Twist1 in T Lymphocytes Augments Kidney Fibrosis after Ureteral Obstruction.
Twist1 is a basic helix-loop-helix domain-containing transcription factor that participates in diverse cellular functions, including epithelial-mesenchymal transition and the cellular immune response. Although Twist1 plays critical roles in the initiation and progression of kidney diseases, the effects of Twist1 in the T lymphocyte on the progression of renal fibrosis require elucidation. 129/SvEv mice with a floxed allele for the gene encoding Twist1 or TNFα were bred with CD4-Cre mice to yield CD4-Cre+ Twist1flox/flox (Twist1-TKO) or CD4-Cre+ TNFflox/flox (TNF-TKO) mice with robust, but selective, deletion of Twist1 or TNFα mRNA in T cells, respectively. Twist1 TKO, TNF TKO, and WT controls underwent UUO with assessment of kidney fibrosis and T-cell phenotype at 14 days. Compared with WT controls, obstructed kidneys from Twist1 TKO mice had attenuated extracellular matrix deposition. Despite this diminished fibrosis, Twist1 TKO obstructed kidneys contained more CD8+ T cells than in WTs. These intrarenal CD8+ T cells exhibited greater activation and higher levels of TNFα expression than those from WT obstructed kidneys. Further, we found that selective deletion of TNFα from T cells exaggerated renal scar formation and injury after UUO, highlighting the capacity of T-cell TNF to constrain fibrosis in the kidney. Twist1 in T cells promotes kidney fibrogenesis, in part, by curtailing the renal accumulation of TNF-elaborating T cells.


Corrigendum to "Endodontic and Restorative Treatment Patterns of Pulpally Involved Immature Permanent Posterior Teeth".
[This corrects the article DOI: 10.1155/2018/2178535.].


Technetium-99m complexes of dimethylaminomethylene diphosphonate (DMAD)--I. Anion exchange HPLC characterization of 99mTc(NaBH4)-DMAD mixtures.
Radiopharmaceutical analogs prepared by sodium borohydride reduction of 99mTcO4- in the presence of DMAD have been characterized by anion exchange HPLC (high performance liquid chromatography) separation of the resulting mixture into component 99mTc-DMAD complexes. The distribution of complexes within a radiopharmaceutical formulation can be manipulated by controlling technetium concentration, pH, presence or absence of air, and time post reaction.


A routine method for contrasting elastin at the ultrastructural level.
A reliable, simple, and inexpensive method for ultrastructural investigation of elastin is described. This method uses uranyl acetate dissolved in absolute methanol, followed by an optional lead citrate counterstain. The procedure was tested on a number of animal and human tissues that had been fixed and processed differently.


Global assessment for quality and safety of control in type 2 diabetic patients.
HbA1c (glycated haemoglobin) suffers from obvious limitations in type 2 diabetic patients at risk of hypoglycaemia or requiring rapid therapeutic adjustments. This study was conducted to discern whether the monitoring of one particular plasma glucose (PG) value of the diurnal profile can be used in such situations. Four diurnal PG concentrations (at 08:00, 11:00, 14:00 and 17:00 h) were measured in standardized conditions in 480 (246 men, 234 women) noninsulin-using type 2 diabetic patients. Sensitivities for predicting treatment success, i.e. HbA1c<7%, with a specificity > or =90% were calculated and compared using receiver-operating characteristic (ROC) curves. The probabilities (areas under ROC curves) for predicting HbA1c<7% were significantly higher at 11:00, 14:00 and 17:00 h than at 08:00 h. The optimal PG cut-off values for predicting treatment success were, respectively, 6, 9, 7 and 6 mmol L(-1) at 08:00 h, 11:00, 14:00 and 17:00 h. In most patients the lowest PG values of the diurnal profile were at 17:00 h, and 17.5% of the patients with HbA1c<7% (54.5% of them treated with sulphonylureas) exhibited a PG value less than 4.4 mmol L(-1) at 17:00 h (P=0.0034 vs. the other timepoints). Glucose monitoring at 17:00 h, i.e. during the extended postlunch period, appears as a global marker of control in noninsulin-using type 2 diabetic patients both for detecting patients at risk of hypoglycaemia and for assessing the short-term quality of diabetic control.


Balancing osteoblast functions and bacterial adhesion on functionalized titanium surfaces.
The demand for orthopedic and dental implants will continue to grow, and for these applications, titanium and its alloys have been used extensively. While these implants have achieved high success rates, two major complications may be encountered: the lack of bone tissue integration and implant-centered infection. The surface of the implant, through its interactions with proteins, bacteria and tissue cells, plays a determining role in the success or failure of the implant. Ideally, to enhance the success of implants, their surfaces should inhibit bacterial colonization and concomitantly promote osteoblast functions. In this article, we discuss strategies for tailoring implant surfaces by exploiting the differences in the response of bacteria and osteoblasts to proteins and surface structures. Nevertheless, limitations still exist in the quest for an ideal implant surface. Further advances in this field will require concurrent development in surface modification techniques and a better understanding of the complex and highly inter-related events occurring at the implant surface after implantation.


