Synaptotagmin 7 confers frequency invariance onto specialized depressing synapses.
At most synapses in the brain, short-term plasticity dynamically modulates synaptic strength. Rapid frequency-dependent changes in synaptic strength have key roles in sensory adaptation, gain control and many other neural computations. However, some auditory, vestibular and cerebellar synapses maintain constant strength over a wide range of firing frequencies, and as a result efficiently encode firing rates. Despite its apparent simplicity, frequency-invariant transmission is difficult to achieve because of inherent synaptic nonlinearities. Here we study frequency-invariant transmission at synapses from Purkinje cells to deep cerebellar nuclei and at vestibular synapses in mice. Prolonged activation of these synapses leads to initial depression, which is followed by steady-state responses that are frequency invariant for their physiological activity range. We find that synaptotagmin 7 (Syt7), a calcium sensor for short-term facilitation, is present at both synapses. It was unclear why a sensor for facilitation would be present at these and other depressing synapses. We find that at Purkinje cell and vestibular synapses, Syt7 supports facilitation that is normally masked by depression, which can be revealed in wild-type mice but is absent in Syt7 knockout mice. In wild-type mice, facilitation increases with firing frequency and counteracts depression to produce frequency-invariant transmission. In Syt7-knockout mice, Purkinje cell and vestibular synapses exhibit conventional use-dependent depression, weakening to a greater extent as the firing frequency is increased. Presynaptic rescue of Syt7 expression restores both facilitation and frequency-invariant transmission. Our results identify a function for Syt7 at synapses that exhibit overall depression, and demonstrate that facilitation has an unexpected and important function in producing frequency-invariant transmission.


The diagnosis of delirium among elderly patients presenting to the emergency department of an acute hospital.
Delirium is prevalent among elderly people presenting to an emergency department (ED). However, despite the fact that delirium is associated with longer hospital stays, an increased rate of institutionalization and higher mortality (especially in the case of undiagnosed delirium), this condition often goes undiagnosed by ED doctors. We examined the rate of mental status assessment and the prevalence of delirium in the ED among patients older than 65 years in a large teaching hospital in Southern Israel via a retrospective chart review. Surprisingly we found no diagnosis of delirium in the medical charts of representative sample of 319 elderly people. Furthermore, only 12.5% of people received either an adequate or even a partially adequate mental status assessment by the ED doctors. We attribute these negative findings not to a low incidence of delirium but probably to a combination of a heavy workload along with a lack of adequate training of ED physicians. We suggest that part of the solution involves providing appropriate education to ED physicians as well as adding a geriatric consultant to the ED roster.


Discovering Biomarkers within the Genomic Landscape of Renal Cell Carcinoma.
Recent advances in molecular sequencing technology have led to the discovery of numerous biomarkers in renal cell carcinoma (RCC). These biomarkers have the potential to predict clinical outcomes and aid in clinical management decisions. The following commentary is a review of the preliminary data on some of the most promising genetic biomarker candidates.


Preclinical evaluation of Raman nanoparticle biodistribution for their potential use in clinical endoscopy imaging.
Raman imaging offers unsurpassed sensitivity and multiplexing capabilities. However, its limited depth of light penetration makes direct clinical translation challenging. Therefore, a more suitable way to harness its attributes in a clinical setting would be to couple Raman spectroscopy with endoscopy. The use of an accessory Raman endoscope in conjunction with topically administered tumor-targeting Raman nanoparticles during a routine colonoscopy could offer a new way to sensitively detect dysplastic lesions while circumventing Raman's limited depth of penetration and avoiding systemic toxicity. In this study, the natural biodistribution of gold surface-enhanced Raman scattering (SERS) nanoparticles is evaluated by radiolabeling them with (64) Cu and imaging their localization over time using micropositron emission tomography (PET). Mice are injected either intravenously (IV) or intrarectally (IR) with approximately 100 microcuries (μCi) (3.7 megabecquerel (MBq)) of (64) Cu-SERS nanoparticles and imaged with microPET at various time points post injection. Quantitative biodistribution data are obtained as % injected dose per gram (%ID g(-1)) from each organ, and the results correlate well with the corresponding microPET images, revealing that IV-injected mice have significantly higher uptake (p < 0.05) in the liver (5 h = 8.96% ID g(-1); 24 h = 8.27% ID g(-1)) than IR-injected mice (5 h = 0.09% ID g(-1); 24 h = 0.08% ID g(-1)). IR-injected mice show localized uptake in the large intestine (5 h = 10.37% ID g(-1); 24 h = 0.42% ID g(-1)) with minimal uptake in other organs. Raman imaging of excised tissues correlate well with biodistribution data. These results suggest that the topical application of SERS nanoparticles in the mouse colon appears to minimize their systemic distribution, thus avoiding potential toxicity and supporting the clinical translation of Raman spectroscopy as an endoscopic imaging tool.


Product matrix. Patient-centered care the IS/MM response.
No single MMIS vendor has the total solution to meet the needs of patient-centered care. Addressing it should be one of their top priorities, since this is not fleeting fancy, but rather a new era of healthcare delivery. Elements that will be necessary include: increased communication between care centers and materiel management; electronic ordering and purchasing of goods with prime vendors; the ability to relieve inventory and charge patients without intruding on the care of the patient; the ability to track extensive usage data per care center and nurse server. Usage data can be employed during price negotiations and provide materiel management with important "gatekeeping" information. The more usage data that materiel management has, the more bargaining power will exist with the prime vendor, distributor and care center. It is important to note, however, that information must be concise and easy to obtain. Graphical information has more impact and provides the best visual guide for the materiel manager. A 400-page document containing the month's usage will not "cut it" anymore--if it ever did. The transference and reduction of inventory from the warehouses to the care center probably presents the biggest obstacle for materiel management and nursing. The more work that can done upfront by the prime vendor (such as separating the purchased items into bin-type devices for delivery to specific care centers), the faster the goods can be administered to the patient. With care mapping, the items may even be broken down further, based on case mix information. The items could, and sometimes actually are, stored in the patient's room. It is a nurse's dream to have at his or her fingertips all the supplies needed at the time of request. One key for MMIS in realizing this dream is to track and monitor the on-line, real-time information. In fact, some companies' business is providing immediate inventory replacement information using bed-side terminals. I believe everyone--materiel management, nursing, and information systems--must collaborate and be open to new roles in order to ensure the success of patient-centered care.


Implementation of an IMU Aided Image Stacking Algorithm in a Digital Camera for Unmanned Aerial Vehicles.
Images acquired with a long exposure time using a camera embedded on UAVs (Unmanned Aerial Vehicles) exhibit motion blur due to the erratic movements of the UAV. The aim of the present work is to be able to acquire several images with a short exposure time and use an image processing algorithm to produce a stacked image with an equivalent long exposure time. Our method is based on the feature point image registration technique. The algorithm is implemented on the light-weight IGN (Institut national de l'information géographique) camera, which has an IMU (Inertial Measurement Unit) sensor and an SoC (System on Chip)/FPGA (Field-Programmable Gate Array). To obtain the correct parameters for the resampling of the images, the proposed method accurately estimates the geometrical transformation between the first and the N-th images. Feature points are detected in the first image using the FAST (Features from Accelerated Segment Test) detector, then homologous points on other images are obtained by template matching using an initial position benefiting greatly from the presence of the IMU sensor. The SoC/FPGA in the camera is used to speed up some parts of the algorithm in order to achieve real-time performance as our ultimate objective is to exclusively write the resulting image to save bandwidth on the storage device. The paper includes a detailed description of the implemented algorithm, resource usage summary, resulting processing time, resulting images and block diagrams of the described architecture. The resulting stacked image obtained for real surveys does not seem visually impaired. An interesting by-product of this algorithm is the 3D rotation estimated by a photogrammetric method between poses, which can be used to recalibrate in real time the gyrometers of the IMU. Timing results demonstrate that the image resampling part of this algorithm is the most demanding processing task and should also be accelerated in the FPGA in future work.


[Arsenic and retinoic acid, towards targeted treatments of acute promyelocytic leukemia?].
Acute promyelocytic leukaemia is a key model system in cancer biology. Its exquisite sensitivity to retinoic acid constitutes the first example of differentiation therapy. The PML/RAR alpha fusion protein generated by the t(15; 17) translocation is the molecular basis of transformation. PML/RAR alpha induces transformation most likely through a dominant negative interference with the function of nuclear receptors leading to a differentiation block. The fusion protein also delocalizes PML and other nuclear body antigens and this alteration of nuclear protein traffic seems to play a role in growth control and apoptosis. The clinical response of this disease to retinoids and arsenic trioxide, both of which induce the degradation of the fusion protein, constitute the first example of a therapy directly targeted to a specific genetic lesion in a human cancer.


[Experience in examining the small bowel with the agent Enteroview].
The paper presents data of small bowel X-ray study in 20 patients by using the contrast agent Enteroview. Thirteen patients were found to have changes typical of chronic enteritis (n = 9); atypical location of the cecum and inflammatory ileocecal lesion (n = 2); Peutz-Jeghers syndrome (n = 10); Crohn's disease (n = 1). The X-ray semiotics of the normal and abnormally changed small bowel is given. The advantages of Interview during X-ray study are shown.


Physical activity and other health behaviors in adults with hypertrophic cardiomyopathy.
The clinical expression of hypertrophic cardiomyopathy (HC) is undoubtedly influenced by modifying genetic and environmental factors. Lifestyle practices such as tobacco and alcohol use, poor nutritional intake, and physical inactivity are strongly associated with adverse cardiovascular outcomes and increased mortality in the general population. Before addressing the direct effect of such modifiable factors on the natural history of HC, it is critical to define their prevalence in this population. A voluntary survey, drawing questions in part from the 2007 to 2008 National Health and Nutrition Examination Survey (NHANES), was posted on the HC Association website and administered to patients with HC at the University of Michigan. Propensity score matching to NHANES participants was used. Dichotomous and continuous health behaviors were analyzed using logistic and linear regression, respectively, and adjusted for body mass index and propensity score quintile. Compared to the matched NHANES participants, the patients with HC reported significantly less alcohol and tobacco use but also less time engaged in physical activity at work and for leisure. Time spent participating in vigorous or moderate activity was a strong predictor of self-reported exercise capacity. The body mass index was greater in the HC cohort than in the NHANES cohort. Exercise restrictions negatively affected emotional well-being in most surveyed subjects. In conclusion, patients with HC are less active than the general United States population. The well-established relation of inactivity, obesity, and cardiovascular mortality might be exaggerated in patients with HC. More data are needed on exercise in those with HC to strike a balance between acute risks and the long-term health benefits of exercise.


