[State of collective immunity against poliomyelitis in some regions of Russia].
Study the state of collective immunity against poliomyelitis in 7 regions of Russia in the last 3 years. 2579 sera were studied for antibodies against poliomyelitis virus. Antibodies (AT) against 3 types of viruses were determined in neutralization reaction in RD cell culture, the state of collective immunity in the examined individuals was evaluated by the percent of individuals with AT against a type of poliovirus and geometric mean AT titer. The circulation of wild polioviruses was judged by the presence of strain specific AT against wild and vaccine viruses in the examined children (311 sera were studied). The indicators of collective immunity against poliomyelitis in both select examined regions and select age groups were generally high. The data obtained allow to make a conclusion that the quality of vaccine prophylaxis in the examined regions is good. Introduction of wild poliovirus type 1 from Tajikistan in 2010 caused disease in 7 residents of Russia whereas an epidemic that had affected more than 700 individuals emerged in Tajikistan. The studies carried out confirmed the necessity to continue qualitative poliomyelitis vaccine prophylaxis in the country despite the lack of circulation of wild polioviruses that can be introduced at any time.


Analyses of Ehrlichia canis and a canine granulocytic Ehrlichia infection.
Ehrlichia canis and canine granulocytic Ehrlichia sp. (CGE) infect canine monocytes and granulocytes, respectively. E. canis has been cultured in vitro and used to develop an immunofluorescence assay. CGE has not been cultured, and a serologic assay is not available. The sera of dogs infected with CGE were reported to react with E. canis by immunofluorescence. In this study, the temporal response of immunoglobulin G (IgG) was determined by an enzyme-linked immunosorbent assay (ELISA) with purified E. canis antigen in four dogs experimentally infected with E. canis, in two dogs experimentally infected with CGE, and in one dog infected with E. canis and subsequently infected with CGE. E. canis-infected dogs developed an IgG ELISA result of 1.5 or greater for the optical density signal/noise ratio by 2 months postinfection. CGE challenge of a dog with a previous E. canis infection induced an anamnestic increase in the IgG ELISA result; however, CGE infection alone did not induce a significant IgG ELISA response. Western immunoblot analysis showed that dogs infected with E. canis developed antibodies initially that reacted with low-molecular-mass proteins (30, 24, and 21 kDa) and subsequently with higher-molecular-mass proteins (160, 100, 78, 64, 47, and 40 kDa). In contrast, CGE-infected dogs showed reactions with the same higher-molecular-mass proteins of E. canis but, unlike E. canis-infected dogs, not with the low-molecular-mass proteins of E. canis. Of 10 serum samples collected in the field of Indonesia from dogs with tropical canine pancytopenia, all had an optical density signal minus noise value of 2.54 or greater in the IgG ELISA and reacted with E. canis antigen in a pattern similar to that of serum samples from dogs experimentally infected with E. canis in Western immunoblotting. This study suggests that the IgG ELISA and Western immunoblotting with purified E. canis as the antigen are useful in distinguishing between E. canis and CGE infections in dogs.


The H2 robotic exoskeleton for gait rehabilitation after stroke: early findings from a clinical study.
Stroke significantly affects thousands of individuals annually, leading to considerable physical impairment and functional disability. Gait is one of the most important activities of daily living affected in stroke survivors. Recent technological developments in powered robotics exoskeletons can create powerful adjunctive tools for rehabilitation and potentially accelerate functional recovery. Here, we present the development and evaluation of a novel lower limb robotic exoskeleton, namely H2 (Technaid S.L., Spain), for gait rehabilitation in stroke survivors. H2 has six actuated joints and is designed to allow intensive overground gait training. An assistive gait control algorithm was developed to create a force field along a desired trajectory, only applying torque when patients deviate from the prescribed movement pattern. The device was evaluated in 3 hemiparetic stroke patients across 4 weeks of training per individual (approximately 12 sessions). The study was approved by the Institutional Review Board at the University of Houston. The main objective of this initial pre-clinical study was to evaluate the safety and usability of the exoskeleton. A Likert scale was used to measure patient's perception about the easy of use of the device. Three stroke patients completed the study. The training was well tolerated and no adverse events occurred. Early findings demonstrate that H2 appears to be safe and easy to use in the participants of this study. The overground training environment employed as a means to enhance active patient engagement proved to be challenging and exciting for patients. These results are promising and encourage future rehabilitation training with a larger cohort of patients. The developed exoskeleton enables longitudinal overground training of walking in hemiparetic patients after stroke. The system is robust and safe when applied to assist a stroke patient performing an overground walking task. Such device opens the opportunity to study means to optimize a rehabilitation treatment that can be customized for individuals. This study was registered at ClinicalTrials.gov ( https://clinicaltrials.gov/show/NCT02114450 ).


[Evaluation of Cystic Echinococcosis Suspected Patients Applied to National Parasitology Reference Laboratory of Public Health Institution of Turkey Between 2009-2013].
Cystic echinococcosis (CE) caused by the metacestode form of Echinococcus granulosus is an important public health problem common in our country. In this study, anti-E. granulosus antibodies were aimed to investigate in the serum samples of CE suspected patients who applied to the National Parasitology Reference Laboratory of Public Health Institution of Turkey. In the study, serum samples of 2921 patients which were sent to our laboratories from different hospitals between 1 January 2009 and 31 December 2013 were evaluated with at least one of the following tests: Enzyme-Linked Immunosorbent Assay (ELISA), Indirect Hemaglutination Assay (IHA) and Western Blot (WB) techniques. Four hundred thirty nine (15.03%) of inspected 2921 samples were determined seropositive with at least one of the methods. When the results analyzed by gender, 13% of males and 16.40% of females were found positive. Examined the distribution of the results by years, with a maximum of 25% positivity was observed in 2009. Compatibility was determined at the rate of 91.4% among ELISA and IHA results; also 89.7% among WB and the other tests results. Despite the gradual decreases the CE in Ankara and its surroundings, it is still continues to be a major public health problem. Essential prevention and control measures should be taken to reduce the prevalence of the disease. Also in the diagnosis of the disease, more reliable results can obtained with applying two tests (ELISA/IHA) together and confirm the positivity with WB.


Multifeature landmark-free active appearance models: application to prostate MRI segmentation.
Active shape models (ASMs) and active appearance models (AAMs) are popular approaches for medical image segmentation that use shape information to drive the segmentation process. Both approaches rely on image derived landmarks (specified either manually or automatically) to define the object's shape, which require accurate triangulation and alignment. An alternative approach to modeling shape is the levelset representation, defined as a set of signed distances to the object's surface. In addition, using multiple image derived attributes (IDAs) such as gradient information has previously shown to offer improved segmentation results when applied to ASMs, yet little work has been done exploring IDAs in the context of AAMs. In this work, we present a novel AAM methodology that utilizes the levelset implementation to overcome the issues relating to specifying landmarks, and locates the object of interest in a new image using a registration based scheme. Additionally, the framework allows for incorporation of multiple IDAs. Our multifeature landmark-free AAM (MFLAAM) utilizes an efficient, intuitive, and accurate algorithm for identifying those IDAs that will offer the most accurate segmentations. In this paper, we evaluate our MFLAAM scheme for the problem of prostate segmentation from T2-w MRI volumes. On a cohort of 108 studies, the levelset MFLAAM yielded a mean Dice accuracy of 88% ± 5%, and a mean surface error of 1.5 mm ±.8 mm with a segmentation time of 150/s per volume. In comparison, a state of the art AAM yielded mean Dice and surface error values of 86% ± 9% and 1.6 mm ± 1.0 mm, respectively. The differences with respect to our levelset-based MFLAAM model are statistically significant . In addition, our results were in most cases superior to several recent state of the art prostate MRI segmentation methods.


Transcriptomic and Proteomic Investigation of HSP90A as a Potential Biomarker for HCC.
BACKGROUND Hepatocellular carcinoma (HCC) is the third most frequent cause of cancer-related death in adults. Despite recent advances in the clinical technologies, the screening and diagnostic efficacy for HCC remains poor. Discovering novel and reliable HCC biomarkers is urgently needed. MATERIAL AND METHODS We performed a transcriptome-proteome integrated assay to track the possible HCC biomarkers from the process of HCC-derived gene expression in malignant cells to its protein product released into serum. RESULTS Our screening results demonstrated that heat shock protein 90A (HSP90A), which participates in the PI3K-Akt signaling pathway and many other cancer-related pathways, warrants further investigation. The expression of HSP90A was increased in the HCC cells, serum, and tissues. Immunohistochemistry analysis on 76 clinical tissue samples also suggested the relevance between HSP90A expression and HCC metastatic behavior. CONCLUSIONS These findings suggest a role for HSP90A in HCC pathogenesis and the potential use of HSP90A for the screening and diagnosis of this malignancy.


Asymmetrical labeling of giant phospholipid vesicles.
The method for labeling of inner membrane leaflet in unilamellar giant POPC vesicles was developed and characterised. Symmetrically NBD-PC labeled vesicles were treated by sodium dithionite, which undergoes an irreversible chemical reaction with NBD-PC molecule making it non-fluorescent. After the addition of dithionite the fluorescence on single vesicles as well as on vesicle suspension showed a 50% decrease of its initial value corresponding to marker quenching in the outer leaflet. Hence, fluorimetry as well as fluorescence microscopy prove that dithionite quenching is a suitable method to induce an asymmetrical labeling of the NBD-PC marked giant vesicles.


Protective effects of fisetin against myocardial ischemia/reperfusion injury.
The underlying mechanism of the myocardial protective effect of fisetin was studied in a rat ischemia/reperfusion injury model. Sprague-Dawley rats were randomly assigned to seven groups and pretreated with different solutions by gavage administration. A rat model of cardiac ischemia/reperfusion injury was established. Plasma levels of Von Willebrand factor (vWF) were determined by ELISA, flow cytometry was used to determine the level of cardiomyocyte apoptosis and 2,3,5-triphenyltetrazolium staining was used to determine the size of myocardial infarcts. Hematoxylin and eosin-stained sections of myocardial tissues were examined for pathological changes. Expressions of nuclear factor (NF)-κB and matrix metallopeptidase 9 (MMP-9) were measured by immunohistochemistry. Compared with the model group, rats pretreated with fisetin, quercetin and aspirin showed significant prolongation of clotting time, prothrombin time, thrombin time and activated partial thromboplastin time. Fisetin treatment better maintained the integrity of myocardial fibers and nuclear integrity, reduced the percentage of apoptotic myocardial cells, inhibited expression of NF-κB, decreased the loss of MMP-9 and reduced nuclear translocation of NF-kB. Rats pretreated with fisetin also demonstrated a significant decrease in plasma levels of vWF. In addition, the protective effect of fisetin on myocardial cells was found to be dose dependent.


