Epistemic phase transitions in mathematical proofs.
Mathematical proofs are both paradigms of certainty and some of the most explicitly-justified arguments that we have in the cultural record. Their very explicitness, however, leads to a paradox, because the probability of error grows exponentially as the argument expands. When a mathematician encounters a proof, how does she come to believe it? Here we show that, under a cognitively-plausible belief formation mechanism combining deductive and abductive reasoning, belief in mathematical arguments can undergo what we call an epistemic phase transition: a dramatic and rapidly-propagating jump from uncertainty to near-complete confidence at reasonable levels of claim-to-claim error rates. To show this, we analyze an unusual dataset of forty-eight machine-aided proofs from the formalized reasoning system Coq, including major theorems ranging from ancient to 21st Century mathematics, along with five hand-constructed cases including Euclid, Apollonius, Hernstein's Topics in Algebra, and Andrew Wiles's proof of Fermat's Last Theorem. Our results bear both on recent work in the history and philosophy of mathematics on how we understand proofs, and on a question, basic to cognitive science, of how we justify complex beliefs.


Clinically determined and self-reported dental status during and after pregnancy among low-income Hispanic women.
This analysis assessed, during and 1 year after pregnancy: a) the prevalence of and relationship between self-reported and clinically determined dental caries and oral health status, and whether self-reports are a potential proxy for professional determination; and b) factors associated with high levels of professionally determined or self-reported oral disease. Data are from a randomized clinical trial of 301 pregnant, low-income Hispanic women at the California-Mexico border to compare two interventions to prevent early childhood caries. Interviews and dental examinations were conducted at enrollment (second trimester) and 1-year postpartum (PP). During pregnancy and PP, 93 percent had untreated caries and most had gingival inflammation. Sensitivity and specificity of self-reported measures compared to dentists' determinations were modest (ranging from 45-80 percent for sensitivity and 41-77 percent for specificity at both time points); positive predictive values for women reporting current tooth decay or fair/poor oral health were high (>94 percent), but negative predictive values were low (<23 percent). In a bivariate GEE model, factors associated with fair/poor self-reported oral health during and after pregnancy included self-reported dental symptoms (current tooth decay, bleeding gums without brushing), dental behaviors (not flossing) and number of decayed tooth surfaces. In a logistic regression model, the only significant factor PP associated with less extensive untreated disease was if women ever had their teeth cleaned professionally (OR = 0.44). There is a great need for dental treatment in this underserved population both during pregnancy and PP. Women may not be able to accurately recognize or act on their treatment needs. At baseline and PP, few demographic or behavioral factors were associated with either self-reported or clinically determined oral disease (e.g., being less educated or acculturated and not flossing) in the bivariate analyses. Ever having a professional teeth cleaning significantly predicted less disease PP.


Presence of a modifier gene(s) affecting early renal carcinogenesis in the Tsc2 mutant (Eker) rat model.
The Eker (Tsc2 mutant) rat model of renal carcinoma is an example of Mendelian dominantly inherited predisposition to a specific cancer. Effects of genetic background on renal carcinogenesis in the Eker rat model (Eker/Eker > Eker/BN strain) indicate the presence in the BN rat genome of a modifier gene(s) that suppresses tumorigenesis. The identification of such a modifier gene(s) might help clarify the diversity of tuberous sclerosis in humans. i) We found that preneoplastic lesions in 8-week-old F1 rats [(Eker x LE) and (Eker x BN)] were more numerous in the LE strain than in the BN strain although the difference was not large. ii) We next administered N-ethyl-N-nitrosourea (ENU; single injection, i.p.) at the age of 4 weeks to amplify the strain difference in tumorigenesis, as we had done in an earlier study to identify the predisposing gene. iii) This experiment was also done in BN congenic Eker rats to confirm the strain difference in tumorigenesis. Preneoplastic lesions were fewer in BN congenic rats than in Eker rats by a factor of 100. We used this ENU system to perform a backcross experiment [F1(Eker x BN) x Eker] and finally succeeded in mapping a new modifier locus on rat chromosome 5 (the LOD score of the D5Rat12 was 3.13).


Ablating putative Ku70 phosphorylation sites results in defective DNA damage repair and spontaneous induction of hepatocellular carcinoma.
Multiple pathways mediate the repair of DNA double-strand breaks (DSBs), with numerous mechanisms responsible for driving choice between the pathways. Previously, we reported that mutating five putative phosphorylation sites on the non-homologous end joining (NHEJ) factor, Ku70, results in sustained retention of human Ku70/80 at DSB ends and attenuation of DSB repair via homologous recombination (HR). In this study, we generated a knock-in mouse, in which the three conserved putative phosphorylation sites of Ku70 were mutated to alanine to ablate potential phosphorylation (Ku703A/3A), in order to examine if disrupting DSB repair pathway choice by modulating Ku70/80 dynamics at DSB ends results in enhanced genomic instability and tumorigenesis. The Ku703A/3A mice developed spontaneous and have accelerated chemical-induced hepatocellular carcinoma (HCC) compared to wild-type (Ku70+/+) littermates. The HCC tumors from the Ku703A/3A mice have increased γH2AX and 8-oxo-G staining, suggesting decreased DNA repair. Spontaneous transformed cell lines from Ku703A/3A mice are more radiosensitive, have a significant decrease in DNA end resection, and are more sensitive to the DNA cross-linking agent mitomycin C compared to cells from Ku70+/+ littermates. Collectively, these findings demonstrate that mutating the putative Ku70 phosphorylation sites results in defective DNA damage repair and disruption of this process drives genomic instability and accelerated development of HCC.


Influence of bleaching on flavor of 34% whey protein concentrate and residual benzoic acid concentration in dried whey proteins.
Previous studies have shown that bleaching negatively affects the flavor of 70% whey protein concentrate (WPC70), but bleaching effects on lower-protein products have not been established. Benzoyl peroxide (BP), a whey bleaching agent, degrades to benzoic acid (BA) and may elevate BA concentrations in dried whey products. No legal limit exists in the United States for BP use in whey, but international concerns exist. The objectives of this study were to determine the effect of hydrogen peroxide (HP) or BP bleaching on the flavor of 34% WPC (WPC34) and to evaluate residual BA in commercial and experimental WPC bleached with and without BP. Cheddar whey was manufactured in duplicate. Pasteurized fat-separated whey was subjected to hot bleaching with either HP at 500 mg/kg, BP at 50 or 100 mg/kg, or no bleach. Whey was ultrafiltered and spray dried into WPC34. Color [L*(lightness), a* (red-green), and b* (yellow-blue)] measurements and norbixin extractions were conducted to compare bleaching efficacy. Descriptive sensory and instrumental volatile analyses were used to evaluate bleaching effects on flavor. Benzoic acid was extracted from experimental and commercial WPC34 and 80% WPC (WPC80) and quantified by HPLC. The b* value and norbixin concentration of BP-bleached WPC34 were lower than HP-bleached and control WPC34. Hydrogen peroxide-bleached WPC34 displayed higher cardboard flavor and had higher volatile lipid oxidation products than BP-bleached or control WPC34. Benzoyl peroxide-bleached WPC34 had higher BA concentrations than unbleached and HP-bleached WPC34 and BA concentrations were also higher in BP-bleached WPC80 compared with unbleached and HP-bleached WPC80, with smaller differences than those observed in WPC34. Benzoic acid extraction from permeate showed that WPC80 permeate contained more BA than did WPC34 permeate. Benzoyl peroxide is more effective in color removal of whey and results in fewer flavor side effects compared with HP and residual BA is decreased by ultrafiltration and diafiltration.


Oncocytic carcinoma of the lacrimal gland in a patient with neurofibromatosis.
Oncocytic carcinoma (OCA) is rare, and although its occurrence in the lacrimal gland has been documented, clinical and histologic data are lacking. The authors report the first case of OCA of the lacrimal gland histologically proven in a patient with neurofibromatosis (NF). An 81-year-old man affected by type 1 NF presented with a 2-year history of left proptosis and visual loss. Orbital CT scan showed a mass in the lacrimal gland fossa infiltrating the globe, lateral rectus muscle, and bone. An incisional biopsy revealed a primary high-grade malignancy, and the patient underwent orbital exenteration followed by postoperative adjunctive radiotherapy. Six months after the operation, the patient was alive, without evidence of recurrent or metastatic disease. OCA is a high-grade neoplasm with infiltrative growth pattern and tendency to recur and metastasize. Its occurrence in association with NF has not been documented before, but clinicians should be aware of this possibility when evaluating proptosis in NF patients. Radical surgical excision, followed by adjunctive radiotherapy, is considered the treatment of choice, but the prognosis remains guarded.


High-Fat Diet Induces Resistance to Ghrelin and LEAP2 Peptide Analogs in Mice.
Recent data suggest that the orexigenic peptide ghrelin and liver-expressed antimicrobial peptide 2 (LEAP2) have opposing effects on food intake regulation. Although circulating ghrelin is decreased in obesity, peripheral ghrelin administration does not induce food intake in obese mice. Limited information is available on ghrelin resistance in relation to LEAP2. In this study, the interplay between ghrelin and LEAP2 in obesity induced by a high-fat (HF) diet in mice was studied. First, the progression of obesity and intolerance to glucose together with plasma levels of active and total ghrelin, leptin, as well as liver LEAP2 mRNA expression at different time points of HF diet feeding was examined. In addition, the impact of switch from a HF diet to a standard diet on plasma ghrelin and LEAP2 production was studied. Second, sensitivity to the stable ghrelin analogue [Dpr3]Ghrelin or our novel LEAP2 analogue palm-LEAP2(1-14) during the progression of HF diet-induced obesity and after the switch for standard diet was investigated. Food intake was monitored after acute subcutaneous administration. HF diet feeding decreased both active and total plasma ghrelin and increased liver LEAP2 mRNA expression along with intolerance to glucose and the switch to a standard diet normalized liver LEAP2 mRNA expression and plasma level of active ghrelin, but not of total ghrelin. Additionally, our study demonstrates that a HF diet causes resistance to [Dpr3]Ghrelin, reversible by switch to St diet, followed by resistance to palm-LEAP2(1-14). Further studies are needed to determine the long-term effects of LEAP2 analogues on obesity-related ghrelin resistance.