Proteasomes: unfoldase-assisted protein degradation machines.
Proteasomes are the principal molecular machines for the regulated degradation of intracellular proteins. These self-compartmentalized macromolecular assemblies selectively degrade misfolded, mistranslated, damaged or otherwise unwanted proteins, and play a pivotal role in the maintenance of cellular proteostasis, in stress response, and numerous other processes of vital importance. Whereas the molecular architecture of the proteasome core particle (CP) is universally conserved, the unfoldase modules vary in overall structure, subunit complexity, and regulatory principles. Proteasomal unfoldases are AAA+ ATPases (ATPases associated with a variety of cellular activities) that unfold protein substrates, and translocate them into the CP for degradation. In this review, we summarize the current state of knowledge about proteasome - unfoldase systems in bacteria, archaea, and eukaryotes, the three domains of life.


Optical coherence tomography angiography in primary eye care.
Optical coherence tomography angiography (OCT-A) is a non-invasive imaging modality for assessing the vasculature within ocular structures including the retina, macula, choroid and optic nerve. OCT-A has a wide range of clinical applications in various optometric conditions which have been independently reported in the literature. This paper aims to present a review of the current literature on the clinical application of OCT-A in optometric practice as well as to analyse and evaluate the quality of the available evidence. This review included 78 articles from a literature search conducted on 26 May 2019 across the following databases: Cochrane Library of Systematic Reviews, Medline, Scopus and Web of Science. Primary ocular pathologies discussed in this review include glaucoma, diabetic retinopathy, age-related macular degeneration, myopia, acquired and congenital macular dystrophies, epiretinal membrane, retinal vein occlusion, retinitis pigmentosa, choroidal melanoma, uveitis, central serous chorioretinopathy, amblyopia and optic neuropathies. Primary outcome variables included vessel density, foveal avascular zone area and diameter, flow velocity and flow index. This review aims to evaluate the evidence available for OCT-A applications in diagnosis and prognosis of ocular conditions in an optometric setting.


Representing the Glasgow Coma Scale in IT: Proper Specification is Required for Assessment Scales.
In healthcare a huge amount of assessment scales and score systems are in use to abbreviate and summarize the results of clinical observations to interpret a patient's condition in a valid and reliable manner. It is challenging to convey the information in a semantic interoperable form to other systems. A bad approach would be to invent individual models for each of them. Within this paper we would like to demonstrate that a generic model is sufficient by demonstrating the realization with the Glasgow Coma Scale.


Forensic psychiatric reports for victims of sexual assault and consensus problems among expertise institutes.
It is known that sexual assault sets the stage for various mental diseases. Post-traumatic stress disorder, depression, anxiety disorder, and adjustment disorder are most commonly encountered. In this paper, the aim was to determine the demographic characteristics of the sex crimes which were prosecuted at the courts in the city of Eskisehir, to evaluate the forensic reports which were prepared by different institutes for sex crime victims in order to clarify the impairment of physical or mental health, to discuss the contradictions between the institutions about this subject; and within this context, to determine the troubles which were experienced at the stage of implementing clauses of the Criminal Code related to sexual assault. The files of legal investigations of the sex crime cases which were transferred to the legal authorities between 01.06.2005 and 31.12.2008 were analyzed and the process of trial and court verdicts were evaluated. It was established that there was no consensus on the evaluation of impairment of the mental health between local institutes and the Council of Forensic Medicine. It was concluded that parallel evaluations between the Council of Forensic Medicine and other health institutes on 'the impairment of physical or mental health' are necessary, and units should be established at local levels where forensic medicine specialists, psychiatrists and child and adolescent psychiatrists can work together and where the victim is listened to and examined only one time and, if necessary, biological samples can be taken and evaluated, which will make a great contribution to the solution of the problems.


Risk of death or incapacitation after heart transplantation, with particular reference to pilots.
Pilots who have received a heart transplant may subsequently want to resume flying. This study was undertaken to determine whether a group of heart transplant recipients who had a particularly low risk of sudden unexpected death could be identified from clinical data. An event, "rapid-onset death," was defined incorporating a number of possible causes of death that could result in a heart transplant recipient-pilot losing control of an airplane. The survival of 3676 patients undergoing a first heart transplantation was 85% and 73% at 1 and 5 years, respectively, the hazard function having a high early phase of risk. When time zero was moved to the beginning of the second year after transplantation, the freedom from "rapid-onset death" at posttransplantation year 2 and posttransplantation year 5 was 96.8% and 88%, respectively. For patients who had both a "normal" coronary angiogram and no episodes of acute heart rejection during the first year transplantation, the probability of "rapid onset death" during the second posttransplantation year was 1.4%, and given the same circumstances, during the third posttransplantation year the risk of "rapid-onset death" was 1.6%. This information is potentially useful to the Federal Aviation Administration for policy decisions regarding this issue.


Technological advances in laparoscopic aorto-occlusive surgery.
Minimally invasive surgery (MIS) has been recognized as increasingly beneficial to patients undergoing various cardiovascular surgical procedures. Cardiac applications with MIS techniques and technologies are being shown as beneficial in heart valve replacement and in coronary artery bypass. In vascular surgery, benefits are being reported for endoscopic saphenous vein harvesting as well as endoscopic ligation of incompetent perforators. Since 1993, applications of laparoscopy to aortic surgery have been reported. Until these reports, percutaneous interventional procedures have been the mainstay of MIS vascular work for aortoiliac disease. Reported laparoscopic techniques have ranged from laparoscopically assisted techniques to procedures performed completely laparoscopically. Several studies show that laparoscopic aortic surgery is feasible. These show the known advantages of MIS for patients, with decreased use of analgesics, shortened ileus, earlier ambulation, and shortened length of stay. Laparoscopy has been showing a growing role in the armamentarium of the modern vascular surgeon.


Efficacy and safety evaluations of anlotinib in patients with advanced non-small cell lung cancer treated with bevacizumab.
Objective: The purpose of this study is to evaluate the efficacy and safety of anlotinib in patients with advanced non-small cell lung cancer (NSCLC) who had previously received bevacizumab. Methods: The participants were histopathologically or cytologically diagnosed advanced NSCLC patients whose disease progressed after at least one type of systemic therapy and who had previously received bevacizumab treatment. The patients were on 3-week administration cycles, including 2 weeks on-treatment (12 mg anlotinib oral route, once a day) and 1 week off-treatment. The primary end point of the trial was overall survival (OS). The secondary end points were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and safety. Results: As of the data collection deadline (31 March 2021), 30 patients were enrolled in the study and received anlotinib treatment. All patients were included in the data set except one, who withdrew their consent after the start of treatment. The median follow-up period was 12.1 months (range, 3.6-25.0 months), and 29 patients were included in the evaluation of the treatment. Of the 29 patients, no CR cases occurred. In total, three patients (10.2%) showed a PR, 21 (72.4%) had SD, and five patients (17.2%) had PD. The objective response rate (ORR) was 10.2% (3 of 29 patients), and the disease control rate (DCR) was 82.7% (24 of 29 patients). The median progression-free survival (PFS) was 5.6 months (95% CI, 5.0-6.1 months; Figure 2). The median overall survival (OS) was 10.6 months (95% CI, 9.4-11.8 months; Figure 3). The overall tolerance of the anlotinib treatment was high among the enrolled patients. No treatment-related grade four or five toxicities were observed. Of the 29 patients, one patient's anlotinib administration was reduced to 8 mg/day due to hypertension and headache. Most adverse events (AEs) were grade one or two; the most common AEs were fatigue (51.7%), hypertension (41.3%), hand-foot syndrome (41.4%), anorexia (34.5%) and hypertriglyceridemia (34.5%). Conclusion: Anlotinib demonstrated favourable activity and manageable toxicity in NSCLC patients who were treated with bevacizumab previously.


Automatically recognizing strategic cooperative behaviors in various situations of a team sport.
Understanding multi-agent cooperative behavior is challenging in various scientific and engineering domains. In some cases, such as team sports, many cooperative behaviors can be visually categorized and labeled manually by experts. However, these actions which are manually categorized with the same label based on its function have low spatiotemporal similarity. In other words, it is difficult to find similar and different structures of the motions with the same and different labels, respectively. Here, we propose an automatic recognition system for strategic cooperative plays, which are the minimal, basic, and diverse plays in a ball game. Using player's moving distance, geometric information, and distances among players, the proposed method accurately discriminated not only the cooperative plays in a primary area, i.e., near the ball, but also those distant from a primary area. We also propose a method to classify more detailed types of cooperative plays in various situations. The proposed framework, which sheds light on inconspicuous players to play important roles, could have a potential to detect well-defined and labeled cooperative behaviors.


Magnesium protoporphyrin chelatase activity in Rhodopseudomonas spheroides. Studies with whole cells.
1. Whole cells of Rhodopseudomonas spheroides grown under semi-anaerobic conditions in the light incorporated magnesium into exogenous protoporphyrin when incubated with EDTA or the related chelators EGTA, N-(2-hydroxyethyl)-ethylenediamine-NN'N'- triacetate and trans-1,2-diaminocyclohexanetetra-acetate. 2. The reaction was demonstrated under anaerobic conditions in the light or at low oxygen partial pressure in the dark. Partial pressures of oxygen greater than 15% inhibited the reaction. 3. Cells grown under pure oxygen were completely inactive, but on adaptation to growth under low oxygen partial pressure (O(2)+N(2), 5:95) the development of activity paralleled the synthesis of bacteriochlorophyll. 4. The reaction with normal cells did not require protein synthesis, but cells that had lost their activity by being illuminated in Mg(2+)-deficient medium did not recover it in the absence of protein synthesis. 5. The product of the reaction was magnesium protoporphyrin monomethyl ester. 6. Evidence is presented that insertion of magnesium is obligatorily coupled with methylation and it is concluded that the reaction is dependent on a multienzyme complex.