Correlation of bone age, dental age, and chronological age in survivors of childhood acute lymphoblastic leukaemia.
There is little information about oncotherapy-related dental development in childhood acute lymphoblastic leukaemia (ALL). The objective of this study was to compare bone age (BA) and dental age (DA) to chronological age (CA) in childhood ALL survivors. We retrospectively reviewed hand-wrist and panoramic radiographs of patients treated on contemporary single institution protocols for ALL between 1991 and 2004. We recorded patient demographics, therapeutic protocol, CA, DA, and BA. The cohort was divided into three categories based on age at diagnosis (< 6 years, 6-9 years, > 9 years). Of 73 patients, 39 (53.4%) were boys; 55 (75.3%) were Caucasian. Median CA at diagnosis was 4.5 years (range: 0.1-11.0 years); time to study was 4.1 years (range: 0.3-11.4 years). BA was normal in 61 (83.6%), delayed in 10 (13.7%), and advanced in 2 (2.7%). DA was normal in 41 (56.9%), delayed in 8 (11.1%), and advanced in 23 (31.9%). Abnormal BA, abnormal DA, and discrepancy between BA and DA are not statistically significantly associated with investigated patient or treatment factors. DA may be altered in 43.1% of patients treated for ALL. A large prospective study is warranted to better define our observations and to determine their impact on dental and orthodontic management.


A multiscale approach to sampling nascent peptide chains in the ribosomal exit tunnel.
We present a new multiscale method that combines all-atom molecular dynamics with coarse-grained sampling, towards the aim of bridging two levels of physiology: the atomic scale of protein side chains and small molecules, and the huge scale of macromolecular complexes like the ribosome. Our approach uses all-atom simulations of peptide (or other ligand) fragments to calculate local 3D spatial potentials of mean force (PMF). The individual fragment PMFs are then used as a potential for a coarse-grained chain representation of the entire molecule. Conformational space and sequence space are sampled efficiently using generalized ensemble Monte Carlo. Here, we apply this method to the study of nascent polypeptides inside the cavity of the ribosome exit tunnel. We show how the method can be used to explore the accessible conformational and sequence space of nascent polypeptide chains near the ribosome peptidyl transfer center (PTC), with the eventual aim of understanding the basis of specificity for co-translational regulation. The method has many potential applications to predicting binding specificity and design, and is sufficiently general to allow even greater separation of scales in future work.


Tuning the speed-accuracy trade-off to maximize reward rate in multisensory decision-making.
For decisions made under time pressure, effective decision making based on uncertain or ambiguous evidence requires efficient accumulation of evidence over time, as well as appropriately balancing speed and accuracy, known as the speed/accuracy trade-off. For simple unimodal stimuli, previous studies have shown that human subjects set their speed/accuracy trade-off to maximize reward rate. We extend this analysis to situations in which information is provided by multiple sensory modalities. Analyzing previously collected data (Drugowitsch et al., 2014), we show that human subjects adjust their speed/accuracy trade-off to produce near-optimal reward rates. This trade-off can change rapidly across trials according to the sensory modalities involved, suggesting that it is represented by neural population codes rather than implemented by slow neuronal mechanisms such as gradual changes in synaptic weights. Furthermore, we show that deviations from the optimal speed/accuracy trade-off can be explained by assuming an incomplete gradient-based learning of these trade-offs.


Congenital vascular malformations: a series of five prenatally diagnosed cases.
In the literature there are single case reports of mediastinal/chest and limb combined vascular malformations (previously labeled "hemangiolymphangiomas"). A variable outcome in such prenatally diagnosed cases is reported. Presented here is the only series of patients reported with these macrocystic, predominantly lymphatic malformations. Prenatal ultrasound scan and post-mortem examination findings are described. In our experience the outcome has been poor and this highlights the dilemma faced by clinicians and parents when these lesions are diagnosed prenatally. We present a series of five, prenatally diagnosed vascular (combined vascular malformations and simple localized lymphatic malformations) malformations. Three cases had lower leg involvement with extension into the abdomen and two cases had lymphatic malformations of the chest wall with involvement of the upper limb(s). Management of a twin pregnancy, in which one twin was affected, is described. In two cases, termination of pregnancy was undertaken because of the extensive nature of the lesion. One case died in utero and one in the neonatal period. The fifth case is an 11-year-old boy, whose lower limb deformity illustrates the considerable morbidity associated with this condition.


3D image understanding in radiology.
The role of 3-D imaging in medicine and the questions it raises regarding what should be automated and how the information is to be used are addressed. The discussion then turns to imagery generated by equipment using computed tomography (CT), magnetic resonance (MR) images, or positron/single-photon emission tomograms (PET/SPECT). Such image data are considered as spatial image sequences. Low-level and high-level processing for spatial image sequence understanding are examined. Conclusions are drawn regarding the value of 3-D imaging and the issues to be considered in its future development.


Randomized comparison of mefloquine-artesunate versus quinine in the treatment of multidrug-resistant falciparum malaria in pregnancy.
Since no effective malaria prevention measures have been identified for pregnant women living on the western border of Thailand, prompt diagnosis and efficient treatment are paramount, although drug resistance in Plasmodium falciparum has narrowed the treatment options. An open randomized comparison of supervised quinine (10 mg salt/kg every 8 h) for 7 days (Q7) versus mefloquine 25 mg base/kg (total dose) plus artesunate 4 mg/kg per day for 3 days (MAS3) was conducted in 1995-97 in 108 Karen women with acute uncomplicated falciparum malaria in the second or third trimesters of pregnancy. The MAS3 regimen was more effective than the Q7 regimen: day 63 cure rates were 98.2% (95% CI 94.7-100) (n = 65) for MAS3 and 67.0% (95% CI 43x3-90x8) (n = 41) for Q7, P = 0x001. The MAS3 regimen was also associated with less gametocyte carriage; the average person-gametocyte-weeks for MAS3 was 2.3 (95% CI 0-11) and for Q7 was 46x9 (95% CI 26-78) per 1000 person-weeks, respectively (P < 0.001). MAS3 was significantly better tolerated. These evident advantages must be balanced against a possible increased risk of stillbirth with the use of mefloquine in pregnancy. Further randomized studies assessing the safety and efficacy of other artemisinin-containing combination regimens in pregnancy are needed urgently.


Comparison of cognitive function between patients on chronic hemodialysis who carry out assisted physical activity and inactive ones.
Physical inactivity is a determinant of clinical disorders and psychological problems in patients with chronic kidney disease patients. In two satellite clinics, a program of physical activity (PA) was offered to 86 patients undergoing hemodialysis. Of those, 49 patients entered the PA program spontaneously and 37 remained inactive. After six months, a satisfaction self-reported questionnaire and the Modified Mini-Mental State (3MS) Examination for assessment of cognitive function were applied. Cognition was compared between inactive patients and those participating in the PA program for at least three months. Regardless of age and duration of dialysis, patients showed a cognitive deficit greater than expected. In the general group, better cognitive function was observed in active patients as compared to the inactive ones (p < 0.05). When separated by age groups, active patients over the age of 60 years had better results than the inactive ones (p < 0.05). We concluded that patients with better cognitive responses are more physically active and/or physical activity contributes to better cognitive function.


Trends in suicide mortality among Brazilian adults and elderly, 1980 - 2006.
To describe mortality from suicide in Brazil, with emphasis on the older adult population. Temporal analysis and trend analysis by polynomial regression were conducted on suicide in the population above 10 years old in Brazil and the State of Rio de Janeiro (Southeastern Brazil) from 1980-2006. The data were extracted from the Mortality Information System, and the rates calculated by gender and age per 100,000 inhabitants, considering the resident population provided by DATASUS. For the period between 1980 and 1995, the ninth revision of International Statistical Classification of Diseases and Related Health Problems was used, and for 1996 to 2006, the tenth revision. Suicide rates significantly increased in Brazil and in Rio de Janeiro (respectively reaching 5.7 and 3.1 deaths per 100,000 inhabitants in 2006). The change was caused by the increase in suicides among the male population at all ages. The increase occurred especially among men over 60 years. In Rio de Janeiro, the increase was not statistically significant among men, while there was a decrease among women. The principal means utilized for suicide by men were hanging, suffocation, strangulation and firearms. For women, death by hanging also ranks first, followed by ingestion of solids or liquids, smoke or fire, and jumping from heights. The high rate of suicide by unspecified means reveals problems with data quality. Suicides are important events in the male population, especially among older men over time. In Rio de Janeiro, the suicide rate is also higher in men, although the difference is not statistically significant. According to the World Health Organization and the Ministry of Health, suicide is preventable, and established interventions exist for each age group.


Novel Strategy in Breast Cancer Therapy: Revealing The Bright Side of Ginsenosides.
Breast cancer is one of the leading causes of death worldwide. Breast cancer cells demonstrate uncontrolled proliferation and high metastatic capacity. They can obtain resistance to chemotherapy and radiotherapy. This has resulted in troublesome treatment of breast cancer. Nature as a rich source of plant derived-natural products with anti-tumor activity can be of interest in breast cancer therapy. Ginsenosides are triterpenoid saponins and considered as secondary metabolites exclusively found in Panax species. From immemorial times, ginsenosides have been applied in the treatment of various disorders such as diabetes, inflammatory diseases, neurological disorders, and particularly, cancer. In the present review, we highlight the anti-tumor activity of ginsenosides against breast cancer cells. Ginsenosides are able to induce apoptosis and cell cycle arrest. They interfere with breast cancer metastasis via inhibiting epithelial-to-mesenchymal transition, matrix metalloproteinase proteins and angiogenesis. Ginsenosides can promote the efficacy of chemotherapy via suppressing migration and proliferation. Molecular pathways such as phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), insulin-like growth factor-1, Wnt, microRNAs and long non-coding RNAs are affected by ginsenosides in suppressing breast cancer malignancy. Consequently, ginsenosides are versatile compounds in breast cancer therapy by suppressing the growth and invasion, as well as promoting their sensitivity to chemotherapy.