Characterization of a double cellulose-binding domain. Synergistic high affinity binding to crystalline cellulose.
Most cellulose-degrading enzymes have a two-domain structure that consists of a catalytic and a cellulose-binding domain (CBD) connected by a linker region. The linkage and the interactions of the two domains represent one of the key questions for the understanding of the function of these enzymes. The CBDs of fungal cellulases are small peptides folding into a rigid, disulfide-stabilized structure that has a distinct cellulose binding face. Here we describe properties of a recombinant double CBD, constructed by fusing the CBDs of two Trichoderma reesei cellobiohydrolases via a linker peptide similar to the natural cellulase linkers. After expression in Escherichia coli, the protein was purified from the culture medium by reversed phase chromatography and the individual domains obtained by trypsin digestion. Binding of the double CBD and its single CBD components was investigated on different types of cellulose substrates as well as chitin. Under saturating conditions, nearly 20 micromol/g of the double CBD was bound onto microcrystalline cellulose. The double CBD exhibited much higher affinity on cellulose than either of the single CBDs, indicating an interplay between the two components. A two-step model is proposed to explain the binding behavior of the double CBD. A similar interplay between the domains in the native enzyme is suggested for its binding to cellulase.


Serological markers in Arabs with lupus nephritis.
The aim of this study was to characterize the autoantibody profile of Arabs with lupus nephritis (LN). Therefore, the records of 42 Arabs with classical systemic lupus erythematosus (SLE) were reviewed. Twenty one (50%) with LN and 21 without. Most patients with LN have developed their nephropathy within the first five years of the disease. Only C3 hypocomplementemia achieved statistically significant correlation in nephritic patients and anti ribonucleoprotein (RNP) antibodies in non-nephritic patients. The difference in anti double stranded DNA (dsDNA) antibodies was insignificant (P=0.107), as both groups had markedly high prevalence of these antibodies. In addition, there was no significant negative association between detectable rheumatoid factor (RI) and patients with LN. We also examined the spectrum of specific entities of antibodies that had previously been reported in association with LN in other series (anti Smith (Sm), RNP and SS-A without anti SS-B, anti SS-A and SS-B, anti RNP and Smith, anti RNP and dsDNA and anti RNP and SS-A antibodies). None has shown any correlation with renal disease, P=1.00, P=0.591, P=0.613, P=0.195 and P=0.148, respectively. In conclusion, the study demonstrates that Arab patients with LN do not exhibit a distinctive serological profile, nonetheless it provides useful information to studies of SLE in different ethnic or racial groups.


What Substances Are Adolescents Vaping? Estimating Nicotine-Specific and Cannabis-Specific Vaping from US National Youth Surveys.
Youth use of electronic cigarettes ("e-cigarettes") is an ongoing concern. Vaping is usually assumed to be of nicotine, but survey responses may also include vaping of non-nicotine substances (particularly cannabis), which can impose different risks. The current study quantifies the proportions of nicotine-specific and cannabis-specific vaping among adolescents. Data from the Monitoring the Future (MTF) 2021 survey were analyzed with respect to the substance vaped: nicotine, cannabis, or flavoring only. Past-30-day (P30D) nicotine-specific vaping (exclusively, or also having vaped other substances) and cannabis-specific vaping were calculated. Results were also broken down by grade level, cigarette smoking history (current, former, or never), and frequency of e-cigarette use (<20 vs. 20+ days in P30D). Among 4706 P30D e-cigarette users, 84.2% vaped nicotine; the remaining 15.8% reported not vaping any nicotine in P30D. Cannabis vaping was reported by 48.4% of P30D vapers. Vaping both nicotine and cannabis in P30D was more common in current and former smokers than in never-smokers, and in frequent vapers (of any substance). Conversely, never-smokers were more commonly vaping cannabis but not nicotine, compared to current and former smokers. Supplementary NYTS 2022 analyses were consistent with these findings. A notable proportion of self-reported P30D vapers reported not vaping nicotine; nearly half vaped cannabis. Capturing the variety of substances used in vaping devices is imperative for accurate public health surveillance of both nicotine and cannabis vaping among US adolescents, considering their different respective harms and regulatory frameworks.


[ToeFit-Plus system for replacement of the first metatarsophalangeal joint].
Hallux rigidus is a frequent disease of the first metatarsophalangeal (MTP) joint. It is a painful condition markedly reducing joint motion. For grade-3 and grade-4 disease, as classified by Coughlin, first MTP joint replacement is another option of surgical treatment, in addition to resection arthroplasty or arthrodesis. In a group of 27 patients with symptomatic hallux rigidus, 28 MTP joint replacements using a TOEFIT-PLUS implant were carried out in the 2005-2009 period. There were 24 women and three men, with an average age of 56.3 years. The average follow-up was 24 months (range, 4 to 48). Indication for surgery included hallux rigidus in 20, conditions following Keller's arthroplasty in five, necrosis of the first metatarsus head in two cases and a condition after the Austin procedure in one patient. Pain, assessed by the Kitaoka score, and the range of joint motion; were evaluated before the surgery and at the final follow-up visit this also included the radiographic assessment of implant position and its integration. Of the 28 implants used, nine were hemiprosthetic and 19 total joint replacements. The average time between surgery and full weight-bearing was 6.6 weeks (range, 5 to 8) in both groups. The post-operative Kitaoka score was 87.1 (68-100) as compared with the preoperative value of 36.3 (24-52), and this difference was statistically significant.The range of motion at the first MTP improved from 14.7 degrees pre-operatively to 38.5 degrees post-operatively. There was no statistically significant difference in joint function, as assessed by the Kitaoka score and range of motion, between the two groups (hemiprosthetic vs. total joint replacements). The complications included prolonged skin healing with minor dehiscence in four cases. Revision surgery was required in three cases because of restricted joint motion associated with pain. In three cases of the total joint replacement group, there was radiographic evidence of asymptomatic osteolysis around both the phalangeal and the metatarsal component. In the hemiarthroplasty group, no osteolysis was recorded. Up to now several types of implants have been developed to alleviate pain and restore and maintain the first MTP motion in patients with hallux rigidus.The TOEFIT-PLUS implant belongs to the most recent ones. Our results are in agreement with those of other currently used replacements in terms of clinical and functional evaluation. The complications recorded in our study are also similar to those reported in the literature, which include aseptic loosening, dislocation and mechanical failure of the implant. There is no consistent approach to their treatment. Arthrodesis with tricortical graft seems to be an option, but it carries a considerable risk of failure. Since in our patients aseptic loosening was recorded only in the total joint replacement group, hemiarthroplasty has recently been preferred, because it has clinical and functional outcomes as good as total joint replacement. Our results with the use of TOEFIT-PLUS replacement show that this implant is effective in the treatment of hallux rigidus advanced stages and has good clinical outcomes, i.e., maintenance of motion at the MTP joint of the big toe, pain alleviation and early weight bearing. Since hemiarthroplasty is associated with fewer complications whose potential treatment is easier, this approach seems to have a better prospect than total joint replacement.


Enhanced human hematopoietic stem and progenitor cell engraftment by blocking donor T cell-mediated TNFα signaling.
Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy, but the large number of HSCs required limits its widespread use. Host conditioning and donor cell composition are known to affect HSCT outcomes. However, the specific role that the posttransplantation signaling environment plays in donor HSC fate is poorly understood. To mimic clinical HSCT, we injected human umbilical cord blood (UCB) cells at different doses and compositions into immunodeficient NOD/SCID/IL-2Rgc-null (NSG) mice. Surprisingly, higher UCB cell doses inversely correlated with stem and progenitor cell engraftment. This observation was attributable to increased donor cell-derived inflammatory signals. Donor T cell-derived tumor necrosis factor-α (TNFα) was specifically found to directly impair the survival and division of transplanted HSCs and progenitor cells. Neutralizing donor T cell-derived TNFα in vivo increased short-term stem and progenitor cell engraftment, accelerated hematopoietic recovery, and altered donor immune cell compositions. This direct effect of TNFα on transplanted cells could be decoupled from the indirect effect of alleviating graft-versus-host disease (GVHD) by interleukin-6 (IL-6) blockade. Our study demonstrates that donor immune cell-derived inflammatory signals directly influence HSC fate, and provides new clinically relevant strategies to improve engraftment efficiency during HSCT.


Super multi-view display with a lower resolution flat-panel display.
A lenticular-type super multi-view (SMV) display normally requires an ultra high-resolution flat-panel display. To reduce this resolution requirement, two or more views are generated around each eye with an interval smaller than the pupil diameter. Cylindrical lenses constituting a lenticular lens project a group of pixels of the flat-panel display to generate a group of viewing zones. Pixel groups generating left and right viewing zones through the same cylindrical lens are partitioned to separate the two zones. The left and right pixel groups for different cylindrical lenses are interlaced horizontally. A prototype SMV display is demonstrated.


A dataset of housing market and self-attitudes towards housing location choices in Alexandria, Egypt.
A survey, of sample size 224, is designed to include the different related-factors to housing location choice, such as; socioeconomic factors, housing characteristics, travel behavior, current self-selection factors, housing demand and future location preferences. It comprises 16 questions, categorized into three different sections; socioeconomic (5 Questions), current dwelling unit characteristics (7 Questions), and housing demand characteristics (4 Questions). The first part, socioeconomic, covers the basic information about the respondent, such as; age, gender, marital status, employment, and car ownership. While the second part, current dwelling unit characteristics, covers different aspect concerning the residential unit typology, financial aspects, and travel behavior of the respondent. It includes the tenure types of the residential unit, estimation of the unit price (in the case of ownership or renting), housing typologies, the main reason for choosing the unit, in case of working, the modes of travel to work, and time to reach it, residential mobility in the last decade, and the ownership of any other residential units. The last part, housing demand characteristics, covers the size of the demand for a residential unit, preference in living in a certain area and the reason to choose it, and the preference of residential unit׳s tenure. This survey is a representative sample for the population in Alexandria, Egypt. The data in this article is represented in: How do people select their residential locations in Egypt? The case of Alexandria; JCIT1757.