Cytogenetic abnormalities and overexpression of receptors for growth factors in normal bronchial epithelium and tumor samples of lung cancer patients.
A cytogenetic analysis was performed on direct preparations and short-term cell cultures of lung tumor and normal bronchial epithelium of 19 patients carrying either a first or a second primary lung cancer. In 9 tumors (6 squamous cell carcinomas, 1 adenocarcinoma, 1 mucoepidermoid carcinoma, and 1 small cell lung carcinoma) successfully analyzed, pseudodiploid and hyperdiploid karyotypes were observed with a heterogeneous pattern of chromosome abnormalities but with a consistent involvement (5 cases) of the short or the long arm of chromosome 3. The normal bronchial epithelial cells had a normal karyotype in 11 patients, whereas in 6 patients clonal and nonclonal chromosomal abnormalities were observed. Involvement of chromosome 7 was present in 4 cases. In addition, overexpression of the growth factor receptors, epidermal growth factor receptor and HER-2/neu, was found in 9 of 18 tumors and in 6 of 13 bronchial epithelium samples. These findings suggest that early genetic lesions could be present in the normal bronchial epithelial cells that are the target of further complex and multiple genetic changes occurring during the pathogenesis of lung cancer.


Characterization of Stachybotrys from water-damaged buildings based on morphology, growth, and metabolite production.
Stachybotrys was found to be associated with idiopathic pulmonary hemorrhage in infants in Cleveland, Ohio. Since that time, considerable effort has been put into finding the toxic components responsible for the disease. The name Stachybotrys chartarum has been applied to most of these isolates, but inconsistent toxicity results and taxonomic confusion prompted the present study. In this study, 122 Stachybotrys isolates, mainly from water-damaged buildings, were characterized and identified by combining three different approaches: morphology, colony characteristics, and metabolite production. Two different Stachybotrys taxa, S. chartarum and one undescribed species, were found in water-damaged buildings regardless of whether the buildings were in Denmark, Finland, or the USA. Furthermore, two chemotypes could be distinguished in S. chartarum. One chemotype produced atranones, whereas the other was a macrocyclic trichothecene-producer. The second undescribed taxon produced atranones and could be differentiated from S. chartarum by its growth characteristics and pigment production. Our results correlate with different inflammatory and toxicological properties reported for these same isolates and show that the three taxa/chemotypes should be treated separately. The co-occurrence of these three taxa/chemotypes in water-damaged buildings explains the inconsistent results in the literature concerning toxicity of Stachybotrys isolated from that environment.


A Priori Identifiability of Target-Mediated Drug Disposition Models and Approximations.
A priori identifiability of mathematical models assures that for a given input/output experiment, the parameter set has one unique solution within a defined space, independent of the experimental design. Many biologic therapeutics exhibit target-mediated drug disposition (TMDD), and use of the full compartmental model describing this system is well documented. In practice, estimation of the full parameter set for TMDD models, given real-world clinical data, is characterized by convergence difficulties and unstable solutions. Still, the formal assessment of the a priori identifiability of these systems has yet to be reported. The exact arithmetic rank (EAR) approach was used to test the a priori identifiability of a TMDD model as well as model approximations. The full TMDD and quasi-equilibrium/rapid binding (QE/RB), quasi-steady state (QSS), and Michaelis-Menten (MM) approximations were fully identifiable, a priori, regardless of whether observations were taken from a single or multiple compartments. The results of these identifiability analyses indicated that the difficulty with TMDD model convergence, a posteriori, lies in the experimental design, not in the mathematical identifiability in the lack of samples from several compartments. Experiments can be tailored to resolve these structurally non-identifiable parameters, notwithstanding practical implementation challenges. This work highlights the importance of identifiability analyses, specifically how they can influence experimental design and selection of the appropriate model structure to describe a dynamic biological system.


Cloning, characterization, and DNA sequence of the rfaLK region for lipopolysaccharide synthesis in Salmonella typhimurium LT2.
We have cloned and sequenced the rfaL and rfaK genes for lipopolysaccharide synthesis in Salmonella typhimurium LT2 on a 4.28-kb HindIII fragment from the previously described R' factor pKZ3 (S. K. Kadam, A. Rehemtulla, and K. E. Sanderson, J. Bacteriol. 161:277-284, 1985). rfaL is thought to encode a component of the O-antigen ligase, and rfaK is believed to encode the N-acetylglucosamine transferase. The genes were identified by the loss of complementation of prototype rfaL and rfaK mutations after Tn1000 mutagenesis. Translation of the nucleotide sequence predicted sizes of 45.9 and 43.1 kDa for the rfaL and rfaK gene products, respectively. Hydropathy analysis of the rfaL product suggested that it was an integral membrane protein. A third gene, rfaZ, was found to be an 808-bp open reading frame on the pyrE side of rfaK. Insertions into rfaZ reduced rfaK complementation, suggesting cotranscription in the pyrE-cysE direction. The rfaL gene is transcribed in the opposite direction in a separate operon which may also include rfaC. An incomplete open reading frame with homology to an Escherichia coli gene in the same region, rfaY, was found on the pyrE side of rfaZ. Complementation studies with Tn1000 insertions in rfaL showed that rfaL446 and rfaL447 are allelic. With the cloning of the rfaL and -K genes, the order of genes within the rfa cluster at 79 units on the linkage map was found to be cysE-rfaDFCLKZYJIBG-pyrE.


Large-scale land acquisitions exacerbate local farmland inequalities in Tanzania.
Land inequality stalls economic development, entrenches poverty, and is associated with environmental degradation. Yet, rigorous assessments of land-use interventions attend to inequality only rarely. A land inequality lens is especially important to understand how recent large-scale land acquisitions (LSLAs) affect smallholder and indigenous communities across as much as 100 million hectares around the world. This paper studies inequalities in land assets, specifically landholdings and farm size, to derive insights into the distributional outcomes of LSLAs. Using a household survey covering four pairs of land acquisition and control sites in Tanzania, we use a quasi-experimental design to characterize changes in land inequality and subsequent impacts on well-being. We find convincing evidence that LSLAs in Tanzania lead to both reduced landholdings and greater farmland inequality among smallholders. Households in proximity to LSLAs are associated with 21.1% (P = 0.02) smaller landholdings while evidence, although insignificant, is suggestive that farm sizes are also declining. Aggregate estimates, however, hide that households in the bottom quartiles of farm size suffer the brunt of landlessness and land loss induced by LSLAs that combine to generate greater farmland inequality. Additional analyses find that land inequality is not offset by improvements in other livelihood dimensions, rather farm size decreases among households near LSLAs are associated with no income improvements, lower wealth, increased poverty, and higher food insecurity. The results demonstrate that without explicit consideration of distributional outcomes, land-use policies can systematically reinforce existing inequalities.


Gamifying Breastfeeding for Fathers: Process Evaluation of the Milk Man Mobile App.
Mobile technology offers unique opportunities to reach people with health promotion interventions. Breastfeeding is an important public health issue, and fathers are a key support. Milk Man is a father-focused breastfeeding app that sought to engage fathers with information and conversation about breastfeeding, with the goal to impact positively on breastfeeding duration. The study aimed to describe the process evaluation of the Milk Man app that was trialed in the Parent Infant Feeding Initiative randomized controlled trial. The app used an information library, gamification, push notifications, and social connectivity via a Web-based conversation forum, which included polls and conversation starters, to engage fathers with breastfeeding information. Fathers had access to the app from approximately 32 weeks of gestation to 6 months postpartum. Process evaluation data were collected from a self-completed questionnaire administered via a Web-based link sent to participants at 6 weeks postpartum, and app analytics data were collected directly from the app. Quantitative data from both sources and qualitative responses to open-ended questions were used to triangulate findings to investigate patterns of usage and the effectiveness of each app engagement strategy to motivate and engage users. A total of 80.3% (586/730) of participants, who were randomized to receive the app, downloaded Milk Man. Push notifications and interest in what other fathers had posted in the forum were the 2 main motivators to app use. Fathers used the app most while their partners were still pregnant and in the weeks immediately after the birth of their baby. Perspectives on the gamification strategy were varied. However, at 6 weeks postpartum, approximately one-third of fathers still using the app said that the gamification elements were encouraging the app use. The ease of use of the app and the design were important elements that were rated positively. The conversation forum emerged as the hub of app activity; all but 1 of the most accessed library articles and external organization links had been prompted as part of a conversation starter. Fathers posted comments in the conversation forum 1126 times (average of 2.21 per user) and voted in polls 3096 times (average of 6 per user). These results demonstrate that the Milk Man app was an acceptable source of breastfeeding information and support that fathers and fathers-to-be are prepared to use throughout the perinatal period. The app showed encouraging results with facilitating conversation between partners. The conversation forum was clearly central to the success of the app, and fathers provided suggestions for improvement. Gamification results were varied, yet it was a key motivator for some users. These results provide valuable insight into the acceptability of the engagement strategies, including motivations for use and user perspectives on the app. Australian New Zealand Clinical Trials Registry ACTRN12614000605695; https://www.anzctr.org.au /Trial/Registration/TrialReview.aspx?ACTRN=12614000605695.


Dimeric ferulic acid conjugate as a prodrug for brain targeting after nasal administration of loaded solid lipid microparticles.
Ferulic acid (Fer) displays antioxidant/anti-inflammatory properties useful against neurodegenerative diseases. To increase Fer uptake and its central nervous system residence time, a dimeric prodrug, optimizing the Fer loading on nasally administrable solid lipid microparticles (SLMs), was developed. The prodrug was synthesized as Fer dimeric conjugate methylated on the carboxylic moiety. Prodrug antioxidant/anti-inflammatory properties and ability to release Fer in physiologic environments were evaluated. Tristearin or stearic acid SLMs were obtained by hot emulsion technique. In vivo pharmacokinetics were quantified by HPLC. The prodrug was able to release Fer in physiologic environments (whole blood and brain homogenates) and induce in vitro antioxidant/anti-inflammatory effects. Its half-life in rats was 18.0 ± 1.9 min. Stearic acid SLMs, exhibiting the highest prodrug loading and dissolution rate, were selected for nasal administration to rats (1 mg/kg dose), allowing to obtain high prodrug bioavailability and prolonged residence in the cerebrospinal fluid, showing AUC (Area Under Concentration) values (108.5 ± 3.9 μg∙mL-1∙min) up to 30 times over those of Fer free drug, after its intravenous/nasal administration (3.3 ± 0.3/5.16 ± 0.20 μg∙mL-1∙min, respectively) at the same dose. Chitosan presence further improved the prodrug brain uptake. Nasal administration of prodrug-loaded SLMs can be proposed as a noninvasive approach for neurodegenerative disease therapy.