[Characteristics of morphofunctional state of the pancreas in children with metabolic syndrome].
The paper presents the results of a study of the morphofunctional state of the pancreas in children with metabolic syndrome. It is shown that in the absolute majority of children identified various changes in the structure of the pancreas. Decrease Postprandial response and uneven increase in gland due to a head in the postprandial period, indicating a decrease in body adaptation abilities and a high risk of pancreatitis in children with MS. The interrelation between total size and size of the head of the pancreas on an empty stomach with disorders of carbohydrate metabolism. Obtained data indicate the need for in-depth examination of children with metabolic syndrome in order to timely diagnosis of chronic pancreatitis.


Sensory and cognitive influences on the training-related improvement of reading speed in peripheral vision.
Reading speed in normal peripheral vision is slow but can be increased through training on a letter-recognition task. The aim of the present study is to investigate the sensory and cognitive factors responsible for this improvement. The visual span is hypothesized to be a sensory bottleneck limiting reading speed. Three sensory factors-letter acuity, crowding, and mislocations (errors in the spatial order of letters)-may limit the size of the visual span. Reading speed is also influenced by cognitive factors including the utilization of information from sentence context. We conducted a perceptual training experiment to investigate the roles of these factors. Training consisted of four daily sessions of trigram letter-recognition trials at 10° in the lower visual field. Subjects' visual-span profiles and reading speeds were measured in pre- and posttests. Effects of the three sensory factors were isolated through a decomposition analysis of the visual span profiles. The impact of sentence context was indexed by context gain, the ratio of reading speeds for ordered and unordered text. Following training, visual spans increased in size by 5.4 bits of information transmitted, and reading speeds increased by 45%. Training induced a substantial reduction in the magnitude of crowding (4.8 bits) and a smaller reduction for mislocations (0.7 bits), but no change in letter acuity or context gain. These results indicate that the basis of the training-related improvement in reading speed is a large reduction in the interfering effect of crowding and a small reduction of mislocation errors.


The effect of a required residency based student clerkship on resident selection.
Over the past decade, the Department of Family Medicine at Jefferson Medical College has used a network of seven residency-based family practice centers each year to teach 223 third-year medical students in their required family medicine clerkship. A comparison of these affiliated residency programs with a control group of the other family medicine residency programs in Pennsylvania and Delaware (with minimal third-year teaching responsibilities) from 1976 to 1984 has shown that the affiliated programs had a significantly higher National Residency Matching Program (NRMP) fill rate (92% v. 77%), had a higher percentage of programs with fill rates above the national average (71% v. 41%), and filled their full complement of residents more often (82% v. 52%) than the control programs. This success in residency recruitment was due in part to the fact that the affiliated programs filled one-third of their positions with Jefferson graduates, three times the percentage found in the control programs. For family medicine residency programs, teaching third-year medical students in a required clerkship offers a major opportunity to improve their residency selection results in the NRMP.


Distal interphalangeal joint arthrodesis: treatment with Herbert screw.
From 1996 to 2000, 20 patients with a mean age of 53 underwent 20 arthrodeses with Herbert screws. There were 16 (80%) distal interphalangeal joint (DIP) and 4 (20%) thumb interphalangeal (IP) joint arthrodeses. Average follow-up was 25 months (range, 6-39 months). The diagnoses included rheumatoid arthritis in 10 patients, degenerative arthritis in 4, and post-traumatic arthritis in 6. Arthrodesis relieved pain and restored stability in all patients. Solid osseous union occurred in 19 patients (95%). The average interval to fusion was 8 weeks for DIP and 12 weeks for IP joint arthrodesis. Solid osseous union occurred in 19 patients (95%). The average interval to fusion was 8 weeks for distal interphalangeal joint arthrodesis and 12 weeks for interphalangeal joint of the thumb. There were three complications: one delayed union, one nonunion because of a short screw, and one dorsal skin necrosis with amputation. It was shown that distal interphalangeal joint arthrodesis with a Herbert screw is a technique with several advantages: good clinical results, high rates of fusion, early mobilization, and the screw does not need to be removed after the fusion heals. Potential complications may be avoided by using the Herbert mini-screw.


Transforming growth factor-beta1 triggers hepatocellular carcinoma invasiveness via alpha3beta1 integrin.
Metastasis occurrence in the course of hepatocellular carcinoma (HCC) severely affects prognosis and survival. We have shown that HCC invasive cells express alpha3beta1-integrin whereas noninvasive cells do not. Here we show that transforming growth factor (TGF)-beta1 stimulates alpha3-integrin expression at a transcriptional level in noninvasive HCC cells, causing transformation into a motile and invasive phenotype. Such activities are inhibited by neutralizing anti-alpha3- but not anti-alpha6-integrin monoclonal antibodies. HCC invasive cells secrete abundant levels of active TGF-beta1 in comparison with noninvasive cells, but in the latter, addition of active matrix metalloproteinases-2 increases the concentration of active TGF-beta1. In this way, the cells express alpha3-integrin at a transcriptional level and acquire motility on Ln-5. By contrast, an anti-TGF-beta1-neutralizing antibody reduces alpha3-integrin expression and the invasive ability of HCC invading cells. In HCC patients, TGF-beta1 serum concentrations and alpha3-integrin expression are strongly correlated. The integrin, absent in normal and peritumoral liver parenchyma, is abundantly expressed in HCC primary and metastatic tissue. In particular, patients with metastasis show higher levels of TGF-beta1 serum concentrations and stronger expression of TGF-beta1 and alpha3-integrin in HCC tissues. In conclusion, TGF-beta1 may play an important role in HCC invasiveness by stimulating alpha3-integrin expression, and could therefore be an important target for new therapies.


Mechanical muscle and tendon properties of the plantar flexors are altered even in highly functional children with spastic cerebral palsy.
Recent ultrasound studies found increased passive muscle stiffness and no difference in tendon stiffness in highly impaired children and young adults with cerebral palsy. However, it is not known if muscle and tendon mechanical properties are already altered in highly functional children with cerebral palsy. Therefore, the purpose of this study was to compare the mechanical and material properties of the plantar flexors in highly functional children with cerebral palsy and typically developing children. Besides strength measurements, ultrasonography was used to assess gastrocnemius medialis and Achilles tendon elongation and stiffness, Achilles tendon stress, strain, and Young's modulus in twelve children with cerebral palsy (GMFCS levels I and II) and twelve typically developing peers during passive dorsiflexion rotations as well as maximum voluntary contractions. Despite no difference in ankle joint stiffness (P>0.05) between groups, passive but not active Achilles tendon stiffness was significantly decreased (-39%) and a tendency of increased passive muscle stiffness was observed even in highly functional children with cerebral palsy. However, material properties of the tendon were not altered. Maximum voluntary contraction showed reduced plantar flexor strength (-48%) in the cerebral palsy group. Even in children with mild spastic cerebral palsy, muscle and tendon mechanical properties are altered. However, it appears that the Achilles tendon stiffness is different only when low forces act on the tendon during passive movements. Although maximum voluntary force is already decreased, forces acting on the Achilles tendon during activity appear to be sufficient to maintain typical material properties.


Primary events in the blue light sensor plant cryptochrome: intraprotein electron and proton transfer revealed by femtosecond spectroscopy.
Photoreceptors are chromoproteins that undergo fast conversion from dark to signaling states upon light absorption by the chromophore. The signaling state starts signal transduction in vivo and elicits a biological response. Therefore, photoreceptors are ideally suited for analysis of protein activation by time-resolved spectroscopy. We focus on plant cryptochromes which are blue light sensors regulating the development and daily rhythm of plants. The signaling state of these flavoproteins is the neutral radical of the flavin chromophore. It forms on the microsecond time scale after light absorption by the oxidized state. We apply here femtosecond broad-band transient absorption to early stages of signaling-state formation in a plant cryptochrome from the green alga Chlamydomonas reinhardtii. Transient spectra show (i) subpicosecond decay of flavin-stimulated emission and (ii) further decay of signal until 100 ps delay with nearly constant spectral shape. The first decay (i) monitors electron transfer from a nearby tryptophan to the flavin and occurs with a time constant of τ(ET) = 0.4 ps. The second decay (ii) is analyzed by spectral decomposition and occurs with a characteristic time constant τ(1) = 31 ps. We reason that hole transport through a tryptophan triad to the protein surface and partial deprotonation of tryptophan cation radical hide behind τ(1). These processes are probably governed by vibrational cooling. Spectral decomposition is used together with anisotropy to obtain the relative orientation of flavin and the final electron donor. This narrows the number of possible electron donors down to two tryptophans. Structural analysis suggests that a set of histidines surrounding the terminal tryptophan may act as proton acceptor and thereby stabilize the radical pair on a 100 ps time scale.


The association between candidate migraine susceptibility loci and severe migraine phenotype in a clinical sample.
The objective of the study was to follow up and to test whether 12 previously identified migraine-associated single nucleotide polymorphisms were associated as risk factors and/or modifying factors for severe migraine traits in a Danish clinic-based population. Semi-structured migraine interviews, blood sampling and genotyping were performed on 1806 unrelated migraineurs recruited from the Danish Headache Center. Genotyping was also performed on a control group of 6415 people with no history of migraine. Association analyses were carried out using logistic regression and odds ratios were calculated assuming an additive model for risk. The proxies for severe migraine traits (early onset of migraine; many lifetime attacks, prolonged migraine and tendency to chronification of migraine) were tested against the 12 single nucleotide polymorphisms and a combined genetic score in both a case-control and case-only logistic regression model. We successfully replicated five out of the 12 previously reported loci and confirmed the same direction of effects for all the 12 single nucleotide polymorphisms. In line with the recently published genome-wide association meta-analysis, the associations were significant for all migraine and migraine without aura but not for migraine with typical aura. Two single nucleotide polymorphisms (rs2274316 and rs11172113) conferred risk of many lifetime attacks inthe case-control analysis. In the case-only analysis, only three single nucleotide polymorphisms showed nominal association with many lifetime attacks and prolonged migraine attacks. Our study supports previously reported findings on the association of several single nucleotide polymorphisms with migraine. It also suggests that the migraine susceptibility loci may be risk factors for severe migraine traits.