Influence of ultra-low oxygen (2%) tension on in-vitro human embryo development.
Is a reduction in the oxygen tension from 5 to 2% during extended culture from Day 3 onwards beneficial for human blastocyst development in vitro? A reduction in oxygen concentration from 5 to 2% O2 after Day 3 did not improve embryo development, quality and utilization rate. The human embryo leaves the fallopian tube to reach the uterine cavity around Day 3-4 post-ovulation. As the oxygen concentration ranges from 5 to 7% in the fallopian tube and decreases to 2% in the uterus, reducing the oxygen tension during extended culture from Day 3 onwards seems more physiological. We aim to mimic the in-vivo environment during in-vitro embryo culture. Therefore, we compared the effect of extended culture performed at 5% (control arm) or 2% oxygen (O2; study arm) tension on blastocyst formation and quality. Between December 2016 and September 2017, in two prospective studies, sibling embryos were randomized on Day 3 to either 5% O2 (control) or 2% O2 (study) for extended culture. In the control arms of both studies 1 and 2, the dishes with blastocyst medium were pre-equilibrated overnight in 5% O2, 6% CO2 and 89% N2 at 37°C. In the 2% study groups, the overnight pre-equilibration of blastocyst media was performed in either 2% O2 (study 1, 99 cycles) or 5% O2 (study 2, 126 cycles). The latter provides a gradual transition from 5 to 2% O2 environment for the study arm. Embryo culture until Day 3 was always performed in 5% O2; if at least four embryos of moderate to excellent quality were obtained on Day 3, the sibling embryos were randomized to either 5% O2 or 2% O2 for extended culture. The endpoints were embryo development and quality on Day 5/6 and the utilization rate (embryos transferred and cryopreserved). Statistical analysis was performed using the chi-square test, a P-value of <0.05 was considered significantly different. In study 1, 811 embryos were randomized on Day 3: 405 to the 2% O2 and 406 to the 5% O2 condition. No differences were observed in the blastulation rate (68.6 versus 71.9%; P = 0.319) and the proportion of good quality blastocysts on Day 5 (55.8 versus 55.2%; P = 0.888), nor in the utilization rate (53.1 versus 53.2%; P = 1.000). In study 2, 1144 embryos were randomized: 572 in each arm. Similarly, no significant difference was demonstrated in terms of the blastulation rate (63.6 versus 64.7%; P = 0.758), the proportion of good quality blastocysts (46.9 versus 48.8%; P = 0.554) or the utilization rate (49.8 versus 48.1%; P = 0.953). This study evaluated embryo development only until Day 5/6. The effect of oxidative stress on the developing embryo may only become evident at later stages (i.e. during implantation) and should therefore be studied in an RCT. The question also remains as to whether the switch to ultra-low oxygen tension from Day 4 onwards, when the embryo arrives in the uterus in vivo, would be preferential. Based on the present study results, there is no benefit in lowering the oxygen tension from 5 to 2% from Day 3 onwards during extended human embryo culture. No funding was received for this study and the authors have no conflicts of interest to declare. N/A.


Zinc coordination geometry and ligand binding affinity: the structural and kinetic analysis of the second-shell serine 228 residue and the methionine 180 residue of the aminopeptidase from Vibrio proteolyticus.
The chemical properties of zinc make it an ideal metal to study the role of coordination strain in enzymatic rate enhancement. The zinc ion and the protein residues that are bound directly to the zinc ion represent a functional charge/dipole complex, and polarization of this complex, which translates to coordination distortion, may tune electrophilicity, and hence, reactivity. Conserved protein residues outside of the charge/dipole complex, such as second-shell residues, may play a role in supporting the electronic strain produced as a consequence of functional polarization. To test the correlation between charge/dipole polarity and ligand binding affinity, structure-function studies were carried out on the dizinc aminopeptidase from Vibrio proteolyticus. Alanine substitutions of S228 and M180 resulted in catalytically diminished enzymes whose crystal structures show very little change in the positions of the metal ions and the protein residues. However, more detailed inspections of the crystal structures show small positional changes that account for differences in the zinc ion coordination geometry. Measurements of the binding affinity of leucine phosphonic acid, a transition state analogue, and leucine, a product, show a correlation between coordination geometry and ligand binding affinity. These results suggest that the coordination number and polarity may tune the electrophilicity of zinc. This may have provided the evolving enzyme with the ability to discriminate between reaction coordinate species.


Transcriptome-wide analysis of UTRs in non-small cell lung cancer reveals cancer-related genes with SNV-induced changes on RNA secondary structure and miRNA target sites.
Traditional mutation assessment methods generally focus on predicting disruptive changes in protein-coding regions rather than non-coding regulatory regions like untranslated regions (UTRs) of mRNAs. The UTRs, however, are known to have many sequence and structural motifs that can regulate translational and transcriptional efficiency and stability of mRNAs through interaction with RNA-binding proteins and other non-coding RNAs like microRNAs (miRNAs). In a recent study, transcriptomes of tumor cells harboring mutant and wild-type KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) genes in patients with non-small cell lung cancer (NSCLC) have been sequenced to identify single nucleotide variations (SNVs). About 40% of the total SNVs (73,717) identified were mapped to UTRs, but omitted in the previous analysis. To meet this obvious demand for analysis of the UTRs, we designed a comprehensive pipeline to predict the effect of SNVs on two major regulatory elements, secondary structure and miRNA target sites. Out of 29,290 SNVs in 6462 genes, we predict 472 SNVs (in 408 genes) affecting local RNA secondary structure, 490 SNVs (in 447 genes) affecting miRNA target sites and 48 that do both. Together these disruptive SNVs were present in 803 different genes, out of which 188 (23.4%) were previously known to be cancer-associated. Notably, this ratio is significantly higher (one-sided Fisher's exact test p-value = 0.032) than the ratio (20.8%) of known cancer-associated genes (n = 1347) in our initial data set (n = 6462). Network analysis shows that the genes harboring disruptive SNVs were involved in molecular mechanisms of cancer, and the signaling pathways of LPS-stimulated MAPK, IL-6, iNOS, EIF2 and mTOR. In conclusion, we have found hundreds of SNVs which are highly disruptive with respect to changes in the secondary structure and miRNA target sites within UTRs. These changes hold the potential to alter the expression of known cancer genes or genes linked to cancer-associated pathways.


Role of corin in trophoblast invasion and uterine spiral artery remodelling in pregnancy.
In pregnancy, trophoblast invasion and uterine spiral artery remodelling are important for lowering maternal vascular resistance and increasing uteroplacental blood flow. Impaired spiral artery remodelling has been implicated in pre-eclampsia, a major complication of pregnancy, for a long time but the underlying mechanisms remain unclear. Corin (also known as atrial natriuretic peptide-converting enzyme) is a cardiac protease that activates atrial natriuretic peptide (ANP), a cardiac hormone that is important in regulating blood pressure. Unexpectedly, corin expression was detected in the pregnant uterus. Here we identify a new function of corin and ANP in promoting trophoblast invasion and spiral artery remodelling. We show that pregnant corin- or ANP-deficient mice developed high blood pressure and proteinuria, characteristics of pre-eclampsia. In these mice, trophoblast invasion and uterine spiral artery remodelling were markedly impaired. Consistent with this, the ANP potently stimulated human trophoblasts in invading Matrigels. In patients with pre-eclampsia, uterine Corin messenger RNA and protein levels were significantly lower than that in normal pregnancies. Moreover, we have identified Corin gene mutations in pre-eclamptic patients, which decreased corin activity in processing pro-ANP. These results indicate that corin and ANP are essential for physiological changes at the maternal-fetal interface, suggesting that defects in corin and ANP function may contribute to pre-eclampsia.


A unified model of human hemoglobin switching through single-cell genome editing.
Key mechanisms of fetal hemoglobin (HbF) regulation and switching have been elucidated through studies of human genetic variation, including mutations in the HBG1/2 promoters, deletions in the β-globin locus, and variation impacting BCL11A. While this has led to substantial insights, there has not been a unified understanding of how these distinct genetically-nominated elements, as well as other key transcription factors such as ZBTB7A, collectively interact to regulate HbF. A key limitation has been the inability to model specific genetic changes in primary isogenic human hematopoietic cells to uncover how each of these act individually and in aggregate. Here, we describe a single-cell genome editing functional assay that enables specific mutations to be recapitulated individually and in combination, providing insights into how multiple mutation-harboring functional elements collectively contribute to HbF expression. In conjunction with quantitative modeling and chromatin capture analyses, we illustrate how these genetic findings enable a comprehensive understanding of how distinct regulatory mechanisms can synergistically modulate HbF expression.


The impact of depressive symptoms on health-related quality of life in patients with subjective cognitive decline, mild cognitive impairment, and Alzheimer's disease.
Health-related quality of life (HRQOL) is an important issue in the context of dementia care. The purpose of this study was to investigate the association between HRQOL and depressive symptoms in patients with subjective cognitive decline (SCD) and subtypes of mild cognitive impairment (MCI) and Alzheimer´s disease (AD). In this cross-sectional, observational study, a control group and four experimental groups (SCD, non-amnestic MCI, amnesticMCI, AD) were compared. Neuropsychological measurers (NTBV) and psychological questionnaires were used for data collection. The control group scored higher than patients with SCD, naMCI, aMCI, or AD for the Mental Health Component Score (MHCS) of the Short Form of the Health Survey (SF-36). The Physical Health Component Score (PHCS) of the SF-36 differed only between some groups. Furthermore, cognitive variables were more strongly associated with the physical aspects of HRQOL, whereas depressive symptoms were more strongly related with the mental aspects of HRQOL. HRQOL and depressive symptoms are closely related in patients with cognitive impairments. Therefore, it is of great importance to assess patients with subjective impairment carefully in terms of depressive symptoms.


Screening of Metal and Antibiotic Resistance in Beta-lactamase Producing Coliform Bacteria from Hospital Wastewater of Northern India.
Our exploration work has uncovered the different anti-toxin/metal tolerance and patterns against the heavy metal resistant coliform microscopic organisms from the aquatic waste of the hospital. It might give new routes for the treatment of irresistible ailments particularly by coliform and critical for hazard evaluation as well as hazard management associated with the effluents of the hospital. The higher use of pharmaceuticals, Radionuclides, and other antimicrobial solvents are the major source of metals in hospital wastewater. The hospital aquatic environment has a high content of both organic and inorganic matter with living organisms. Bacteria can resist an antimicrobial agent by producing extracellular enzymes that eliminate antibiotics and metal toxicity. In this study, we covered the existing patent literature in this area. New patents in the areas of topically applied antibiotics and agents that can potentiate the achievement of existing antibiotics may extend their helpful lifetime. Samples were collected from three different Departments of King George Medical University, Lucknow during the month of December to May (2015-16). Isolation and metal tolerance of coliform isolates were done on metal amended plates. The antibiotic sensitivity test was done by disc diffusion method. The plasmid DNA of bacterial isolates was done by the alkaline lysis method. The conjugation study was also performed in wastewater as well as a nutrient medium. Maximum isolates demonstrated their MICs at 400, 800 and 1600 μg/ml against all the metals, respectively. The high level of resistance was observed against Methicillin (88.32%, 80.60%) followed by penicillin (75%, 76%), Cephradin (59.52%, 28.84%) and least to Gentamycine (1.92%, 5.76) in E. coli and Enterobacter, respectively. Of 70%, 78% E. coli and Enterobacter isolates produce beta-lactamase activity. Six amino acid residues namely, Glu104, Tyr105, Asn132, Asn170, Ala237, and Gly238 of the beta-lactamase were found in the common interaction with the selected drugs. Plasmid DNA size ranged between 48-58.8 kb. The conjugation experiments showed a higher transfer frequency (5.5×10-1 and 3.6×10-1) rate among antibiotics and metals tested. The finding of this study presents a potential health problem as the predominant coliform species have increasingly been associated with outbreaks of hospital infections. It is recommended that hospital waste must be properly treated before its release into the environment.