Case Report: Challenges of Diagnosing Malaria in Returning Travelers at the Height of COVID-19 Pandemic.
In 2021, we treated three patients in Southern California who contracted malaria while traveling in Uganda. Two patients visited the Nile River in Uganda in the months of July and August 2021, and upon returning to the United States, diagnosis was delayed due to limited access to care during the COVID-19 pandemic. One of the patients developed severe malaria, and the second developed parasitemia after he stopped taking malaria prophylaxis. The third patient, who traveled to Kampala, Uganda, in December 2021 returned home and was admitted for chronic medical conditions. Later in the clinical course, he developed symptoms consistent with malaria, but due to SARS-CoV-2 diagnosis, there was no suspicion of malaria infection until it was incidentally discovered while performing a blood manual differential. All patients were treated for malaria and recovered uneventfully.


Synthesis, characterization and biological evaluation of ureidofibrate-like derivatives endowed with peroxisome proliferator-activated receptor activity.
A series of ureidofibrate-like derivatives was prepared and assayed for their PPAR functional activity. A calorimetric approach was used to characterize PPARγ-ligand interactions, and docking experiments and X-ray studies were performed to explain the observed potency and efficacy. R-1 and S-1 were selected to evaluate several aspects of their biological activity. In an adipogenic assay, both enantiomers increased the expression of PPARγ target genes and promoted the differentiation of 3T3-L1 fibroblasts to adipocytes. In vivo administration of these compounds to insulin resistant C57Bl/6J mice fed a high fat diet reduced visceral fat content and body weight. Examination of different metabolic parameters showed that R-1 and S-1 are insulin sensitizers. Notably, they also enhanced the expression of hepatic PPARα target genes indicating that their in vivo effects stemmed from an activation of both PPARα and γ. Finally, the capability of R-1 and S-1 to inhibit cellular proliferation in colon cancer cell lines was also evaluated.


Long-term regulation of fat sensing in rainbow trout (Oncorhynchus mykiss) fed a vegetable diet from the first feeding: focus on free fatty acid receptors and their signalling.
Taste plays a fundamental role in an animal's ability to detect nutrients and transmits key dietary information to the brain, which is crucial for its growth and survival. Providing alternative terrestrial ingredients early in feeding influences the growth of rainbow trout (RT, Oncorhynchus mykiss). Thus, the present study aimed to assess the influence, via long-term feeding (from the first feeding to 8 months), of alternative plant ingredients (V diet for vegetable diet v. C diet for a control diet) in RT on the mechanism of fat sensing at the gustatory level. After the feeding trial, we studied the pathways of the fat-sensing mechanism in tongue tissue and the integrated response in the brain. To this end, we analysed the expression pattern of free fatty acid receptors (ffar) 1 and 2, markers of calcium-signalling pathways (phospholipase Cβ, Orai, Stim or Serca), the serotonin level (a key neurotransmitter in taste buds) and the expression pattern of appetite-regulating neuropeptides in the hypothalamus (central area of appetite regulation). The results revealed that the V diet modified the expression pattern of ffar1 and paralogs of ffar2 genes in tongue tissue, along with differential regulation of calcium-signalling pathways and a defect in serotonin level and brain turnover, without influencing neuropeptide expression. This study is the first to support that changes in feeding behaviour of RT fed a V diet could be due to the difference in nutrient sensing and a decrease in hedonic sensation. We revealed that RT have similar fat-detection mechanisms as mammals.


Guidelines and quality criteria for artificial intelligence-based prediction models in healthcare: a scoping review.
While the opportunities of ML and AI in healthcare are promising, the growth of complex data-driven prediction models requires careful quality and applicability assessment before they are applied and disseminated in daily practice. This scoping review aimed to identify actionable guidance for those closely involved in AI-based prediction model (AIPM) development, evaluation and implementation including software engineers, data scientists, and healthcare professionals and to identify potential gaps in this guidance. We performed a scoping review of the relevant literature providing guidance or quality criteria regarding the development, evaluation, and implementation of AIPMs using a comprehensive multi-stage screening strategy. PubMed, Web of Science, and the ACM Digital Library were searched, and AI experts were consulted. Topics were extracted from the identified literature and summarized across the six phases at the core of this review: (1) data preparation, (2) AIPM development, (3) AIPM validation, (4) software development, (5) AIPM impact assessment, and (6) AIPM implementation into daily healthcare practice. From 2683 unique hits, 72 relevant guidance documents were identified. Substantial guidance was found for data preparation, AIPM development and AIPM validation (phases 1-3), while later phases clearly have received less attention (software development, impact assessment and implementation) in the scientific literature. The six phases of the AIPM development, evaluation and implementation cycle provide a framework for responsible introduction of AI-based prediction models in healthcare. Additional domain and technology specific research may be necessary and more practical experience with implementing AIPMs is needed to support further guidance.


Recommendations for Structure and Content for a School-Based Adolescent Immunization Curriculum.
Despite high utilization of childhood vaccinations, adolescent immunization coverage rates lag behind recommended coverage levels. The four vaccines recommended for adolescents ages 11 to 18 years are tetanus, diphtheria, and pertussis vaccine; human papillomavirus vaccine; meningococcal conjugate vaccine; and an annual influenza vaccine. The Healthy People 2020 goal is 80% coverage for each recommended immunization, but coverage rates in Georgia among adolescents fall below those goals for all but the tetanus, diphtheria, and pertussis vaccine. We developed a multicomponent intervention that included a school-based, teacher-delivered educational curriculum to increase adolescent vaccination coverage rates in Richmond County, Georgia. We facilitated focus group discussions with middle- and high school science teachers who delivered the immunization curriculum in two consecutive school years. The objective of the focus group was to understand teachers' perspectives about the curriculum impact and to synthesize recommendations for optimal dissemination of the curriculum content, structure, and packaging. Teachers provided recommendations for curriculum fit within existing classes, timing of delivery, and dosage of delivery and recommended creating a flexible tool kit, such as a downloadable online package. Teachers also recommended increasing emphasis on disease transmission and symptoms to keep students engaged. These findings can be applied to the development of an online, cost-effective tool kit geared toward teaching adolescents about the immune system and adolescent vaccinations.


Perceptual Ranges, Information Gathering, and Foraging Success in Dynamic Landscapes.
How organisms gather and utilize information about their landscapes is central to understanding land-use patterns and population distributions. When such information originates beyond an individual's immediate vicinity, movement decisions require integrating information out to some perceptual range. Such nonlocal information, whether obtained visually, acoustically, or via chemosensation, provides a field of stimuli that guides movement. Classically, however, models have assumed movement based on purely local information (e.g., chemotaxis, step-selection functions). Here we explore how foragers can exploit nonlocal information to improve their success in dynamic landscapes. Using a continuous time/continuous space model in which we vary both random (diffusive) movement and resource-following (advective) movement, we characterize the optimal perceptual ranges for foragers in dynamic landscapes. Nonlocal information can be highly beneficial, increasing the spatiotemporal concentration of foragers on their resources up to twofold compared with movement based on purely local information. However, nonlocal information is most useful when foragers possess both high advective movement (allowing them to react to transient resources) and low diffusive movement (preventing them from drifting away from resource peaks). Nonlocal information is particularly beneficial in landscapes with sharp (rather than gradual) patch edges and in landscapes with highly transient resources.


Long-term drift and continued efficacy after multiyear timolol therapy.
The clinical courses of 41 patients who received timolol maleate for experimental protocols were reviewed. We reevaluated the conditions of 17 patients with the elevated pressures of primary open angle glaucoma who had received timolol alone or in combination with other glaucoma medications for a maximum of 35 months (average, 26 months). Withdrawal of timolol led to an average intraocular pressure rise of 5 mm Hg. Eight patients treated with timolol alone showed a progressive, significant, 3-mm Hg upward rise, or "long-term drift" in IOP during the follow-up period. Pressure rise after timolol withdrawal, however, was not significantly less than pressure reduction when timolol was initiated. At least two weeks are required for "washout" or disappearance of timolol effect after timolol is withdrawn, and re-treatment for one week restores IOP to prewithdrawal levels.


Tetra-phenyl-phospho-nium iodide-1,3,5-tri-fluoro-2,4,6-tri-iodo-benzene-methanol (3/4/1).
The crystallization of a 1:1 molar solution of 1,3,5-tri-fluoro-2,4,6-di-iodo-benzene (TFTIB) and tetra-phenyl-phosponium iodide (TPPI) from methanol produced tetra-gonal needles of pure TPPI and tabular pseudo-hexa-gonal truncated bipyramids of the title compound, 3C24H20P(+)·3I(-)·4C6F3I3·CH4O or (TPPI)3(TFTIB)4·MeOH. The asymmetric unit is composed of six TPPI mol-ecules, eight TFTIB mol-ecules and two methanol mol-ecules, overall 16 constituents. The formation of the architecture is essentially guided by a number of C-I⋯I(-) halogen bonds (XB), whose lengths are in the range 3.276 (1)-3.625 (1) Å. Layers of supra-molecular polyanions are formed parallel to (10-1) wherein iodide anions function as penta-, tetra- or bidentate XB acceptors. The structure is not far from being P21/n, but the centrosymmetry is lost due to a different conformation of a single couple of cations and the small asymmetry in the formed supra-molecular anion. One methanol mol-ecule is hydrogen bonded to an iodide anion, while the second is linked to the first one via an O-H⋯O contact. This second methanol mol-ecule is more loosely pinned in its position than the first and presents very high anisotropic displacement parameters and a seeming shortening of the C-O bond length. The crystal studied was refined as a perfect inversion twin.