Identification of alanine dehydrogenase and its role in mixed secretion of ammonium and alanine by pea bacteroids.
N2-fixation by Rhizobium-legume symbionts is of major ecological and agricultural importance, responsible for producing a substantial fraction of the biosphere's nitrogen. On the basis of 15N-labelling studies, it had been generally accepted that ammonium is the sole secretion product of N2-fixation by the bacteroid and that the plant is responsible for assimilating it into amino acids. However, this paradigm has been challenged in a recent 15N-labelling study showing that soybean bacteroids only secrete alanine. Hitherto, nitrogen secretion has only been assessed from in vitro 15N-labelling studies of isolated bacteroids. We show that both ammonium and alanine are secreted by pea bacteroids. The in vitro partitioning between them will depend on whether the system is open or closed, as well as the ammonium concentration and bacteroid density. To overcome these limitations we identified and mutated the gene for alanine dehydrogenase (aldA) and demonstrate that AldA is the primary route for alanine synthesis in isolated bacteroids. Bacteroids of the aldA mutant fix nitrogen but only secrete ammonium at a significant rate, resulting in lower total nitrogen secretion. Peas inoculated with the aldA mutant are green and healthy, demonstrating that ammonium secretion by bacteroids can provide sufficient nitrogen for plant growth. However, plants inoculated with the mutant are reduced in biomass compared with those inoculated with the wild type. The labelling and plant growth studies suggest that alanine synthesis and secretion contributes to the efficiency of N2-fixation and therefore biomass accumulation.


Anatomical Variations in the Celiac Trunk: A Short Review.
The objective of the current study was the examination of possible variants of the celiac trunk. An advanced review of the literature search was undertaken by means of the PubMed database and Google Scholar, searching for new studies published up to October 2022. Additional articles provided useful information in relation to the aim of this review. Hence, articles that met the inclusion criteria were included in this review and the collected data were organized into a table. The search of the literature retrieved 10 articles that referred to the anatomical variations of the celiac trunk. According to the available literature, the most common anatomical variations are: hepatosplenic trunk where the left gastric artery originates from the abdominal aorta, hepatosplenic trunk, where the left gastric artery originates from the splenic artery, and hepatogastric trunk and splenic artery origin from the superior mesenteric artery. Many other anatomical variations of the celiac trunk may exist, such as tetrafurcation, pentafurcation and hexafurcation, that refer to the division of the celiac trunk into four, five or six branches, respectively, and should be reported as they can affect surgical approaches and the development of the appropriate treatment strategy in patients. Every visceral surgeon, interventional radiologist and abdominal imager should be familiar with these variants.


Interactions of amiloride with alpha- and beta-adrenergic receptors: amiloride reveals an allosteric site on alpha 2-adrenergic receptors.
Interaction of amiloride with adrenergic receptors was studied using radioligand binding techniques. Amiloride competed for [3H]prazosin binding to alpha 1-adrenergic receptors on rat renal cortical membranes and BC3H-1 muscle cell membranes. Non-linear regression analysis of radioligand binding isotherms showed that amiloride increased Kd without a change in Bmax, suggesting the drug binds competitively in a mutually exclusive manner with the radioligand at the receptor-binding site. Similarly, amiloride competitively blocked [125I]iodocyanopindolol binding to beta-adrenergic receptors on both tissues. The addition of guanylyl 5'-imidodiphosphate or sodium chloride did not alter the interaction of amiloride with alpha 1- or beta-adrenergic receptors. The interaction of amiloride with alpha 2-adrenergic receptors was more complex and revealed an allosteric site. In both rat renal cortical membranes and intact human platelets, amiloride increased the Kd for [3H]rauwolscine binding, as well as decreasing the apparent Bmax. In binding experiments where amiloride competed for [3H]rauwolscine-binding sites, pseudo-Hill slopes of less than 1.0 were obtained for both platelet and renal alpha 2 receptors. In addition, amiloride increased the rate of [3H]rauwolscine dissociation from renal alpha 2 receptors. In the presence of 100-120 mM sodium chloride, the Ki for amiloride competition was decreased an average of 54% in renal membranes; in contrast, sodium increased the Kd of the agonist epinephrine. Taken together, these data support the hypothesis that alpha 2-adrenergic receptors, but not alpha 1- or beta-adrenergic receptors, have an allosteric site to which amiloride binds and which we propose to be a cation-binding site.


X.a.f.s. studies of chicken dicupric ovotransferrin.
A comparison of Cu K-edge x.a.f.s. spectra with that of the equivalent Fe K-edge for chicken ovotransferrin (COT) indicates that the metal ions occupy essentially the same binding sites in the protein. However, in the case of the Cu2+ complex the metal appears to have reduced co-ordination. Changes are observed in the x.a.f.s. of 90%-saturated COT (Cu1.8COT) on freeze-drying. The three-dimensional X-ray structures of rabbit serum transferrin and human lactoferrin have shown that the ferric cations are co-ordinated by four protein ligands and a bidentate carbonate anion in a distorted octahedral arrangement [Anderson, Baker, Dodson, Norris, Rumball, Waters & Baker (1987) Proc. Natl. Acad. Sci. U.S.A. 84, 1768-1774; Anderson, Baker, Norris, Rice and Baker (1989) J. Mol. Biol. 209, 711-734; Bailey, Evans, Garratt, Gorinsky, Hasnain, Horsburgh, Jhoti, Lindley, Mydin, Sarra & Watson (1988) Biochemistry 27, 5804-5812]. This structural information, together with the differences in e.x.a.f.s. spectra for solution and freeze-dried samples of diferric COT [Hasnain, Evans, Garratt & Lindley (1987) Biochem. J. 247, 369-375] suggests that the synergistic carbonate anion may be capable of behaving as a unidentate linkage to the Cu2+ in the dicupric complex. Data for Cu1.8COT are consistent with only three protein ligands bound to Cu2+, monodentate binding of the synergistic anion in one lobe and its bidentate binding in the other lobe. Such flexibility in the anion co-ordination may be a requirement for the uptake and release of metals by the transferrins.


Genome-wide analysis of zygotic linkage disequilibrium and its components in crossbred cattle.
Linkage disequilibrium (LD) between genes at linked or independent loci can occur at gametic and zygotic levels known asgametic LD and zygotic LD, respectively. Gametic LD is well known for its roles in fine-scale mapping of quantitative trait loci, genomic selection and evolutionary inference. The less-well studied is the zygotic LD and its components that can be also estimated directly from the unphased SNPs. This study was set up to investigate the genome-wide extent and patterns of zygotic LD and its components in a crossbred cattle population using the genomic data from the Illumina BovineSNP50 beadchip. The animal population arose from repeated crossbreeding of multiple breeds and selection for growth and cow reproduction. The study showed that similar genomic structures in gametic and zygotic LD were observed, with zygotic LD decaying faster than gametic LD over marker distance. The trigenic and quadrigenic disequilibria were generally two- to three-fold smaller than the usual digenic disequilibria (gametic or composite LD). There was less power of testing for these high-order genic disequilibria than for the digenic disequilibria. The power estimates decreased with the marker distance between markers though the decay trend is more obvious for the digenic disequilibria than for high-order disequilibria. This study is the first major genome-wide survey of all non-allelic associations between pairs of SNPs in a cattle population. Such analysis allows us to assess the relative importance of gametic LD vs. all other non-allelic genic LDs regardless of whether or not the population is in HWE. The observed predominance of digenic LD (gametic or composite LD) coupled with insignificant high-order trigenic and quadrigenic disequilibria supports the current intensive focus on the use of high-density SNP markers for genome-wide association studies and genomic selection activities in the cattle population.


The ectomycorrhizal fungus Amanita phalloides was introduced and is expanding its range on the west coast of North America.
The deadly poisonous Amanita phalloides is common along the west coast of North America. Death cap mushrooms are especially abundant in habitats around the San Francisco Bay, California, but the species grows as far south as Los Angeles County and north to Vancouver Island, Canada. At different times, various authors have considered the species as either native or introduced, and the question of whether A. phalloides is an invasive species remains unanswered. We developed four novel loci and used these in combination with the EF1α and IGS loci to explore the phylogeography of the species. The data provide strong evidence for a European origin of North American populations. Genetic diversity is generally greater in European vs. North American populations, suggestive of a genetic bottleneck; polymorphic sites of at least two loci are only polymorphic within Europe although the number of individuals sampled from Europe was half the number sampled from North America. Endemic alleles are not a feature of North American populations, although alleles unique to different parts of Europe were common and were discovered in Scandinavian, mainland French, and Corsican individuals. Many of these endemic European haplotypes were found together at single sites in California. Early collections of A. phalloides dated prior to 1963 and annotated using sequences of the ITS locus proved to be different species of Amanita. The first Californian collections that we confirmed as A. phalloides were made from the Del Monte Hotel (now the Naval Postgraduate School) in Monterey, and on the campus of the University of California, Berkeley, in 1938 and in 1945. These historical data are used in combination with data on A. phalloides' current distribution to estimate a rate of spread for A. phalloides in California. Many species of ectomycorrhizal (EM) fungi have been introduced across and among continents, but with this evidence, the death cap becomes the only known invasive EM fungus in North America.


