Gene Expression Commons: an open platform for absolute gene expression profiling.
Gene expression profiling using microarrays has been limited to comparisons of gene expression between small numbers of samples within individual experiments. However, the unknown and variable sensitivities of each probeset have rendered the absolute expression of any given gene nearly impossible to estimate. We have overcome this limitation by using a very large number (>10,000) of varied microarray data as a common reference, so that statistical attributes of each probeset, such as the dynamic range and threshold between low and high expression, can be reliably discovered through meta-analysis. This strategy is implemented in a web-based platform named "Gene Expression Commons" (https://gexc.stanford.edu/) which contains data of 39 distinct highly purified mouse hematopoietic stem/progenitor/differentiated cell populations covering almost the entire hematopoietic system. Since the Gene Expression Commons is designed as an open platform, investigators can explore the expression level of any gene, search by expression patterns of interest, submit their own microarray data, and design their own working models representing biological relationship among samples.


Bilirubin metabolism and kernicterus.
Neonatal jaundice continues to be a common problem. Kernicterus, although rare, continues to be a very real concern in both full-term and preterm infants. The diagnosis of kernicterus requires not only bilirubin staining in a characteristic pattern in the brain but also neuronal damage. With careful pathologic evaluation, kernicterus should be distinguishable from the brain damage associated with asphyxia and hypoxia. Early hospital discharge is a risk factor for the development of kernicterus. Combining the use of traditional phototherapy from above and a fiberoptic blanket from below has improved the effectiveness of phototherapy. Clinical trials with SnMP as an inhibitor of heme oxygenase appear encouraging; no adverse effects were noted, except for mild, occasional photosensitization manifest by erythema in babies receiving phototherapy. One theoretical toxicity of inhibitors of heme oxygenase involves the recent observation that carbon monoxide (CO) is a neurotransmitter in certain regions of the brain, possibly comparable to nitric oxide (NO), and the consequences of such inhibition are unknown. More research is needed to improve our understanding about the entry of bilirubin into the brain, the predilection of bilirubin for certain brain regions, and the cytotoxicity of bilirubin. In the United States, there is currently no generally accepted method to predict hyperbilirubinemia or kernicterus. Brain stem auditory evoked responses and MRI can both be used effectively to monitor the effects of severe hyperbilirubinemia.


Therapeutic strategies for targeting BRAF in human cancer.
Constitutive ERK activation is a common finding in human cancer and is often the result of activating mutations of BRAF and RAS. BRAF missense mutations occur in approximately 8% of human tumors, most frequently in melanoma, papillary thyroid cancer and colon cancer. Mutations in BRAF have been found predominantly in tumors in which RAS is commonly mutated but concurrent mutations of both BRAF and RAS are extremely rare. Though over 40 different kinase domain mutations in BRAF have been identified, a single base-pair substitution in exon 15 at codon 600 (V600E) is found in over 80% of cases. These mutations cluster in the glycine-rich loop and activation segments of the kinase and are predicted to induce kinase activation by disrupting the inhibitory glycine-rich loop/activation segment interaction which characterizes the inactive conformation. The majority of mutations identified cause constitutive kinase activation with the V600E mutation demonstrating approximately 500-fold greater kinase activity than wild-type BRAF. Supporting its classification as an oncogene, V600E BRAF stimulates ERK signaling, induces proliferation and is capable in model systems of promoting transformation. However, BRAF mutations are common in nevi and colon polyps suggesting that BRAF mutation alone is insufficient for tumorigenesis and additional mutations are required for cancer development. Though such data suggest that BRAF mutation is likely an early initiating event in tumors such as melanoma and colon cancer, preclinical studies suggest that tumors with V600E BRAF mutation remain dependent upon BRAF for proliferation and survival. Given its frequent occurrence in human cancer and the continued requirement for BRAF activity in tumors with BRAF mutation, efforts are underway to develop targeted inhibitors of BRAF and its downstream effectors. The first generation of RAF inhibitors, including sorafenib, were notable for their lack of specificity and potency for RAF and these agents have shown limited efficacy in tumors with a high incidence of BRAF mutation such as melanoma. Novel inhibitors of the pathway with greater selectivity for BRAF and MEK are now in Phase 1 and 2 clinical trials with promising early results. To maximize the likelihood of success with these agents, clinical trials enriched with patients whose tumors possess BRAF and RAS mutations have been proposed.


Permeabilization of plant cells: (31)P NMR studies on the permeability of the tonoplast.
A suspension culture of Catharanthus roseus has been used to study the permeability of cell membranes after treatment with various concentrations of a permeabilizing agent (DMSO). The uptake and release (after permeabilization) of inorganic phosphate (Pi) by cells have been investigated by (32)P radiotracer and non-invasive phosphorus-31 NMR experiments. These studies have demonstrated that measurements of the Pi-efflux from plant cells provide a reliable measure of the permeability of the tonoplast.


High prevalence of plasmid-mediated quinolone resistance genes qnr and aac(6')-Ib-cr in clinical isolates of Enterobacteriaceae from nine teaching hospitals in China.
Quinolone resistance is an emerging problem in China. To investigate the prevalence of the plasmid-mediated quinolone resistance genes qnr and aac(6')-Ib-cr, a total of 265 clinical isolates of Escherichia coli, Klebsiella pneumoniae, Citrobacter freundii, and Enterobacter cloacae with ciprofloxacin MICs of > or =0.25 microg/ml were screened at nine teaching hospitals in China. The qnrA, qnrB, qnrS, and aac(6')-Ib genes were detected by PCR. The aac(6')-Ib-cr gene was further identified by digestion with BtsCI and/or direct sequencing. The qnr gene was present in significantly smaller numbers of isolates with cefotaxime MICs of <2 microg/ml than isolates with higher MICs (> or =2.0 microg/ml) (20.6% and 42.1%, respectively; P < 0.05). aac(6')-Ib-cr was present in 17.0% of the isolates tested, and 7.9% of the isolates carried both the qnr and the aac(6')-Ib-cr genes. Among the isolates with cefotaxime MICs of > or =2.0 microg/ml, qnr and aac(6')-Ib-cr were present in 65.7% and 8.6% of E. cloacae isolates, respectively; 65.5% and 21.8% of K. pneumoniae isolates, respectively; 63.3% and 26.7% of C. freundii isolates, respectively; and 6.5% and 16.9% of E. coli isolates, respectively. The 20 transconjugants showed 16- to 128-fold increases in ciprofloxacin MICs, 14 showed 16- to 2,000-fold increases in cefotaxime MICs, and 5 showed 8- to 32-fold increases in cefoxitin MICs relative to those of the recipient due to the cotransmission of bla(CTX-M-14), bla(CTX-M-3), bla(DHA-1), bla(SHV-2), and bla(SHV-12) with the qnr and aac(6')-Ib-cr genes. Southern hybridization analysis showed that these genes were located on large plasmids of different sizes (53 to 193 kb). These findings indicate the high prevalence of qnr and aac(6')-Ib-cr in members of the family Enterobacteriaceae and the widespread dissemination of multidrug resistance in China.


Anatomy of a defective barrier: sequential glove leak detection in a surgical and dental environment.
a) To determine the frequency of perforations in latex surgical gloves before, during, and after surgical and dental procedures; b) to evaluate the topographical distribution of perforations in latex surgical gloves after surgical and dental procedures; and c) to validate methods of testing for latex surgical glove patency. Multitrial tests under in vitro conditions and a prospective sequential patient study using consecutive testing. An outpatient dental clinic at a university dental school, the operating suite in a medical school affiliated with the Veteran's Hospital, and a biomechanics laboratory. Surgeons, scrub nurses, and dental technicians participating in 50 surgical and 50 dental procedures. We collected 679 latex surgical gloves after surgical procedures and tested them for patency by using a water pressure test. We also employed an electronic glove leak detector before donning, after sequential time intervals, and upon termination of 47 surgical (sequential surgical), 50 dental (sequential dental), and in three orthopedic cases where double gloving was used. The electronic glove leak detector was validated by using electronic point-by-point surface probing, fluorescein dye diffusion, as well as detecting glove punctures made with a 27-gauge needle. The random study indicated a leak rate of 33.0% (224 out of 679) in latex surgical gloves; the sequential surgical study demonstrated patency in 203 out of 347 gloves (58.5%); the sequential dental study showed 34 leaks in the 106 gloves used (32.1%); and with double gloving, the leak rate decreased to 25.0% (13 of 52 gloves tested). While the allowable FDA defect rate for unused latex surgical gloves is 1.5%, we noted defect rates in unused gloves of 5.5% in the sequential surgical, 1.9% in the sequential dental, and 4.0% in our electronic glove leak detector validating study. In the sequential surgical study, 52% of the leaks had occurred by 75 mins, and in the sequential dental study, 75% of the leaks developed by 30 mins. In terms of the anatomical localization, the thumb and forefinger accounted for more than 60% of the defects. There were no differences in the frequency of glove leaks between the left and right hand. Leak rates were highest for the surgeon (52%), followed by the first assistant (29%) and the scrub nurse (25%). No false negatives were noted using the electronic glove leak detector; one false positive was seen out of 225 gloves tested (0.44%), as noted in our validation studies. Significantly high glove leak rates were noted after surgical and dental procedures, indicating that the present day latex surgical gloves can become an incompetent barrier once they are used. Unused latex surgical gloves demonstrated a higher rate of defects than allowed by the Food and Drug Administration standards, indicating substantial noncompliance of quality control standards by manufacturers as well as inadequate governmental oversight. Double gloving, or the use of thicker latex surgical gloves, would probably reduce the frequency of glove leaks. Latex surgical gloves should be tested for patency before use and during surgical and dental procedures.


Dependence of benzo[a]pyrene metabolic profile on the concentration of cumene hydroperoxide with uninduced and induced rat liver microsomes.
The effect of cumene hydroperoxide (CHP) in microsomal metabolism of benzo [a]pyrene (BP) was studied using liver microsomes from mature male Wistar rats induced with phenobarbital (PB), 3-methylcholanthrene (MC), Aroclor 1254 or olive oil (uninduced). In contrast to NADPH-supported metabolism, these inducers did not increase the CHP-dependent metabolism. Total BP metabolism was dependent on CHP concentration and was maximal at 0.15 mM, except for PB-induced microsomes, which had a maximum at 0.5 mM CHP. At 0.05 mM CHP, the major metabolites were phenols. However, increasing CHP concentration enhanced the formation of dihydrodiols, quinones and protein-bound BP but reduced phenol production. At and above 0.15 mM CHP, the profile of BP metabolites was essentially constant, with at least 66% quinones but no more than 10% phenols. The effect of CHP on inhibition of phenol formation and enhancement of quinone formation was reversed by preincubation of microsomes with BP or by increasing BP concentration. These results suggest that CHP-dependent metabolism of BP is selectively mediated by constitutive cytochrome P-450 isozyme(s) and that two forms of BP binding sites exist in cytochrome P-450 isozymes and are responsible for the hydroxylation of BP at C-3 and C-6.