Comparison of changes in diastolic functions after aortic valve replacement with freestyle stentless porcine xenografts in patients with restrictive and nonrestrictive physiology.
In this study, the effect of valve replacement on diastolic parameters was evaluated preoperatively and postoperatively at 3, 6, and 12 months by comparing diastolic parameters in patients after aortic valve replacement with freestyle stentless porcine xenografts for aortic stenosis. Depending on deceleration time (DT) and isovolumetric relaxation time (IVRT) with preoperative echocardiographic assessment, patients were divided into two groups: restrictive physiology (DT < or = 150 msec and IVRT < 100 msec, 20 patients), and nonrestrictive physiology (DT > 150 msec and IVRT > or = 100 msec, 27 patients). Although left ventricular mass index significantly decreased in both groups, improvement in DT, IVRT, and ejection fraction occurred only in patients with restrictive physiology. As a result, the patients with restrictive diastolic characteristics had more benefit than the patients with nonrestrictive physiology after aortic valve replacement.


Use of the Biopharmaceutical Classification System in early drug development.
The Biopharmaceutics Classification System (BCS) is not only a useful tool for obtaining waivers for in-vivo bioequivalence studies but also for decision making in the discovery and early development of new drugs. Measurement of solubility and permeability in the discovery/development settings is described. These data can be utilized for the preliminary BCS classification of pipeline compounds. A decision tree is described in the prioritization of salt and polymorph screening studies prior to in vivo studies in animals. For BCS class 1 and 3 compounds, polymorphism is less likely to impact on bioavailability. The polymorph screening study may be postponed after animal studies. The BCS classification can also be used in the design of animal and human formulations. A BCS-based animal formulation development decision tree is presented. A compound is triaged based on a series of decision points into one of the five formulation strategies. Human formulation has different requirements than animal formulation. A comparison between animal and human formulation strategies is presented. In conclusion, for non-BCS 1 compounds, the right-first-time polymorph and formulation selection ensures consistent pharmacokinetic performance and avoids bridging BA/BE studies. It is in line with FDA's initiative to reduce R&D cycle time through quality by design for pharmaceutical products.


Infidelity and kin selection: does cheating seem as bad when it's "all in the family"?
The current study explored people's perceptions of how they would feel if their partners cheated on them by having sex with their relatives, such as if a man's wife had sex with his brother. Kin selection theory suggests that in such situations, victims of infidelity might feel slightly better if their partners had sex with biological relatives (compared to sex with nonrelatives) because some of the victims' genes could still get passed on through their relatives. In two experiments, participants reported how they would feel in various scenarios involving their partners having sex with participants' relatives and nonrelatives. As expected, participants generally reported being very disapproving of a partner's hypothetical infidelity with both their relatives and nonrelatives. However, contrary to predictions generated by kin selection theory, participants tended to report that they would feel worse if their partners had sex with their relatives. We propose several explanations for the current findings and discuss their implications for kin selection theory.


Survival for older patients with acute myeloid leukemia: a population-based study.
Acute myeloid leukemia is the second most common leukemia among United States adults with a median age of 69 years. We investigated recent clinical practices related to treatments and disease outcomes in older patients with acute myeloid leukemia in the United States. In this retrospective cohort study, we used Surveillance, Epidemiology, and End Results program data from 2000 through 2007 linked to Medicare enrollment and utilization data in the United States. Among 5,480 patients with acute myeloid leukemia (median age 78 years, range 65-93), 38.6% received leukemia therapy within three months of diagnosis (treated group). Practice changed with 16.3% of treated patients receiving hypomethylating agents after 2004 when those agents became available. Median survival was two months in the untreated group versus six months in the treated group (P<0.01) with the biggest improvements seen in those aged 65-69 years (10 months vs. 4 months; P<0.01) and 70-74 years (8 months vs. 3 months; P<0.01). In 46 patients receiving allogeneic hematopoietic cell transplantation (0.8%), the median survival from diagnosis was 22 months. Therapy for leukemia improves overall survival in older acute myeloid leukemia patients. Based on their comorbidities, most patients up to 80 years of age should be considered for treatment. New therapies including hypomethylating agents and allogeneic hematopoietic cell transplantation are promising and must be compared with other chemotherapy regimens.


Antagonizing IL-6 in ankylosing spondylitis: a short review.
Ankylosing spondylitis (AS) is a chronic inflammatory disorder with predilection for the axial skeleton, leading to progressive restricted mobility and deformity of the spine. The fundamental mechanism involves autoimmunity orchestrated by T cells. Similar to other rheumatic diseases, the complex interplay of cytokines such as tumour necrosis factor alpha, interleukin-6 (IL 6) and interleukin-10 (IL 10) has been implicated in the pathogenesis of the disease. Despite extensive research over the past decades, the treatment options for AS, are limited. Non steroidal antiinflammatory drugs are the first line of therapy, whereas anti TNF drugs are administered for refractory cases which fail to respond to the treatment. There have been conflicting views on the correlation of IL 6 with disease activity in AS. As such, the debate on the role of anti IL6 in AS is still ongoing. Anti IL 6 such as tocilizumab and siltuximab have proven efficacy based on the large randomized controlled trials. The Food and Drug Administration (FDA) has approved these drugs for treating rheumatoid arthritis and systemic juvenile idiopathic arthritis. Researchers have adventurously experimented anti IL 6 therapy in AS but the conclusions made were not consolidated into international guidelines or consensus statement for clinical practice. In the present review, we explore the role of anti IL6 in the treatment of AS based on the cumulative evidence over recent years.


Aberrant Development and Synaptic Transmission of Cerebellar Cortex in a VPA Induced Mouse Autism Model.
Autistic spectral disorder (ASD) is a prevalent neurodevelopmental disease that affects multiple brain regions. Both clinical and animal studies have revealed the possible involvement of the cerebellum in ASD pathology. In this study, we generated a rodent ASD model through a single prenatal administration of valproic acid (VPA) into pregnant mice, followed by cerebellar morphological and functional studies of the offspring. Behavioral studies showed that VPA exposure led to retardation of critical motor reflexes in juveniles and impaired learning in a tone-conditioned complex motor task in adults. These behavioral phenotypes were associated with premature migration and excess apoptosis of the granular cell (GC) precursor in the cerebellar cortex during the early postnatal period, and the decreased cell density and impaired dendritic arborization of the Purkinje neurons. On acute cerebellar slices, suppressed synaptic transmission of the Purkinje cells were reported in the VPA-treated mice. In summary, converging evidence from anatomical, electrophysiological and behavioral abnormalities in the VPA-treated mice suggest cerebellar pathology in ASD and indicate the potential values of motor dysfunction in the early diagnosis of ASD.


Immunomodulatory leptin receptor+ sympathetic perineurial barrier cells protect against obesity by facilitating brown adipose tissue thermogenesis.
Adipose tissues (ATs) are innervated by sympathetic nerves, which drive reduction of fat mass via lipolysis and thermogenesis. Here, we report a population of immunomodulatory leptin receptor-positive (LepR+) sympathetic perineurial barrier cells (SPCs) present in mice and humans, which uniquely co-express Lepr and interleukin-33 (Il33) and ensheath AT sympathetic axon bundles. Brown ATs (BATs) of mice lacking IL-33 in SPCs (SPCΔIl33) had fewer regulatory T (Treg) cells and eosinophils, resulting in increased BAT inflammation. SPCΔIl33 mice were more susceptible to diet-induced obesity, independently of food intake. Furthermore, SPCΔIl33 mice had impaired adaptive thermogenesis and were unresponsive to leptin-induced rescue of metabolic adaptation. We therefore identify LepR+ SPCs as a source of IL-33, which orchestrate an anti-inflammatory BAT environment, preserving sympathetic-mediated thermogenesis and body weight homeostasis. LepR+IL-33+ SPCs provide a cellular link between leptin and immune regulation of body weight, unifying neuroendocrinology and immunometabolism as previously disconnected fields of obesity research.


Pachymic Acid Prevents Hemorrhagic Shock-Induced Cardiac Injury by Suppressing M1 Macrophage Polarization and NF-[Formula: see text]B Signaling Pathway.
Hemorrhagic shock (HS) is the leading cause of death in trauma patients. Inflammation following HS can lead to cardiac damage. Pachymic acid (PA), a triterpenoid extracted from Poria cocos, has been found to possess various biological activities, including anti-inflammatory and anti-apoptotic properties. Our research aims to investigate the protective effects of PA against HS-induced heart damage and the underlying mechanisms involved. Male Sprague-Dawley rats were intraperitoneally injected with PA (7.5 or 15[Formula: see text]mg/kg) daily for three days. Subsequently, we created a rat model of HS by drawing blood through a catheter inserted into the femoral artery followed by resuscitation. The results revealed that HS led to abnormalities in hemodynamics, serum cardiac enzyme levels, and cardiac structure, as well as induced cardiac apoptosis. However, pretreatment with PA effectively alleviated these effects. PA-pretreatment also suppressed mRNA and protein levels of interleukin (IL)-1[Formula: see text], IL-6, and tumor necrosis factor [Formula: see text] (TNF-[Formula: see text]) in the heart tissues of HS rats. Additionally, PA-pretreatment reduced inflammatory cell infiltration and M1 macrophage polarization while exaggerating M2 polarization in HS rat hearts. The study observed a decreased proportion of the expression of of M1 macrophages (CD86[Formula: see text]) and their marker (iNOS), along with an increased proportion of the expression of M2 macrophages (CD206[Formula: see text]) and their marker (Arg-1). Notably, PA-pretreatment suppressed NF-[Formula: see text]B pathway activation via inhibiting NF-[Formula: see text]B p65 phosphorylation and its nuclear translocation. In conclusion, PA-pretreatment ameliorates HS-induced cardiac injury, potentially through its inhibition of the NF-[Formula: see text]B pathway. Therefore, PA treatment holds promise as a strategy for mitigating cardiac damage in HS.


[Statins and unstable angina: MIRACL].
Statins have demonstrated their aptitude to lower hypercholesterolemia, and to prevent the occurrence of arterial, coronary, and cerebral events, by primary and secondary prevention in patients with low or high risk to develop coronary artery disease. In the first time, with MIRACL and Atrovastatine, statins are proposed in the therapeuty of unstable angina. This study was successful. In fact, in this comparative study, high dose of Atrovastatine (80 mg/day) administrated in the acute phase of non Q-wave myocardial infarction or unstable angina, reduce ischemic events (RR=0.84, p=0.048 ). After anticoagulants and a wide group of platelets antiagregants, this statin brings a new agent to the chemotherapy of the atherosclerotic unstable lesion. The TACTICS-TIMI 18 and the sub-group of the FRISC II study, demonstrate the necessity to stratify the unstable angina risk by electric and biologic arguments. They confirm the efficacy of invasive strategy, with coronarography, and immediate revascularisation, in patients with high risk with persistent modifications of ST segment, and increasing Troponins level. Under the cover of a large medical treatment composed of anti-ischemic, Aspirine, LMWH, and now a high dose of statins, the acute coronary syndrome invasive attitude must be guided by electric, biologic and the invasive attitude prognostic risk.