Prognosis of patients with adult T-cell leukemia/lymphoma in Japan: A nationwide hospital-based study.
Adult T-cell leukemia/lymphoma (ATL) is a mature T-cell neoplasm and is classified into four subtypes (acute, lymphoma, chronic, and smoldering) according to the Shimoyama classification, established in 1991 through several nationwide surveys based on the clinical diversity of patients diagnosed in 1983-1987 in Japan. Thereafter, no such studies have been conducted. Recently, we conducted a nationwide hospital survey using the method of the 1980s studies, collected baseline data on 996 ATL patients diagnosed in 2010-2011 from 126 hospitals, and reported their unique epidemiological characteristics. Here, we report the follow-up results of registered ATL patients with the goal of evaluating current prognoses and treatment modalities as of 2016-2017. Of 770 evaluable patients, 391 (50.8%) had acute-type, 192 (24.9%) had lymphoma-type, 106 (13.8%) had chronic-type, and 81 (10.5%) had smoldering-type ATL. The initial therapy regimens used for acute/lymphoma-type ATL were vincristine, cyclophosphamide, doxorubicin and prednisone, followed by doxorubicin, ranimustine, and prednisone and then by vindesine, etoposide, carboplatin, and prednisone (VCAP-AMP-VECP)-like in 38.5/41.7% and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-like in 14.6/13.7% of patients. Allogeneic hematopoietic stem cell transplantation was used to treat 15.9/10.4% of acute/lymphoma-type ATL patients. The 4-year survival rates (the median survival time, days) for acute-, lymphoma-, unfavorable chronic-, favorable chronic-, and smoldering-type ATL were 16.8% (252), 19.6% (305), 26.6% (572), 62.1% (1937), and 59.8% (1851), respectively. The 4-year survival rates for acute- and lymphoma-type ATL improved compared with those reported in 1991, but those for chronic- and smoldering-type ATL were not. Further efforts are warranted to develop more efficient therapeutic strategies to improve the prognosis of ATL in Japan.


Expression of IL-8, IL-6 and IL-1β in tears as a main characteristic of the immune response in human microbial keratitis.
Corneal infections are frequent and potentially vision-threatening diseases, and despite the significance of the immunological response in animal models of microbial keratitis (MK), it remains unclear in humans. The aim of this study was to describe the cytokine profile of tears in patients with MK. Characteristics of ocular lesions such as size of the epithelial defect, stromal infiltration, and hypopyon were analyzed. Immunological evaluation included determination of interleukine (IL)-1β, IL-6, IL-8, IL-10, IL-12 and tumor necrosis factor (TNF)-α in tear samples obtained from infected eyes of 28 patients with MK and compared with their contralateral non-infected eyes. Additionally, frequency of CD4+, CD8+, CD19+ and CD3-CD56+ cells was also determined in peripheral blood mononuclear cells in patients with MK, and compared with 48 healthy controls. Non-significant differences were observed in the size of the epithelial defect, stromal infiltration, and hypopyon. Nevertheless, we found an immunological profile apparently related to MK etiology. IL-8 > IL-6 in patients with bacterial keratitis; IL-8 > IL-6 > IL-1β and increased frequency of circulating CD3-CD56+ NK cells in patients with gram-negative keratitis; and IL-8 = IL-6 > IL-1β in patients with fungal keratitis. Characterization of tear cytokines from patients with MK could aid our understanding of the immune pathophysiological mechanisms underlying corneal damage in humans.


Papulonecrotic tuberculid with scrofuloderma: an uncommon association.
Cutaneous tuberculosis can be classified as true cutaneous tuberculosis and tuberculids which is regarded as a hypersensitivity reaction to M. tuberculosis in patients with a high degree of tuberculin sensitivity. Papulonecrotic tuberculid (PNT) is a form of tuberculid. It is an uncommon manifestation even in areas with high prevalence of tuberculosis. We report a case of 35-year-old man who presented with necrotizing papules in symmetrical fashion over the trunk and extremities for last one year along with a discharging sinus in right axilla for last two months. Papulonecrotic tuberculid (PNT) with scrofuloderma were suspected on clinical examination. Mantoux test was strongly positive with 20x20mm. He was treated successfully with ATT without any further appearance of new lesions.


Controlling liposomal drug release with low frequency ultrasound: mechanism and feasibility.
The ability of low-frequency ultrasound (LFUS) to release encapsulated drugs from sterically stabilized liposomes in a controlled manner was demonstrated. Three liposomal formulations having identical lipid bilayer compositions and a similar size ( approximately 100 nm) but differing in their encapsulated drugs and methods of drug loading have been tested. Two of the drugs, doxorubicin and methylpredinisolone hemisuccinate, were remote loaded by transmembrane gradients (ammonium sulfate and calcium acetate, respectively). The third drug, cisplatin, was loaded passively into the liposomes. For all three formulations, a short exposure to LFUS (<3 min) released nearly 80% of the drug. The magnitude of drug release was a function of LFUS amplitude and actual exposure time, irrespective of whether irradiation was pulsed or continuous. Furthermore, no change in liposome size distribution or in the chemical properties of the lipids or of the released drugs occurred due to exposure to LFUS. Based on our results, we propose that the mechanism of release is a transient introduction of porelike defects in the liposome membrane, which occurs only during exposure to LFUS, after which the membrane reseals. This explains the observed uptake of the membrane-impermeable fluorophore pyranine from the extraliposomal medium during exposure to LFUS. The implications of these findings for clinical applications of controlled drug release from liposomes are discussed.


Hydrophilized 3D porous scaffold for effective plasmid DNA delivery.
In this study, hydrophilic PLGA/Pluronic F127 scaffolds loaded with a pDNA/PEI-PEG complex were prepared to estimate their potential use as a polymeric matrix for pDNA delivery. The scaffold was fabricated by a novel precipitation/particulate leaching method. The prepared pDNA/PEI-PEG complex-loaded PLGA/Pluronic F127 scaffold exhibited a highly porous (porosity, 93-95%) and open pore structure, as well as hydrophilicity, which can provide the good environment for cell adhesion and growth. The pDNA/PEI-PEG complexes were efficiently loaded into the PLGA/Pluronic F127 scaffold and continuously released from the scaffolds up to ~90% of the initial loading amount over a period of 8 wk, which may lead to continuous gene transfection into human bone marrow mesenchymal stem cells (hBMMSCs). From the in vitro cell culture in the scaffolds for transfection, it was observed that the pDNA/PEI-PEG complex-loaded hydrophilic PLGA/Pluronic F127 scaffold has a higher transfection efficiency of the pDNA/PEI-PEG complexes into hBMMSCs than the hydrophobic PLGA ones. The cell viability associated with the pDNA/PEI-PEG complexes released from the PLGA/Pluronic F127 scaffold was not significantly different from that of the PLGA/Pluronic F127 scaffold without pDNA, indicating its low cytotoxicity, probably due to the sustained release of the pDNA/PEI-PEG complex from the scaffolds. From these results, we could suggest that the pDNA/PEI-PEG complex-loaded hydrophilic PLGA/Pluronic F127 scaffold can be an effective gene delivery system for 3D tissue formation.


Fine mapping of canine parvovirus B cell epitopes.
In this report we describe the topological mapping of neutralizing domains of canine parvovirus (CPV). We obtained 11 CPV-specific monoclonal antibodies (MAbs), six of which are neutralizing. The reactivities were as determined by ELISA and Western blot (immunoblot) analysis. VP2, the most abundant protein of the CPV capsid, seemed to contain all the neutralization sites. Also, an almost full-length genomic clone of CPV was constructed in the bacterial plasmid pUC18 to enable expression of CPV proteins. All the neutralizing MAbs recognized recombinant VP2 when it was expressed as a free protein in Escherichia coli but not when expressed as a fusion protein with glutathione-S-transferase. When two large fragments containing about 85% and 67% of the C terminus of VP2 were expressed, no neutralization sites were detected. When fusion proteins containing the N terminus were expressed, two linear determinants were mapped, one between residues 1 to 10 of VP2, and the other between amino acids 11 and 23. The peptide 11 GQPAVRNERATGS 23, recognized by MAb 3C9, was synthesized chemically and checked for immunogenicity, not being able to induce neutralizing activity. Although the antibody response in rabbits to all the fusion proteins was uniformly high, the anti-CPV response was very variable. Protein from pCPVEx11, which contains a T cell epitope (peptide PKIFINLAKKKKAG) present in the VP1-specific region as well as the B cell epitopes, seemed to be the most effective in inducing virus neutralization.


Simulation studies on the evolution of amino acid sequences.
A model of molecular evolution in which the parameter (intrinsic rate of amino acid substitution) fluctuates from time to time was investigated by simulating the process. It was found that the usual method of estimation such as Poisson fitting underestimates this variation of the parameter when remote comparisons are made. At the same time, four distance measures (minimun base difference, Poisson fitting, random nucleotide substitutions and negative binomial fitting) were tested for their accuracy. When the substitution rate is not uniform among the amino acid sites, the negative bionomial fitting gives most satisfactory results, however, one needs to know the parameter beforehand in order to use this method. It was pointed out that the fluctuation of the evolutionary rate is expected if the nearly neutral but very slightly deleterious mutations play an important role on molecular evolution.


ICP0 induces the accumulation of colocalizing conjugated ubiquitin.
Herpes simplex virus type 1 (HSV-1) immediate-early protein ICP0 is a general activator of viral gene expression which stimulates the initiation of lytic infection and reactivation from quiescence and latency. The importance of ICP0 to the biology of HSV-1 infection has stimulated interest in its mode of action. Previous studies have reported its interactions with other viral regulatory molecules, with the translation apparatus, with cyclin D3, and with a ubiquitin-specific protease. It has been demonstrated that ICP0 is able to induce the proteasome-dependent degradation of a number of cellular proteins, including components of centromeres and small nuclear substructures known as ND10 or PML nuclear bodies. ICP0 has a RING finger zinc-binding domain which is essential for its functions. In view of several recent examples of other RING finger proteins which modulate the stability of specific target proteins by acting as components of E3 ubiquitin ligase complexes, this study has explored whether ICP0 might operate via a similar mechanism. Evidence that the foci of accumulated ICP0 in transfected and infected cells contain enhanced levels of conjugated ubiquitin is presented. This effect was dependent on the RING finger region of ICP0, and comparison of the properties of a number of ICP0 mutants revealed an excellent correlation between previously established functions of ICP0 and its ability to induce concentrations of colocalizing conjugated ubiquitin. These results strongly support the hypothesis that a major factor in the mechanism by which ICP0 influences virus infection is its ability to induce the degradation of specific cellular targets by interaction with the ubiquitin-proteasome pathway.