Prolactinomas Resistant to Dopamine Agonists: Pathophysiology and Treatment.
Prolactinomas are the most common functional pituitary tumors, accounting for 40% of all pituitary adenomas. Medical treatment with dopamine agonists (DA), mainly cabergoline, is considered the primary therapy for these patients. Prolactin normalization is achieved in 80-90% of prolactinomas treated with cabergoline. Patients resistant to the standard dose can escalate the dose of cabergoline up to the maximum tolerated dose. The expression of dopamine (D2) receptors and dopamine affinity is decreased in aggressive and resistant prolactinomas. Patients with aggressive and DA-resistant adenomas or with rare PRL-secreting carcinomas can be treated off-label with temozolomide (TMZ), a DNA alkylating agent. TMZ is effective in 40-50% of treated lactotroph tumors showing at least a partial response. However, patients tend to escape from the effect of TMZ after a limited time of response. Other therapeutic options include aromatase inhibitors, the somatostatin receptor ligand pasireotide, peptide receptor radionuclide therapy (PRRT), immune-checkpoint inhibitors, tyrosine-kinase inhibitors, or everolimus, the mammalian target of rapamycin inhibitor. These experimental treatments were effective in some patients carrying refractory prolactinomas showing usually partial tumor control. However, the number of treated patients with any of these new therapeutic options is very limited and treatment results are inconsistent, thus additional experience with more patients is required.


Comprehensive Cardiac Rehabilitation for Secondary Prevention After Transient Ischemic Attack or Mild Stroke: PSYCHOLOGICAL PROFILE AND OUTCOMES.
Having previously reported that comprehensive cardiac rehabilitation (CCR) is effective for secondary prevention post-transient ischemic attack (TIA)/mild nondisabling stroke (MNDS), we present psychometric findings for the same sample that elucidate subacute TIA/MNDS psychological outcomes and test whether CCR would be independently associated with psychological improvements. In this prospective cohort trial patients with ≥1 risk factor, recruited from a stroke prevention clinic within 12 months (mean = 11.5 weeks) post-TIA/MNDS, entered CCR. Of the 110 recruited patients, 100 (mean age = 65.4 years; 46 females) entered CCR and 80 completed CCR (mean duration = 7.6 months). At CCR entry, 16.5% and 39.2% screened positively for depression and anxiety, decreasing nonsignificantly at exit to 4.2%, and significantly to 16.9% (P = .008), respectively. Age-corrected deficits occurred more frequently than expected (P ≤ .03); at entry, mental health status (13.3%), clock-drawing (31.6%), oral-verbal fluency (16.9%), word-list learning (11.2%), and recall (12.6%); at exit, clock-drawing (30.0%). Entry-to-exit, mean depression, anxiety, mental and physical health status, word-list learning, memory, digit-symbol coding, and oral-verbal fluency scores improved significantly (P ≤ .031). No reliable change indices were significant. Psychological service recipients improved significantly more than nonrecipients in depression (P = .049). Baseline North American Adult Reading Test score predicted exercise attendance (R = 0.275; P = .044); New York Heart Association (NYHA) class and depression score predicted exit physical health status (R = 0.770, P < .001); and depression score predicted exit mental health status (R = 0.523, P < .001). Anxiety and executive dysfunction persisted post-TIA/MNDS. Although promising for secondary prevention post-TIA/MNDS, CCR was not independently associated with psychological improvements. CCR psychological treatment may benefit depression. Subacute NYHA class and depression may later affect quality of life.


Gait and Glasgow Coma Scale scores can predict functional recovery in patients with traumatic brain injury.
Fifty-one patients with mild (n = 14), moderate (n = 10) and severe traumatic brain injury (n = 27) received early rehabilitation. Level of consciousness was evaluated using the Glasgow Coma Score. Functional level was determined using the Glasgow Outcome Score, whilst mobility was evaluated using the Mobility Scale for Acute Stroke. Activities of daily living were assessed using the Barthel Index. Following Bobath neurodevelopmental therapy, the level of consciousness was significantly improved in patients with moderate and severe traumatic brain injury, but was not greatly influenced in patients with mild traumatic brain injury. Mobility and functional level were significantly improved in patients with mild, moderate and severe traumatic brain injury. Gait recovery was more obvious in patients with mild traumatic brain injury than in patients with moderate and severe traumatic brain injury. Activities of daily living showed an improvement but this was insignificant except for patients with severe traumatic brain injury. Nevertheless, complete recovery was not acquired at discharge. Multiple regression analysis showed that gait and Glasgow Coma Scale scores can be considered predictors of functional outcomes following traumatic brain injury.


The case against mandatory continuing education.
Requiring continuing education (CE) for RN relicensure began in the 1970s and has remained a controversial issue over the past 25 years. This article is a description of the process used by nurses in one state to investigate the complex issues surrounding mandatory continuing education for relicensure and the factors that led state nursing leaders to support the continuation of a voluntary CE system. Included are the findings of a survey of all states currently requiring continuing education for relicensure. The primary reason given for mandating CE was to protect the public, however, no data are available to support this premise.


Cytomegalovirus infection in immunosuppressed patients after kidney transplantation.
The first kidney transplantation was performed in 1951 and ever since then living donor transplantation became a more and more important solution for patients with end-stage renal disease (ESRD). Renal transplantation is a life-saving procedure. Morbidity and mortality on waiting-lists are strongly correlated with the time of dialysis and end-stage renal disease is one of the most important causes of death; this is the reason why transplantation has to be performed as soon as possible in order to reduce the time of dialysis. Once the transplantation is performed, a number of complications may occur in post-transplant evolution, the most important of which is rejection. The rejection may appear through several mechanisms, but one of the most frequent causes of rejection is cytomegalovirus (CMV) infection. It is very important to have a precocious and fast diagnosis of CMV infection in order to maintain the functionality and survival of the graft. PP65 CMV antigenemia has proven its effectiveness in detecting and monitoring the CMV infection in transplanted patients. In the laboratory of the Clinical Institute of Urology and Renal Transplantation (ICUTR) of Cluj Napoca the CMV infection is evidenced by two methods: PP65antigenemia and IgM antibody identification by chemiluminiscence.


Methods and goals of speech production research.
A personal view of current issues in speech production research is presented with some historical comments. Particular emphasis is placed on issues directly concerned with the relation between abstract phonological representations and speech signals, using a model of speech organization in reference to articulatory movement patterns. Experimental methods to support such linguistic research efforts, including some instrumental methods for recording articulatory data, are also reviewed from this particular point of view. Preparatory sections review the physical process and some physiological studies. The discussion focuses on the temporal organization of speech, deviating from the classical segmental concatenation and coarticulation principles, and discussing new possibilities about phonetic implementation in conjunction with an abstract representation framework of nonlinear phonology.


A population-based analysis of spirometry use and the prevalence of chronic obstructive pulmonary disease in lung cancer.
Chronic obstructive pulmonary disease (COPD) and lung cancer are associated diseases. COPD is underdiagnosed and thus undertreated, but there is limited data on COPD diagnosis in the setting of lung cancer. We assessed the diagnosis of COPD with lung cancer in a large public healthcare system. Anonymous administrative data was acquired from ICES, which links demographics, hospital records, physician billing, and cancer registry data in Ontario, Canada. Individuals age 35 or older with COPD were identified through a validated, ICES-derived cohort and spirometry use was derived from physician billings. Statistical comparisons were made using Wilcoxon rank sum, Cochran-Armitage, and chi-square tests. From 2002 to 2014, 756,786 individuals were diagnosed with COPD, with a 2014 prevalence of 9.3%. Of these, 51.9% never underwent spirometry. During the same period, 105,304 individuals were diagnosed with lung cancer, among whom COPD was previously diagnosed in 34.9%. Having COPD prior to lung cancer was associated with lower income, a rural dwelling, a lower Charlson morbidity score, and less frequent stage IV disease (48 vs 54%, p < 0.001). Spirometry was more commonly undertaken in early stage disease (90.6% in stage I-II vs. 54.4% in stage III-IV). Over a third of individuals with lung cancer had a prior diagnosis of COPD. Among individuals with advanced lung cancer, greater use of spirometry and diagnosis of COPD may help to mitigate respiratory symptoms.


A Survey-Based Study Examining Differences in Perception of Postural Orthostatic Tachycardia Syndrome Between Patients and Primary Care Physicians.
Introduction Postural orthostatic tachycardia syndrome (POTS) is an underdiagnosed and undertreated dysautonomia. We hypothesize that there are differences between primary care physicians (PCPs) and patients' perceptions of POTS and that correcting these discrepancies may improve patient care. Methods Two groups were surveyed: Patients who received care for POTS symptoms from a Cleveland Clinic neurologist or nurse practitioner and patients who received care from Cleveland Clinic family medicine or internal medicine physicians. Results PCPs (81%) rated lightheadedness as the symptom with the most significant negative impact on patient's quality of life with POTS, while patients rated fatigue (32%) as their worst symptom. PCPs were somewhat comfortable managing POTS but were less confident recommending cardiac rehabilitation and daily behavioral measures. Conclusion PCPs may need to continue review the negative impact of fatigue on the quality of life of POTS patients as well symptoms of body pain and lightheadedness. Although they are relatively comfortable managing POTS, PCPs may benefit from training on several aspects of POTS treatment.