Malaria transmission and fetal growth.
In view of the known relation between infection of the maternal circulation of the placenta with Plasmodium falciparum and impaired fetal growth a study was made of the effect on birth weights of a malaria eradication campaign in the British Solomon Islands. Mean birth weights rose substantially within months of starting antimalarial operations. The increases between 1969 and 1971 averaged 252 g in babies of primigravidae and 165 g in all babies. The proportion of babies with birth weights of less than 2,500 g fell by 8% overall and by 20% among babies of primigravidae. The adverse effect of malaria transmission on fetal growth was apparently reversible if transmission of infection in the community was interrupted up to as late as the third trimester of pregnancy. The beneficial effects of malaria eradication operations on infant survival, child development, and social attitudes in developing countries are discussed.


Measurement of Antiproton Production in p-He Collisions at sqrt[s_{NN}]=110 GeV.
The cross section for prompt antiproton production in collisions of protons with an energy of 6.5 TeV incident on helium nuclei at rest is measured with the LHCb experiment from a data set corresponding to an integrated luminosity of 0.5 nb^{-1}. The target is provided by injecting helium gas into the LHC beam line at the LHCb interaction point. The reported results, covering antiproton momenta between 12 and 110 GeV/c, represent the first direct determination of the antiproton production cross section in p-He collisions, and impact the interpretation of recent results on antiproton cosmic rays from space-borne experiments.


Pharmacological Tests in Atrial Fibrillation Ablation.
The invasive management of atrial fibrillation (AF) has been considerably changed by the identification of major sites of AF initiation and/or maintenance within the pulmonary vein antra. Percutaneous catheter ablation of these targets has become the standard of care for sustained maintenance of sinus rhythm. Long-term failure of ablation is related to an inability to create a durable transmural lesion or to identify all of the non-pulmonary vein arrhythmia triggers. Pharmacological challenges during catheter ablation have been suggested to improve outcomes in both paroxysmal and persistent AF. Herein we review the mechanism and evidence for the use of pharmacological adjuncts during the catheter ablation of AF.


Relative Protein Intake and Physical Function in Older Adults: A Systematic Review and Meta-Analysis of Observational Studies.
(1) Background: The present work aims to conduct a systematic review and meta-analysis of observational studies, in order to investigate the association of relative protein intake and physical function in older adults; (2) Methods: Observational studies, that investigated the association between protein intake and physical function in older adults, were retrieved from MEDLINE, SCOPUS, CINAHL, AgeLine, EMBASE, and Cochrane-CENTRAL. Two independent researchers conducted study selection and data extraction; (3) Results: Very high protein intake (≥1.2 g/kg/day) and high protein intake (≥1.0 g/kg/day) groups showed better lower limb physical functioning and walking speed (WS) performance, respectively, in comparison to individuals who present relative low protein (<0.80 g/kg/day) intake. On the other hand, relative high protein intake does not seem to propitiate a better performance on isometric handgrip (IHG) and chair rise in comparison to relative low protein intake. In addition, there were no significant differences in the physical functioning of high and middle protein intake groups; (4) Conclusions: In conclusion, findings of the present study indicate that a very high (≥1.2 g/kg/day) and high protein intake (≥1.0 g/kg/day) are associated with better lower-limb physical performance, when compared to low protein (<0.80 g/kg/day) intake, in community-dwelling older adults. These findings act as additional evidence regarding the potential need to increase protein guidelines to above the current recommendations. However, large randomized clinical trials are needed to confirm the addictive effects of high-protein diets (≥1.0 g/kg/day) in comparison to the current recommendations on physical functioning. All data are available in the Open ScienceFramework.


Silk amino acids improve physical stamina and male reproductive function of mice.
The effects of a silk amino acid (SAA) preparation on the physical stamina and male reproductive function of mice were investigated. Eight-week-old male ICR mice (29-31 g) were orally administered SAA (50, 160 or 500 mg/kg) for 44 d during 30-min daily swimming exercise. The mice were subjected to a weight-loaded (5% of body weight) forced swimming on the 14th, 28th and 42nd day to determine maximum swimming time, and after a 2-d recovery period (treated with SAA without swimming exercise), parameters related to fatigue and reproductive function were analyzed from blood, muscles and reproductive organs. Repeated swimming exercise increased the maximum swimming time to some extent, in spite of a marked reduction in body weight gain, and SAA further enhanced the stamina in a dose-dependent manner. Forced swimming exercises increased blood parameters of tissue injury, but depleted blood glucose and tissue glycogen, which were substantially prevented by SAA treatment. In addition, SAA significantly reduced the muscular thiobarbituric acid-reactive substances and blood corticosterone content increased by forced swimming. Swimming exercise decreased the blood testosterone level, which was recovered by SAA, leading to enhanced sperm counts. These combined results indicate that SAA not only enhances physical stamina by minimizing damage to tissues, including muscles, as well as preventing energy depletion caused by swimming stress, but also improves male reproductive function by increasing testosterone and sperm counts.


John Browne (1642-1702): anatomist and plagiarist.
In contrast to many other physicians of his age, John Browne (1642-1702), an English anatomist and surgeon, managed to strike a balance in his career that spanned relative obscurity, prestige, and notoriety. Among his more prestigious credits, Browne was Surgeon in Ordinary to King Charles II and William III. He also had numerous publications to his name, some of which are credited as great innovations. His career, however, was tempered by his most important book, which has been critiqued by his contemporaries as well as modern historians as plagiarism. Although Browne undeniably copied the works of others and published them under his name, he was not alone in this practice. Various forms of intellectual thievery were common in Browne's day, and there were many perpetrators. The life of this overlooked figure in the history of anatomy and the stigma attached to him will be examined.


Neurally adjusted ventilatory assist in ventilated very preterm infants: A crossover study.
To assess the effects of neurally adjusted ventilatory assist (NAVA) ventilation on oxygenation and respiratory parameters in preterm infants. An observational crossover study with a convenience sample of 19 infants born before 30 gestational weeks. Study parameters were recorded during 3-h periods of both NAVA and conventional ventilation. The proportion of time peripheral oxygen saturation (SpO2 ) and cerebral regional oxygen saturation (cRSO2 ) were within their target ranges, plus the number and severity of desaturation episodes were analyzed. In addition, electrical activity of the diaphragm (Edi), neural respiratory rates, and peak inspiratory pressures (PIPs) were recorded. Infants were born at a median age of 264/7 gestational weeks (range: 230/7 -293/7 ); the study was performed at a median age of 20 days (range: 1-82). The proportion of time SpO2 was within the target range, the number of peripheral desaturations or cRSO2 did not differ between the modes. However, the desaturation severity index was lower (131 vs. 152; p = .03) and fewer manual supplemental oxygen adjustments (1.3 vs. 2.2/h; p = .006) were needed during the period of NAVA ventilation following conventional ventilation. The mean Edi (8.1 vs. 11.4 µV; p < .006) and PIP values (14.9 vs. 19.1; p < .001) were lower during the NAVA mode. Although NAVA ventilation did not increase the proportion of time with optimal saturation, it was associated with decreased diaphragmatic activity, lower PIPs, less severe hypoxemic events, and fewer manual oxygen adjustments in very preterm infants.


Optical aberrations of intraocular lenses measured in vivo and in vitro.
Corneal and ocular aberrations were measured in a group of eyes before and after cataract surgery with spherical intraocular lens (IOL) implantation by use of well-tested techniques developed in our laboratory. By subtraction of corneal from total aberration maps, we also estimated the optical quality of the intraocular lens in vivo. We found that aberrations in pseudophakic eyes are not significantly different from aberrations in eyes before cataract surgery or from previously reported aberrations in healthy eyes of the same age. However, aberrations in pseudophakic eyes are significantly higher than in young eyes. We found a slight increase of corneal aberrations after surgery. The aberrations of the IOL and the lack of balance of the corneal spherical aberrations by the spherical aberrations of the intraocular lens also degraded the optical quality in pseudophakic eyes. We also measured the aberrations of the IOL in vitro, using an eye cell model, and simulated the aberrations of the IOL on the basis of the IOL's physical parameters. We found a good agreement among in vivo, in vitro, and simulated measures of spherical aberration: Unlike the spherical aberration of the young crystalline lens, which tends to be negative, the spherical aberration of the IOL is positive and increases with lens power. Computer simulations and in vitro measurements show that tilts and decentrations might be contributors to the increased third-order aberrations in vivo in comparison with in vitro measurements.


Fertility, segregation at a herbicide-resistance locus, and genome structure in BC hybrids from two important weedy Amaranthus species.
Field studies have established high potential for hybridization between two important and often coexisting weedy species, Amaranthus hybridus and Amaranthus tuberculatus. Prezygotic reproductive barriers between these species are believed to be limited to pollen competition and availability. A greenhouse study showed that a herbicide-resistance gene (ALS) from A. hybridus could be introgressed into an advanced A. tuberculatus background (BC2). However, evidence is lacking in support of such transfer in nature. Postzygotic reproductive barriers may minimize, if not preclude, natural introgression. Indeed, A. hybridus xA. tuberculatus hybrids are characterized by reduced fertility and even floral neuterism. The purpose of this study was to assess hybrid fertility in the BC1 generation and its relationship with genome structure and segregation at ALS. Fertility was assessed by measuring seed output and by pollen evaluation, and segregation at ALS was determined via a molecular marker system. The two parental species have the same ploidy (2n = 32) but differ in DNA content (2C) values, with A. tuberculatus chromosomes being on average 29% greater than those of A. hybridus. Given that most (98%) BC(1)s were homoploid, 2C values were used as indicators of relative genomic constitution. Fertility in the BC1 generation was greater than that of F1s, and 3% of BC1s had seed output similar to that of the parental species. Fertility in the BC1 did not correlate (in a strict way) with reconstitution of parental genomes. Hybrid sterility appeared to be controlled by relatively few loci. Heterozygosity at ALS was negatively correlated with fertility. Also, the A. tuberculatus ALS allele was not observed in the A. hybridus sexual condition, monoecism. Linkage of ALS to a locus associated (directly or via epistasis) with hybrid sterility may explain the fertility penalty observed with ALS introgression. Moreover, this linkage might explain why sequenced herbicide-resistance ALS alleles from sympatric A. tuberculatus and A. hybridus populations show independent evolution.


