerobic degradation of aromatic compounds by heterologous expression of a cosmid library in a phylogenetically related organism.


A comparison of African American and white college students' affective and attitudinal reactions to lesbian, gay, and bisexual individuals: an exploratory study.
African American (n = 70) university students were compared with White students (n = 140) on their affective (homophobia) and attitudinal (homonegativity) reactions to lesbian, gay, and bisexual individuals. The results initially suggested that African Americans had modestly higher homophobia and homonegativity scores than Whites. However, those ethnic differences vanished after controlling for frequency of church attendance, religious commitment, and socioeconomic status. For both ethnic groups, gender and religiosity variables significantly predicted homophobia and homonegativity. Men in both ethnic groups had significantly higher homophobia and homonegativity scores than their female counterparts. Lastly, additional regression analyses revealed that one aspect of African American culture--family practices--significantly predicted homophobia, but not homonegativity, above the predictive ability of religiosity. Implications of the results are discussed.


The effect of water absorption on acrylic surface properties.
The aim of the present study was to determine whether an increased water content during thermal cycling of hot water-treated acrylic was associated with a reduction in surface hardness and an increased opacity or whitening of the surface. Ten acrylic samples were treated with 30 soak cycles (cycle duration, 24 hours), using warm water (40 degrees C) and an alkaline peroxide tablet (Efferdent control group); a further ten samples were treated with boiling water (100 degrees C) and one Efferdent tablet (experimental group). Indentation hardness of the acrylic specimens was measured prior to and immediately following the completion of the warm and hot water treatments, using an automated micro-indentation system. The hydrated acrylic specimens were then allowed to air dry at room temperature (20 degrees C) and were weighed weekly until they had obtained a constant dry weight. The loss in weight of the acrylic specimens represented the maximum water absorption. The hot water-treated specimens were much whiter than the warm water-treated specimens. The mean reduction in hardness (H(IT)) of the acrylic specimens following the treatment with hot water and alkaline peroxide tablet was 12.9%. Treatment with warm water and alkaline peroxide resulted in a slight increase in mean hardness (2.63%). There was a significant correlation between the water content of the acrylic specimens after treatment and the percentage of change in indentation hardness (r= 0.495, p= 0.026). The hot water treatment of the acrylic was associated with a significant reduction in hardness. We attribute the whitening and reduction in the hardness of the hot water-treated specimens to absorption of water and a disruption of the acrylic surface structure.


Comparing and Contrasting the Properties of the Inner Heliosphere for the Three Most Recent Solar Minima.
The previous three solar cycles have ended in progressively more quiescent conditions, suggesting a continual slide into an ever deeper minimum state. Although the Sun's magnetic field is undoubtedly responsible for this quiescence, it is not clear how changes in its structure and strength modulate the properties of the solar wind. In this study, we compare the statistical properties of the solar wind during the three most recent minima (08/1996, 12/2008, and 12/2019) and develop global MHD model solutions to help interpret these observations. We find that, counter-intuitively, the statistical properties of the solar wind for the most recent minimum lie midway between the 08/1996 and 12/2008 minima. For example, while the minimum speed dropped by 40 km s-1 between 08/1996 and 12/2008, they rose by 20 km s-1 around the 12/2019 minimum. From the model results, we infer that the 12/2008 and 12/2019 minima were structurally similar to one another, with the presence of corotating interaction regions driven by equatorial coronal holes, while the 08/1996 minimum represented a more "standard" tilted dipole configuration associated with those of earlier space age minima. Comparison of the statistical properties derived from the model results with data suggest several opportunities to improve model parameters, as well as to apply more sophisticated modeling approaches. Overall, however, the model results capture the essential features of the observations and, thus, allow us to infer the global structure of the inner heliosphere, of which the in-situ measurements provide only a glimpse.