Zoonotic potential of Giardia duodenalis and Cryptosporidium spp. and prevalence of intestinal parasites in young dogs from different populations on Prince Edward Island, Canada.
The prevalence of Giardia duodenalis, Cryptosporidium spp. and other intestinal parasites was determined in dogs <1 year old from Prince Edward Island, Canada. Fecal samples were collected from the local animal shelter (n=62), private veterinary clinics (n=78) and a pet store (n=69). Intestinal parasites isolated included G. duodenalis, Cryptosporidium spp., Toxocara canis, Isospora spp. and Uncinaria stenocephala. To estimate the zoonotic risk associated with these infections, genotypes of G. duodenalis and Cryptosporidium spp. were determined using 16S rRNA and Hsp70 gene sequencing, respectively. Dogs from the pet store had the highest prevalence of intestinal parasites (78%, 95% CI: 68-88%), followed by the private veterinary clinics (49%, 95% CI: 37-60%), and the local animal shelter (34%, 95% CI: 22-46%). The majority G. duodenalis belonged to host-adapted assemblages D (47%, 95% CI: 31-64%) and C (26%, 95% CI: 13-43%), respectively. Zoonotic assemblages A and B were isolated alone or in mixed infections from 16% (95% CI: 6-31%) of G. duodenalis-positive dogs. All Cryptosporidium spp. were the host-adapted C. canis. While host-adapted, non-zoonotic G. duodenalis genotypes were more common, the presence of G. duodenalis assemblages A and B, T. canis, and U. stenocephala suggests that these dogs may present a zoonotic risk. The zoonotic risk from Cryptosporidium-infected dogs was minimal.


Prognostic and Clinicopathological Significance of the Systemic Immune-Inflammation Index in Patients With Renal Cell Carcinoma: A Meta-Analysis.
The systemic immune-inflammation index (SII) is a hematological parameter based on neutrophil, platelet, and lymphocyte counts. Studies that have investigated the prognostic value of SII in patients with renal cell carcinoma (RCC) have reported controversial results. In this study, we systematically investigated the prognostic value of SII in patients with RCC. We systematically searched English articles in the PubMed, Embase, Web of Science, and Cochrane Library databases up to October 2021. Hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were used to obtain pooled results. The meta-analysis included 10 studies that enrolled 3,180 patients. A high SII was associated with poor overall survival (HR 1.75, 95% CI 1.33-2.30, p<0.001) in patients with RCC. However, a high SII was not shown to be a significant prognostic factor for progression-free survival/disease-free survival (HR 1.22, 95% CI 0.84-1.76, p=0.293) or poor cancer-specific survival (HR 1.46, 95% CI 0.68-3.12, p=0.332) in patients with RCC. A high SII was correlated with male sex (OR 1.51, 95% CI 1.11-2.04, p=0.008), Fuhrman grade G3-G4 (OR 1.80, 95% CI 1.08-3.00, p=0.024), and poor risk based on the International Metastatic Renal Cell Carcinoma Database Consortium criteria (OR 19.12, 95% CI 9.13-40.06, p<0.001). A high SII was independently associated with poor survival outcomes in patients with RCC. Additionally, an elevated SII indicated more aggressive disease. The SII may serve as a useful cost-effective prognostic indicator in patients with RCC.


[Evaluation of the efficacy of a carbon brace ("Corset monocoque carbone respectant la respiration" [CMCR]) preserving lung capacity to treat idiopathic scoliosis in children and adolescents: a retrospective study of 115 patients].
The purpose of this retrospective study was to investigate whether treatment with a carbon brace (CMCR) stops the progression of idiopathic scoliosis in children and adolescents affected by combined or thoraco-lumbar scoliosis. We compared clinical features (hump and vital capacity) and radiolographic data (Cobb angle, sacral slope, lumbar lordosis and thoracic kyphosis) at brace set-up and removal in 115 children and adolescents with combined or thoraco-lumbar scoliosis. The impact of the brace was evaluated in 2 subgroups: patients who started the treatment at Risser stages 0, 1 or 2 and those who started the treatment at Risser stages 3 or 4. With 95 patients, a questionnaire was used to evaluate the physical and psychological tolerance of the brace and technical difficulties during treatment with the orthosis. At brace set-up, the immediate angular correction was about 50% compared to the pre-brace angle; the reduction of the vital capacity was weak. After brace removal, radiographic data showed significant improvement in thoraco-lumbar scoliosis and in the lumbar curve of patients with combined scoliosis, although the thoracic curvature of the combined scoliosis was unchanged. No significant efficiency on the hump was observed. The CMCR brace can stop the progression of moderate combined or thoraco-lumbar scoliosis in growing children and adolescents, with little consequence to vital capacity, but seems to have no efficacy on the hump. This type of orthosis provides a better outcome in terms of thoracic mobility and vital capacity. The CMCR brace is indicated for children and growing teenagers with flexible, progressive scoliosis. This "mobile" brace definitely has its place in the current therapeutic arsenal.


Energy relations of winter roost-site utilization by American goldfinches (Carduelis tristis).
American goldfinches (Carduelis tristis) were observed roosting in Colorado blue spruce (Picea pungens), which comprised part of a mixed stand of conifers. Their winter roost-sites were distally situated among the most densely-needled branches on the leeward sides of these trees. Heated and unheated taxidermic goldfinch mounts were placed within these sites and at the same height in an adjacent clearing. The radiative and convective characteristics of these locations were monitored simultaneously and compared to predicted power requirements of live goldfinches (based on laboratory calibration of heated mounts) and operative temperatures (T e ; based on body temperatures of unheated mounts). The winter roost-sites significantly reduced radiative and convective heat exchanges between goldfinches and the environment. Based on body composition data for winter goldfinches, all but two birds sampled could endure a 15-h roost period at average overnight T e 's as low as-40°C. In contrast, if these birds were prevented from feeding the following day, only 30% could survive the imposition of a 39-h fast at average T e 's of-2°C. Winter roost-site selection may be more constrained by thermoregulatory considerations in small birds than in larger species.