Mediterranean diet and the incidence of cardiovascular disease: a Spanish cohort.
The Mediterranean diet is considered a model for healthy eating. However, prospective evidence in Mediterranean countries evaluating the relationship between this dietary pattern and non-fatal cardiovascular events is scarce. The aim of the present study was to evaluate the association between the adherence to the Mediterranean diet and the incidence of fatal and non-fatal cardiovascular events among initially healthy middle-aged adults from the Mediterranean area. We followed-up 13,609 participants (60 percent women, mean age: 38 years) initially free of cardiovascular disease (CVD) during 4.9 years. Participants were part of a prospective cohort study of university graduates from all regions of Spain. Baseline diet was assessed using a validated 136-item food-frequency questionnaire. A 9-point score was used to appraise adherence to the Mediterranean diet. Incident clinical events were confirmed by a review of medical records. We observed 100 incident cases of CVD. In multivariate analyses, participants with the highest adherence to the Mediterranean diet (score>6) exhibited a lower cardiovascular risk (hazard ratio=0.41, 95% confidence interval [CI]: 0.18-0.95) compared to those with the lowest score (<3). For each 2-point increment in the score, the adjusted hazard ratios were 0.80 (95% CI: 0.62-1.02) for total CVD and 0.74 (0.55-0.99) for coronary heart disease. There is an inverse association between adherence to the Mediterranean diet and the incidence of fatal and non-fatal CVD in initially healthy middle-aged adults.


Proteomic profiling of aging in glomeruli of mice by using two-dimensional differential gel electrophoresis.
Glomerular proteins were analyzed by proteomics to screen proteins participating in maturation of glomeruli before senescence and to find key proteins involved in the aging process. Glomeruli of C57BL/6 mice at 8 and 20 weeks were separated by kidney perfusion. Proteomic profiles of glomeruli were investigated by using two-dimensional differential gel electrophoresis and MALDI-TOF mass spectrometry. We identified 22 differentially expressed proteins. Among them, 3 proteins were significantly up-regulated and 19 proteins were significantly down-regulated in mature mice. Out of these 22 proteins, 18% take part in protein transport, protein targeting, and proteolysis; 5% in glycolysis; 14% in transcription; 9% in electron transport; 9% were chaperones; and 9% were hydrolases. Our results provide insights into the glomerular differentially expressed proteins correlated with renal aging. In this study we found that aging altered the expression of ATP synthase subunit beta. Further studies on this protein might help to understand the mechanism of renal aging.


Loss of desiccation tolerance in Copaifera langsdorffii Desf. seeds during germination.
This study evaluated the loss of desiccation tolerance in C. langsdorffii seeds during the germination process. Seeds were imbibed for 24, 48, 72, 96, 120 and 144 hours and dried to the initial moisture content, kept in this state for 3 days after which they were submitted to pre-humidification and rehydration. Ultraestructural evaluations were done aiming to observe the cell damage caused by the dry process. Desiccation tolerance was evaluated in terms of the percentage of normal seedlings. Seeds not submitted to the drying process presented 61% of normal seedlings, and after 24 hours of imbibition, followed by drying, the seeds presented the same percentage of survival. However, after 48 hours of imbibition, seeds started to lose the desiccation tolerance. There was twenty six percent of normal seedlings formed from seeds imbibed for 96 hours and later dried and rehydrated. Only 5% of seeds imbibed for 144 hours, dried and rehydrated formed normal seedlings. At 144 hours of imbibition followed the dry process, there was damage into the cell structure, indicating that the seeds were unable to keep the cell structure during the drying process. Copaifera langsdorffii seeds loses the desiccation tolerance at the start of Phase 2 of imbibition.


Factors That Affect Medical Students' Perception and Impression of a Plastic Surgery Program: The Role of Elective Rotations and Interviews.
Securing a residency training position in plastic surgery is highly competitive each year with a limited quota of positions and numerous qualified applicants. Although previous studies have highlighted the importance of residency programs and applicants seeking a "good fit," it remains poorly understood what influences a medical student's impression and desire to train at a certain program over others. The objective of this cross-sectional study was to identify which specific potentially modifiable factors during elective rotations and program interviews were most important to Canadian medical students when ranking plastic surgery programs. An electronic survey with 42 questions was administered to Canadian final year medical students who applied through the 2017 Canadian Residency Match Service to the plastic surgery training program at the University of Toronto. The survey consisted of 7-point Likert scale questions related to demographics, general factors affecting impression of a plastic surgery program, and specific factors related to the elective and interview experiences. Survey responses were collected anonymously for analysis. Twenty-three of 46 applicants completed the survey (50% response rate). The most important general factors affecting a medical student's impression and desire to train at a residency program were mentors at a specific program (weighted average, 6.39) and geographic location of a program (weighted average, 5.65). During elective rotations, the most important factors identified were overall impression of resident and staff collegiality (weighted average, 6.57), overall impression of resident happiness (weighted average, 6.52), and having a formal rotation-end debrief evaluation with the supervising staff (weighted average, 6.04). At program interviews, perceiving an atmosphere of collegiality (weighted average, 6.45) and opportunities to interact with residents and faculty at an organized social event (weighted average, 5.95) were considered of greatest importance. Current applicants to plastic surgery in Canada prioritize resident happiness, program collegiality, and meaningful faculty relationships, such as those with a mentor, when ranking residency programs. Although finding a mutually "good fit" between applicant and program will remain a major aim, these findings indicate the importance of certain tangible, potentially modifiable factors that affect how medical students ultimately perceive and rank plastic surgery programs.


Condensed tannins and nutrient utilization by lambs and goats fed low-quality diets.
In the first of two experiments, four wether lambs (BW = 26.8 kg) and four wether Angora goats (BW = 31.7 kg) were used in two simultaneous 4 x 4 Latin squares to study the influence of condensed tannins (CT) on nutrient usage and concentrations of serum urea N, somatotropin (GH), and insulin (INS) when the animals were fed low-quality diets containing mountain mahogany (MM; Cercocarpus montanus) leaves. Diets were 8% CP and contained 25% or 50% MM (with hay or straw, respectively), either untreated or treated with polyethylene glycol (PEG; molecular weight 3,350) to reduce total reactive CT. Diets treated with PEG and 25% MM diets had less (P less than .05) CT than diets without PEG or those with 50% MM. Diets containing 50% MM resulted in greater N balance and lower serum urea N (P less than .01) than 25% MM diets. Concentrations of GH and INS were similar in animals fed the 25% and 50% MM diets. Reducing CT by adding PEG did not affect N balance or improve nutrient digestion by lambs or goats fed low-quality diets. In Exp. 2, four wether lambs (BW = 28.4 kg) were used in a 4 x 4 Latin square and fed the same diets as animals in Exp. 1 to study the influence of CT on ruminal fermentation and digesta kinetics. Dietary PEG treatment did not affect digesta kinetics except for a 30% increase in ruminal volume; 50% MM diets had faster particulate passage rates (P less than .05) than 25% MM diets. Ruminal ammonia N was greater (P less than .01) in lambs fed PEG-containing or 25% MM diets; however, rate of in situ NDF disappearance was not reduced by the lower ammonia N in the latter diets.


CD38 plays key roles in both antioxidation and cell survival of H2O2-treated primary rodent astrocytes.
CD38 is an ecto-enzyme that consumes NAD(+) to produce cyclic ADP-ribose (cADPR) --- a potent agonist of ryanodine receptors. Recent studies have suggested CD38 may play significant roles in both ischemic brain injury and traumatic brain injury, while the mechanisms underlying the roles of CD38 in neurological diseases remain unclear. Because oxidative stress plays key roles in both ischemic brain damage and traumatic brain damage, in this study we used primary astrocyte cultures as a experimental model to test our hypothesis that CD38 may play significant roles in oxidative stress-induced neural cell death. We found CD38 siRNA-produced decrease in CD38 levels can lead to a significant increase in H2O2-induced astrocyte death. Moreover, the CD38 siRNA treatment can significantly aggravate oxidative stress in the H2O2-treated cells, as indicated by increases in both superoxide and lipid peroxidation, suggesting that CD38 is required for maintaining the antioxidation capacity of the cells. We also found that H2O2 can induce increased CD38 expression. Collectively, our study has obtained novel findings suggesting that CD38 plays a significant role in both antioxidation and cell survival of reactive oxygen species-exposed primary astrocytes, suggesting that CD38 may become a novel target for decreasing the oxidative damage in neurological disorders.


Microsurgery in the clinic and laboratory.
Laboratory animals have been crucial to the development of modern microsurgical techniques which are now routinely used in many clinical departments worldwide. In return, microsurgical techniques are important in biomedical research as they allow many surgical procedures to be performed on rodents instead of dogs, pigs or primates. This has obvious advantages in terms of low cost, the use statistically valid numbers for comparison and the availability of genetically defined animals which are more likely to give valid answers to immunological questions. Microsurgical reconstruction is important in plastic, orthopaedic, urogenital, vascular and peripheral nerve surgery in man and it is likely that it will become part of every surgeon's training in the near future. In this review, the instrumentation essential to any microsurgical enterprise and the sutures available are described. Basic microsurgical techniques for end-to-end and end-to-side anastomosis of small vessels and for joining peripheral nerves, oviducts and other tubular structures are given in outline. Techniques for transplanting kidney, heart, heart and lung, liver, spleen, pancreas, small bowel, stomach, testicle, ovary and whole joint are only outlined but key references are given. Finally, some of the clinical indications for microsurgical reconstruction are reviewed.