Prevalence of BRCA1 and BRCA2 mutations in women with breast carcinoma In Situ and referred for genetic testing.
Ductal and lobular carcinoma in situ (CIS) accounted for 62,280 (24.5%) of all new breast cancer diagnoses in 2009. BRCA1/2 mutations confer an extremely high risk of breast cancer, and management guidelines for BRCA1/2 mutation carriers advise close follow-up, intensive screening, and consideration of prophylactic surgery to lower this risk. The limited relevant previous data are not definitive in establishing the prevalence of BRCA1/2 mutations in breast CIS patients, creating uncertainty as to whether referral for cancer risk assessment and genetic testing is appropriate for this group. Therefore, we conducted a cross-sectional analysis of the Myriad Genetics BRCA1/2 database to determine the prevalence of these mutations in breast CIS patients. All statistical tests were 2-sided, and confidence intervals (CI) are reported at the 95% level (α = 0.05). The source population was 64,717 consecutive women who were not Ashkenazi Jewish, underwent BRCA1/2 testing, and provided a personal and family history of invasive breast and ovarian cancer; 7,295 (11.3%) reported a diagnosis of CIS (ductal or lobular) and had an overall 5.9% prevalence of mutated BRCA1/2 (mBRCA). Subgrouped by history (personal or family) of invasive breast and/or ovarian cancer, these CIS patients had the following prevalences of mBRCA: (1) no personal or family history, 2.3%; (2) personal history, 5.2%; (3) family history, 5%; and (4) personal and family history, 10.3%. mBRCA risk was significantly higher in women with early-onset (<50 years old) CIS than with late-onset (≥ 50 years old) CIS [odds ratio (OR) = 1.5; 95% CI = 1.1-2.1). Disease onset at less than 40 years age was associated with an even higher mBRCA risk (OR = 1.8; 95% CI = 1.3-2.3). By far the largest analysis of BRCA1/2 mutation prevalence in non-Ashkenazi Jewish breast CIS patients, this study shows that early-onset CIS is associated with mBRCA1/2 in patients referred for genetic testing. When a family history of breast and/or ovarian cancer are also present, testing women with early-onset CIS may increase both the likelihood of detecting BRCA1/2 mutations and opportunities for carriers to consider additional cancer prevention strategies.


Hyperbaric oxygen and radiotherapy.
Hyperbaric oxygen (HBO) therapy is the inhalation of 100% oxygen at a pressure of at least 1.5 atmospheres absolute (150 kPa). It uses oxygen as a drug by dissolving it in the plasma and delivering it to the tissues independent of hemoglobin. For a variety of organ systems, HBO is known to promote new vessel growth into areas with reduced oxygen tension due to poor vascularity, and therewith promotes wound healing and recovery of radiation-injured tissue. Furthermore, tumors may be sensitized to irradiation by raising intratumoral oxygen tensions. A network of hyperbaric facilities exists in Europe, and a number of clinical studies are ongoing. The intergovernmental framework COST B14 action "Hyperbaric Oxygen Therapy" started in 1999. The main goal of the Working Group Oncology is preparation and actual implementation of prospective study protocols in the field of HBO and radiation oncology in Europe. In this paper a short overview on HBO is given and the following randomized clinical studies are presented: a) reirradiation of recurrent squamous cell carcinoma of the head and neck after HBO sensitization; b) role of HBO in enhancing radiosensitivity on glioblastoma multiforme; c) osseointegration in irradiated patients; adjunctive HBO to prevent implant failures; d) the role of HBO in the treatment of late irradiation sequelae in the pelvic region. The two radiosensitization protocols (a, b) allow a time interval between HBO and subsequent irradiation of 10-20 min. Recruitment of centers and patients is being strongly encouraged, detailed information is given on www.oxynet.org.


[Increased debts and mental health].
Millions of people in industrialised countries are deeply involved in debts including two million households in Germany. Sociologists discuss the gap between modern consumers' wishes and disposable money. There is no research on the psychiatric impacts of debt and mental health. Bankruptcy is often caused by psychiatric difficulties. This is shown by case reports. Consequences for the individual and society are discussed, including the limits of freedom to indebtedness.


What do you want to be when you grow up? pearls for postresidency planning.
Dermatology is an exciting and rewarding specialty. Looking for jobs after training can be a daunting task. From deciding to pursue a fellowship or a job in private practice, the opportunities are extensive. I have collected advice from recent dermatology graduates to help jump-start the planning process.


Association Between Excess Leisure Sedentary Time and Risk of Stroke in Young Individuals.
The association between physical activity (PA) and lower risk of stroke is well established, but the relationship between leisure sedentary time and stroke is less well studied. We used 9 years of the Canadian Community Health Survey between 2000 and 2012 to create a cohort of healthy individuals without prior stroke, heart disease, or cancer. We linked to hospital records to determine subsequent hospitalization or emergency department visit for stroke until December 31, 2017. We quantified the association between self-reported leisure sedentary time (categorized as <4, 4 to <6, 6 to <8, and 8+ hours/day) and risk of stroke using Cox regression models and competing risk regression, assessing for modification by PA, age, and sex and adjusting for demographic, vascular, and social factors. There were 143 180 people in our cohort and 2965 stroke events in follow-up. Median time from survey response to stroke was 5.6 years. There was a 3-way interaction between leisure sedentary time, PA, and age. The risk of stroke with 8+ hours of sedentary time was significantly elevated only among individuals <60 years of age who were in the lowest PA quartile (fully adjusted hazard ratio, 4.50 [95% CI, 1.64–12.3]). The association was significant across multiple sensitivity analyses, including adjustment for mood disorders and when accounting for the competing risk of death. Excess leisure sedentary time of 8+ hours/day is associated with increased risk of long-term stroke among individuals <60 years of age with low PA. These findings support efforts to enhance PA and reduce sedentary time in younger individuals.


Effects of butylphthalide on cognitive decline in diabetic rats.
Butylphthalide, a component extracted from seeds of Chinese celery, is an effective neuroprotective agent used for the treatment of ischemic stroke and dementia. Diabetes may cause central nervous system damage, and diabetes is closely associated with dementia. The aim of the present study was to investigate the effects of butylphthalide on cognitive impairment in a streptozotocin‑induced diabetic rat model, and the underlying mechanisms of action. A total of 30 healthy male Sprague Dawley rats were randomly divided into the following 2 groups: Normal control (NC; n=10) and diabetes model (DM) groups (n=20). Diabetes was induced in rats in the DM group by intraperitoneal injection of streptozotocin, and these rats were further subdivided into the following 2 groups: Diabetic control (n=10) and butylphthalide‑treated groups (n=10). Following 8 consecutive weeks of treatment, a Morris water maze test was performed and the levels of blood fasting plasma glucose (FPG), superoxide dismutase (SOD), malondialdehyde (MDA) and tumor necrosis factor‑α (TNF‑α), interleukin (IL)‑1β, and IL‑6 inflammatory cytokines in the hippocampus were measured. FPG levels were significantly decreased in the butylphthalide‑treated group when compared with the DM group. In addition, cognitive deficits in diabetic rats were improved following butylphthalide treatment. Furthermore, butylphthalide significantly increased the level of SOD, reduced MDA levels, and reduced TNF‑α, IL‑1β, and IL‑6 levels in the hippocampus when compared with the DM group. The results of the present study suggest that butylphthalide may be an effective neuroprotective agent to improve cognitive dysfunction during diabetes.


Plating Versus Intramedullary Nailing of OTA/AO 43C1 and C2 Intra-articular Distal Tibia Fractures: A Propensity Score and Multivariate Analysis.
To compare rates of reduction loss, nonunion, and infection in intra-articular distal tibia fractures (IADTF) treated with limited open reduction internal fixation and intramedullary nailing (IMN) as compared to open reduction internal fixation with plate and screws (plate fixation [PF]). Retrospective review. Level-I academic trauma center. Patients age ≥ 18 with OTA/AO 43C1 and C2 IADTF treated with IMN or PF between 2013-2021. Loss of reduction, surgical site infection (SSI), nonunion, and patient-reported outcomes (PROs) were compared for IMN versus PF treatments. One hundred ten patients met the inclusion criteria (IMN 33 and PF 77). There was no loss of reduction found. Seventeen nonunions (15% overall; IMN 4/33 and PF 13/77) and 13 SSIs (12% overall; IMN 2/33 and PF11/77) were identified. Despite several risk factors being identified for nonunion and SSI in bivariate analysis, only open fracture remained significant as a risk factor for both nonunion (odds ratio 0.09 for closed fracture, 95% confidence interval, 0.02-0.56, P = 0.009) and SSI (odds ratio 0.07 for closed fracture, 95% confidence interval, 0.06-0.26, P = 0.012) in the multivariate model. Propensity scoring based on presurgical variables was significantly different between patients who received IMN versus PF ( P = 0.03); however, logistic regression incorporating the propensity score revealed no significant association with nonunion and SSI. Adjusting for the propensity score, there remained no association comparing IMN versus PF with nonunion and SSI ( P = 0.54 and P = 0.17, respectively). There was also no difference in PROs between IMN and PF (physical function: P = 0.25 and pain interference: P = 0.21). Overall nonunion and SSI prevalence was 15% and 12%, respectively, in operatively treated OTA/AO 43C1 and C2 IADTF. An open fracture was a significant risk factor for nonunion and SSI. Metaphyseal fixation through IMN or PF did not affect loss of reduction, nonunion, SSI, or PROs. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.


On the origin of the nucleus: a hypothesis.
SUMMARYIn this hypothesis article, we explore the origin of the eukaryotic nucleus. In doing so, we first look afresh at the nature of this defining feature of the eukaryotic cell and its core functions-emphasizing the utility of seeing the eukaryotic nucleoplasm and cytoplasm as distinct regions of a common compartment. We then discuss recent progress in understanding the evolution of the eukaryotic cell from archaeal and bacterial ancestors, focusing on phylogenetic and experimental data which have revealed that many eukaryotic machines with nuclear activities have archaeal counterparts. In addition, we review the literature describing the cell biology of representatives of the TACK and Asgardarchaeaota - the closest known living archaeal relatives of eukaryotes. Finally, bringing these strands together, we propose a model for the archaeal origin of the nucleus that explains much of the current data, including predictions that can be used to put the model to the test.


Natural-abundance 43Ca solid-state NMR spectroscopy of bone.
Structural information about the coordination environment of calcium present in bone is highly valuable in understanding the role of calcium in bone formation, biomineralization, and bone diseases like osteoporosis. While a high-resolution structural study on bone has been considered to be extremely challenging, NMR studies on model compounds and bone minerals have provided valuable insight into the structure of bone. Particularly, the recent demonstration of (43)Ca solid-state NMR experiments on model compounds is an important advance in this field. However, application of (43)Ca NMR is hampered due to the low natural-abundance and poor sensitivity of (43)Ca. In this study, we report the first demonstration of natural-abundance (43)Ca magic angle spinning (MAS) NMR experiments on bone, using powdered bovine cortical bone samples. (43)Ca NMR spectra of bovine cortical bone are analyzed by comparing to the natural-abundance (43)Ca NMR spectra of model compounds including hydroxyapatite and carbonated apatite. While (43)Ca NMR spectra of hydroxyapatite and carbonated apatite are very similar, they significantly differ from those of cortical bone. Raman spectroscopy shows that the calcium environment in bone is more similar to carbonated apatite than hydroxyapatite. A close analysis of (43)Ca NMR spectra reveals that the chemical shift frequencies of cortical bone and 10% carbonated apatite are similar but the quadrupole coupling constant of cortical bone is larger than that measured for model compounds. In addition, our results suggest that an increase in the carbonate concentration decreases the observed (43)Ca chemical shift frequency. A comparison of experimentally obtained (43)Ca MAS spectra with simulations reveal a 3:4 mol ratio of Ca-I/Ca-II sites in carbonated apatite and a 2.3:3 mol ratio for hydroxyapatite. 2D triple-quantum (43)Ca MAS experiments performed on a mixture of carbonated apatite and the bone protein osteocalcin reveal the presence of protein-bound and free calcium sites, which is in agreement with a model developed from X-ray crystal structure of the protein.