Role of peripheral group I and II metabotropic glutamate receptors in IL-1beta-induced mechanical allodynia in the orofacial area of conscious rats.
The present study investigated the role of peripheral group I and II metabotropic glutamate receptors (mGluRs) in interleukin-1beta (IL-1beta)-induced mechanical allodynia in the orofacial area. Experiments were carried out on Sprague-Dawley rats weighing between 230 and 280 g. After subcutaneous administration of 0.01, 0.1, 1, or 10 pg of IL-1beta, we examined withdrawal behavioral responses produced by 10 successive trials of a ramp of air-puffs pressure applied ipsilaterally or contralaterally to the IL-1beta injection site. The thresholds of air puffs were measured 10, 30, 60, 120, or 180 min after 25 microl of IL-1beta was administered through an implanted tube. Subcutaneous injection of IL-1beta produced bilateral mechanical allodynia. While the IL-1beta-induced mechanical allodynia was blocked by pretreatment with an IL-1 receptor antagonist, the IL-1beta-induced mirror-image mechanical allodynia was not blocked by an IL-1 receptor antagonist injected into the contralateral side. Subcutaneous administration of CPCCOEt or LY367385, an mGluR1 antagonist, or MPEP or SIB1893, an mGluR5 antagonist, 10 min prior to injection of IL-1beta abolished IL-1beta-induced mechanical allodynia. Pretreatment with APDC or DCG4, a group II mGluR agonist, blocked the IL-1beta-induced mechanical allodynia. The anti-allodynic effect induced by APDC was inhibited by pretreatment with LY341495, a group II mGluR antagonist. These results suggest that peripheral group I and II mGluRs participate in IL-1beta-induced mechanical allodynia in the orofacial area. Peripheral group I mGluR antagonists blocked the IL-1beta-induced mechanical allodynia, while peripheral group II mGluR agonists produced anti-allodynic effects on IL-1beta-induced mechanical allodynia in the orofacial area of rats.


Antiepileptic drug management in pediatric patients with brain tumor-related epilepsy.
Patients with brain tumor-related epilepsy (BTRE) are at a higher risk of significant morbidity, lower quality of life, and increased risk of mortality. We surveyed providers regarding anti-seizure medication (ASM) management in pediatric BTRE to determine if practices are standard or markedly variable. An anonymous voluntary online survey was sent to members of the Child Neurology Society. Providers were asked specific questions regarding initiation and wean of ASMs and if this was dependent on multiple factors. Demographic information was collected. Fifty-one providers responded to the survey. Ninety-four percent of providers would start an ASM after a second seizure. Eighty-four percent chose levetiracetam as the preferred ASM. Management was variable when based on tumor location, extent of surgical resection, pathology, and tumor prognosis. Statistically significant differences in responses regarding management were identified when comparing neurologists and epileptologists, providers with formal neuro-oncology or epilepsy training, providers at large institutions, and years of experience. For patients who underwent a gross total resection of the tumor, neuro-oncology and epilepsy-trained providers were more likely to wean off ASMs (p < 0.049). Providers without formal training in neuro-oncology or epilepsy were more likely to get an EEG prior to making a decision about weaning off ASMs (p < 0.016). These results suggest that ASM management in BTRE varies greatly according to sub-specialty and experience. Further studies and potential development of guidelines are needed to identify the most appropriate management of ASMs for BTRE.


Digital phagograms: predicting phage infectivity through a multilayer machine learning approach.
Machine learning has been broadly implemented to investigate biological systems. In this regard, the field of phage biology has embraced machine learning to elucidate and predict phage-host interactions, based on receptor-binding proteins, (anti-)defense systems, prophage detection, and life cycle recognition. Here, we highlight the enormous potential of integrating information from omics data with insights from systems biology to better understand phage-host interactions. We conceptualize and discuss the potential of a multilayer model that mirrors the phage infection process, integrating adsorption, bacterial pan-immune components and hijacking of the bacterial metabolism to predict phage infectivity. In the future, this model can offer insights into the underlying mechanisms of the infection process, and digital phagograms can support phage cocktail design and phage engineering.


Experimental study on killing tumor cells by activation of hematoporphyrin derivatives by bi-frequency focal ultrasound in vitro.
Tumor cells K562 were killed by the hematoporphyrin derivatives (HpD) activated by bi-frequency focal ultrasound in which a choice of irradiating parameter of ultrasound was tested by experiment. The effect of killing tumor cells was investigated by MTT method and compared with the contrast group. The results showed that the bi-frequency ultrasound exhibited an improved effect of killing tumor cells than single frequency ultrasound. It was 2-3 times higher than the single frequency ultrasound for the killing effect of tumor cells. After the irradiation of ultrasound, the cell-killing effect of hatching 16 h is better than that of hatching 4 h in the hatching tank. This might be due to delay of cell apoptosis.


A hybrid neural network of addressable and content-addressable memory.
We investigate the memory structure and retrieval of the brain and propose a hybrid neural network of addressable and content-addressable memory which is a special database model and can memorize and retrieve any piece of information (a binary pattern) both addressably and content-addressably. The architecture of this hybrid neural network is hierarchical and takes the form of a tree of slabs which consist of binary neurons with the same array. Simplex memory neural networks are considered as the slabs of basic memory units, being distributed on the terminal vertexes of the tree. It is shown by theoretical analysis that the hybrid neural network is able to be constructed with Hebbian and competitive learning rules, and some other important characteristics of its learning and memory behavior are also consistent with those of the brain. Moreover, we demonstrate the hybrid neural network on a set of ten binary numeral patters


Epidemiological explanation of an outbreak of gastro-enteritis in Sweden in the absence of detailed microbiological information.
Waterborne gastroenteritis outbreaks have often gone undetected or been incompletely defined in terms of source and extent. Methods which allow detection or clarification of such events are therefore useful. We describe the methods used to detect and investigate such an outbreak. In autumn 1996 high school absence rates and the rate of parents absent from work to care for sick children suggested a health problem in a Swedish town which had a history of unexplained outbreaks of gastrointestinal disease. A systematic sample of 300 households was surveyed by post. Respondents represented 10% of the total population of the town. Questions concerning symptoms and exposures were included. The same questionnaire was used in a nearby town as a control. Sixty four percent of respondents reported an acute gastrointestinal illness during a two month period. Diarrhoea (90%) and abdominal pain (88%) were the most frequent symptoms among the sick. Two percent of those sick sought medical care. Exposures associated with disease were being a member of a large household, young age, and consumption of water from the community water supply. Attack rate showed a dose response relationship with increasing frequency of water consumption. The peak incidence of gastrointestinal illness occurred shortly after raw water quality control data had shown a rise in indicator bacteria. Further analysis, dividing those infected into groups according to when they became ill and whether they were the first member of their household to fall ill, supported the hypothesis of primary cases being infected from the water supply with some secondary person to person spread.