Investigating the sonophoresis effect on the permeation of diclofenac sodium using 3D skin equivalent.
Ultrasound temporally increases skin permeability by altering stratum corneum SC function (sonophoresis). The objective of this study was to evaluate the effect of variable ultrasound conditions on the permeation of diclofenac sodium DS with range of physicochemical properties through EpiDerm™. Permeation studies were carried out in vitro using Franz diffusion cell. HPLC method was used for the determination of the concentration of diclofenac sodium in receiving compartment. Parameters like ultrasound frequency, application time, amplitude, and mode of sonication and distance of ultrasound horn from skin were investigated, and the conditions where the maximum enhancement rate obtained were determined. Application of ultrasound enhanced permeation of diclofenac sodium across EpiDerm™ by fivefolds. The most effective enhancing parameters were power sonication of 20kHz frequency, 20% amplitude at continuous mode for 5min.


Cell-type specific expression of ATP-sensitive potassium channels in the rat hippocampus.
1. The distribution of ATP-sensitive K+ channels (KATP channels) was investigated in four cell types in hippocampal slices prepared from 10- to 13-day-old rats: CA1 pyramidal cells, interneurones of stratum radiatum in CA1, complex glial cells of the same area and granule cells of the dentate gyrus. The neuronal cell types were identified visually and characterized by the shapes and patterns of their action potentials and by neurobiotin labelling. 2. The patch-clamp technique was used to study the sensitivity of whole-cell currents to diazoxide (0.3 mM), a KATP channel opener, and to tolbutamide (0.5 mM) or glibenclamide (20 microM), two KATP channel inhibitors. The fraction of cells in which whole-cell currents were activated by diazoxide and inhibited by tolbutamide was 26% of pyramidal cells, 89 % of interneurones, 100% of glial cells and 89% of granule cells. The reversal potential of the diazoxide-induced current was at the K+ equilibrium potential and a similar current activated spontaneously when cells were dialysed with an ATP-free pipette solution. 3. Using the single-cell RT-PCR method, the presence of mRNA encoding KATP channel subunits (Kir6.1, Kir6.2, SUR1 and SUR2) was examined in CA1 pyramidal cells and interneurones. Subunit mRNA combinations that can result in functional KATP channels (Kir6.1 together with SUR1, Kir6.2 together with SUR1 or SUR2) were detected in only 17% of the pyramidal cells. On the other hand, KATP channels may be formed in 75% of the interneurones, mainly by the combination of Kir6.2 with SUR1 (58% of all interneurones). 4. The results of these combined analyses indicate that functional KATP channels are present in principal neurones, interneurones and glial cells of the rat hippocampus, but at highly different densities in the four cell types studied.


Screening for lung cancer.
In 1968, the first of three screening projects employing chest x-ray and sputum cytology was begun at Johns Hopkins. Subsequently, Mayo Clinic and Preventive Medicine Institute were added to form the Early Lung Cancer Detection Group. The Johns Hopkins and Mayo Clinic projects employ a chest x-ray annually for all participants and a quarterly sputum cytology for the study group. The Mayo Clinic utilizes a chest x-ray and sputum cytology quarterly for the study group and follow-up only for the comparison group. Entry in the study requires a screening examination for all participants, and those who have lung cancer at the initial examination constitute a "prevalence" group. Those who do not have a lung cancer at the initial examination are randomized into study and comparison groups. The goal was to determine if mortality from lung cancer could be reduced and if so, how much? That evaluation is not yet available. Prevalence data and incidence rate, stage at diagnosis, and survival by stage are now available. The diagnostic value of each modality, chest x-ray, and sputum cytology has been determined and varies by tumor cell type and location.


CD99: A potential Diagnostic Marker for Differentiating Sub-ependymal Giant Cell Astrocytoma From Other Mimickers: A Report of Five Cases.
Tuberous sclerosis (TSC) is inherited as an autosomal dominant disease, characterized by skin lesion and tubers in vital organs, especially brain in three categories including subependymal nodules, cortical tubers and subependymal giant cell astrocytoma. Subependymal giant cell astrocytoma (SEGA) is an indolent neoplasm which usually arises at the cauda thalamic groove near foramen monro, although it occurs usually in the clinical settings of TSC, a few number of SEGA has been reported without such history. Its morphology with special cytoarchitecture could be mistaken with other glial brain tumors with similar morphology. Therefore, investigating new markers for differentiating SEGA from other mimickers seems logical rather than other glioneural immunohistochemical markers introduced before. We investigated CD99 expression in SEGA as an adjunctive marker for diagnostic purposes. Five reported cases of SEGA were studied and all of them showed CD99 expression besides usual glioneural markers. CD99 may be a useful adjunctive marker in differentiating SEGA from other mimickers.


Pediatric Intensivist and Pediatric Neurologist Perspectives and Practices on Death by Neurologic Criteria.
Controversies surrounding the determination of death by neurologic criteria (DNC), also known as brain death, have become increasingly common over the last decade, occasionally leading to parental refusal of all or part of an evaluation or declaration of DNC. We performed a prospective, cross-sectional study of pediatric neurologists and intensivists who participate in professional listservs to ascertain perspectives and practices concerning the evaluation of DNC, specifically on obtaining permission for evaluations and managing refusals. Of the 334 respondents who had performed an evaluation for DNC, 35 percent reported they had experienced at least one parental refusal, and 64.4 percent reported that they did not seek permission to perform an evaluation. Pediatric neurologists, careproviders who had less experience doing evaluations, and careproviders who had experienced parental refusal of an evaluation were more likely to obtain permission from parents. Most (80.8 percent) of respondents reported that their institution had a DNC policy. We found variability in many aspects of DNC evaluations and declarations, as well as the handling of refusals. Lack of consistency may make it more difficult for careproviders and families. Greater understanding of parental refusal of DNC evaluation is essential to inform efforts to increase consistency.


Roll-your-own tobacco use among Canadian youth: is it a bigger problem than we think?
Despite the apparent decline in the popularity of roll-your-own (RYO) cigarettes over the past few decades, RYO tobacco products are widely available and used by a substantial number of adult smokers. Considering research has yet to examine the prevalence of RYO tobacco use among youth populations, this manuscript examines the prevalence of RYO tobacco use and factors associated with RYO use in a nationally representative sample of youth smokers from Canada. This study used data collected from 3,630 current smokers in grades 9 to 12 as part of the 2008-09 Canadian Youth Smoking Survey (YSS). Descriptive analyses of the sample demographic characteristics, smoking status, cigarettes per day, weekly spending money, and frequency of marijuana use were examined by RYO tobacco ever use and RYO tobacco current use. Two logistic regression models were used to examine factors associated with RYO tobacco ever use and RYO tobacco current use. We identified that 51.2% of current smokers were RYO ever users and 24.2% were RYO current users. The prevalence of RYO current users was highest in Atlantic Canada (40.1%) and lowest in Quebec (12.3%). RYO current users were more likely to be male (OR 1.27), to be daily smokers (OR 1.75), to use marijuana once a month or more (OR 2.74), and to smoke 11 or more cigarettes per day (OR 6.52). RYO current users were less likely to be in grade 11 (OR 0.65) or grade 12 (OR 0.40) and less likely to have between $20 to $100 (OR 0.44) or more than $100 (OR 0.45) of disposable income. Developing a better understanding of RYO tobacco use among youth is important for advancing population-level tobacco control prevention strategies and cessation programs. We identified that RYO tobacco use is not a negligible problem among Canadian youth. Ongoing research is needed to continue monitoring the prevalence of RYO use among youth and the factors associated with its use, but to also monitor if this more affordable tobacco product is being targeted to price sensitive youth smokers.


Low-power optical bistability and hysteresis in the laser system with absorbing nanosuspension.
We demonstrate an optical bistability in a laser system with incoherent optical feedback and a nanosuspension as a nonlinear element. The optical transfer function is shown to exhibit a hysteresis loop for the light power in the range of a few milliwatts. It has been found that the optical bistability relies on the incoherent optical feedback and thermal defocusing nonlinear optical response of the nanosuspension.


Sports-related concussions and the Louisiana Youth Concussion Act.
Concussion, also referred to as mild traumatic brain injury (TBI), is defined as a "complex pathophysiological process affecting the brain, induced by traumatic biomechanical forces." Various symptoms may be observed in patients with concussions. All of these might not be evident at the time of the injury and be intermittent in their nature. It is estimated that 300,000 of the yearly TBIs in the United States are sports-related, the second leading cause for TBIs after motor vehicle accidents among people aged 15 to 24 years old. Due to some recently reported high profile injuries and deaths of sports personalities, sports-related concussion has seen increasing media and public interest in the last decade. We review the role of football in youth concussions and analyze the Nationwide Inpatient Sample from 2007 to 2009 to elucidate the outcome and costs associated with sports-related concussions of the youth in the United States. We also review the latest state legislative efforts to decrease the incidence of dangerous sports-related concussions in youth--the Louisiana Youth Concussion Act.


Distribution of florfenicol resistance genes fexA and cfr among chloramphenicol-resistant Staphylococcus isolates.
A total of 302 chloramphenicol-resistant Staphylococcus isolates were screened for the presence of the florfenicol/chloramphenicol resistance genes fexA and cfr and their localization on mobile genetic elements. Of the 114 isolates from humans, only a single Staphylococcus aureus isolate showed an elevated MIC to florfenicol, but did not carry either of the known resistance genes, cfr or fexA. In contrast, 11 of the 188 staphylococci from animal sources were considered florfenicol resistant and carried either cfr (one isolate), fexA (five isolates), or both resistance genes (five isolates). In nine cases we confirmed that these genes were carried on a plasmid. Five different types of plasmids could be differentiated on the basis of their sizes, restriction patterns, and resistance genes. The gene fexA, which has previously been shown to be part of the nonconjugative transposon Tn558, was identified in 10 of the 11 resistant isolates from animals. PCR assays were developed to detect different parts of this transposon as well as their physical linkage. Complete copies of Tn558 were found in five different isolates and shown by inverse PCR to be functionally active. Truncated copies of Tn558, in which the tnpA-tnpB area was in part deleted by the integration of a 4,674-bp segment including the gene cfr and a novel 2,446-bp IS21-like insertion sequence, were seen in a plasmid present in three staphylococcal isolates.