Inhibition of homodimerization of poly(ADP-ribose) polymerase by its C-terminal cleavage products produced during apoptosis.
The biochemical role of the C-terminal fragment of poly(ADP-ribose) polymerase (PARP) was investigated in HeLa cells undergoing UV-mediated apoptosis. During the course of apoptosis, the C-terminal cleavage product of PARP interacted with intact PARP and down-regulated PARP activity by blocking the homodimerization of PARP. The basic leucine zipper motif in the auto-modification domain of the C-terminal fragment of PARP represented the site of association, and Leu(405) was critical to the ability of the basic leucine zipper motif to associate with intact PARP. The expression of the C-terminal fragment of PARP stimulated UV-mediated apoptosis. These results suggest that the C-terminal cleavage product of PARP produced during apoptosis blocks the homodimerization of PARP and inhibits the cellular PARP activity. The inhibition of the cellular PARP activity might prevent cellular NAD(+) depletion and stimulate apoptosis by maintaining the basal cellular energy level required for the completion of apoptosis.


Delayed adverse reaction to a natural dermal filler mimicking salivary gland neoplasia.
Cosmetic dermal fillers are a sought-after procedure globally. However, despite the safety claims of filler materials by the manufacturers, adverse reactions still occur. This case report is of a 66-year-old female who presented with a late-onset complication of a hyaluronic acid dermal filler that clinically mimicked a salivary gland neoplasm. The patient presented with firm peri-oral swellings of short duration that clinically mimicked a pleomorphic adenoma and mucoepidermoid carcinoma. The diagnosis was that of a foreign-body granulomatous response to dermal fillers. Although other mimics of a similar nature are reported a knowledgeable clinician, careful choice of filler material, knowledge of the product, thorough pre-procedural history taking and post-procedural patient follow-up can drastically minimize a possible misdiagnosis. The reaction was treated with a combination of hyaluronidase, betamethasone and 5-flurouracil intra-lesional injections monthly for 11 consecutive months, with total clinical resolution. Patient education of the procedure, product name and the possibility of an adverse reaction occurring, even years later or at a site distant to the initial site of placement, is vital. Further, we review the recent reported adverse association of the new mRNA COVID-19 vaccines and dermal filler placement.


Fast and convenient divergent synthesis of aliphatic ester dendrimers by anhydride coupling.
A novel divergent approach was developed for the synthesis of dendritic aliphatic polyester structures using an acetal-protected anhydride derivative of 2,2-bis(hydroxymethyl)propionic acid as the acylating agent. This divergent synthesis is remarkable, because unlike all others, it only requires a small excess of reagent to achieve quantitative growth, and it requires no means of purification other than a simple solvent extraction or precipitation. A monodisperse sixth generation dendrimer with molecular weight of 30 711 Dalton and 192 masked hydroxyl groups was prepared in high yield and purity using 1,1,1-tris(hydroxyphenyl)ethane as the core molecule. Linear and star-shaped poly(ethylene glycol) (PEG) derivatives of narrow polydispersity were also used as core molecules in the divergent synthesis of dendritic-linear copolymer hybrids up to the fourth generation without requiring any chromatographic purification.


Vibratory Urticaria Associated with a Missense Variant in ADGRE2.
Patients with autosomal dominant vibratory urticaria have localized hives and systemic manifestations in response to dermal vibration, with coincident degranulation of mast cells and increased histamine levels in serum. We identified a previously unknown missense substitution in ADGRE2 (also known as EMR2), which was predicted to result in the replacement of cysteine with tyrosine at amino acid position 492 (p.C492Y), as the only nonsynonymous variant cosegregating with vibratory urticaria in two large kindreds. The ADGRE2 receptor undergoes autocatalytic cleavage, producing an extracellular subunit that noncovalently binds a transmembrane subunit. We showed that the variant probably destabilizes an autoinhibitory subunit interaction, sensitizing mast cells to IgE-independent vibration-induced degranulation. (Funded by the National Institutes of Health.).


A PAGE screening approach for identifying CRISPR-Cas9-induced mutations in zebrafish.
The introduction of CRISPR-Cas9 technology for targeted mutagenesis has revolutionized reverse genetics and made genome editing a realistic option in many model organisms. One of the difficulties with this technique is screening for mutations in large numbers of samples. Many screening approaches for identifying CRISPR-Cas9 mutants have been published; however, in practice these methods are time consuming, expensive, or often yield false positives. This report describes a PCR-based screening approach using non-denaturing PAGE. This approach does not depend on the formation of heteroduplexes and reliably detects changes as small as 1 base-pair (bp) in nucleic acid length at the target site. This approach can be used to identify novel mutations and is also useful as a routine genotyping method.