Pre-emptive analgesia by nerve stimulator guided pudendal nerve block for posterior colpoperineorrhaphy.
To assess the effect of pre-emptive analgesia by bilateral nerve stimulator-guided pudendal nerve block (PNB) on pain intensity and consumption of analgesics following posterior colpoperineorrhaphy. Prospective randomized observer-blinded study. The study included 130 patients who were scheduled to undergo posterior colpoperineorrhaphy under general anesthesia (GA). They were invited to enroll in the study during the period from October 2009 to August 2011 at TAIBA Hospital in Kuwait. Patients were randomly allocated to two groups of 65 patients each: GA alone or GA combined with pre-emptive nerve stimulator-guided PNB with 10 mL of 0.25% bupivacaine in each side. The primary outcome measures were VAS pain scores and postoperative analgesic consumption. Postoperative average VAS pain scores, IM pethidine consumption and IV paracetamol consumption during the first 24 h; were highly significantly lower in the PNB group compared to the GA alone group. This technique was also associated with a significantly higher overall patient satisfaction compared to GA alone, without obvious side effects. Pre-emptive analgesia by bilateral nerve stimulator-guided PNB is a simple and useful technique that when combined with GA was found to substantially reduce postoperative pain and consumption of analgesics during the first 24 h postoperatively, and shorten the time to return to normal activities compared to GA alone for patients undergoing posterior colpoperineorrhaphy. The use of PNB was also associated with a high overall patient satisfaction. Thus, the results of the present study may recommend the use of nerve stimulator-guided PNB in posterior colpoperineorrhaphy patients.


Status for clinically complete remission rectal cancer after concomitant chemo-radiotherapy in Taiwan.
Treatment for Rectal cancer changed after the induction of concomitant chemo-radiotherapy, CCRT. Complete remission of the tumor leads to debate of the necessity of surgical intervention. We evaluate the treatment outcome to know if operation is beneficial to these patients. Patients received long course concomitant chemo-radiotherapy for advanced rectal cancer between 2004 and 2013 in Taiwan were enrolled. Total 2780 patients diagnosed advanced rectal cancer were enrolled. In these patients, 2578 received surgical intervention and 202 were in wait and see for complete remission tumor. Higher local recurrence rate was found with wait and see group (8.9% vs. 2.7%). Also, better overall survival, disease free survival and local recurrence free survival were seen with the surgical intervention group. Surgical intervention may be benefit for some misdiagnosed completed response to CCRT.


Oxidation state, local structure distortion, and defect structure analysis of Cu doped α-MnO2 correlated to conductivity and dielectric properties.
Cu-doped MnO2 with the composition of Mn1-xCuxO2 (x = 0-0.15) was synthesized and characterized. The synthesis was carried out by hydrothermal method at 140 °C for 5 h of reaction dwell time. The characterizations include X-Ray Diffraction (XRD), Microscopy, X-ray Absorption Spectroscopy (XAS), and Impedance complex analysis. It was revealed that all samples have nanorod morphology. Their size increases with the increasing dopant. Additionally, K ions are detected by EDX. All samples pose α-MnO2 type structures performing (2 × 2) and (1 × 1) tunnels permitting large ions incorporated and oxygen deficiency. The octahedron was distorted to elongate up to x = 0.10, then compressed for x = 0.15, inducing the Jan Teller effect. Oxidation state analysis revealed that the manganese has Mn3+ and Mn4+, while the copper is mainly attributed to Cu2+ and Cu3+ respectively. The small ionic size and highly oxidized Cu3+ substitute Mn4+, while Cu2+ substitutes Mn3+ or simultaneously with the larger K+ incorporated in the tunnel. Accordingly, the defects to exist in the sample, namely C u M n ' , M n M n ' , V O • • , and e ' . Electrical characterization at room temperature revealed that the conductivity of Cu-doped MnO2 is dominated by electrons influenced by the various oxidation state of the cations in the octahedron sites, while space charges dominate the dielectric response.


Assessment of dynamic finger forces in pianists: effects of training and expertise.
Playing a musical instrument requires complex sensorimotor programming of hand and finger movements. During musical training motor programs are optimized to achieve highest accuracy with a minimum of effort. In the lack of handy measurement tools these rational assumptions of piano theorists did not undergo an experimental evaluation up to now. In the present pilot study we used a dynamic pressure measurement system with the pianoforte. Three finger exercises with increasing degrees of difficulty had to be performed by a group of musical amateurs and a group of expert players. From the dynamic force measurements we calculated (a) the mean pulse per touch and (b) the mean touch-duration for each exercise and each subject. To achieve the same tempo and the same loudness, amateurs applied significantly more and longer force to the keys, leading to higher mean pulses per touch. Pulse and duration values increased with higher demands on finger coordination in both, expert pianists and amateurs. The results show that dynamic force measurement systems can support music learners and teachers in training a relaxed piano technique and preventing musicians from overuse injuries.