Homologs of the Tumor Suppressor Protein p53: A Bioinformatics Study for Drug Design.
Sequence and structure of proteins related to the tumor suppressor protein p53 were studied from the perspective of gaining insight for the development of therapeutic drugs. Our study addresses two major issues encumber bringing novel drugs to market: side effects and artifacts from animal models. In the first phase of our study, we performed a genome-wide search to identify potentially similar proteins to p53 that may be susceptible to off target effects. In the second phase, we chose a selection of common model organisms that could potentially be available to undergraduate researchers in the university setting to assess which ones utilize p53 most similar to humans on the basis of sequence homology and structural similarity from predicted structures. Our results confirm the proteins in the humans significantly similar to p53 are known paralogs within the p53 family. In considering model organisms, murine p53 bore great similarity to human p53 in terms of both sequence and structure, but others performed similarly well. We discuss the findings against the background of other structural benchmarks and point out potential benefits and drawbacks of various alternatives for use in future drug design pilot studies.


[Acupuncture and sciatica in the acute phase. Double-blind study of 30 cases].
Responses to acupuncture were studied in 30 patients with acute sciatica. Objective and subjective criteria were analyzed before treatment and after five sessions of acupuncture. The study was double blind. Patients were randomly assigned to one of two groups: 15 were treated on electrically detected points and 15 on "placebo" points. In the "placebo" group, no significant improvement was recorded. Conversely, in the treated group, study of objective criteria showed improvement of the Lasegue sign. Among subjective symptoms, positive responses were recorded in the duration of improvement, degree of improvement in decubitus and after ten minutes standing, and use of analgesics. Compared to the "placebo" group these changes are statistically significant.


Genetic approaches to the study of the molecular basis of human cancer.
During the past few years molecular genetics has been providing answers concerning the mechanisms that are involved in the pathogenesis of human malignancies. Essentially two different mechanisms are involved. One results in the activation of cellular protooncogenes. This activation can occur by activation of transcription, mutation, or gene fusion. Chromosomal translocations and inversions in malignant cells have provided very powerful tools to identify and characterize genes involved in malignant transformation and to probes specific for breakpoint cluster regions are being used extensively for the diagnosis, prognosis, and clinical monitoring of hematopoietic malignancies. The other mechanism results in loss of function of cancer suppressor genes or antioncogenes. Loss of heterozygosity at specific sites of the human genome has provided the means to identify, by the molecular genetic approach, genes the function of which is eliminated or suppressed in human cancers. During the last few years a number of such genes, such as Rb and p53, have been identified and characterized. By this approach a potential candidate involved in the 3p deletion characteristic of lung cancer has been identified. Interestingly, this gene codes for a protein tyrosine phosphatase (14). If this gene should turn out to be involved in the pathogenesis of lung and kidney tumors, it will indicate that transmembrane protein tyrosine phosphatase may represent a class of tumor suppressors.


Virus-host protein co-expression networks reveal temporal organization and strategies of viral infection.
Viral replication is a complex dynamical process involving the global remodeling of the host cellular machinery across several stages. In this study, we provide a unified view of the virus-host interaction at the proteome level reconstructing protein co-expression networks from quantitative temporal data of four large DNA viruses. We take advantage of a formal framework, the theory of competing networks, to describe the viral infection as a dynamical system taking place on a network of networks where perturbations induced by viral proteins spread to hijack the host proteome for the virus benefit. Our methodology demonstrates how the viral replication cycle can be effectively examined as a complex interaction between protein networks, providing useful insights into the viral and host's temporal organization and strategies, key protein nodes targeted by the virus and dynamical bottlenecks during the course of the infection.


Decreased factor XIII activity in a patient with subcutaneous bleeding after double filtration plasmapheresis.
Double filtration plasmapheresis (DFPP) is often performed as a treatment for autoimmune diseases including pemphigus vulgaris. We report a pemphigus vulgaris patient with subcutaneous bleeding, gradually spreading over a period of 10 days after DFPP. In this patient, factor XIII activity was markedly decreased. In three other patients, factor XIII activities were markedly reduced the day following DFPP, were but restored by days 7-10. From these findings, subcutaneous bleeding may have occurred in the present patient due to a delayed recovery of the decreased factor XIII activity after DFPP. Therefore, decreased factor XIII activity could be a critical cause of subcutaneous bleeding after DFPP.


Immunoinformatics-guided design of an epitope-based vaccine against severe acute respiratory syndrome coronavirus 2 spike glycoprotein.
With a large number of fatalities, coronavirus disease-2019 (COVID-19) has greatly affected human health worldwide. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that causes COVID-19. The World Health Organization has declared a global pandemic of this contagious disease. Researchers across the world are collaborating in a quest for remedies to combat this deadly virus. It has recently been demonstrated that the spike glycoprotein (SGP) of SARS-CoV-2 is the mediator by which the virus enters host cells. Our group comprehensibly analyzed the SGP of SARS-CoV-2 through multiple sequence analysis and a phylogenetic analysis. We predicted the strongest immunogenic epitopes of the SGP for both B cells and T cells. We focused on predicting peptides that would bind major histocompatibility complex class I. Two optimal epitopes were identified, WTAGAAAYY and GAAAYYVGY. They interact with the HLA-B*15:01 allele, which was further validated by molecular docking simulation. This study also found that the selected epitopes are able to be recognized in a large percentage of the world's population. Furthermore, we predicted CD4+ T-cell epitopes and B-cell epitopes. Our study provides a strong basis for designing vaccine candidates against SARS-CoV-2. However, laboratory work is required to validate our theoretical results, which would lay the foundation for the appropriate vaccine manufacturing and testing processes.


'I didn't want to pass that on to my child, being afraid to go to the dentist': making sense of oral health through narratives of connectedness over the life course.
While previous sociological research on oral health has identified the relevance of personal relationships, there is more scope to analyse the mouth through a lens of connectedness. Recent qualitative interviews with 43 older people (65+) in England and Scotland found that participants constructed relational narratives to make sense of their oral health practices. By drawing on ideas of family practices, family display and personal life, we illustrate how the mouth can be understood relationally. Participants presented their own embodied experiences as connected to the actions of their parents. Narratives also reflected how, as parents and grandparents themselves, participants tried to shape the experiences of others. In this way, oral health practices were conceptualised as being about family. This can be seen in self-narratives that demonstrated how participants located themselves as embedded in webs of ongoing relationships. We highlight the importance of narrated practices of thinking and feeling, whereby participants imagined doing oral health, and indeed family, in different ways. We thereby demonstrate how oral health practices are constituted through family connectedness and at the same time how these practices contribute to the constitution of family. Policy should therefore pay attention to family relations when promoting improvements in oral health practices.


Pharmacologic issues in geriatric emergency medicine.
The challenge for the practitioner is to balance incomplete evidence about efficacy of medications in frail older people against the problems related to adverse drug reactions without denying people potentially valuable pharmacotherapeutic interventions. Prescribers need to be diligent in reviewing medications periodically as well as when new medications are being considered. Review of updated explicit criteria is essential to understand and prescribe appropriately in this special population.


Computational and experimental research on infrared trace by human being contact.
The indoor detection of the human body's thermal trace plays an important role in the fields of infrared detecting, scouting, infrared camouflage, and infrared rescuing and tracking. Currently, quantitative description and analysis for this technology are lacking due to the absence of human infrared radiation analysis. To solve this problem, we study the heating and cooling process by observing body contact and removal on an object, respectively. Through finite-element simulation and carefully designed experiments, an analytical model of the infrared trace of body contact is developed based on infrared physics and heat transfer theory. Using this model, the impact of body temperature on material thermal parameters is investigated. The sensitivity of material thermal parameters, the thermal distribution, and the changes of the thermograph's contrast are then found and analyzed. Excellent matching results achieved between the simulation and the experiments demonstrate the strong impact of temperature on material thermal parameters. Conclusively, the new model, simulation, and experimental results are beneficial to the future development and implementation of infrared trace technology.


Birdshot retinochoroidopathy review.
Birdshot retinochoroidopathy (BSRC) is a distinct type of posterior uveitis originally described in the 1940s. Its characteristics include minimal anterior segment inflammation and diffuse posterior choroidopathy with vitritis and retinal vasculitis. The precise etiology of this disease is yet to be elucidated. However, various treatment modalities have been employed with the ultimate goal of durable remission of this vision threatening intraocular disease. The purpose of this review is not only to emphasize the importance of recognizing BSRC, but also to discuss the new discoveries, immune mediators, current and new therapies, and techniques applied to monitor and accomplish disease remission.


Antimicrobial resistance in foodborne pathogens--a cause for concern?
The widespread use of antibiotics in food animal production systems has resulted in the emergence of antibiotic resistant zoonotic bacteria that can be transmitted to humans through the food chain. Infection with antibiotic resistant bacteria negatively impacts on public health, due to an increased incidence of treatment failure and severity of disease. Development of resistant bacteria in food animals can result from chromosomal mutations but is more commonly associated with the horizontal transfer of resistance determinants borne on mobile genetic elements. Food may represent a dynamic environment for the continuing transfer of antibiotic resistance determinants between bacteria. Current food preservation systems that use a combination of environmental stresses to reduce growth of bacteria, may serve to escalate development and dissemination of antibiotic resistance among food related pathogens. The increasing reliance on biocides for pathogen control in food production and processing, heightens the risk of selection of biocide-resistant strains. Of particular concern is the potential for sublethal exposure to biocides to select for bacteria with enhanced multi-drug efflux pump activity capable of providing both resistance to biocides and cross-resistance to multiple antibiotics. Although present evidence suggests that biocide resistance is associated with a physiological cost, the possibility of the development of adaptive mutations conferring increased fitness cannot be ruled-out. Strategies aimed at inhibiting efflux pumps and eliminating plasmids could help to restore therapeutic efficacy to antibiotics and reduce the spread of antibiotic resistant foodborne pathogens through the food chain.