Electromyogram whitening for improved classification accuracy in upper limb prosthesis control.
Time and frequency domain features of the surface electromyogram (EMG) signal acquired from multiple channels have frequently been investigated for use in controlling upper-limb prostheses. A common control method is EMG-based motion classification. We propose the use of EMG signal whitening as a preprocessing step in EMG-based motion classification. Whitening decorrelates the EMG signal and has been shown to be advantageous in other EMG applications including EMG amplitude estimation and EMG-force processing. In a study of ten intact subjects and five amputees with up to 11 motion classes and ten electrode channels, we found that the coefficient of variation of time domain features (mean absolute value, average signal length and normalized zero crossing rate) was significantly reduced due to whitening. When using these features along with autoregressive power spectrum coefficients, whitening added approximately five percentage points to classification accuracy when small window lengths were considered.


[Hypoxia-inducible factor-1α and CD133 predicts pathological complete response and survival for locally advanced rectal cancer patients after neoadjuvant chemoradiotherapy].
Objective: To investigate the expression of hypoxia-inducible factor 1α (HIF-1α) and CD133 in predicting pathologic remission and survival of patients with locally advanced rectal cancer undergoing neoadjuvant chemoradiotherapy. Methods: One hundred and fourteen patients with locally advanced rectal cancer undergoing neoadjuvant chemoradiotherapy from January 2010 to December 2015 in Jinhua Municipal Central Hospital were enrolled in the study. RT-PCR and immunohistochemistry methods were used to detect the mRNA and protein expression of HIF-1α and CD133 before and after chemoradiotherapy. Spearman rank correlation was used to analyze the correlation between HIF-1α and CD133 mRNA expression. Univariate and logistic multivariate analyses were used to determine the factors related to pathological complete response (pCR). Logistic regression analysis and Cox's proportional hazard model were used to determine factors related to overall survival and recurrence-free survival. Results: The expression of HIF-1α and CD133 mRNA was correlated with pT, ypTNM, pCR, recurrence and metastasis of rectal cancer, while not correlated with sex, age and BMI of patients. HIF-1α mRNA expression was positively correlated with CD133 mRNA expression ( α=0.579, P=0.000). Immunohistochemistry analysis showed that residual cancer cells strongly expressing HIF-1α also expressed CD133 strongly. Univariate analysis showed that HIF-1α mRNA and CD133 mRNA were significantly correlated with pCR ( P=0.001, P=0.022, respectively). Multivariate analysis showed that HIF-1α and CD133 mRNA expression were independent prognostic factors of pCR ( P=0.012, P=0.047, respectively). Cox regression analysis showed that the expression of HIF-1α mRNA and CD133 mRNA were independent predictors of recurrence-free survival and overall survival ( P=0.025, P=0.033, respectively). Conclusion: The study indicates that HIF-1α and CD133 can predict pathological complete remission and survival of patients with locally advanced rectal cancer.


Autocrine-mediated ErbB-2 kinase activation of STAT3 is required for growth factor independence of pancreatic cancer cell lines.
Pancreatic ductal adenocarcinoma (PDAC) cell lines, MIA PaCa-2, and UK Pan-1, were used to investigate the role of ErbB2 in PDAC oncogenesis. Both these cell lines exhibit exogenous growth factor-independent proliferation that was attributed to the production of autocrine growth factors and/or overexpression of growth factor receptors. The exogenous growth factor-independent phenotype displayed by these PDAC cell lines was dependent on ErbB2 kinase activity since treatment of cells with tyrphostin AG879 prevented serum-free media (SFM) induction of cell proliferation. We determined that ErbB2 kinase contributed to aberrant cell cycle regulation in PDAC through the induction of cyclin D1 levels and the suppression of p21(Cip1) and p27(Kip1). Inhibition of ErbB2 kinase led to cell cycle arrest marked by an increased association of p27(Kip1) with cdk2 and reduced levels of phosphorylated pRb. We further observed constitutive STAT3 activation in the PDAC cell lines and an increase in STAT3 activation upon stimulating quiescent cells with SFM. Inhibitors of ErbB2 kinase blocked STAT3 activation, whereas inhibition of EGFR kinase led to a slight reduction of STAT3 activation. STAT3 was coimmunoprecipitated with ErbB2. SFM stimulation caused an increase in the association of ErbB2 and STAT3, which was blocked by inhibition of ErbB2 kinase. Expression of a STAT3 dominant negative prevented SFM-stimulated cell proliferation of MIA PaCa-2 cells, suggesting that activation of STAT3 by ErbB2 is required for a growth factor-independent phenotype of these cells. Consistent with this observation in PDAC cell lines, we found that most PDAC tumor specimens (10 of 11) showed constitutive activation of STAT3 and that ErbB2 was readily detected in most of these tumors (nine of 11). We believe that these findings indicate a novel mechanism of oncogenesis in PDAC and may suggest future therapeutic strategies in the treatment of PDAC.


[Evaluation of various methods effectiveness for aphakia correction in patients with myopic refraction and glaucoma].
The efficiency of various methods for correcting postoperative aphakia was evaluated in 113 patients (118 eyes) with medium and high myopia and glaucoma. In group 1 (44 eyes) extraocular correction of aphakia was planned after cataract extraction, in group 2 (33 eyes) intraocular lenses were implanted, in group 3 (21 eyes) combined interventions were performed (cataract extraction with antiglaucoma component), and in group 4 (20 eyes) cataract extraction was performed simultaneously with sinusotrabeculectomy and intraocular correction of aphakia. The number of patients with visual acuity higher than 0.1 was significantly more in groups 2 and 4 after implantation of intraocular lenses than in groups 1 and 3, who needed extraocular correction of aphakia: 59.1% in group 1, 42.9% in group 3, 78.8% in group 2, and 60% in group 4. Intraocular correction of aphakia in patients with glaucoma and myopia helps attain the maximum possible visual acuity even in patients with far-advanced stages of the disease with residual visual field. Individual approach to estimation of optic force of implanted intraocular lens helps reduce the myopic refraction of the operated eye.


Targeted hepatitis B vaccination--a cost effective immunisation strategy for the UK?
To compare the potential cost effectiveness of vaccination against hepatitis B virus (HBV) targeted at genitourinary clinic (GU) attendees with that of universal infant vaccination. A mathematical model of sexual and perinatal transmission of HBV was used to compare the effectiveness among heterosexual and homosexual populations of programmes of mass infant vaccination and targeted immunisation of genitourinary medicine (GU) clinic attendees. Each was applied to 90% of the eligible population with differing assumptions about rates of compliance and seroconversion - problems of delivery (obtaining high compliance) was considered a significant drawback of targeted vaccination. Observed relationships between GU clinic attendance and sex partner change rates for heterosexuals and for homosexuals were used to define the rates of vaccination uptake within sexual activity risk groups. England and Wales. Model results showed that for heterosexuals universal infant vaccination became more effective than clinic based vaccination only approximately 40 years after the start of the programme and that the predicted cost effectiveness of GU clinic vaccination was greater at all times. For homosexuals, clinic vaccination was always more effective over the time frame considered, but by 50 years if it were carried out without prior screening it had become appreciably less cost effective than a mass infant programme. With prior screening in GU clinics this cost effectiveness deficit was only marginal. Targeted vaccination might have a much greater potential than is realised at present, particularly if it were possible to improve compliance of clinic attendees. A fuller comparison between mass infant and targeted vaccination must await the specific inclusion in the model of other risk groups such as intravenous drug users. An important determinant of the relative merits of the two approaches is the relationship between rates of attendance and of changing sexual partners. Further research on this is required.


HEMOGLOBINS A AND F: FORMATION IN THALASSEMIA AND OTHER HEMOLYTIC ANEMIAS.
Rates of synthesis of hemoglobin A by erythroid cells from thalassemic subjects are markedly decreased. Formation of hemoglobin F, however, proceeds at similar rates in cells from subjects with thalassemia and other types of hemolytic anemias. A mechanism is suggested regarding the altered patterns of hemoglobin synthesis under conditions of erythropoietic stimulation in subjects with and without thalassemia.


Neocortex size predicts deception rate in primates.
Human brain organization is built upon a more ancient adaptation, the large brain of simian primates: on average, monkeys and apes have brains twice as large as expected for mammals of their size, principally as a result of neocortical enlargement. Testing the adaptive benefit of this evolutionary specialization depends on finding an association between brain size and function in primates. However, most cognitive capacities have been assessed in only a restricted range of species under laboratory conditions. Deception of conspecifics in social circumstances is an exception, because a corpus of field data is available that encompasses all major lines of the primate radiation. We show that the use of deception within the primates is well predicted by the neocortical volume, when observer effort is controlled for; by contrast, neither the size of the rest of the brain nor the group size exert significant effects. These findings are consistent with the hypothesis that neocortical expansion has been driven by social challenges among the primates. Complex social manipulations such as deception are thought to be based upon rapid learning and extensive social knowledge; thus, learning in social contexts may be constrained by neocortical size.


Visually guided pecking in the pigeon (Columba livia).
High-speed cinematography was used (1) to analyze the sequence of head movements made by pigeons pecking at small visual targets and (2) to determine where on the retina the target fell at different points in the sequence. In both key-pecking for food reward and normal feeding, the decision to peck the target was made during a head fixation that occurred over 80 mm from the surface on which the target was located (as measured from the center of the eyes). Once the decision to peck had been made, a second fixation (F2) occurred at an average distance of 55 mm allowing the bird to calculate the size, depth, and location of the target. Moreover, during both fixations, the target was located in the pigeon's binocular field within a region corresponding to the red area of the upper temporal quadrant of the retina.