Inequality in healthcare-seeking behavior among women with pelvic organ prolapse: a systematic review and narrative synthesis.
Pelvic organ prolapse (POP) affects women's quality of life in various aspects. However, evidence on the healthcare-seeking behavior of women with POP is limited. Therefore, this review aimed to identify and synthesize the existing evidence on the healthcare-seeking behavior among women with POP. This systematic review and narrative synthesis of the literature on healthcare-seeking behavior among women with POP was conducted from 20 June to 07 July 2022. The electronic databases PubMed, African Journals Online, Cumulative Index to Nursing and Allied Health Literature, African Index Medicus and Directory of Open Access Journal, and Google Scholar were searched for relevant literature published from 1996 to April 2022. The retrieved evidence was synthesized using a narrative synthesis approach. The characteristics of included studies and the level of healthcare-seeking behavior were summarized in a table and texts. Error bar was used to show the variability across different studies. A total of 966 articles were retrieved of which only eight studies with 23,501 women (2,683 women with pelvic organ prolapse) were included in the synthesis. The level of healthcare-seeking behavior ranges from 21.3% in Pakistan to 73.4% in California, USA. The studies were conducted in four different populations, used both secondary and primary data, and were conducted in six different countries. The error bar shows variation in healthcare-seeking behavior. The level of health-care seeking behavior among women with POP is low in low-income countries. There is substantial variability in the characteristics of the reviewed studies. We recommend a large-scale and robust study which will help to better understand the healthcare-seeking behavior among women with POP.


Discovery of diarylurea P2Y(1) antagonists with improved aqueous solubility.
Preclinical data suggests that P2Y1 antagonists, such as diarylurea compound 1, may provide antithrombotic efficacy similar to P2Y12 antagonists and may have the potential of providing reduced bleeding liabilities. This manuscript describes a series of diarylureas bearing solublizing amine side chains as potent P2Y1 antagonists. Among them, compounds 2l and 3h had improved aqueous solubility and maintained antiplatelet activity compared with compound 1. Compound 2l was moderately efficacious in both rat and rabbit thrombosis models and had a moderate prolongation of bleeding time in rats similar to that of compound 1.


Pulmonary surfactant-associated polypeptide C in a mixed organic solvent transforms from a monomeric alpha-helical state into insoluble beta-sheet aggregates.
In the 35-residue pulmonary surfactant-associated lipopolypeptide C (SP-C), the stability of the valyl-rich alpha-helix comprising residues 9-34 has been monitored by circular dichroism, nuclear magnetic resonance, and Fourier transform infrared spectroscopy in both a mixed organic solvent and in phospholipid micelles. The alpha-helical form of SP-C observed in freshly prepared solutions in a mixed solvent of CHCl3/CH3OH/0.1 M HCl 32:64:5 (v/v/v) at 10 degrees C undergoes within a few days an irreversible transformation to an insoluble aggregate that contains beta-sheet secondary structure. Hydrogen exchange experiments revealed that this conformational transition proceeds through a transition state with an Eyring free activation enthalpy of about 100 kJ mol(-1), in which the polypeptide segment 9-27 largely retains a helical conformation. In dodecylphosphocholine micelles, the helical form of SP-C was maintained after seven weeks at 50 degrees C. The alpha-helical form of SP-C thus seems to be the thermodynamically most stable state in this micellar environment, whereas its presence in freshly prepared samples in the aforementioned mixed solvent is due to a high kinetic barrier for unfolding. These observations support a previously proposed pathway for in vivo synthesis of SP-C through proteolytic processing from a 21-kDa precursor protein.


The NLRP3 inflammasome in age-related eye disease: Evidence-based connexin hemichannel therapeutics.
The inflammasome pathway is a fundamental component of the innate immune system, playing a key role especially in chronic age-related eye diseases (AREDs). The inflammasome is of particular interest because it is a common disease pathway that once instigated, can amplify and perpetuate itself leading to chronic inflammation. With aging, it becomes more difficult to shut down inflammation after an insult but the common pathway means that a shared solution may be feasible that could be effective across multiple disease indications. This review focusses on the NLRP3 inflammasome, the most studied and characterized inflammasome in the eye. It describes the two-step signalling required for NLRP3 inflammasome complex activation, and provides evidence for its role in AREDs. In the final section, the article gives an overview of potential NLRP3 inflammasome targeting therapies, before presenting evidence for connexin hemichannel regulators as upstream blockers of inflammasome activation. These have shown therapeutic efficacy in multiple ocular disease models.


The effect of apolipoprotein E genotype on serum lipoprotein particle response to exercise.
Exercise affects lipoprotein metabolism and apolipoprotein E (Apo E) genotype may alter changes in lipoprotein subclasses that occur with exercise. The present study examined the effects of Apo E genotype (APOE) on the response of lipoprotein subclass concentrations to long-term exercise. A prospective longitudinal study, conducted at seven centers, genetically screened 566 individuals to create three cohorts of healthy adults, equal for gender and the most common APOE variants: E2/3 (n = 35), E3/3 (n = 40), and E3/4 (n = 31). Subjects with body mass index (BMI) > or = 31 or evidence of dyslipidemia or metabolic disease were excluded. All subjects exercised aerobically at 75% of maximal heart rate for 40 min, four times weekly for 6 months. Fasting lipoprotein subpopulations were measured before and after exercise training using proton nuclear magnetic resonance spectroscopy. Serum lipids for the entire cohort did not change with exercise training, but the LDL subpopulation response varied by APOE. Small-sized LDL particles decreased only in the APOE3 homozygotes whereas medium-sized LDL particles increased only in this group. These changes were directionally different from the responses in the E2/3 and E3/4 subjects (p < 0.05). Neither exercise nor APOE variant affected overall LDL or HDL size or cholesterol concentration, but exercise decreased VLDL diameter by 3.5 nm (p < 0.001) attributable to decreases in large VLDL in each APOE group. In conclusion, APOE variants influence the serum LDL subpopulation response to exercise training in normolipidemic subjects. Subjects homozygous for APOE3 experienced the most beneficial lipid effects from exercise training.