MAL overexpression leads to disturbed expression of genes that influence cytoskeletal organization and differentiation of Schwann cells.
In the developing peripheral nervous system, a coordinated reciprocal signaling between Schwann cells and axons is crucial for accurate myelination. The myelin and lymphocyte protein MAL is a component of lipid rafts that is important for targeting proteins and lipids to distinct domains. MAL overexpression impedes peripheral myelinogenesis, which is evident by a delayed onset of myelination and reduced expression of the myelin protein zero (Mpz/P0) and the low-affinity neurotrophin receptor p75(NTR). This study shows that MAL overexpression leads to a significant reduction of Mpz and p75(NTR) expression in primary mouse Schwann cell cultures, which was already evident before differentiation, implicating an effect of MAL in early Schwann cell development. Their transcription was robustly reduced, despite normal expression of essential transcription factors and receptors. Further, the cAMP response element-binding protein (CREB) and phosphoinositide 3-kinase signaling pathways important for Schwann cell differentiation were correctly induced, highlighting that other so far unknown rate limiting factors do exist. We identified novel genes expressed by Schwann cells in a MAL-dependent manner in vivo and in vitro. A number of those, including S100a4, RhoU and Krt23, are implicated in cytoskeletal organization and plasma membrane dynamics. We showed that S100a4 is predominantly expressed by nonmyelinating Schwann cells, whereas RhoU was localized within myelin membranes, and Krt23 was detected in nonmyelinating as well as in myelinating Schwann cells. Their differential expression during early peripheral nerve development further underlines their possible role in influencing Schwann cell differentiation and myelination.


A short neuropeptide F analog (sNPF), III-2 may particularly regulate juvenile hormone III to influence Spodoptera frugiperda metamorphosis and development.
Allatostatin (AS) or Allatotropin (AT) is a class of insect short neuropeptide F (sNPF) that affects insect growth and development by inhibiting or promote the synthesis of juvenile hormone (JH) in different insects. III-2 is a novel sNPF analog derived from a group of nitroaromatic groups connected by different amino acids. In this study, we found that III-2 showed high insecticidal activity against S. frugiperda larvae with a LC50 of 18.7 mg L-1. As demonstrated by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), III-2 particularly facilitated JH III and hindered 20E synthesis in S. frugiperda. The results of RNA-Seq and quantitative real-time polymerase chain reaction (qPCR) showed that III-2 treatment promoted the expression of key genes such as SfCYP15C1 in JH synthesis pathway and inhibited the expression of SfCYP314A1 and other genes in the 20E synthetic pathway. Significant differences were also observed in the expression of the genes related to cuticle formation. We report for the first time that sNPF compounds specifically interfere with the synthesis and secretion of a certain JH in insects, thus affecting the ecdysis and growth of insects, and leading to death. This study may provide a new plant conservation concept for us to seek the targeted control of certain insects based on specific interference with different JH.


Cytokinin oxidase gene expression in maize is localized to the vasculature, and is induced by cytokinins, abscisic acid, and abiotic stress.
Cytokinins are hormones that play an essential role in plant growth and development. The irreversible degradation of cytokinins, catalyzed by cytokinin oxidase, is an important mechanism by which plants modulate their cytokinin levels. Cytokinin oxidase has been well characterized biochemically, but its regulation at the molecular level is not well understood. We isolated a cytokinin oxidase open reading frame from maize (Zea mays), called Ckx1, and we used it as a probe in northern and in situ hybridization experiments. We found that the gene is expressed in a developmental manner in the kernel, which correlates with cytokinin levels and cytokinin oxidase activity. In situ hybridization with Ckx1 and transgenic expression of a transcriptional fusion of the Ckx1 promoter to the Escherichia coli beta-glucuronidase reporter gene revealed that the gene is expressed in the vascular bundles of kernels, seedling roots, and coleoptiles. We show that Ckx1 gene expression is inducible in various organs by synthetic and natural cytokinins. Ckx1 is also induced by abscisic acid, which may control cytokinin oxidase expression in the kernel under abiotic stress. We hypothesize that under non-stress conditions, cytokinin oxidase in maize plays a role in controlling growth and development via regulation of cytokinin levels transiting in the xylem. In addition, we suggest that under environmental stress conditions, cytokinin oxidase gene induction by abscisic acid results in aberrant degradation of cytokinins therefore impairing normal development.


Regulation of superoxide dismutase in primary cultures of rat colonic smooth muscle cells.
We have observed a rapid induction of manganese superoxide dismutase (MnSOD) in epithelial, neuronal, and smooth muscle cells (SMC) after acetic acid-induced colitis. To examine the regulation of MnSOD in the SMC more specifically, primary cultures of colonic SMC were developed by enzymatic digestion of the circular muscle layer from an adult rat. SMC were treated for 2-72 h with 0.5 microgram/ml Escherichia coli endotoxin [lipopolysaccharide (LPS)], 10 ng/ml tumor necrosis factor (TNF)-alpha, or 2 ng/ml interleukin-1 beta (IL-1 beta). Cotreatments were performed with IL-1 beta and 4 microM actinomycin or 50 microM cycloheximide. Northern analysis demonstrated 23-fold, 8-fold, and 6-fold inductions of MnSOD mRNA by IL-1 beta, LPS, and TNF-alpha, respectively. Induction of MnSOD by IL-1 beta was eliminated by actinomycin but not by cycloheximide, implicating a requirement for de novo transcription. Western analysis resulted in a 23.7-fold induction of MnSOD protein after 48-h treatment with IL-1 beta. Induction of MnSOD by IL-1 beta and other inflammatory mediators may serve as a protective mechanism to reduce oxygen free radical- and nitric oxide-mediated cell damage during inflammation.


Mechanisms for de novo biogenesis of an apical membrane compartment in groups of simple epithelial cells surrounded by extracellular matrix.
In open monolayers of epithelial cells grown in vitro, the apical membrane domain forms on the free cell surface that faces the culture medium. However, in vivo, the apical lumenal compartment arises within groups of cells that do not have a free cell surface. We designed in vitro culture conditions, using small colonies of MDCK cells overlaid with collagen, in which formation of the apical membrane must occur de novo by remodeling existing membrane domains that are contacted by other cells or extracellular matrix. Within 12 hours of collagen overlay, the apical membrane glycoprotein gp135 is removed from the free cell surface, while lateral membrane proteins (e.g. Na+,K+-ATPase) remain at sites of cell-cell contacts. Subsequently, lumenal structures, containing gp135 and the apically secreted protein gp81, formed within these cell-cell contacts. Na+,K+-ATPase, adherens junction (E-cadherin, alpha- and beta-catenins) and tight junction (ZO-1) proteins were localized on the lateral membrane adjacent to, but excluded from the gp135-positive lumenal compartment. Therefore, each lumen represents a newly formed apical compartment on the lateral membrane. The Golgi complex (alpha-mannosidase II and Golgi beta-spectrin), centrosomes (gamma-tubulin) and microtubules reorient to a cytoplasmic position adjacent to the newly-forming apical lumenal compartments. Significantly, addition of colchicine, nocodazole or brefeldin A inhibits apical lumen formation. These results demonstrate that simple epithelial cells form an apical lumenal compartment de novo through initial intermixing, and then sorting of apical and basal-lateral membrane proteins at sites of cell-cell contacts. In addition, apical lumen formation requires an intact microtubule network, microtubule-dependent reorientation of the Golgi complex and secretory apparatus, and fully functional protein delivery from the Golgi complex to the forming apical cell surface.


[Clinical pharmacokinetics of the antitumor antibiotic reumycin: an analysis of individual variability].
The pharmacokinetics of reumycin, an antitumor antibiotic, was studied with high performance liquid chromatography in patients with tumors of the brain and kidneys. The drug was injected intravenously in single doses of 30-300 mg. It was shown that the pharmacokinetics of reumycin was nonlinear and within every dose could be depicted by a three- or two-compartmental model. Its nonlinearity was due to saturation of the antibiotic binding to blood plasma proteins. 20-40 per cent of the intact antibiotic was excreted with the urine unchanged, which indicated a significant role of extrarenal excretion of the antibiotic. The dose dependence of the pharmacokinetic parameters and in the particular of the area under the reumycin blood concentration on the time curve and cumulative renal excretion varied with patients. Distribution of patients by these parameters was bimodal. This factor and the differences in renal excretion caused significant variability in the reumycin pharmacokinetics, which required individualization and control of the antibiotic use in patients. The reumycin half-life in man predicted with the use of the Dedrick pharmacokinetic time scale by the data of experiments on rats appeared close to that established in patients (41 and 33.5 hours, respectively).


Development of a database of health insurance claims: standardization of disease classifications and anonymous record linkage.
Health insurance claims (ie, receipts) record patient health care treatments and expenses and, although created for the health care payment system, are potentially useful for research. Combining different types of receipts generated for the same patient would dramatically increase the utility of these receipts. However, technical problems, including standardization of disease names and classifications, and anonymous linkage of individual receipts, must be addressed. In collaboration with health insurance societies, all information from receipts (inpatient, outpatient, and pharmacy) was collected. To standardize disease names and classifications, we developed a computer-aided post-entry standardization method using a disease name dictionary based on International Classification of Diseases (ICD)-10 classifications. We also developed an anonymous linkage system by using an encryption code generated from a combination of hash values and stream ciphers. Using different sets of the original data (data set 1: insurance certificate number, name, and sex; data set 2: insurance certificate number, date of birth, and relationship status), we compared the percentage of successful record matches obtained by using data set 1 to generate key codes with the percentage obtained when both data sets were used. The dictionary's automatic conversion of disease names successfully standardized 98.1% of approximately 2 million new receipts entered into the database. The percentage of anonymous matches was higher for the combined data sets (98.0%) than for data set 1 (88.5%). The use of standardized disease classifications and anonymous record linkage substantially contributed to the construction of a large, chronologically organized database of receipts. This database is expected to aid in epidemiologic and health services research using receipt information.