Brachypodium distachyon - A Useful Model in the Qualification of Mutagen-Induced Micronuclei Using Multicolor FISH.
Brachypodium distachyon (Brachypodium) is now intensively utilized as a model grass species in various biological studies. Its favorable cytological features create a unique foundation for a convenient system in mutagenesis, thereby potentially enabling the 'hot spots' and 'cold spots' of DNA damage in its genome to be analyzed. The aim of this study was to analyze the involvement of 5S rDNA, 25S rDNA, the Arabidopsis-type (TTTAGGG)n telomeric sequence and the Brachypodium-originated centromeric BAC clone CB33J12 in the micronuclei formation in Brachypodium root tip cells that were subjected to the chemical clastogenic agent maleic hydrazide (MH). To the best of our knowledge, this is the first use of a multicolor fluorescence in situ hybridization (mFISH) with four different DNA probes being used simultaneously to study plant mutagenesis. A quantitative analysis allowed ten types of micronuclei, which were characterized by the presence or absence of specific FISH signal(s), to be distinguished, thus enabling some specific rules governing the composition of the MH-induced micronuclei with the majority of them originating from the terminal regions of chromosomes, to be identified. The application of rDNA sequences as probes showed that 5S rDNA-bearing chromosomes are involved in micronuclei formation more frequently than the 25S rDNA-bearing chromosomes. These findings demonstrate the promising potential of Brachypodium to be a useful model organism to analyze the effects of various genotoxic agents on the plant nuclear genome stability, especially when the complex FISH-based and chromosome-specific approaches such as chromosome barcoding and chromosome painting will be applied in future studies.


Interparietal bones in Nigerian skulls.
The study was conducted on 40 adult Nigerian skulls which were examined for the presence of interparietal and pre-interparietal bones. Only one interparietal bone was found (2.5% of the present series) while a single pre-interparietal bone was found in four skulls (10%) and multiple pre-interparietal bones in one skull (2.5%).


Effect of decoquinate on the control of coccidiosis in young ruminating calves.
Twenty-five 6-week-old Holstein male calves were each inoculated with 500,000 sporulated oocysts of Eimeria bovis. Two nontreated (control) and 3 treated calves (1.5 mg of decoquinate/kg of body weight in feed) were necropsied 7 days after inoculation. Similar groups of calves were necropsied at 12, 18, 22, and 28 days after inoculation. Treated calves were started on medicated feed 2 days before inoculation or at 7, 12, or 15 days after inoculation or were on continuous medication from the day of inoculation. Control calves were not given medication. Early schizonts were in the small intestines of control calves at 7 days after inoculation, but none was in the treated calves that were started on medicated feed 2 days before inoculation. Schizonts were present in the small intestine of both treated and control calves at 12 days after inoculation. At 18 days after inoculation, control calves had schizonts in the small intestine and gamonts and oocysts in the cecum and large intestines, but treated calves only had schizonts in the small intestine. At 22 days, control calves had schizonts in the small intestine and gamonts and oocysts in the large intestine; treated calves had schizonts in the small intestine. At 28 days, controls still had schizonts in the small intestine and gamonts and oocysts in the cecum and large intestine; the treated calves that had been on continuous medication did not have schizonts, gamonts, or oocysts in the tissues. Decoquinate apparently kills sporozoites or arrests development and release of merozoites from the schizonts when fed at 1.5 mg/kg of body weight in the feed.


Survival after curative pelvic exenteration for primary or recurrent cervical cancer: a retrospective multicentric study of 167 patients.
Evaluate the survival of patients who underwent pelvic exenteration (PE) with curative intent for primary persistent or recurrent cervical cancer. We retrospectively investigated 167 consecutive patients, referred to the gynecological oncology units of 4 centers in Germany or Italy, who underwent PE. Data regarding surgery, histology, and oncologic outcomes were collected and statistically evaluated. Survival was determined from the day of exenteration until last follow-up or death. The median age was 51 years. Twenty-seven patients (16.2%) underwent PE owing to advanced primary tumors (group A), 34 patients (20.4%) underwent PE owing to persistent cancer after chemotherapy or chemoradiation (group B), and 106 patients (63.4%) underwent PE owing to recurrence (group C). The prevalent histologic type was squamous cell cancer. A complete tumor resection (R0), was achieved in 121 patients (72.5%). Forty-nine patients (29.3%) had pelvic lymph node metastases and 44 patients (26.3%) had pelvic sidewall involvement. Overall survival at the end of the study was 40.7%. The cumulative 5-year overall survival for the entire cohort was 38%. Resection margins, pelvic lymph node state, and sidewall involvement were independent prognostic factors in multivariate analysis. Pelvic exenteration is a valid therapeutic option for patients with locally advanced primary persistent or recurrent cervical cancer, with a long-term survival in 40% of the patients.


Observations on pedestrian pre-crash reactions during simulated accidents.
Pedestrian protection systems, both active and passive systems, are being introduced in the EU and Japan to comply with regulatory requirements. Their designs are specific and, in general, reflect an accident scenario of the pedestrian being struck on the side by a vehicle traveling at a maximum travel speed of 40 kph. The present study is an effort to quantify the effects of pedestrian reaction prior to an accident and identify characteristics that may help minimize or prevent the pedestrian to vehicle interaction. Accident situations were simulated with volunteers using a non-impacting methodology. Fifty one reactions from 23 volunteers of two age groups were observed. Most of the volunteers were found to run, step-back or stop in fright in a dangerous situation. Volunteer speed was an important parameter which could help in differentiating these reactions. Age related differences were also observed, both for reaction strategy and reaction times. While the majority of young subjects ran, elderly stopped as often as they run. Volunteers' posture at the time of impact was found to be highly variable irrespective of the type of reactions. The exception was when a volunteer stopped/braced in apparent fright and raised their arms to form a triangle covering their face and their head. Results of the present study may be helpful when selecting or evaluating the benefit of pedestrian safety strategies by allowing the inclusion of information about types of reaction, pedestrian speed, reaction time and age differences in the scenarios. In addition, pedestrian pre-crash postures and muscle activities could be utilized for evaluating/improving the passive safety systems and active models.


Mitochondrial DNA G10398A polymorphism and invasive breast cancer in African-American women.
Mitochondria generate oxygen-derived free radicals that damage mitochondrial DNA (mtDNA) as well as nuclear DNA and in turn promote carcinogenesis. The mtDNA G10398A polymorphism alters the structure of Complex I in the mitochondrial electron transport chain, an important site of free radical production. This polymorphism is associated with several neurodegenerative disorders. We hypothesized that the 10398A allele is also associated with breast cancer susceptibility. African mitochondria harbor the 10398A allele less frequently than Caucasian mitochondria, which predominantly carry this allele. Mitochondrial genotypes at this locus were therefore determined in two separate populations of African-American women with invasive breast cancer and in controls. A preliminary study at Vanderbilt University (48 cases, 54 controls) uncovered an association between the 10398A allele and invasive breast cancer in African-American women, [odds ratio (OR), 2.90; 95% confidence interval (95% CI), 0.61-18.3; P = 0.11]. We subsequently validated this finding in a large, population-based, case-control study of breast cancer, the Carolina Breast Cancer Study at the University of North Carolina (654 cases, 605 controls). African-American women in this study with the 10398A allele had a significantly increased risk of invasive breast cancer (OR, 1.60; 95% CI, 1.10-2.31; P = 0.013). The 10398A allele remained an independent risk factor after adjustment for other well-accepted breast cancer risk factors. No association was detectable in white women (879 cases, 760 controls; OR, 1.03; 95% CI, 0.81-1.31; P = 0.81). This study provides novel epidemiologic evidence that the mtDNA 10398A allele influences breast cancer susceptibility in African-American women. mtDNA polymorphisms may be underappreciated factors in breast carcinogenesis.


Cyclic strain stimulates proliferative capacity, alpha2 and alpha5 integrin, gene marker expression by human articular chondrocytes propagated on flexible silicone membranes.
Chondrocytes comprise less than 10% of cartilage tissue but are responsible for sensing and responding to mechanical stimuli imposed on the joint. However, the effect of mechanical signals at the cellular level is not yet fully defined. The purpose of this study was to test the hypothesis that mechanical stimulation in the form of cyclic strain modulates proliferative capacity and integrin expression of chondrocytes from osteoarthritic knee joints. Chondrocytes isolated from articular cartilage during total knee arthroplasty were propagated on flexible silicone membranes. The cells were subjected to cyclic strain for 24 h using a computer-controlled vacuum device, with replicate samples maintained under static conditions. Our results demonstrated increase in proliferative capacity of the cells subjected to cyclic strain compared with cells maintained under static conditions. The flexed cells also exhibited upregulation of the chondrocytic gene markers type II collagen and aggrecan. In addition, cyclic strain resulted in increased expression of the alpha2 and alpha5 integrin subunits, as well as an increased expression of vimentin. There was also intracellular reconfiguration of the enzyme protein kinase C. Our findings suggest that these molecules may play a role in the signal transduction pathway, eliciting cellular response to mechanical stimulation.


Truth or Trend - Misinformation Spreading Fast on TikTok: A Cross-Sectional Analysis of Onychomycosis Content.
Onychomycosis is the most frequently diagnosed nail condition in clinical practice. With the growing popularity of TikTok and online health information-seeking behavior, it is imperative to understand onychomycosis-related content on this platform. Our objective was to assess content and quality of the most popular onychomycosis-related content on TikTok. We queried TikTok for videos using the search terms "onychomycosis" and "nail fungus" for the top 100 videos by view count, with DISCERN scoring used to rate videos for quality. Average DISCERN score was 1.77 and dermatologists posted videos with the highest mean score (2.56). Most of the videos were educational (72%) and/or related to treatment (69%). Home remedies were recommended more often (58%) than FDA-approved therapies (7%). Physician versus nonphysician posted videos had higher mean DISCERN score (2.28 vs. 1.44) (p < 0.001), greater view number (1,209,953 vs. 343,993) (p < 0.05), and more often discussed medical therapy (p < 0.05). While social media is a valuable resource for providing medical information to an interminable audience, there are significant shortcomings. Therefore, we recommend that dermatologists advise patients against relying on social media for medical information and consider using social media to provide accessible evidence-based health education on onychomycosis.


[Intimal lipoidosis of the coronary arteries of newborn infants and infants in the 1st year of life].
Post-mortem morphological examination of the coronary arteries in 76 newborns and children of the first year of life was performed. Cases of the cardio-vascular pathology were not included into the study. Intimal thickening, either diffuse or focal, was revealed in 58 cases. The degree and frequency of the diffuse thickening of the intima (DTI) were higher in boys. DTI was present predominantly in the anterior interventricular artery and much less frequently in the circumflexal coronary artery. Intimal lipoidosis was found un 21 cases, with the same incidence in both boys and girls, but somewhat more frequently in the right coronary artery. Topography of both intimal lipoidosis and DTI was similar. The traces of cholesterol, its esters and predominantly neutral fat were defected histochemically in the foci of intimal lipoidosis.