CT and MRI features of undifferentiated carcinomas with osteoclast-like giant cells of the pancreas: a case series.
The purpose of this case series was to describe computed tomography (CT) and magnetic resonance imaging (MRI) features of undifferentiated carcinoma with osteoclast-like giant cells of the pancreas. Institutional ethics review board approval was obtained, and informed consent was waived for this case series. We reviewed CT and MRI of patients with pathologically confirmed undifferentiated carcinoma with osteoclast-like giant cells of the pancreas found in the medical records of our hospital between 2006 and 2016. Seven patients (3 males and 4 females; age, 59-82 years (mean, 71)) with confirmation by surgical resection (n = 3) or biopsy (n = 4) were identified. They underwent CT (n = 7) and MRI (n = 6). The tumors 26-83 mm in diameter (mean, 44 mm) were located in the head (n = 4) or body (n = 3) of the pancreas. They were demonstrated as lower attenuation areas relative to the adjacent pancreas on CT images obtained in both pancreatic and portal vein phases (n = 7) with a well-defined smooth margin (n = 5). They were demonstrated as hypointense areas relative to the pancreas on T2-weighted images (n = 4) and T2*-weighted images (n = 4) and diffusion-weighted images (n = 3). They contained hemosiderin deposits on histology (n = 7). Undifferentiated carcinoma with osteoclast-like giant cells of the pancreas might be present as low attenuation areas with a well-defined smooth margin on CT images obtained in pancreatic and portal vein phases, and hypointense areas on T2-, T2*-, and diffusion-weighted images caused by hemosiderin deposits.


Interrogating the Human Diplome: Computational Methods, Emerging Applications, and Challenges.
Human DNA sequencing protocols have revolutionized human biology, biomedical science, and clinical practice, but still have very important limitations. One limitation is that most protocols do not separate or assemble (i.e., "phase") the nucleotide content of each of the maternally and paternally derived chromosomal homologs making up the 22 autosomal pairs and the chromosomal pair making up the pseudo-autosomal region of the sex chromosomes. This has led to a dearth of studies and a consequent underappreciation of many phenomena of fundamental importance to basic and clinical genomic science. We discuss a few protocols for obtaining phase information as well as their limitations, including those that could be used in tumor phasing settings. We then describe a number of biological and clinical phenomena that require phase information. These include phenomena that require precise knowledge of the nucleotide sequence in a chromosomal segment from germline or somatic cells, such as DNA binding events, and insight into unique cis vs. trans-acting functionally impactful variant combinations-for example, variants implicated in a phenotype governed by compound heterozygosity. In addition, we also comment on the need for reliable and consensus-based diploid-context computational workflows for variant identification as well as the need for laboratory-based functional verification strategies for validating cis vs. trans effects of variant combinations. We also briefly describe available resources, example studies, as well as areas of further research, and ultimately argue that the science behind the study of human diploidy, referred to as "diplomics," which will be enabled by nucleotide-level resolution of phased genomes, is a logical next step in the analysis of human genome biology.


Sex differences in the biotransformation of 2-acetylaminofluorene in cultured rat hepatocytes.
Sex-related differences in susceptibility to 2-acetylaminofluorene (2-AAF) hepatocarcinogenicity and in vivo biotransformation of 2-AAF have been observed. In order to determine the contribution of hepatocytes to these differences, 2-AAF biotransformation was investigated in monolayer cultures of hepatocytes freshly isolated from male and female F-344 rats. In cultured hepatocytes from both sexes, ring and N-hydroxylated, deacetylated and conjugated metabolites were formed. The half-life of 2-AAF was similar at concentrations of 5 x 10(-6) and 10(-5) M; however, at 10(-4) M a slower rate was observed in cultures from males. Although the total formation of aqueous metabolites was similar, the ratio of sulfate to glucuronide conjugates of 2-AAF formed by hepatocytes from male and female rats differed. Sulfate conjugates predominated in hepatocytes from male rats, whereas in females, glucuronides predominated. The demonstration of sex-dependent variations in the rate of metabolism at a high concentration of 2-AAF and in conjugation provides evidence that in vivo differences are a function, at least in part, of the biotransformation characteristics of hepatocytes.


Corrigendum: Insulin- like Growth Factor-Binding Protein Action in Bone Tissue: A Key Role for Pregnancy- Associated Plasma Protein-A.
[This corrects the article DOI: 10.3389/fendo.2018.00031.].


Water intoxication by the oral route in an infant.
Symptomatic water intoxication is common when hypo-osmolar fluids are given therapeutically, usually intravenously, but it is rare after drinking voluntarily (Wynn and Rob, 1954). We report a case of water intoxication caused by voluntary drinking in an infant.


Thiamine deficiency--a neglected problem of infants and mothers--possible relationships to sudden infant death syndrome.
An unexpectedly high incidence of biochemical thiamine deficiency (erythrocyte transketolase) was found in groups of mothers and infants, selected for apparent health from a westernized Caucasian community in Australia. Deficiency was common in mothers at term but not their infants, and in apparently healthy older infants but not their mothers. These findings can be explained by preferential delivery of thiamine to the fetus, at the expense of the pregnant mother; after delivery the mother recovers, and the infant becomes depleted. The incidence of thiamine deficiency was high in 'near-miss' sudden infant death syndrome (SIDS) infants and their mothers, and in siblings of SIDS. The thiamine deficient infants had a high familial incidence of SIDS deaths. These 'high risk families' might reflect poor nutrition or genetic defects of thiamine uptake and metabolism. Since apparently thriving infants with thiamine deficiency can sometimes die unexpectedly, thiamine status deserves more attention in clinical practice and research.