Effect of Hypothyroidism and Hyperthyroidism on Tissue Thyroid Hormone Concentrations in Rat.
The present study was aimed at determining the effects of experimental hypothyroidism and hyperthyroidism on tissue thyroid hormones by a mass spectrometry-based technique. Rats were subjected to propylthiouracil treatment or administration of exogenous triiodothyronine (T3) or thyroxine (T4). Tissue T3 and T4 were measured by liquid chromatography tandem mass spectrometry in the heart, liver, kidney, visceral and subcutaneous adipose tissue, and brain. Baseline tissue T3 and T4 concentrations ranged from 0.2 to 20 pmol ∙ g(-1) and from 3 to 125 pmol ∙ g(-1), respectively, with the highest values in the liver and kidney, and the lowest values in the adipose tissue. The T3/T4 ratio (expressed as a percentage) was in the 7-20% range in all tissues except the brain, where it averaged 75%. In hypothyroidism, tissue T3 was more severely reduced than serum free T3, averaging 1-6% of the baseline versus 30% of the baseline. The extent of tissue T3 reduction, expressed as percentage of the baseline, was not homogeneous (p < 0.001), with liver = kidney > brain > heart > adipose tissue. The tissue T3/T4 ratio significantly increased in all organs except the kidney, averaging 330% in the brain and 50-90% in the other tissues. By contrast, exogenous T3 and T4 administration produced similar increases in serum free T3 and in tissue T3, and the relative changes were not significantly different between different tissues. While the response to increased thyroid hormones availability was similar in all tissues, decreased thyroid hormone availability induced compensatory responses, leading to a significant mismatch between changes in serum and in specific tissues.


Liquid Biopsies and Critical Illness Insurance: Uncomfortable Bedfellows?
Liquid biopsies hold great promise for the diagnosis and treatment of cancer. Earlier recognition of recurrent and metastatic disease and better treatment choices based on liquid biopsies seem achievable in the near future. However, earlier cancer diagnosis, the most heralded application, will remain the most challenging. The impact of liquid biopsies on life insurance will be positive. The impact on critical illness insurance will be more nuanced. It will depend on 2 factors: the success of liquid biopsies as cancer screening tests and the ability of an insurer to use "genetic information" during risk selection. In jurisdictions where use is prohibited, critical illness insurance, as presently designed, may not be sustainable.


Phylogenomic revision of the family Streptosporangiaceae, reclassification of Desertactinospora gelatinilytica as Spongiactinospora gelatinilytica comb. nov. and a taxonomic home for the genus Sinosporangium in the family Streptosporangiaceae.
In recent years, the results of genome-based phylogenetic analyses have contributed to microbial systematics by increasing the availability of sequenced microbial genomes. Therefore, phylogenomic analysis within large taxa in the phylum Actinobacteria has appeared as a useful tool to clarify the taxonomic positions of ambiguous groups. In this study, we provide a revision of the actinobacterial family Streptosporangiaceae using a large collection of genome data and phylogenomics approaches. The phylogenomic analyses included the publicly available genome data of the members of the family Streptosporangiaceae and the state-of-the-art tools are used to infer the taxonomic affiliation of these species within the family. By comparing genome-based and 16S rRNA gene-based trees, as well as pairwise genome comparisons, the recently described genera Spongiactinospora and Desertactinospora are combined in the genus Spongiactinospora. In conclusion, a comprehensive phylogenomic revision of the family Streptosporangiaceae is proposed.


Antiangiogenic mechanisms of PJ-8, a novel inhibitor of vascular endothelial growth factor receptor signaling.
Angiogenesis occurs not only during tissue growth and development but also during wound healing and tumor progression. Angiogenesis is a balanced process controlled by proangiogenic and antiangiogenic molecules. As a critical factor in the induction of angiogenesis, vascular endothelial growth factor (VEGF) has become an attractive target for antiangiogenic and cancer therapeutic agents. In an effort to develop novel inhibitors to block VEGF signaling, we selected Pj-8, a benzimidazole derivative, and investigated its inhibitory mechanisms in human umbilical vascular endothelial cells (HUVECs). Pj-8 concentration-dependently inhibited VEGF-induced proliferation, migration and tube formation of HUVECs. Pj-8 also suppressed VEGF-induced microvessel sprouting from aortic rings ex vivo and suppressed neovascularization of implanted matrigel plugs in vivo. Pj-8 inhibited VEGF-induced phosphorylation of VEGF receptor (VEGFR) 2 and the downstream protein kinases, including Akt, focal adhesion kinase, extracellular signal-regulated kinases and Src. Results from in vitro kinase assay further demonstrated that Pj-8 suppressed the kinase activity of 3-phosphoinositide-dependent kinase 1 (PDK1). Using xenograft tumor angiogenesis model, Pj-8 markedly eliminated tumor-associated angiogenesis. Taken together, our findings suggest that Pj-8 inhibits VEGF and tumor cells MDA-MB-231-induced angiogenesis, and it may be a potential drug candidate in anticancer therapy. Downregulation of VEGFR2-mediated signaling may contribute to its antiangiogenic actions.


Genomic similarity and kernel methods I: advancements by building on mathematical and statistical foundations.
Measures of genomic similarity are the basis of many statistical analytic methods. We review the mathematical and statistical basis of similarity methods, particularly based on kernel methods. A kernel function converts information for a pair of subjects to a quantitative value representing either similarity (larger values meaning more similar) or distance (smaller values meaning more similar), with the requirement that it must create a positive semidefinite matrix when applied to all pairs of subjects. This review emphasizes the wide range of statistical methods and software that can be used when similarity is based on kernel methods, such as nonparametric regression, linear mixed models and generalized linear mixed models, hierarchical models, score statistics, and support vector machines. The mathematical rigor for these methods is summarized, as is the mathematical framework for making kernels. This review provides a framework to move from intuitive and heuristic approaches to define genomic similarities to more rigorous methods that can take advantage of powerful statistical modeling and existing software. A companion paper reviews novel approaches to creating kernels that might be useful for genomic analyses, providing insights with examples [1].


Talking back: Development of the olivocochlear efferent system.
Developing sensory systems must coordinate the growth of neural circuitry spanning from receptors in the peripheral nervous system (PNS) to multilayered networks within the central nervous system (CNS). This breadth presents particular challenges, as nascent processes must navigate across the CNS-PNS boundary and coalesce into a tightly intermingled wiring pattern, thereby enabling reliable integration from the PNS to the CNS and back. In the auditory system, feedforward spiral ganglion neurons (SGNs) from the periphery collect sound information via tonotopically organized connections in the cochlea and transmit this information to the brainstem for processing via the VIII cranial nerve. In turn, feedback olivocochlear neurons (OCNs) housed in the auditory brainstem send projections into the periphery, also through the VIII nerve. OCNs are motor neuron-like efferent cells that influence auditory processing within the cochlea and protect against noise damage in adult animals. These aligned feedforward and feedback systems develop in parallel, with SGN central axons reaching the developing auditory brainstem around the same time that the OCN axons extend out toward the developing inner ear. Recent findings have begun to unravel the genetic and molecular mechanisms that guide OCN development, from their origins in a generic pool of motor neuron precursors to their specialized roles as modulators of cochlear activity. One recurrent theme is the importance of efferent-afferent interactions, as afferent SGNs guide OCNs to their final locations within the sensory epithelium, and efferent OCNs shape the activity of the developing auditory system. This article is categorized under: Nervous System Development > Vertebrates: Regional Development.


Enhanced low-template DNA analysis conditions and investigation of allele dropout patterns.
Forensic DNA analysis applying PCR enables profiling of minute biological samples. Enhanced analysis conditions can be applied to further push the limit of detection, coming with the risk of visualising artefacts and allele imbalances. We have evaluated the consecutive increase of PCR cycles from 30 to 35 to investigate the limitations of low-template (LT) DNA analysis, applying the short tandem repeat (STR) analysis kit PowerPlex ESX 16. Mock crime scene DNA extracts of four different quantities (from around 8-84 pg) were tested. All PCR products were analysed using 5, 10 and 20 capillary electrophoresis (CE) injection seconds. Bayesian models describing allele dropout patterns, allele peak heights and heterozygote balance were developed to assess the overall improvements in EPG quality with altered PCR/CE settings. The models were also used to evaluate the impact of amplicon length, STR marker and fluorescent label on the risk for allele dropout. The allele dropout probability decreased for each PCR cycle increment from 30 to 33 PCR cycles. Irrespective of DNA amount, the dropout probability was not affected by further increasing the number of PCR cycles. For the 42 and 84 pg samples, mainly complete DNA profiles were generated applying 32 PCR cycles. For the 8 and 17 pg samples, the allele dropouts decreased from 100% using 30 cycles to about 75% and 20%, respectively. The results for 33, 34 and 35 PCR cycles indicated that heterozygote balance and stutter ratio were mainly affected by DNA amount, and not directly by PCR cycle number and CE injection settings. We found 32 and 33 PCR cycles with 10 CE injection seconds to be optimal, as 34 and 35 PCR cycles did not improve allele detection and also included CE saturation problems. We find allele dropout probability differences between several STR markers. Markers labelled with the fluorescent dyes CXR-ET (red in electropherogram) and TMR-ET (shown as black) generally have higher dropout risks compared with those labelled with JOE (green) and fluorescein (blue). Overall, the marker D10S1248 has the lowest allele dropout probability and D8S1179 the highest. The marker effect is mainly pronounced for 30-32 PCR cycles. Such effects would not be expected if the amplification efficiencies were identical for all markers. Understanding allele dropout risks and the variability in peak heights and balances is important for correct interpretation of forensic DNA profiles.


Involvement of aldose reductase in the metabolism of atherogenic aldehydes.
Phospholipid peroxidation generates a variety of aldehydes, which includes free saturated and unsaturated aldehydes, and aldehydes that remain esterified to the phosphoglyceride backbone - the so-called 'core' aldehydes. However, little is known in regarding the vascular metabolism of these aldehydes. To identify biochemical pathways that metabolize free aldehydes, we examined the metabolism of 4-hydroxy-trans-2-nonenal in human aortic endothelial cells. Incubation of these cells with [3H]-HNE led to the generation of four main metabolites, i.e. glutathionyl HNE (GS-HNE), glutathionyl dihydroxynonene (GS-DHN), DHN and 4-hydroxynonanoic acid (HNA), which accounted for 5, 50, 6, and 23% of the total HNE metabolized. The conversion of GS-HNE to GS-DHN was inhibited by tolrestat, indicating that it is catalyzed by aldose reductase (AR). The AR was also found to be an efficient catalyst for the reduction of the core aldehyde - 1-palmitoyl-2- (5-oxovaleroyl)-sn-glycero-3-phosphorylcholine, which is generated in minimally modified low-density lipoprotein, and activates the endothelium to bind monocytes. As determined by electrospray mass spectrometry, reduction of POVPC (m/z=594) by AR led to the formation of 1-palmitoyl-2- (5)-hydrovaleryl-sn-glycero-3-phosphorylcholine (PHVPC; m/z=596). These observations suggest that due to its ability to catalyze the reduction of lipid-derived aldehydes AR may be involved in preventing inflammation and diminishing oxidative stress during the early phases of atherogenesis.