Polyomavirus origin for DNA replication comprises multiple genetic elements.
To define the minimal cis-acting sequences required for polyomavirus DNA replication (ori), we constructed a number of polyomavirus-plasmid recombinants and measured their replicative capacity after transfection of a permissive mouse cell line capable of providing polyomavirus large T antigen in trans (MOP cells). Recombinant plasmids containing a 251-base-pair fragment of noncoding viral DNA replicate efficiently in MOP cells. Mutational analyses of these viral sequences revealed that they can be physically separated into two genetic elements. One of these elements, termed the core, contains an adenine-thymine-rich area, a 32-base-pair guanine-cytosine-rich palindrome, and a large T antigen binding site, and likely includes the site from which bidirectional DNA replication initiates. The other, termed beta, is located adjacent to the core near the late region and is devoid of outstanding sequence features. Surprisingly, another sequence element named alpha, located adjacent to beta but outside the borders of the 251-base-pair fragment, can functionally substitute for beta. This sequence too contains no readily recognized sequence features and possesses no obvious homology to the beta element. The three elements together occupy a contiguous noncoding stretch of DNA no more than 345 base pairs in length in the order alpha, beta, and core. These results indicate that the polyomavirus origin for DNA replication comprises multiple genetic elements.


Erythema multiforme and epitheliotropic T-cell lymphoma in the oral cavity of dogs: 1989 to 2009.
To describe the clinical signs, major laboratory findings, diagnostic procedures and outcome in dogs with erythema multiforme or epitheliotropic T-cell lymphoma of the oral cavity. Retrospective analysis identified 14 client-owned dogs with erythema multiforme or epitheliotropic T-cell lymphoma of the oral cavity. Histological changes were combined with immunohistochemistry and clonality testing data in selected cases, and a clinical follow-up was acquired. Ulcerative stomatitis with no significant or only minor abnormalities on haematology and serum biochemistry panels was common. Histological features were diagnostic in seven cases. The use of immunohistochemistry distinguished the two diseases in an additional three cases. In four cases, the diagnosis remained questionable, and clonality testing for T-cell receptor gamma gene rearrangement helped confirm erythema multiforme in one case. Clinical follow-up revealed erythema multiforme in two and epitheliotropic T-cell lymphoma in one of the remaining questionable cases. Erythema multiforme and epitheliotropic T-cell lymphoma may affect, but are rarely limited to the oral cavity of dogs, and they usually present as stomatitis. Histological features alone are not always diagnostic. Immunohistochemistry and clonality testing may assist in the differentiation between the two, but in ambiguous cases, repeated biopsy and clinical follow-up are essential.


HIV and Aging in the Era of ART and COVID-19.
Our understanding of HIV/AIDS has been reframed during the recent past because the use of novel antiretroviral therapy has enabled clinicians and patients to control the progression of the disease. This supplement provides an overview of the HIV and Aging in the Era of ART and COVID-19, a virtual symposium held on February 8-9, 2021, organized by the Miami Center for AIDS Research along with articles contributed by some of the speakers and members of the organizing committee and presentations by junior investigators.


Influence of gangliosides on primary and metastatic neoplastic growth in human and murine cells.
The influence of gangliosides on tumor growth and frequency of metastasis in vivo as well as on growth and motility of neoplastic cells in vitro was tested utilizing human and rodent cell populations. In mice receiving injections of a ganglioside mixture twice daily the tumor volume, the number of spontaneous metastases per animal, and the number of mice with metastasis was approximately double that of controls. Preincubation of neoplastic cells with the ganglioside mixture doubled the number of metastatic foci in the lungs of mice receiving the cells by i.v. injection. Addition of a ganglioside mixture to the culture medium enhanced motility of neoplastic cells about 3-fold. This finding was similar to that observed for capillary endothelium. The presence of gangliosides in the culture media for a 48-h incubation period about doubled the number of neoplastic cells as compared to controls; the same was observed for capillary endothelium. The data are interpreted to indicate that gangliosides improve growth and mobilization of capillary endothelium and neoplastic cells. Both events may concur in enhancing tumor growth in vivo, the first by improving angiogenesis, the second by direct action on the neoplastic cell population.


Identification of neoantigens and immunological subtypes in clear cell renal cell carcinoma for mRNA vaccine development and patient selection.
Clear cell renal cell carcinoma (ccRCC) is a common urological malignancy with diverse histological types. This study aimed to detect neoantigens in ccRCC to develop mRNA vaccines and distinguish between ccRCC immunological subtypes for construction of an immune landscape to select patients suitable for vaccination. Using The Cancer Genome Atlas SpliceSeq database, The Cancer Genome Atlas, and the International Cancer Genome Consortium cohorts, we comprehensively analysed potential tumour antigens of ccRCC associated with aberrant alternative splicing, somatic mutation, nonsense-mediated mRNA decay factors, antigen-presenting cells, and overall survival. Immune subtypes (C1/C2) and nine immune gene modules of ccRCC were identified by consistency clustering and weighted correlation network analysis. The immune landscape as well as molecular and cellular characteristics of immunotypes were assessed. Rho-guanine nucleotide exchange factor 3 (ARHGEF3) was identified as a new ccRCC antigen for development of an mRNA vaccine. A higher tumour mutation burden, differential expression of immune checkpoints, and immunogenic cell death were observed in cases with the C2 immunotype. Cellular characteristics increased the complexity of the immune environment, and worse outcomes were observed in ccRCC cases with the C2 immunotype. We constructed the immune landscape for selecting patients with the C2 immunotype suitable for vaccination.


Comparative cranial ontogeny of Tapirus (Mammalia: Perissodactyla: Tapiridae).
Skull morphology in tapirs is particularly interesting due to the presence of a proboscis with important trophic, sensory and behavioral functions. Several studies have dealt with tapir skull osteology but chiefly in a comparative framework between fossil and recent species of tapirs. Only one study examined an aspect of cranial ontogeny, development of the sagittal crest (Holbrook. J Zool Soc Lond 2002; 256; 215). Our goal is to describe in detail the morphological changes that occur during the postnatal ontogeny of the skull in two representative tapir species, Tapirus terrestris and Tapirus indicus, and to explore possible functional consequences of their developmental trajectories. We compared qualitative features of the skull on a growth series of 46 specimens of T. terrestris ordered on the basis of the sequence of eruption and tooth wear, dividing the sample into three age classes: class Y (very young juvenile), class J (from young juvenile to young adult) and class A (full and old adult). The qualitative morphological analysis consisted of describing changes in the series in each skull bone and major skull structure, including the type and degree of transformation (e.g. appearance, fusion) of cranial features (e.g. processes, foramina) and articulations (sutures, synchondroses, and synovial joints). We then measured 23 cranial variables in 46 specimens of T. terrestris that included the entire ontogenetic series from newborn to old adults. We applied statistical multivariate techniques to describe allometric growth, and compared the results with the allometric trends calculated for a sample of 25 specimens of T. indicus. Results show that the skull structure was largely conserved throughout the postnatal ontogeny in T. terrestris, so class Y was remarkably similar to class A in overall shape, with the most significant changes localized in the masticatory apparatus, specifically the maxillary tuber as a support of the large-sized permanent postcanine dentition, and correlated changes in diastemata, mandibular body, and sagittal and nuchal crests. In the nasal region, ontogenetic remodeling affected the space for the meatal diverticulum and the surfaces for the origin of the proboscis musculature. Overall, ontogenetic trajectories exhibited more negative allometric components in T. indicus than in T. terrestris, and they shared 47.83% of allometric trends. Tapirus indicus differed most significantly from T. terrestris in the allometry of postcanine toothrows, diastemata and mandibular body. Thus, some allometric trends seem to be highly conserved among the species studied, and the changes observed showed a strong functional and likely adaptive basis in this lineage of ungulates.


Analysis of crude protein and allergen abundance in peanuts (Arachis hypogaea cv. Walter) from three growing regions in Australia.
The effects of plant growth conditions on concentrations of proteins, including allergens, in peanut ( Arachis hypogaea L.) kernels are largely unknown. Peanuts (cv. Walter) were grown at five sites (Taabinga, Redvale, Childers, Bundaberg, and Kairi) covering three commercial growing regions in Queensland, Australia. Differences in temperature, rainfall, and solar radiation during the growing season were evaluated. Kernel yield varied from 2.3 t/ha (Kairi) to 3.9 t/ha (Childers), probably due to differences in solar radiation. Crude protein appeared to vary only between Kairi and Childers, whereas Ara h 1 and 2 concentrations were similar in all locations. 2D-DIGE revealed significant differences in spot volumes for only two minor protein spots from peanuts grown in the five locations. Western blotting using peanut-allergic serum revealed no qualitative differences in recognition of antigens. It was concluded that peanuts grown in different growing regions in Queensland, Australia, had similar protein compositions and therefore were unlikely to show differences in allergenicity.


Investigation into the ability of roots of the poikilohydric plant Craterostigma plantagineum to survive dehydration stress.
The ability of the root system of the poikilohydric plant Craterostigma plantagineum to survive dehydration was investigated. The data presented here reveal that the root system is capable of surviving dehydration, but shortly after rehydration the root system senesces. Two weeks after rehydration the growth of a complete new root system is initiated. During dehydration sucrose accumulates from 36 to a maximum of 111 micromol g-1 DW in the roots. It is suggested that the accumulation of sucrose protects the root system during dehydration. There are major stores of stachyose in the roots of Craterostigma (making up over 40% of the dry weight of the tissue) and during dehydration these stores are metabolized. It is suggested that these stachyose stores act as carbohydrate reserves for the synthesis of sucrose. However, over 350 micromol g-1 DW stachyose is metabolized in the roots, which is well in excess of that required for the accumulation of sucrose observed. It is likely that the stachyose reserves in the root system are translocated to other regions of the plant to support carbohydrate metabolism during dehydration of the tissue. During rehydration, the stachyose reserves return to their original level within 96 h. There is no change in the elevated sucrose content of the roots over this period. Thus the roots maintain the protective properties of sucrose much longer than they are needed. The maintenance of high sucrose contents in rehydrating roots is discussed as a possible survival strategy against recurrent desiccation events.