Sequential FDG-PET brachytherapy treatment planning in carcinoma of the cervix.
To evaluate the utility of sequential (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging for brachytherapy treatment planning in patients with carcinoma of the cervix. Twenty-four patients with carcinoma of the cervix were included in this prospective study. The clinical stage of their disease was Ib (7), IIa (1), IIb (7), and IIIb (9). Patients were treated with irradiation and brachytherapy, with the majority receiving concurrent weekly cisplatin chemotherapy. Patients underwent diagnostic FDG-PET imaging before treatment, sequential FDG-PET brachytherapy imaging during treatment, and diagnostic FDG-PET 3 months after treatment completion. Delineation of the gross tumor volume, bladder, and rectum was performed for all scans using a commercially available treatment-planning system. Actual treatment delivery was based on two-dimensional orthogonal planning. The mean gross tumor volume and percent coverage by the target isodose surface for the initial, mid, and last implant were 37 cm3, 17 cm3, and 10 cm3 and 68%, 76%, and 79%, respectively. Nine of 11 patients were found to have continued decrease in tumor volume as measured by FDG-PET, with 3 patients having complete regression of their tumor before treatment was completed. The maximal bladder and rectal doses obtained from three-dimensional dose-volume histograms were significantly higher than the International Commission on Radiation Units and Measurements Report 38 bladder and rectal points obtained by two-dimensional treatment-planning. Sequential FDG-PET brachytherapy imaging identifies the tumor response in individual patients, potentially making patient-specific brachytherapy treatment planning possible.


Ultrastucture of the male rat hypophysis chronically grafted under the kidney capsule.
Male rats were divided in two experimental groups. In group I two partes distales of the hypophysis were grafted under the kidney capsule and in group II two complete hypophyses were transplanted. Animals were killed 5 to 22 months after the operation. The grafted tissue was excised and processed for light and electron microscopy. The transplanted pars distalis tissue showed a well developed vascularisation in contrast to the pars intermedia which appeared poorly vascularised. Six different cell types were observed in grafted pars distalis. They correspond to the different types of cells found in the rat pars distalis "in situ". The predominant cell type in the graft displayed all the morphological characteristics of stimulated prolactotrophs. Pars intermedia cells appeared hypertrophied resembling the MSH cells under stimulation. Two types of syncytial formations were frequently seen. One of them appeared to originate from prolactotrophs and the other from MSH cells. Bodian impregnated fibres and structures resembling either growth cones of axons or typical nerve endings were observed in the pars intermedia of long-term grafted hypophyses. Pituicytes remained as isolated clusters of cells. Canaliculi lined by two or more pituicytes were observed. Saccular formations resembling the hypophyseal cleft appeared in all grafts studied. The present findings suggest that in the male rat the chronically grafted pituitary gland is capable of synthesising most or all the hormones which are known to be produced by the gland "in situ". Furthermore, prolactin and MSH seem to be the predominant secretion of the transplanted pituitary.


Congenital metacarpal malformation.
The findings in two brothers are described in whom there are similar isolated defects of development of their fifth metacarpal bones with normal fingers. There is no evidence of further skeletal, or biochemical abnormality. A mutational genetic basis is postulated.


Surface plasmon resonance immunosensor for the detection of Salmonella typhi antibodies in buffer and patient serum.
Surface plasmon resonance (SPR) immunosensor using 4-mercaptobenzoic acid (4-MBA) modified gold SPR chip was developed first time for the detection of flagellin specific antibodies of Salmonella typhi (S. typhi). Flagellin protein of S. typhi was prepared by recombinant DNA technology. The modification of gold chip with 4-MBA was in-situ characterized by SPR and electrochemical impedance spectroscopy. By using kinetic evaluation software, K(D) and B(max) values were calculated and found to be 26.3 fM and 62.04 m°, respectively, for the immobilized monoclonal antibody (Moab) of recombinant flagellin (r-fla) protein of S. typhi (r-fla S. typhi). In addition, thermodynamic parameters such as ΔG, ΔH and ΔS were determined first time for r-fla S. typhi and Moab of r-fla S. typhi interactions and the values revealed the interaction between r-fla S. typhi and Moab of r-fla S. typhi as spontaneous, endothermic and entropy driven one. Moreover, healthy human serum samples and patient sera (Widal positive and Widal negative) were subjected to SPR analysis. The present SPR based approach provides an alternative way for S. typhi detection in less than 10 min.


Biometric indices, growth pattern, and physiological status of captive-reared indigenous Yellowtail brood catfish, Pangasius pangasius (Hamilton, 1822).
The current study was conducted to comprehend the variation of the growth pattern and the physiological status of Pangasius pangasius (Hamilton, 1822) reared in the pond from July 2021 to September 2021. A total of 90 brood individuals were collected from the Meghna River and studied for the present experiment. The overall growth pattern for P. pangasius was isometric (b = 3.00) in the Meghna River, while the male fish showed positive (b > 3.00) and the female showed a negative allometric growth pattern (b < 3.00). The Fulton's condition factor (KF) value was greater than 1, indicating a healthy population and a habitat with abundant food sources. Moreover, the KF value was found to be substantially related to total body mass. On the other hand, both sexes of P. pangasius had relative weight average values of more than 100, simply indicates the fish is naturally obese and has enough stored energy to maintain its physiology. The calculated form factors suggested an elongated body shape, which is typical of many riverine fishes. In addition, a small number of morphological traits varied significantly in the current study. Likewise, in the case of morphometric features, the principal component analysis showed a considerable degree of connectedness between the male and female individuals. The blood values showed no significant difference between the sexes. This might result from feeding fish the same kind of food and maintaining them in the same environment. However, the higher temperature might have caused slight blood abnormalities in both sexes. The current findings strongly support raising this fish in captivity and would offer useful information for fish farm owners, entrepreneurs, stakeholders, and other concerns in Bangladesh and surrounding nations.