Encapsulating insoluble antifungal drugs into oleic acid-modified silica mesocomposites with enhanced fungicidal activity.
Recently, with increasing medical practices, including organ transplantation and tumor chemotherapy, fungal infections, particularly the occurrence of drug-resistant fungal strains, remain a severe problem for the public health, which cause worse complications in the immunocompromised patients. The search for efficacious yet safe antifungal agents is in high demand in precision medicine. However, fungicides are often poorly water soluble for oral absorption, which is difficult for pharmaceutical efficacy evaluation. In this study, lipophilic oleic acid (OA)-grafted mesoporous silica (SBA-15) was facilely modified by cetyltrimethylammonium bromide (CTAB), which acts as an efficient antifungal drug matrix of itraconazole (ITZ). Characterized by physicochemical methods, the rod-like SBA-15-OA-CTAB/ITZ composite with retained mesostructural regularity shows that the loading amount of ITZ in the mesopore is ∼18%, contributing to the enhanced antifungal activity against Aspergillus fumigatus (A. fumigatus) and Candida albicans (C. albicans). The antimicrobial mechanism study suggests that the reactive oxygen species (ROS) were formed when fungal cells were incubated with the formulated ITZ, while there was no ROS formation in the presence of pure ITZ, which may result from the quaternary ammonium moieties of CTAB in the nanocomposites. Due to the potential toxicity of CTAB on mammalian cells, the as-synthesized mesoporous SBA-15-OA-CTAB/ITZ provides an alternative molecular design for the formulation improvement of a lipophilic antifungal drug applicable for external uses such as topical therapy.


Effects of anti-Ia sera on mitogenic responses. II. Differential expression of the Ia marker on phytohemagglutinin and concanavalin A-reactive T cells.
Genes mapping in the I region of the H-2 complex control a system of lymphocyte alloantigens (Ia) which are expressed on a subpopulation of T cells and on most B cells. Specific anti-Ia serum in the presence of rabbit complement removed the splenic T-cell subpopulation responsive to Con-A, but did not affect the response to phytohemagglutinin (PHA) or Leucoagglutinin. Antibodies specific for Ia, H-2K, or H-2D membrane antigens were used without complement to pretreat spleen cells. These antibody pretreated cells responded normally to Con-A and PHA.


Evaluation of PPP-ABS investment environment based on combined weighting of level difference maximization and TOPSIS method.
Asset-backed securitization (ABS) is currently used to refinance public-private partnership (PPP) projects in the infrastructure field. To stimulate the investors' enthusiasm, this study evaluated the investment environment of PPP projects asset-backed securitization (PPP-ABS). Firstly, we established a PPP-ABS investment environment evaluation indicator system based on the literature review and the practice of PPP-ABS. Then, the optimal weights of each indicator were determined by the combined weighting of level difference maximization method, where the subjective weights were determined by the AHP method, and the objective weights were determined by the entropy method. Finally, we evaluated the PPP-ABS investment environment from 2015 to 2022 with the technique for order preference by similarity to ideal solution (TOPSIS) method. The final valuation results are consistent with the actual situation. The results showed that the PPP-ABS investment environment exhibits a stable and upward trend. Under the overall guidance of the government, the approval process, information disclosure and supervisory systems have continued to improve, the number of ABS products issued has continued to grow, and the overall market risk is controllable. However, some problems still need to be solved and improved, including inadequate accounting and tax systems, insufficient liquidity in the secondary market, and the recovery of economic development in the post-COVID-19 era. This study fills the research gap in PPP-ABS. It proves the rationality and feasibility of PPP-ABS and is expected to provide a reference for investors' decision-making and promote the sustainable and healthy development of PPP-ABS.


Draft genome sequences of two Pseudomonas strains isolated from 129I plumes at the Hanford Site.
Pseudomonas strains DVZ6 and DVZ24 were isolated from a sediment trap incubated in an 129I plume at the Hanford Site (Washington State, USA). Whole-genome sequencing of the strains revealed that both genomes are 5.77 Mb in size, with a G + C content of 64.75%.


Plasmon hybridization reveals the interaction between individual colloidal gold nanoparticles confined in an optical potential well.
The understanding of interaction forces between nanoparticles in colloidal suspension is central to a wide range of novel applications and processes in science and industry. However, few methods are available for actual characterization of such forces at the single particle level. Here we demonstrate the first measurements of colloidal interactions between two individual diffusing nanoparticles using a colorimetric assay based on plasmon hybridization, that is, strong near-field coupling between localized surface plasmon resonances. The measurements are possible because individual gold nanoparticle pairs can be loosely confined in an optical potential well created by a laser tweezers. We quantify the degree of plasmon hybridization for a large number of individual particle pairs as a function of increasing salt concentration. The data reveal a considerable heterogeneity at the single particle level but the estimated average surface separations are in excellent agreements with predictions based on the classical theory of Derjaguin, Landau, Verwey, and Overbeek.


Do alternate modes for transmission of human immunodeficiency virus exist? A review.
Transmission of human immunodeficiency virus (HIV) is known to occur perinatally, through sexual contact, and after exposure to infected blood or blood products. The possibility that breast milk may transmit HIV continues to be evaluated. There is no epidemiologic evidence that contact with saliva, tears, or urine has resulted in HIV infection. However, because HIV has (in some cases rarely) been isolated from these body fluids, guidelines have been developed to reduce more extensive exposures to such secretions. Laboratory and epidemiologic data strongly indicate that HIV is not transmitted through immune globulin preparations, the hepatitis B vaccine, or contact with insects. Increasing evidence from many studies also indicates that HIV is not transmitted through casual contact. All individuals need to be aware of how HIV is and is not transmitted, to reduce high-risk behaviors and to avoid unnecessary fears and actions.


Polyamine biogenesis in the rat mammary gland during pregnancy and lactation.
Polyamines and RNA accumulate in the rat mammary gland during pregnancy, but the major increases occur after parturition. Therefore the major increases occur after the gland has obtained its maximal complement of epithelial cells. During lactation, the spermidine concentration rises above 5mm and RNA content in the lactating mammary gland reaches a value 16 times that of the unstimulated mammary gland. The ratio of spermidine/spermine, an increase of which initially signals an elevation in biosynthetic activity, is near 1 in the normal mammary gland and is greater than 10 in the lactating mammary gland. Putrescine concentration is very low during the entire course of mammary-gland development, with the exception of early pregnancy. The low putrescine concentration probably reflects the very rapid conversion of putrescine into spermidine. Both ornithine decarboxylase, the enzyme that synthesizes putrescine, and putrescine-stimulated S-adenosyl-l-methionine decarboxylase, the enzyme that synthesizes spermidine, increase in activity during middle and late pregnancy; during lactation, both enzyme activities are elevated until the 21st day of lactation, and then decline. These declines are concomitant with involution. Also, it was found that the amount of ribonuclease activity in the mammary gland was very high during lactation, almost double that in the gland during pregnancy.


Evidence for a recurrent microdeletion at chromosome 16p11.2 associated with congenital anomalies of the kidney and urinary tract (CAKUT) and Hirschsprung disease.
Congenital Anomalies of the Kidney and Urinary Tract can be associated with Hirschsprung disease. We report on three children with a similar 16p11.2 microdeletion with a spectrum of clinical anomalies consisting of congenital anomalies of the kidney and urinary tract in two patients (Patients 1 and 2) and Hirschsprung disease in two patients (Patients 1 and 3), leading us to hypothesize that a gene in this region is associated with these phenotypes. Patient 1 presented with left renal agenesis, grade-IV vesicoureteral reflux, and Hirschsprung disease, Patient 2 with left renal agenesis, chronic kidney disease, chronic constipation, seizures, and developmental delay, and Patient 3 with Hirschsprung disease and normal kidneys. Genome-wide microarray analysis demonstrated overlapping microdeletions within 16p11.2. The shortest region of overlap in the three patients contained only eight genes, including the SH2 domain-containing binding protein 1 (SH2B1), an adaptor protein which has been implicated in enhancement of the tyrosine kinase activity of RET, whose role in developmental disease of the kidney and enteric enervation is well established. Our findings suggest that 16p11.2 deletions are associated with abnormalities of renal and enteric development and we hypothesize that deletion of SH2B1 may account for the observed phenotype.


Decrease and increase in residual ridges after extraction of teeth in monkeys (part I).
The purpose of this study is to prevent and control the reduction of residual ridges. The subjects used in this study consisted of 19 crab-eating monkeys which were divided into four groups according to the extraction area. These categories are 1U0L group (extracted on M1), 1U5L group (extracted on M1 and M3M2M1P2P1), 0U5L group (extracted on M3M2M1P2P1), and 5U1L group (extracted on M3M2M1P3P1 and M1). Impressions were taken before the extraction. Further impressions were taken at three week, six week, three month, six month, one year, and two year intervals after the extraction in order to observe morphological changes. Casts were made immediately thereafter and the cross-sectional areas of the residual ridges were measured by a standardized method with the aid of a Kubuskraniophor and a diagraph. The measurements taken of the right side, which was operated on, and the left side, which served as the control, were compared in order to observe changes in the form of the edentulous area. The results were as follows: 1) Increase in the Residual Ridge Areas: It is highly significant that the measurements of the M1 section of the 1U5L group and the M1 section of the 5U1L group gradually decreased until the sixth week, and then began to increase until the areas were approximately equivalent to the measurements of the areas before the extraction after a two-year period. This may be due to the fact that along with the elongation of the neighboring teeth, the alveolar bone grew to such an extent that the resorption rate was surpassed. 2) Decrease in the Residual Ridges Areas: With the exception of the above-mentioned sections, almost all of other sections responded in the expected manner, that is, there was a sharp decrease in the areas of these sections. The decrease took place rapidly. Seventy to 80% of the total loss occurring over the two-year period took place in the first three months. After a sharp decline in the initial three-month period, the process continued at a slow pace. This gradual decrease after a short period of rapid decrease typifies the standard pattern of the edentulous resorption process.