Strain-controlled fluorescence polarization in a CdSe nanoplatelet-block copolymer composite.
By dispersing semi-conducting CdSe nanoplatelets within a styrene-butadiene-styrene block copolymer matrix we form homogeneous fluorescent hybrid films. Reversible orientation control of the nanoplatelets is simply achieved through stretching the film, leading to tuneable fluorescence anisotropy. Such adjustable polarization effects are useful for modulating the optical response in composite materials.


Self-restrained triplet loss for accurate masked face recognition.
Using the face as a biometric identity trait is motivated by the contactless nature of the capture process and the high accuracy of the recognition algorithms. After the current COVID-19 pandemic, wearing a face mask has been imposed in public places to keep the pandemic under control. However, face occlusion due to wearing a mask presents an emerging challenge for face recognition systems. In this paper, we present a solution to improve masked face recognition performance. Specifically, we propose the Embedding Unmasking Model (EUM) operated on top of existing face recognition models. We also propose a novel loss function, the Self-restrained Triplet (SRT), which enabled the EUM to produce embeddings similar to these of unmasked faces of the same identities. The achieved evaluation results on three face recognition models, two real masked datasets, and two synthetically generated masked face datasets proved that our proposed approach significantly improves the performance in most experimental settings.


Effect of adeno-associated virus-specific immunoglobulin G in human amniotic fluid on gene transfer.
Intra-amniotic administration of adeno-associated virus (AAV) vector may be an effective way to deliver gene therapy for treatment of congenital pulmonary and intestinal disorders. In an effort to understand potential barriers to intra-amniotic gene therapy better, we determined whether human amniotic fluid (AF) could act as an inhibitor of AAV2-mediated gene transfer. AF samples were obtained from 21 different human pregnancies during routine amniocentesis at 16-20 weeks of gestation. An immortalized fetal human tracheal epithelial cell line (FHTE) was infected with AAV2 containing a luciferase reporter gene driven by the SV40 promoter in the presence and absence of each AF sample. Inhibition of transgene expression was observed in 8 (38%) of the AF samples (inhibitory AF) and resulted in luciferase levels of only 1.4% +/- 0.6% of those obtained with infection in normal media. Infections in 13 samples (62%) resulted in transgene expression comparable or in excess of infection in media alone (noninhibitory AF). Removal of immunoglobulin G (IgG) from inhibitory AF samples with Protein A returned luciferase expression to control levels (119% +/- 37% of control), suggesting the possible presence of inhibiting antibody. Eleven of the AF samples were evaluated by enzyme-linked immunosorbent assay (ELISA) for specific anti-AAV antibodies. All noninhibitory AF samples were negative (titers of < 1:20; n = 3), and 6 of the 8 inhibitory samples contained specific anti-AAV antibodies at titers ranging from 1:40 to 1:160. These studies demonstrate that AF from some individuals contains AAV-specific IgG that can inhibit gene transfer.


An innovative therapeutic program for aphasia patients and their relatives.
Eleven aphasia patients and seven family members participated in a five-day residential course led by a speech pathologist, a psychologist and a neurologist. The aim of the course was to give the aphasics and their relatives information on the etiology, treatment possibilities and prognosis of aphasia; work on personal and interpersonal problems through psychological counseling; improve language function through comprehensive and intensive stimulation; examine the psychological, linguistic and neurological effects of the intensive course. The course participants met again one year after the course and were found to have changed positively both psychologically and interpersonally but, as expected, only to a minor degree linguistically and neurologically. Through this intensive course it was possible to assess the problems of the families more easily than in the hospital. The patients and their relatives reported that they had learnt how to identify and to deal with their psychological problems in a more constructive way. They also felt that they had support from the other families and were able to share their experiences. We found that this type of intervention had many positive effects on the ability of the participants to cope with the chronic disability.


FR901483, a novel immunosuppressant isolated from Cladobotryum sp. No. 11231. Taxonomy of the producing organism, fermentation, isolation, physico-chemical properties and biological activities.
FR901483, a novel immunosuppressant, has been isolated from the fermentation broth of Cladobotryum sp. No. 11231. The molecular formula of FR901483 has been determined as C20H31N2O6P. FR901483 exerts a potent immunosuppressive activity in vitro and significantly prolongs graft survival time in the rat skin allograft model. This compound has an intriguing tricyclic structure possessing a phosphate ester in its molecule. The ester residue may play an important role in exerting immunosuppressive activity because the desphosphoryl compound is devoid of activity. It is thought that the primary target of immunosuppression by this compound is inhibition of purine nucleotide biosynthesis.


Mechanism of the high coagulation state of breast cancer tissue factor.
We conducted this study to analyze the mechanism behind the high coagulation state induced by circulating plasma microparticle tissue factor (MP-TF) in patients with breast cancer. 87 cases of breast cancer patients (10 cases of TNM stage I, 16 cases of II, 32 cases of III, 29 cases of IV; 8 cases of pathological type in situ carcinoma, 15 cases of ductal carcinoma, 64 cases of invasive cancer) were used as the observation group and 20 cases of benign breast lesions were used as the control group to compare MP-TF levels of plasma and coagulation parameters including prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB) and D-dimer body (D-D) level and NF-κB signaling pathway index including P50, p65, TAK1 and IκBα levels. The plasma MP-TF level in the observation group was significantly higher than that in control group, and the level of MP-TF in the observation group increased with an increase in depth of TNM stage and tumor invasion; differences were statistically significant (p<0.05). In the observation group, the plasma PT and APTT were shortened, and the levels of FIB and D-D were increased; the differences were statistically significant (p<0.05). In the observation group, the levels of P50, p65, TAK1, IκBαin circulating blood were higher than those in control group; the differences were statistically significant (p<0.05). After the Pearson test, the plasma levels of MP-TF in patients with breast cancer were negatively correlated with PT and APTT, and positively correlated with FIB, D-D values and the levels of p50, p65, TAK1 and IκBα (4 p<0.05). MP-TF can lead to high blood coagulation in patients with breast cancer through the activation of NF-κB signaling pathway, which may become a new target for the intervention of the disease.


Nitric oxide-mediated expression of Bcl-2 and Bcl-xl and protection from tumor necrosis factor-alpha-mediated apoptosis in porcine endothelial cells after exposure to low concentrations of xenoreactive natural antibody.
Cardiac and renal allo- and xenografts can acquire a natural resistance to vascular rejection. This "accommodation" involves endothelial cell (EC) expression of "survival genes" such as Bcl family members and hemoxygenase 1. Understanding what initiates this protective process would have profound implications; our hypothesis is that low concentrations of antigraft antibodies may mediate these changes. In vitro cultured primary and immortalized porcine EC were incubated with polyclonal human IgG for 6 days and then examined for phenotype changes. The cells acquired resistance to tumor necrosis factor-alpha-mediated apoptosis (50-100% reduction at 6 hr) and up-regulated expression of Bcl-2 and Bcl-xl; sustained expression was accompanied by inducible nitric oxide (NO) synthase expression and by enhanced production of NO by EC. Two observations suggested that NO was actively involved in the process of Bcl-2 and Bcl-xl induction. First, (z)-1-2-[2-aminoethyl)-N- (2-ammonioethyl)amino]diazen-1-ium-1,2-diolate, an NO donor, was able to induce similar changes in porcine EC to those induced by anti-pig antibodies. Second, an NO synthase inhibitor NG-monomethyl-L-arginine.monoacetate was able to specifically inhibit the anti-pig antibody-mediated expression of Bcl-2 or Bcl-xl. These data strongly support the hypothesis that Bcl-2 and Bcl-xl expression and protection from apoptosis in EC may result from antibody-mediated NO production through the neoexpression of inducible NO synthase.


Postcoital catamenial pneumothorax. Report of a case not associated with endometriosis and successfully treated with tubal ligation.
A 39-year-old woman had a 7-yr history of recurrent right-sided pneumothoraces. These occurred within 1 to 2 days before or after the beginning of the menstrual cycle. The patient recalled often having developed the right-sided pleuritic pain of pneumothorax during or shortly after sexual intercourse. She had no symptoms or signs to suggest endometriosis. A trial of cyclic birth control pills was unsuccessful in preventing recurrent pneumothoraces. Finally, approximately a year ago, laparoscopic tubal ligation was performed. The patient has not had pneumothorax since. We conclude that in our patient, the catamenial pneumothorax was most likely related to transtubal passage of air during sexual intercourse. Passage from the peritoneum to the pleura presumably occurred through a congenital defect or fenestration of the right hemidiaphragm.


Suspected deep vein thrombosis. Management by impedance plethysmography.
Controversy exists as to whether patients suspected of having deep vein thrombosis (DVT) can be studied safely without venography, with its attendant expense, inconvenience, and potential risk. We used impedance plethysmography (IPG) in 1,464 consecutive patients suspected of having DVT, with 96% of these patients with normal IPGs, there were no fatal pulmonary emboli (PE). The incidence of nonfatal PE was 1%. In 284 outpatients suspected of having DVT, but discharged without treatment because of normal IPGs, only one patient returned with subsequent symptoms of DVT (0.4%). Noninvasive testing with IPG is a safe and highly cost-effective alternative to venography for routine management of patients suspected of DVT.