Fluorophore labeling to monitor tRNA dynamics.
Transfer RNA (tRNA) molecules mediate translation of the nucleic acid genetic code into the amino acid building blocks of proteins, thus ensuring the survivability of cells. The dynamic properties of tRNA molecules are crucial to their functions in both activity and specificity. This chapter summarizes two methods that have been recently developed or improved upon previous protocols to introduce fluorophores to site-specific positions in tRNA. One method enables incorporation of fluorophores carrying a primary amine (such as proflavin or rhodamine) to dihydrouridine (D) residues in the tRNA tertiary core, and a second method enables incorporation of pyrroloC and 2-aminopurine to positions 75 and 76, respectively, of the CCA sequence at the 3' end. These site-specific fluorophore labeling methods utilize tRNA transcripts as the substrates to provide the versatility with both wild-type and mutant sequences for examining their motions in space and time during the process of decoding genetic information.


Biochemical Measurements of Free Opsin in Macular Degeneration Eyes: Examining the 11-CIS Retinal Deficiency Hypothesis of Delayed Dark Adaptation (An American Ophthalmological Society Thesis).
To test the hypothesis that delayed dark adaptation in patients with macular degeneration is due to an excess of free unliganded opsin (apo-opsin) and a deficiency of the visual chromophore, 11-cis retinal, in rod outer segments. A total of 50 human autopsy eyes were harvested from donors with and without macular degeneration within 2-24 hrs. postmortem. Protocols were developed which permitted dark adaptation of normal human eyes after death and enucleation. Biochemical methods of purifying rod outer segments were optimized and the concentration of rhodopsin and apo-opsin was measured with UV-visible scanning spectroscopy. The presence of apo-opsin was calculated by measuring the difference in the rhodopsin absorption spectra before and after the addition of 11-cis retinal. A total of 20 normal eyes and 16 eyes from donors with early, intermediate and advanced stages of macular degeneration were included in the final analysis. Dark adaptation was achieved by harvesting whole globes in low light, transferring into dark (light-proof) canisters and dissecting the globes using infrared light and image converters for visualization. Apo-opsin was readily detected in positive controls after the addition of 11-cis retinal. Normal autopsy eyes showed no evidence of apo-opsin. Eyes with macular degeneration also showed no evidence of apo-opsin, regardless of the severity of disease. Methods have been developed to study dark adaptation in human autopsy eyes. Eyes with age-related macular degeneration do not show a deficiency of 11-cis retinal or an excess of apo-opsin within rod outer segments.


Low-fat meat products-technological problems with processing.
Diet and health advice serve as a driving force to redirect the types of foods considered to be most beneficial in terms of improved health and quality of life for Americans. Although meat cuts have become leaner, products such as ground beef, fresh pork sausage, coarse ground sausages and emulsified sausages traditionally have higher levels of fat. However, these products offer the greatest opportunity for fat reduction by reformulation with fat substitutes. Fat replacements should contribute a minimum of calories to a product and should not be detrimental to organoleptic qualities. Most substitutes can be categorized as: leaner meats, added water, protein-based substitutes, carbohydrate-based substitutes and synthetic compounds, Reducing the fat content to ∼10% often results in cooked ground beef that is bland and dry with a hard, rubbery or mealy texture. Reformulation with fat substitutes can cause a reduction in particle binding, darker product color, lack of beef flavor, reduced browning reactions and shorter microbiological shelf-life. Other problems that occur with low-fat (5-10%) fresh or cooked/smoked sausages are reduced cook yields, soft mushy interiors, rubbery skin formation, excessive purge in vacuum packages, shorter shelf-life and changes in sensory qualities after cooking or reheating. However, some combinations of fat replacements that mimic the mouthfeel and textural characteristics of fat offer potential for development of low-fat meat products.