Effectiveness and limitations of the use of the gonadotropin-releasing hormone agonist leuprolide acetate in the diagnosis of delayed puberty in males.
In order to evaluate the effectiveness of the gonadotropin-releasing hormone agonist leuprolide acetate in distinguishing gonadotropin deficiency from delayed puberty, a single subcutaneous dose of 20 micrograms/kg of leuprolide acetate was administered at 07.00 h to 14 patients with constitutionally delayed puberty and to 8 gonadotropin-deficient subjects, and serum gonadotropin and testosterone levels were determined at baseline and 1,2,3,6,12, and 24 h thereafter. The increase in gonadotropin and testosterone levels was significant in patients with delayed puberty, so that the mean peak luteinizing hormone and to a lesser degree the mean peak testosterone levels clearly differentiated normally delayed from gonadotropin-deficient puberty. However, when the peak gonadotropin and testosterone concentrations were analyzed individually, there was a considerable overlap between the two groups of males, limiting the usefulness of this test.


NADPH oxidase of chondrocytes contains an isoform of the gp91phox subunit.
Previously it has been reported that chondrocytic cells produce oxygen free radicals and express the cytosolic components of NADPH oxidase. Here we report the expression of large subunit of the flavocytochrome of NADPH oxidase in chondrocytes and, further, show that the cDNA sequence contains three single base pair differences compared with the phagocyte gp91phox gene sequence. These base-pair differences may account for the different activity profiles reported between phagocytic and non-phagocytic cells.


NK1.1 cells and CD8 T cells mediate the antitumor activity of Cl-IB-MECA in a mouse melanoma model.
Cl-IB-MECA, synthetic A(3) adenosine receptor agonist, is a potential anticancer agent. In this study, we have examined the effect of Cl-IB-MECA in a mouse melanoma model. Cl-IB-MECA significantly inhibited tumor growth in immune-competent mice. Notably, the number of tumor-infiltrating NK1.1(+) cells and CD8(+) T cells was significantly increased in Cl-IB-MECA-treated mice. This effect was correlated with high levels of tumor necrosis factor α (TNF-α) and interferon γ in melanoma tissue. Depletion of either CD8(+) T cells or NK1.1(+) cells completely abrogated the antitumor effect of Cl-IB-MECA. Accordingly, Cl-IB-MECA did not affect tumor growth in nude mice. In addition, we also found that the number of mature and active conventional dendritic cells at the tumor site was increased after Cl-IB-MECA administration. Moreover, Cl-IB-MECA significantly increased TNF-α and IL-12p40 release from splenic CD11c(+) cells. In conclusion, our study provides novel insights into the mechanism by which Cl-IB-MECA leads to an effective antitumor response that involves the activation of natural killer cells and CD8(+) T cells and further highlights its therapeutic potential.


Immune-Related Adverse Events Among COVID-19-Vaccinated Patients With Cancer Receiving Immune Checkpoint Blockade.
Whether COVID-19 vaccination and the associated immune response increases susceptibility to immune-related adverse events (irAEs) among patients treated with immune checkpoint inhibition (ICI) remains unknown. Short-term follow-up can assess the safety of concurrent administration of the vaccine and ICI treatment. We conducted an electronic health record analysis of a cohort of 408 patients with cancer receiving ICI therapy and who were vaccinated for COVID-19 between January 16 and March 27, 2021. Patients were seen in follow-up for 90 days from the day of the first dose in this single-institution tertiary care center. We evaluated the incidence of irAEs and the frequency of each event type and grade among patients who experienced an irAE. We also evaluated the incidence of irAEs in patients who began a new immunotherapy agent after vaccination. Among 408 patients with cancer receiving ICI therapy (median age, 71 years; 217 [53%] male), administration of a COVID-19 mRNA vaccine within 90 days of ICI treatment was not associated with an increased incidence of irAEs. A total of 27 (7%) patients experienced a new irAE within the observation period. Among patients with previous irAEs from ICIs (n=54), 3 (6%) experienced a recurrent irAE, and of those initiating a new immunotherapy (n=52), 9 (17%) experienced an irAE. No excess risk of COVID-19 diagnosis was seen in this subset of patients receiving ICI therapy, and no breakthrough COVID-19 cases were seen after full COVID-19 vaccination. These findings should reassure providers that COVID-19 vaccination during ICI therapy is safe and efficacious.


5mC modification orchestrates choriogenesis and fertilization by preventing prolonged ftz-f1 expression.
DNA methylation at the fifth position of cytosine (5-methylcytosine, 5mC) is a crucial epigenetic modification for regulating gene expression, but little is known about how it regulates gene expression in insects. Here, we pursue the detailed molecular mechanism by which DNMT1-mediated 5mC maintenance regulates female reproduction in the German cockroach, Blattella germanica. Our results show that Dnmt1 knockdown decreases the level of 5mC in the ovary, upregulating numerous genes during choriogenesis, especially the transcription factor ftz-f1. The hypomethylation at the ftz-f1 promoter region increases and prolongs ftz-f1 expression in ovarian follicle cells during choriogenesis, which consequently causes aberrantly high levels of 20-hydroxyecdysone and excessively upregulates the extracellular matrix remodeling gene Mmp1. These changes further impair choriogenesis and disrupt fertilization by causing anoikis of the follicle cells, a shortage of chorion proteins, and malformation of the sponge-like bodies. This study significantly advances our understanding of how DNA 5mC modification regulates female reproduction in insects.


[Athletes with exercise-related pain at the medial side of the lower leg].
Two patients were diagnosed with exercise-related pain at the medial side of the lower leg. The first patient, an 18-year-old woman who had expanded her athletic activities extensively, had developed pain at the inner side of the distal third portion of the left lower leg. She showed over-pronation of the ankle during running. A 3-phase bone scintigram revealed diffuse uptake of the tracer covering a large portion of the medial tibia margin. Based on this evidence, a diagnosis of periostalgia was made. She recovered after a period of relative calf massages and used insoles. The second patient was a 28-year-old male endurance runner who developed pain at the medial shin after intensifying his training regimen. The periods without pain during running became increasingly shorter, and the medial side of the lower leg became sore and tense. Intracompartmental pressure measurements indicated exercise-related posterior deep compartment syndrome of the calf. The patient recovered after fasciotomy. In athletes, exercise-related symptoms of the medial side of the lower leg can be usually attributed to the tibial periosteum or tendons of the deep calfmusculature, tibial stress reaction or fracture, or a compartment syndrome of the deep calf. Surgery is indicated for chronic compartment syndrome, but conservative therapy provides favourable outcomes in the other types of disorders. The optimal conservative therapeutic approach is unknown, but it is advisable to temporary reduce symptom-provoking athletic activity and modify any risk factors present. Ankle over-pronation during running is considered a very relevant intrinsic risk factor.


Localization of Gi alpha proteins in the centrosomes and at the midbody: implication for their role in cell division.
At the plasma membrane, heterotrimeric G proteins act as molecular switches to relay signals from G protein-coupled receptors; however, G(alpha) subunits also have receptor-independent functions at intracellular sites. Regulator of G protein signaling (RGS) 14, which enhances the intrinsic GTPase activity of G(ialpha) proteins, localizes in centrosomes, which suggests the coexpression of G(ialpha). We show expression of G(ialpha1), G(ialpha2), and G(ialpha3) in the centrosomes and at the midbody. Fluorescence resonance energy transfer analysis confirms a direct interaction between RGS14 and G(ialpha1) in centrosomes. Expression of GTPase-deficient G(ialpha1) results in defective cytokinesis, whereas that of wild-type or GTPase-deficient G(ialpha3) causes prolonged mitosis. Cells treated with pertussis toxin, with reduced expression of G(ialpha1), G(ialpha2), and G(ialpha3) or with decreased expression of RGS14 also exhibit cytokinesis defects. These results suggest that G(ialpha) proteins and their regulators at these sites may play essential roles during mammalian cell division.


Reverse Genetics of Hepatitis C Virus Using an RNA Polymerase I-Mediated Transcription.
The reverse genetics system commonly used for the production of hepatitis C virus (HCV), which is a major causative agent of liver diseases, involves introduction of the viral genomic RNA synthesized in vitro into human hepatoma cells by electroporation. As an alternative methodology, we describe a cell culture system based on transfection with an expression plasmid containing a full-length HCV cDNA clone flanked by RNA polymerase I promoter and terminator sequences to generate infectious virus particles from transfected cells.


Chimpanzee minds: suspiciously human?
Chimpanzees undoubtedly form concepts related to the statistical regularities in behavior. But do they also construe such abstractions in terms of mental states - that is, do they possess a 'theory of mind'? Although both anecdotal and experimental data have been marshaled to support this idea, we show that no explanatory power or economy of expression is gained by such an assumption. We suggest that additional experiments will be unhelpful as long as they continue to rely upon determining whether subjects interpret behavioral invariances in terms of mental states. We propose a paradigm shift to overcome this limitation.


17.1% Efficient Single-Junction Organic Solar Cells Enabled by n-Type Doping of the Bulk-Heterojunction.
Molecular doping is often used in organic semiconductors to tune their (opto)electronic properties. Despite its versatility, however, its application in organic photovoltaics (OPVs) remains limited and restricted to p-type dopants. In an effort to control the charge transport within the bulk-heterojunction (BHJ) of OPVs, the n-type dopant benzyl viologen (BV) is incorporated in a BHJ composed of the donor polymer PM6 and the small-molecule acceptor IT-4F. The power conversion efficiency (PCE) of the cells is found to increase from 13.2% to 14.4% upon addition of 0.004 wt% BV. Analysis of the photoactive materials and devices reveals that BV acts simultaneously as n-type dopant and microstructure modifier for the BHJ. Under optimal BV concentrations, these synergistic effects result in balanced hole and electron mobilities, higher absorption coefficients and increased charge-carrier density within the BHJ, while significantly extending the cells' shelf-lifetime. The n-type doping strategy is applied to five additional BHJ systems, for which similarly remarkable performance improvements are obtained. OPVs of particular interest are based on the ternary PM6:Y6:PC71BM:BV(0.004 wt%) blend for which a maximum PCE of 17.1%, is obtained. The effectiveness of the n-doping strategy highlights electron transport in NFA-based OPVs as being a key issue.


phylochipanalyser - a program for analysing hierarchical probe sets.
The recent introduction of phylochips that contain molecular probes facilitates environmental microbial identification in a single experiment without previous cultivation. A set of probes recognizing species at different taxonomic levels is denoted as a hierarchical set. Application of hierarchical probe sets on a DNA microarray allows the assessment of biodiversity with different resolutions. It significantly increases the robustness of the results retrieved from phylochip experiments because of the possible consistency checks of hybridization across different taxonomic levels. Here, we present a computer program, phylo-chipanalyser, for the hierarchy editing and the evaluation of phylochip data generated from hierarchical probe sets.