Human frataxin, the Friedreich ataxia deficient protein, interacts with mitochondrial respiratory chain.
Friedreich ataxia (FRDA) is a rare, inherited neurodegenerative disease caused by an expanded GAA repeat in the first intron of the FXN gene, leading to transcriptional silencing and reduced expression of frataxin. Frataxin participates in the mitochondrial assembly of FeS clusters, redox cofactors of the respiratory complexes I, II and III. To date it is still unclear how frataxin deficiency culminates in the decrease of bioenergetics efficiency in FRDA patients' cells. We previously demonstrated that in healthy cells frataxin is closely attached to the mitochondrial cristae, which contain both the FeS cluster assembly machinery and the respiratory chain complexes, whereas in FRDA patients' cells with impaired respiration the residual frataxin is largely displaced in the matrix. To gain novel insights into the function of frataxin in the mitochondrial pathophysiology, and in the upstream metabolic defects leading to FRDA disease onset and progression, here we explored the potential interaction of frataxin with the FeS cluster-containing respiratory complexes I, II and III. Using healthy cells and different FRDA cellular models we found that frataxin interacts with these three respiratory complexes. Furthermore, by EPR spectroscopy, we observed that in mitochondria from FRDA patients' cells the decreased level of frataxin specifically affects the FeS cluster content of complex I. Remarkably, we also found that the frataxin-like protein Nqo15 from T. thermophilus complex I ameliorates the mitochondrial respiratory phenotype when expressed in FRDA patient's cells. Our data point to a structural and functional interaction of frataxin with complex I and open a perspective to explore therapeutic rationales for FRDA targeted to this respiratory complex.


Microfluidic three-dimensional hydrodynamic flow focusing for the rapid protein concentration analysis.
A simple microfluidic 3D hydrodynamic flow focusing device has been developed and demonstrated quantitative determinations of quantum dot 525 with antibody (QD525-antibody) and hemagglutinin epitope tagged MAX (HA-MAX) protein concentrations. This device had a step depth cross junction structure at a hydrodynamic flow focusing point at which the analyte stream was flowed into a main detection channel and pinched not only horizontally but also vertically by two sheath streams. As a result, a triangular cross-sectional flow profile of the analyte stream was formed and the laser was focused on the top of the triangular shaped analyte stream. Since the detection volume was smaller than the radius of laser spot, a photon burst histogram showed Gaussian distribution, which was necessary for the quantitative analysis of protein concentration. By using this approach, a linear concentration curve of QD525-antibody down to 10 pM was demonstrated. In addition, the concentration of HA-MAX protein in HEK293 cell lysate was determined as 0.283 ± 0.015 nM. This approach requires for only 1 min determining protein concentration. As the best of our knowledge, this is the first time to determinate protein concentration by using single molecule detection techniques.


[Functional regional asymmetry of the EEG intrahemispheric coherence in dogs during conditioning].
Individual features of the regional interhemispheric relations in the brain were studied in dogs during alimentary conditioning. The electrical activity was recorded from symmetrical anterior (frontal and motor cortices) and posterior (visual and auditory cortices) areas of the neocortex. Comparison between the averaged left and right intrahemispheric EEG coherences revealed a dynamic character of interhemispheric relations dependent on the stage of conditioning. Individual features were shown. In a dog with strong type of the nervous system, in the anterior brain regions, the EEG coherence was higher in the left hemisphere than in the right one, whereas, on the contrary, in the posterior regions, the values were higher in the right than in the left hemisphere. In dogs with weak type of the nervous system, there was an inverse relationship. Thus, the spatial organization of the cortical electrical activity in the associative and projection brain areas was different.


History of an abusive head trauma including a lucid interval and a retinal hemorrhage is most likely false.
A lucid interval (LI) is the period of time between regaining consciousness after a short period of unconsciousness, resulting from a head injury and deteriorating after the onset of neurologic signs and symptoms caused by that injury. The incentive for this study was the case of a father who left his 14-week-old infant with the nanny in whose custody the infant had collapsed. The nanny denied involvement in the injury, and the father became a suspect. Of 47 abusive head trauma (AHT) cases, 8 were found to have an LI in the past. The history of the cases were thoroughly analyzed and compared with evidence in the literature. An LI is not compatible with an inertial brain injury. Shaking has either an immediate effect or no effect, which means that an LI occurs only in pure impact or blunt injuries. When "shaking lesions" are found including a retinal hemorrhage while the history mentions an LI, the story most likely is false, regardless of whether the perpetrator confesses. The finding of an LI may change the assessment of an AHT case. Lucid interval is a valuable variable in the diagnostic accuracy of an AHT.


Psychiatric diagnoses (Research Diagnostic Criteria) in symptomatic volunteers.
Symptomatic volunteers (SVs) are increasingly used as subjects for clinical research studies. A total of 362 SVs were recruited, psychiatric diagnoses were made according to Research Diagnostic Criteria (RDC), and standard symptom scale scores on the Hopkins Symptom Check list (HSCL) for the individual diagnostic categories were computed. Of these subjects, 221 were classified as having a depressive disorder (three categories), 112 as having an anxiety disorder (three categories), and 29 as having some other RDC disorder. The HSCL scale scores for the depressive- and anxiety-disorder subject groups were consistent with those for actual patient groups. There were significant differences in HSCL scores for some RDC categories within the broader depressive- or anxiety-disorder groupings. Individual RDC categories should be kept separate in reporting treatment results for depressive or anxiety disorders.


Glucose tolerance and risk of gestational diabetes mellitus in nulliparous women who smoke during pregnancy.
Gestational diabetes mellitus has been associated with adverse maternal and infant outcomes, including preeclampsia and fetal macrosomia. Although cigarette smoking has been associated with increased insulin resistance, its effect on gestational diabetes mellitus risk is uncertain. The authors evaluated the effects of smoking on glucose tolerance in a cohort of pregnant women who participated in the Calcium for Preeclampsia Prevention trial, a randomized study of nulliparous women conducted in five US medical centers from 1992 to 1995. Results of screening and diagnostic testing for gestational diabetes mellitus were analyzed. For 3,774 of the 4,589 women enrolled, plasma glucose concentration 1 hour after a 50-g oral glucose challenge and complete information on pregnancy outcome were available; for 3,602 of the women, gestational diabetes mellitus status was known. Adjusted mean 1-hour plasma glucose concentration (mg/dl) was elevated in women who smoked at study enrollment (112.6, 95% confidence interval: 110.0, 115.3) compared with women who had never smoked (108.3, 95% confidence interval: 106.7, 109.8; p < 0.01). Women who smoked were at increased risk of gestational diabetes mellitus when criteria proposed by the National Diabetes Data Group were used (adjusted odds ratio = 1.9, 95% confidence interval: 1.0, 3.6). These findings support an association between smoking and gestational diabetes mellitus.


Confidence of academic general internists and family physicians to teach ambulatory procedures.
To evaluate and compare the readiness of academic general internal medicine physicians and academic family medicine physicians to perform and teach 13 common ambulatory procedures. Mailed survey. Internal medicine and family medicine residency training programs associated with 35 medical schools in 9 eastern states. Convenience sample of full-time teaching faculty. A total of 331 general internists and 271 family physicians returned completed questionnaires, with response rates of 57% and 65%, respectively. Academic generalists ranked most of the ambulatory procedures as important for primary care physicians to perform; however, they infrequently performed or taught many of the procedures. Overall, compared with family physicians, general internists performed and taught fewer procedures, received less training, and were less confident in their ability to teach these procedures. Physicians' confidence to teach a procedure was strongly associated with training to perform the procedure and performing or precepting a procedure at least 10 times per year. Many academic general internists do not perform or precept common adult ambulatory procedures. To ensure that residents have the opportunity to learn routine ambulatory procedures, training programs may need to recruit qualified faculty, train current faculty, or arrange for academic specialists or community physicians to teach these skills.


Sustainable Practices in Medicinal Chemistry Part 2: Green by Design.
With the development of ever-expanding synthetic methodologies, a medicinal chemist's toolkit continues to swell. However, with finite time and resources as well as a growing understanding of our field's environment impact, it is critical to refine what can be made to what should be made. This review seeks to highlight multiple cheminformatic approaches in drug discovery that can influence and triage design and execution impacting the likelihood of rapidly generating high-value molecules in a more sustainable manner. This strategy gives chemists the tools to design and refine vast libraries, stress "druglikeness", and rapidly identify SAR trends. Project success, i.e., identification of a clinical candidate, is then reached faster with fewer molecules with the farther-reaching ramification of using fewer resources and generating less waste, thereby helping "green" our field.


Fermentation Products of Commensal Bacteria Alter Enterocyte Lipid Metabolism.
Despite the recognized capacity of the gut microbiota to regulate intestinal lipid metabolism, the role of specific commensal species remains undefined. Here, we aimed to understand the bacterial effectors and molecular mechanisms by which Lactobacillus paracasei and Escherichia coli regulate lipid metabolism in enterocytes. We show that L-lactate produced by L. paracasei inhibits chylomicron secretion from enterocytes and promotes lipid storage by a mechanism involving L-lactate absorption by enterocytes, its conversion to malonyl-CoA, and the subsequent inhibition of lipid beta-oxidation. In contrast, acetate produced by E. coli also inhibits chylomicron secretion by enterocytes but promotes lipid oxidation by a mechanism involving acetate absorption by enterocytes, its metabolism to acetyl-CoA and AMP, and the subsequent upregulation of the AMPK/PGC-1α/PPARα pathway. Our study opens perspectives for developing specific bacteria- and metabolite-based therapeutic interventions against obesity, atherosclerosis, and malnutrition by targeting lipid metabolism in enterocytes.


Polatuzumab vedotin for the treatment of adults with relapsed or refractory diffuse large B-cell lymphoma.
Polatuzumab vedotin is an antibody-drug conjugate comprised of an anti-CD79b monoclonal antibody conjugated to monomethyl auristatin (MMAE), a microtubule-disrupting cytotoxin. CD79b is almost exclusively expressed on normal and malignant B-cells, making it an appealing target for novel therapeutics. This article reviews the current literature on polatuzumab vedotin, including its pharmacology, as well as summarizing the results of clinical trials in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) as a single agent and in combination with other chemotherapies and chemoimmunotherapies. The current landscape of approved therapies for relapsed and refractory DLBCL, as well as other promising novel approaches, is discussed. The recent approval of polatuzumab vedotin in combination with bendamustine and rituximab (BR) offers another option to patients with DLBCL who are not eligible for autologous hematopoietic cell transplant or chimeric antigen receptors (CAR)-T cell therapy. In younger patients and those without serious comorbidities, polatuzumab vedotin-BR may serve as bridging therapy to more intensive therapies with reasonable efficacy and tolerability. Polatuzumab vedotin is currently being studied in a randomized trial in the front line setting in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).