Benefits of tight blood pressure control in diabetic patients with hypertension: importance of early and sustained implementation of effective treatment strategies.
In 2008, when the UK Prospective Diabetes Study (UKPDS) group presented their 30-year findings concerning the possible sustained effects of improved glycemic control after 10 years of extended follow-up in type 2 diabetic patients, a so-called "legacy effect" was reported to address the long-term emergent and/or sustained benefits of early improved glycemic control. Opposite results were obtained by the Hypertension in Diabetes Study (HDS) carried out in the frame of UKPDS, with no evidence of any legacy effect on cardiovascular (CV) outcomes for an initial 4-year period of tight blood pressure (BP) control. Thus, it was concluded that BP control has to be continued over time, since, although it had a short time-to-effect relationship in preventing stroke, BP control was associated with a short persistence of its clinical benefits once the intervention was discontinued. These findings are unique because, whereas most interventional trials in hypertension that included diabetic patients have shown a reduction in CV outcomes shortly after starting treatment, only the UKPDS-HDS specifically explored the possible persistence of clinical benefits after discontinuing intensive BP-lowering intervention. This article aims to provide a critical interpretation of the UKPDS findings of lack of BP legacy, in the context of the currently available evidence on the benefits of antihypertensive treatment. The importance of effective BP control in type 2 diabetic patients to prevent CV outcomes and other diabetes-related complications is underlined, with emphasis on early, tight, and continuous BP control to optimize patients' protection.


Cell wall physicochemical properties determine the thallus biomineralization pattern of Padina gymnospora (Phaeophyceae).
Approximately half of the Padina (Dictyotales, Phaeophyceae) species mineralize aragonite needles over the adaxial thallus surface, where mineral bands are interspersed with nonmineralized regions along the thallus from the apical to basal end. However, this calcification pattern and the related algal properties are not well understood. Therefore, this work was performed to elucidate a potential role of cell walls in the inhibition/induction of mineralization in the brown alga Padina gymnospora. In a comparison of specific thallus regions, differences were identified in the cellulose distribution, microfibrils arrangement and thickness, distribution and abundance of phenolic substances, and physical differences among the surfaces of the thallus (deformation, adhesion, topography, and nano-rugosity). In vitro mineralization assays indicated that phenolic substances are strong modulators of calcium carbonate crystals growth. In addition, de novo mineralization assays over cell wall surfaces that were used as templates, even without cellular activity, indicated that the cell wall remains a key factor in the induction/inhibition of mineralization. Overall, the current findings indicate a strong correlation between the physico-chemical and structural properties of the cell wall and the alternation pattern of the mineralization bands over the thallus of P. gymnospora.


PPM1A is a RelA phosphatase with tumor suppressor-like activity.
Nuclear factor-κB (NF-κB) signaling contributes to human disease processes, notably inflammatory diseases and cancer. NF-κB has a role in tumorigenesis and tumor growth, as well as promotion of metastases. Mechanisms responsible for abnormal NF-κB activation are not fully elucidated; however, RelA phosphorylation, particularly at serine residues S536 and S276, is critical for RelA function. Kinases that phosphorylate RelA promote oncogenic behaviors, suggesting that phosphatases targeting RelA could have tumor-inhibiting activities; however, few RelA phosphatases have been identified. Here, we identified tumor inhibitory and RelA phosphatase activities of the protein phosphatase 2C (PP2C) phosphatase family member, PPM1A. We show that PPM1A directly dephosphorylated RelA at residues S536 and S276 and selectively inhibited NF-κB transcriptional activity, resulting in decreased expression of monocyte chemotactic protein-1/chemokine (C-C motif) ligand 2 and interleukin-6, cytokines implicated in cancer metastasis. PPM1A depletion enhanced NF-κB-dependent cell invasion, whereas PPM1A expression inhibited invasion. Analyses of human expression data revealed that metastatic prostate cancer deposits had lower PPM1A expression compared with primary tumors without distant metastases. A hematogenous metastasis mouse model revealed that PPM1A expression inhibited bony metastases of prostate cancer cells after vascular injection. In summary, our findings suggest that PPM1A is a RelA phosphatase that regulates NF-κB activity and that PPM1A has tumor suppressor-like activity. Our analyses also suggest that PPM1A inhibits prostate cancer metastases and as neither gene deletions nor inactivating mutations of PPM1A have been described, increasing PPM1A activity in tumors represents a potential therapeutic strategy to inhibit NF-κB signaling or bony metastases in human cancer.


Frogs model man: In vivo thyroid hormone signaling during development.
Thyroid hormone (TH) signaling comprises TH transport across cell membranes, metabolism by deiodinases, and molecular mechanisms of gene regulation. Proper TH signaling is essential for normal perinatal development, most notably for neurogenesis and fetal growth. Knowledge of perinatal TH endocrinology needs improvement to provide better treatments for premature infants and endocrine diseases during gestation and to counteract effects of endocrine disrupting chemicals. Studies in amphibians have provided major insights to understand in vivo mechanisms of TH signaling. The frog model boasts dramatic TH-dependent changes directly observable in free-living tadpoles with precise and easy experimental control of the TH response at developmental stages comparable to fetal stages in mammals. The hormones, their receptors, molecular mechanisms, and developmental roles of TH signaling are conserved to a high degree in humans and amphibians, such that with respect to developmental TH signaling "frogs are just little people that hop." The frog model is exceptionally illustrative of fundamental molecular mechanisms of in vivo TH action involving TH receptors, transcriptional cofactors, and chromatin remodeling. This review highlights the current need, recent successes, and future prospects using amphibians as a model to elucidate molecular mechanisms and functional roles of TH signaling during post-embryonic development.


LC-MS profiling of N-Glycans derived from human serum samples for biomarker discovery in hepatocellular carcinoma.
Defining clinically relevant biomarkers for early stage hepatocellular carcinoma (HCC) in a high-risk population of cirrhotic patients has potentially far-reaching implications for disease management and patient health. Changes in glycan levels have been associated with the onset of numerous diseases including cancer. In the present study, we used liquid chromatography coupled with electrospray ionization mass spectrometry (LC-ESI-MS) to analyze N-glycans in sera from 183 participants recruited in Egypt and the U.S. and identified candidate biomarkers that distinguish HCC cases from cirrhotic controls. N-Glycans were released from serum proteins and permethylated prior to the LC-ESI-MS analysis. Through two complementary LC-ESI-MS quantitation approaches, global profiling and targeted quantitation, we identified 11 N-glycans with statistically significant differences between HCC cases and cirrhotic controls. These glycans can further be categorized into four structurally related clusters, matching closely with the implications of important glycosyltransferases in cancer progression and metastasis. The results of this study illustrate the power of the integrative approach combining complementary LC-ESI-MS based quantitation approaches to investigate changes in N-glycan levels between HCC cases and patients with liver cirrhosis.


Control Engineering Methods for the Design of Robust Behavioral Treatments.
In this paper, a robust control approach is used to address the problem of adaptive behavioral treatment design. Human behavior (e.g., smoking and exercise) and reactions to treatment are complex and depend on many unmeasurable external stimuli, some of which are unknown. Thus, it is crucial to model human behavior over many subject responses. We propose a simple (low order) uncertain affine model subject to uncertainties whose response covers the most probable behavioral responses. The proposed model contains two different types of uncertainties: uncertainty of the dynamics and external perturbations that patients face in their daily life. Once the uncertain model is defined, we demonstrate how least absolute shrinkage and selection operator (lasso) can be used as an identification tool. The lasso algorithm provides a way to directly estimate a model subject to sparse perturbations. With this estimated model, a robust control algorithm is developed, where one relies on the special structure of the uncertainty to develop efficient optimization algorithms. This paper concludes by using the proposed algorithm in a numerical experiment that simulates treatment for the urge to smoke.


Efficient screening of long terminal repeat retrotransposons that show high insertion polymorphism via high-throughput sequencing of the primer binding site.
Retrotransposons have been used frequently for the development of molecular markers by using their insertion polymorphisms among cultivars, because multiple copies of these elements are dispersed throughout the genome and inserted copies are inherited genetically. Although a large number of long terminal repeat (LTR) retrotransposon families exist in the higher eukaryotic genomes, the identification of families that show high insertion polymorphism has been challenging. Here, we performed an efficient screening of these retrotransposon families using an Illumina HiSeq2000 sequencing platform with comprehensive LTR library construction based on the primer binding site (PBS), which is located adjacent to the 5' LTR and has a motif that is universal and conserved among LTR retrotransposon families. The paired-end sequencing library of the fragments containing a large number of LTR sequences and their insertion sites was sequenced for seven strawberry (Fragaria × ananassa Duchesne) cultivars and one diploid wild species (Fragaria vesca L.). Among them, we screened 24 families with a "unique" insertion site that appeared only in one cultivar and not in any others, assuming that this type of insertion should have occurred quite recently. Finally, we confirmed experimentally the selected LTR families showed high insertion polymorphisms among closely related cultivars.


"Too Many Jobs and Not Enough Hands": Immigrant and Refugee Community Health Workers at the Frontlines of the COVID-19 Pandemic.
Refugees and immigrants have experienced heightened health inequities related to COVID-19. As community-embedded frontline health personnel, refugee and immigrant community health workers (riCHWs) played essential roles in the provision of informational, instrumental, and emotional support during the unprecedented first year of the pandemic. Despite the importance of this workforce, riCHWs are at high risk for burnout due to low recognition and demanding workloads. This was exacerbated as riCHWs navigated a new and uncertain health delivery landscape. We sought to glean insight into riCHWs' stressors, coping strategies and resources, and self-efficacy to identify ways to support their work and wellbeing. Using a narrative inquiry approach, we conducted semi-structured, in-depth interviews with 11 riCHWs working in a midsized city in the midwestern United States. We generated three distinct yet interrelated themes: (1) Rapid and trustworthy information is key, (2) Creativity and perseverance are good … structural support is better, and (3) Integrating riCHW expertise into health promotion programming and decision-making. Although riCHWs were deeply committed to enhancing community wellbeing, quickly shifting responsibilities in tandem with structural-level health inequities diminished their self-efficacy and mental health. riCHWs relied on work-based friends/colleagues for informational and emotional support to enhance their capacity to deliver services. Findings suggest increasing opportunities for peer support and idea-exchange, professional development, and integration of riCHW expertise in health promotion decision-making are effective strategies to enhance riCHWs' professional self-efficacy and personal wellbeing.