Deadenylation-independent stage-specific mRNA degradation in Leishmania.
The life cycle of Leishmania alternates between developmental forms residing within the insect vector (e.g. promastigotes) and the mammalian host (amastigotes). In Leishmania nearly all control of gene expression is post-transcriptional and involves sequences in the 3'-untranslated regions (3'UTRs) of mRNAs. Very little is known as to how these cis-elements regulate RNA turnover and translation rates in trypanosomatids and nothing is known about mRNA degradation mechanisms in Leishmania in particular. Here, we use the amastin mRNA-an amastigote-specific transcript-as a model and show that a approximately 100 nt U-rich element (URE) within its 3'UTR significantly accounts for developmental regulation. RNase-H-RNA blot analysis revealed that a major part of the rapid promastigote-specific degradation of the amastin mRNA is not initiated by deadenylation. This is in contrast to the amastin mRNA in amastigotes and to reporter RNAs lacking the URE, which, in common with most eukaryotic mRNAs studied to-date, are deadenylated before being degraded. Moreover, our analysis did not reveal a role for decapping in the stage-specific degradation of the amastin mRNA. Overall, these results suggest that degradation of the amastin mRNA of Leishmania is likely to be bi-phasic, the first phase being stage-specific and dependent on an unusual URE-mediated pathway of mRNA degradation.


Cocaine induced hypertensive encephalopathy.
A 40 year old chronic cocaine abuser came to hospital with a blood pressure of 260/160, headache, agitation and bilateral papilledema. She was felt to have hypertensive encephalopathy secondary to cocaine abuse. She failed to respond to initial treatment with intravenous nitroprusside alone but was responsive to additional therapy with captopril.


A diterpene as an endogenous signal for the activation of defense responses to infection with tobacco mosaic virus and wounding in tobacco.
In pathogen-infected or wounded tobacco plants, the activation of wound-induced protein kinase (WIPK), a tobacco mitogen-activated protein kinase, has been implicated in the defense response. However, no endogenous signal responsible for the activation has been identified. A WIPK-activating substance was isolated from tobacco leaves and identified as (11E,13E)-labda-11,13-diene-8alpha,15-diol, designated WAF-1. When applied in nanomolar concentrations to leaves, either natural WAF-1 or chemically synthesized WAF-1 activated WIPK as well as salicylic acid-induced protein kinase, a tobacco mitogen-activated protein kinase, and enhanced the accumulation of transcripts of wound- and pathogen-inducible defense-related genes. Quantitative analysis of endogenous WAF-1 revealed that levels increased rapidly in leaves during a hypersensitive response to Tobacco mosaic virus (TMV) and after wounding. Furthermore, treatment of leaves with WAF-1 resulted in enhanced resistance to TMV infection. These results suggest that WAF-1 functions as an endogenous signal to mediate the defense responses of tobacco plants to TMV infection and wounding.


A physical model-based approach to detecting sky in photographic images.
Sky is among the most important subject matter frequently seen in photographic images. We propose a model-based approach consisting of color classification, region extraction, and physics-motivated sky signature validation. First, the color classification is performed by a multilayer backpropagation neural network trained in a bootstrapping fashion to generate a belief map of sky color. Next, the region extraction algorithm automatically determines an appropriate threshold for the sky color belief map and extracts connected components. Finally, the sky signature validation algorithm determines the orientation of a candidate sky region, classifies one-dimensional (1-D) traces within the region based on a physics-motivated model, and computes the sky belief of the region by the percentage of traces that fit the physics-based sky trace model. A small-scale, yet rigorous test has been conducted to evaluate the algorithm performance. With approximately half of the images containing blue sky regions, the detection rate is 96% with a false positive rate of 2% on a per image basis.


Fascioliasis: role of proline in bile duct hyperplasia.
In animals fascioliasis, extensive hyperplasia of the main bile duct occurs that often results in enlargement of the duct to more than 20 times the normal. We report that proline infused into the abdominal cavity of rats caused hyperplasia of the bile duct resembling that produced in the early stages of the disease. We suggest that Fasciola hepatica, which synthesizes and releases large amounts of proline, induces enlargement of the bile duct by a similar mechanism.


Characterization of a murine lung adenocarcinoma (LAC1), a useful experimental model to study progression of lung cancer.
Lung cancer is one of the most important avoidable causes of death around the world, the most widespread carcinoma, with a very poor prognosis, and is the leading cause of cancer death in both developed and developing countries. We report morphological and biological behavior characteristics of a tumor that arose in only one BALB/c mouse of an experimental group treated with urethane, a chemical lung-tumorigenic agent. Morphological and immunochemical analysis indicated phenotypic compatibility with a lung adenocarcinoma. The tumor was named LAC1 (lung adenocarcinoma 1). Implant success in eight LAC1-bearing mice generations was 100%, with a fast evolution (58 survival days) and good metastatic capacity (41% of animals with metastases). The tumor induced a paraneoplastic syndrome characterized by anemia, neutrophilia, cachexia, splenomegaly and thymic atrophy. The lymphoproliferation to Con A was altered in tumor-bearing mice. This lung adenocarcinoma may be a useful experimental model for studying tumor progression, paraneoplastic syndromes and immunology in carcinogenic studies.


Exposure to metal ions regulates mRNA levels of APP and BACE1 in PC12 cells: blockage by curcumin.
Amyloid beta peptide (Abeta), generated by proteolytic cleavage of the amyloid precursor protein (APP), play a pivotal role in the pathogenesis of Alzheimer's disease (AD). The key step in the generation of Abeta is cleavage of APP by beta-site APP-cleaving enzyme 1 (BACE1). There is increasing evidence supporting an interaction between APP, Abeta and metal ions. Both APP and Abeta affect ion homeostasis. Conversely, metal ions may interact with several AD-associated pathways involved in neurofibrillary tangle formation, secretase cleavage of APP, proteolytic degradation of Abeta and the generation of reactive oxygen species. However, the underlying mechanisms remain elusive. Here we first reported the differential effects of AD-related metal ions at subtoxic concentrations on the transcription levels of APP and BACE1 in PC12 cells. Copper (Cu(2+), 50-100 microM) and manganese (Mn(2+), 50-100 microM) potently increased the expression of both APP and BACE1 in a time- and concentration-dependent pattern, while zinc (Zn(2+)), iron (Fe(2+)) and aluminum (Al(3+)) did not. To uncover the mechanism(s) of the increasing expression by these ions, we observed the effects of several antioxidants and some specific inhibitors on the up-expression of APP and BACE1 by metal ions. Curcumin almost completely blocked the effects of these irons, while minocycline and sodium ferulate slightly suppressed the increased BACE1 mRNA level. Signaling pathway specific inhibitors PD98059, SB203580 and CEP11004 modestly blocked the up-transcription of APP induced by copper. These results suggest that these irons cause differential effects on the expression of APP and BACE1 in PC12 cells, and curcumin can significantly reverse their effects.


Troponin measurements, myocardial infarction diagnoses and outcomes. An analysis of linked data from New South Wales, Australia.
Cardiac troponin assays are very widely requested tests, particularly in emergency departments. Thus, many seriously ill patients who may not have heart disease as their primary discharge diagnosis have undergone troponin testing during hospitalisation. To determine associations between cardiac troponin levels and mortality, including from cardiovascular and non-cardiovascular causes, among patients hospitalised in New South Wales, Australia over a 2-year period. Over a 2-year period (2006-2008), 172 753 hospitalised patients had a quantitative or qualitative troponin assay performed in New South Wales (Australia). The associations were examined, using data linked to late outcomes, between elevations in levels of troponins T or I and 1-year mortality. Mortality was determined for International Statistical Classification of Diseases 10th Revision diagnostic groups. Of 172 753 patients undergoing troponin testing, 44 357 (25%) had a cardiovascular diagnosis of whom (7% had myocardial infarction) 47 827 (28%) had a probable ischaemic heart disease diagnosis if the 23 873 (14%) of patients coded with 'chest pain' were included. In patients with a cardiovascular diagnosis and elevated troponin 3060 (1.8%) died in 12 months in comparison to 6262 (3.6%) in those with a non-cardiovascular disease diagnoses and elevated troponin. The 1-year mortality hazard with respect to a troponin elevation was 2.5 (95% confidence interval 2.3-2.7) and 2.0 (95% confidence interval 1.99-2.01) for those with a cardiovascular and non-cardiovascular diagnosis respectively. In a very large state-wide hospitalised patient cohort, among patients with elevated troponin levels and non-cardiac diagnoses, mortality was higher than in those with cardiovascular diagnoses, including MI.


Assessment of Foodborne Disease Hazards in Beverages Consumed in Nigeria: A Systematic Literature Review.
Risk assessment is a formal process of identifying hazards and assessing the risk associated with them (risk is a combination of the severity of illness and the probability of occurrence). This review highlights foodborne disease hazards reported in beverages consumed in Nigeria for the period between 2000 and 2020. Based on a preregistered protocol and search syntax, studies were retrieved from the PubMed, Google Scholar, and ScienceDirect databases. Rayyan QCRI software was used to screen the articles. Data were then extracted from the included full-text articles, into a standardized excel workbook. A total of 18,762 articles were identified, from which 126 were included in the final analyses. The common beverages studied were sachet water (14.9%), borehole/well water (13.9%), cereal-based beverages (12.1%), raw/fresh milk (8.3%) and nono/nunu, which is a fermented milk-cereal beverage (7.2%). Sufficient data were available to undertake pooled prevalence estimates for some hazards within select beverages and revealed contamination rates for Staphylococcus spp. in raw/fresh milk, 12.3% (95% CI 6.3-20.0); Salmonella spp. in borehole/well water, 19.8% (95% CI 13.1-27.4); Klebsiella spp. in sachet water, 40.0% (95% CI 12.4-71.7); Staphylococcus spp. in nono/nunu, 32.6% (95% CI 14.7-53.8), and Escherichia spp. in nono/nunu, 30.7% (95% CI 21.9-40.2). Heterogeneity was present in the aggregate summary estimates. This review has highlighted the presence of several hazards of high importance to public health in commonly consumed beverages in Nigeria. The data presented here provide an entry point for future quantitative risk assessments both to determine the level of exposure of the community to these hazards and also for the identification of the most effective mitigation strategies to reduce these risks and improve health outcomes in Nigeria.