Cell expansion not cell differentiation predominantly co-ordinates veins and stomata within and among herbs and woody angiosperms grown under sun and shade.
It has been proposed that modification of leaf size, driven by epidermal cell size, balances leaf water supply (determined by veins) with transpirational demand (generated by stomata) during acclimation to local irradiance. We aimed to determine whether this is a general pattern among plant species with contrasting growth habits. We compared observed relationships between leaf minor vein density, stomatal density, epidermal cell size and leaf size in four pairs of herbs and woody species from the same families grown under sun and shade conditions with modelled relationships assuming vein and stomatal densities respond passively to epidermal cell expansion. Leaf lignin content was also quantified to assess whether construction costs of herbaceous leaf veins differ from those of woody plants and the leaf mass fraction invested in veins. Modelled relationships accurately described observed relationships, indicating that in all species, co-ordinated changes to the density of minor veins and stomata were mediated by a common relationship between epidermal cell size, vein density and stomatal density, with little or no impact from stomatal index. This co-ordination was independent of changes in leaf size and is likely to be an adaptive process driven by the significant proportion of biomass invested in veins (13·1 % of sun leaf dry weight and 21·7 % of shade leaf dry weight). Relative costs of venation increased in the shade, intensifying selective pressure towards economizing investment in vein density. Modulation of epidermal cell size appears to be a general mechanism among our experimental species to maintain a constant ratio between leaf anatomical traits that control leaf water fluxes independently of habit. We propose that this process may co-ordinate plasticity in hydraulic supply and demand in the majority of eudicot angiosperms.


Improving Mechanical Ventilator Clinical Decision Support Systems with a Machine Learning Classifier for Determining Ventilator Mode.
Clinical decision support systems (CDSS) will play increasing role in improving quality of medical care for critically ill patients. However, due to limitations in current informatics infrastructure, CDSS do not always have complete information on state of supporting physiologic monitoring devices, which can limit input data available to CDSS. This is especially true in use case of mechanical ventilation (MV), where current CDSS have no knowledge of critical ventilation settings, such as ventilation mode. To enable MV CDSS make accurate recommendations related to ventilator mode, we developed a highly performant machine learning model that is able to perform per-breath classification of five of most widely used ventilation modes in USA with average F1-score of 97.52%. We also show how our approach makes methodologic improvements over previous work and is highly robust to missing data caused by software/sensor error.


Response Patterns to Weekly Short Message Service Health Surveys Among Diverse Youth at High Risk for Acquiring HIV.
HIV researchers use short messaging service (SMS)-based surveys to monitor health behaviors more closely than what would be possible with in-person assessment. Benefits are tempered by nonresponse to completing surveys. Understanding response patterns and their associated study participant characteristics would guide more tailored use of SMS-based surveys for HIV studies. We examined response to weekly 7-item SMS surveys administered as part of an HIV prevention trial. Using Mixture hidden Markov models (MHMM), we identified the underlying response patterns shared by subgroups of participants over time and quantified the association between these response patterns and participant characteristics. Three underlying response patterns were identified; responders, responders with phone-related errors, and non-responders. Non-responders versus responders were more likely to be younger, male, cis-gender, Black and Latinx participants with histories of homelessness, incarceration, and social support service utilization. Responders with phone-related errors compared to non-responders were more likely to be Black, Latinx, female, students, and have a history of incarceration and social support service utilization. More nuanced results from MHMM analyses better inform what strategies to use for increasing SMS response rates, including assisting in securing phone ownership/service for responders with phone-related errors and identifying alternative strategies for non-responders. Actively collecting and monitoring non-delivery notification data available from SMS gateway service companies offers another opportunity to identify and connect with participants when they are willing but unable to respond during follow-up.


Effects of conformational selectivity and of overlapping kinetically influential ionizations on the characteristics of pH-dependent enzyme kinetics. Implications of free-enzyme pKa variability in reactions of papain for its catalytic mechanism.
The effects of selection by a small molecule, when binding to a protein, of a particular conformation from an equilibrium stereopopulation on the characteristics of the pH-dependence of reaction with a reactivity probe or substrate were determined by analysis of an appropriate kinetic model. For reaction in one protonic state containing an equilibrium mixture of two conformational isomers, the pH-second-order rate constant (k) profile is of conventional sigmoidal form. The apparent pKa value is a composite of the pKa values of the two conformational states. The value of pKapp. for a given enzyme under given experimental conditions will always be the same (provided that the site-specificity assumed in the model is maintained) irrespective of whether only one conformation reacts or both react, with the same or with different rate constants. The experimentally determined pH-independent rate constant (kapp.) is an average of the reactivities of the two conformational states weighted in favour of the predominant form. The presence of an additional but unreactive conformational state also affects the value of kapp. The possibility that overlapping acid dissociations that affect the reactivity of the enzyme might provide pH-k profiles often indistinguishable in practice from simple sigmoidal dissociation curves and subject to variability in apparent pKa values was evaluated by a simulation study. If two reactive protonic states of the enzyme respond differently to changes in the structure of the substrate or site-specific reactivity probe, differences in apparent pKa values of up to approx. 1 unit can be exhibited without deviation from sigmoidal behaviour being reliably observed. Differences in apparent pKa values observed in some site-specific reactions of papain and their possible consequences for its catalytic mechanism are discussed.


Atypical teratoid rhabdoid tumors (ATRTs): the British Columbia's Children's Hospital's experience, 1986-2006.
As "atypical teratoid rhabdoid tumors" (ATRTs) may mimic "small round blue cell tumors" (SRBCT), we reexamined our ATRT experience focusing upon INI-1 immunohistochemistry (IHC). All high-grade pediatric brain tumors occurring from 1986-2006 at our institution underwent INI-1 IHC. Clinicopathologic data from each INI-1 immunonegative case were reviewed. Additional genetic, epigenetic and IHC analyses (including interrogation of INI-1 and CLDN6) were performed on a subset of the INI-1 immunonegative cases. Twelve INI-1 IHC negative tumors were identified retrospectively, of which only two previously carried the diagnosis of ATRT. Overall, the clinicopathologic and genetic data supported the assertion that all 12 cases represented ATRT. Unexpectedly, three long-term survivors (4.2, 7.0 and 8.5 years) were identified. As hypothesized, "teratoid" and "rhabdoid" histologic features were relatively infrequent despite gross total resections in some cases. Methylation specific polymer chain reaction (PCR) (MSP) revealed a uniform methylation pattern across all cases and gene promoters tested (ie, MGMT, HIC1, MLH3 and RASSF1); notably, all cases demonstrated unmethylated MGMT promoters. Our data demonstate that a primitive non-rhabdoid histophenotype is common among ATRTs and highlights the diagnostic importance of INI-1 IHC. Epigenetically, the MGMT promoter is usually unmethylated in ATRT, suggesting that potential temozolomide-based chemotherapy may be of limited efficacy.


The effects of interelectrode distance on electromyographic amplitude and mean power frequency during isokinetic and isometric muscle actions of the biceps brachii.
The purpose of this study was to examine the effects of interelectrode distance (IED) on the absolute and normalized electromyographic (EMG) amplitude and mean power frequency (MPF) versus isokinetic and isometric torque relationships for the biceps brachii muscle. Ten adults [mean+/-SD age=22.0+/-3.4 years] performed submaximal to maximal, isokinetic and isometric muscle actions of the dominant forearm flexors. Following determination of isokinetic peak torque (PT) and the isometric maximum voluntary contraction (MVC), the subjects performed randomly ordered, submaximal step muscle actions in 10% increments from 10% to 90% PT and MVC. Surface EMG signals were recorded simultaneously from bipolar electrode arrangements placed over the biceps brachii muscle with IEDs of 20, 40, and 60mm. Absolute and normalized EMG amplitude (muVrms and %max) increased linearly with torque during the isokinetic and isometric muscle actions (r(2) range=0.988-0.998), but there were no significant changes for absolute or normalized EMG MPF (Hz or %max) from 10% to 100% PT and MVC. In some cases, there were significant (p<0.05) differences among the three IED arrangements for absolute EMG amplitude and MPF values, but not for the normalized values. These findings suggested that for the biceps brachii muscle, IEDs between 20 and 60mm resulted in similar patterns for the EMG amplitude or MPF versus dynamic and isometric torque relationships. Furthermore, unlike the absolute EMG amplitude and MPF values, the normalized EMG data were not influenced by changes in IED between 20 and 60mm. Thus, normalized EMG data can be compared among previous studies that have utilized different IED arrangements.


A systematic review of biochar research, with a focus on its stability in situ and its promise as a climate mitigation strategy.
Claims about the environmental benefits of charring biomass and applying the resulting "biochar" to soil are impressive. If true, they could influence land management worldwide. Alleged benefits include increased crop yields, soil fertility, and water-holding capacity; the most widely discussed idea is that applying biochar to soil will mitigate climate change. This claim rests on the assumption that biochar persists for hundreds or thousands of years, thus storing carbon that would otherwise decompose. We conducted a systematic review to quantify research effort directed toward ten aspects of biochar and closely evaluated the literature concerning biochar's stability. We identified 311 peer-reviewed research articles published through 2011. We found very few field studies that addressed biochar's influence on several ecosystem processes: one on soil nutrient loss, one on soil contaminants, six concerning non-CO2 greenhouse gas (GHG) fluxes (some of which fail to support claims that biochar decreases non-CO2 GHG fluxes), and 16-19 on plants and soil properties. Of 74 studies related to biochar stability, transport or fate in soil, only seven estimated biochar decomposition rates in situ, with mean residence times ranging from 8 to almost 4,000 years. Our review shows there are not enough data to draw conclusions about how biochar production and application affect whole-system GHG budgets. Wide-ranging estimates of a key variable, biochar stability in situ, likely result from diverse environmental conditions, feedstocks, and study designs. There are even fewer data about the extent to which biochar stimulates decomposition of soil organic matter or affects non-CO2 GHG emissions. Identifying conditions where biochar amendments yield favorable GHG budgets requires a systematic field research program. Finally, evaluating biochar's suitability as a climate mitigation strategy requires comparing its effects with alternative uses of biomass and considering GHG budgets over both long and short time scales.