Modelling the influence of the incubation temperature upon the estimated heat resistance of heated bacillus spores.
In this study, the influence of the incubation temperature on the D-values was described according to a simple Bigelow-like model. Model parameters were estimated from different sets of data from the literature and from our own data. For different Bacillus species and heat-treatment conditions, the influence of the recovery temperature was quantified and the optimal recovery temperature was determined. The impacts of species, bacterial strains belonging to the same species, heat-treatment temperature and composition of recovery media on the model parameters were analysed. The optimum recovery temperatures differ greatly from one species to another; however, no difference appears clearly between strains belonging to the same species. D values were significantly affected by recovery temperature. This influence of recovery temperature was dependent on the species, and affected by the composition of recovery media but not by the heating temperature. The developed model could be useful for determining the optimal incubation temperature and quantifying the weight of the recovery temperature influence for safe security control in the canning industry.


Taking into Account the Quality of the Relationship in HIV Disclosure.
Despite growing interest in HIV disclosure, most theoretical frameworks and empirical studies focus on individual and social factors affecting the process, leaving the contribution of interpersonal factors relatively unexplored. HIV transmission and disclosure often occur within a couple however, and this is where disclosure has the most scope as a HIV transmission intervention. With this in mind, this study explores whether perceived relationship quality influences HIV disclosure outcomes. Ninety-five UK individuals with HIV participated in a cross-sectional survey. Retrospective data were collected on their perceived relationship quality prior to disclosing their HIV positive status, and on disclosure outcomes. Perceived relationship quality was found to significantly affect disclosure outcomes. Positive qualities in the relationship were associated with positive outcomes, whereas negative qualities were associated with negative outcomes. Results further confirmed that this association was not merely correlational, but demonstrated predictive power. Relationship quality might act as either a risk or a resilience factor in the disclosure process, and thus warrants greater attention in future research.


Molecular diagnostics in dermatology: An online survey to study usage, obstacles and requirements in Germany.
Molecular diagnostics (MDx) increasingly gains importance in dermatology and its application is a prerequisite for personalized medicine. The goal of this cross-sectional study was to determine how MDx is implemented in dermatologists' offices in the three fields of oncology, inflammation and infectiology and which hurdles office-based dermatologists face in terms of MDx. Physician members of the Association of the German Dermatologists (Berufsverband der Deutschen Dermatologen e. V.; BVDD) were surveyed via an online questionnaire on MDx. 39.6 % of the 192 participants reported using MDx. Of these, the vast majority used MDx for diagnosing infectious diseases (86.5 % and 44.3 % of users perform MDx for detection of funghi and sexually transmitted diseases, respectively). Only a small minority applied MDx to answer oncological or immunological questions. The major obstacles for non-users as compared to users were difficulties in implementation, lack of expertise as well as time, personnel, and technical availability. Reimbursement was a main issue in both groups. Despite availability of specific therapies requiring precision medicine, MDx has not yet been broadly implemented in office-based dermatology. To advance MDx, more needs to be done in terms of continuous education, availability of reliable and valid tests, and reimbursability.


Pediatric Obesity: Pharmacokinetics and Implications for Drug Dosing.
Clinicians are increasingly likely to have under their care obese children with diseases requiring pharmacotherapy. Optimal drug dosing for this population is unclear. Excess weight likely leads to alterations in pharmacokinetics. The purpose of this article was to describe the pharmacokinetics and pharmacodynamics in overweight and obese children and, where possible, provide recommendations for drug dosing. EMBASE (1980-May 2015), MEDLINE (1950-May 2015), and International Pharmaceutical Abstracts (1970-May 2015) databases were searched by using the following terms: obesity, morbid obesity, overweight, pharmacokinetics, pharmacodynamics, drug, dose, drug levels, pediatric, and child. The search was limited to English-language articles. References of relevant articles were searched to identify additional studies. Total body weight (TBW) is an appropriate size descriptor for dosing antineoplastic agents, succinylcholine, and cefazolin. Obese children seem to require less heparin, enoxaparin, and warfarin per kilogram TBW than normal-weight children; providing standard adult doses may be insufficient, however. Obese children may also require less vancomycin and aminoglycosides per kilogram TBW than normal-weight children. For these medications, an alternate size descriptor in children has not been described, and initial dosing based on TBW and monitoring serum concentrations (vancomycin and aminoglycosides) or coagulation parameters (heparin, enoxaparin, and warfarin) is warranted. Obese children require less propofol than normal-weight children; however, there is limited information about the dosing of other anesthetics or opioids. Limitations to the available data include the inherent design constraints to case reports and retrospective cohort studies, as well as the small numbers of children in some of the studies. Use of normal-weight historical control subjects for obese children in the context of a pharmacokinetic study is not ideal. Although more information is becoming available, our understanding of the pharmacokinetics in obese children is still limited. When dosing information is not available for obese children, it may be necessary to extrapolate from available data in obese adults, but one should consider the effects of the child's age on pharmacokinetics.


Electrophysiological studies of indecainide hydrochloride, a new antiarrhythmic agent, in canine cardiac tissues.
The intracellular electrophysiological properties of a new, orally effective antiarrhythmic agent, indecainide hydrochloride, were studied in isolated canine myocardial preparations stimulated at 1 Hz and superfused with Tyrode's solution. In Purkinje fibers, indecainide (10(-6) and 3 X 10(-6) M) decreased the maximal rate of rise of phase 0 (Vmax), conduction velocity, action potential duration APD, and effective refractory period, and shifted the membrane response curve by 5 mV in a hyperpolarizing direction. In papillary muscle, APD was unchanged, but Vmax was decreased. The effect of the drug on Vmax was rate dependent, but over physiologically relevant cycle lengths (370 to 1,000 ms), Vmax remained relatively constant. In the presence of indecainide (3 X 10(-6) M) and at a basic cycle length of 333 ms, the rate constant for block onset was 0.06 and 0.1 action potentials-1 in Purkinje fiber and papillary muscle, respectively. The recovery of Vmax from maximum steady-state block was half completed in Purkinje fibers and muscle in 52 and 49 s, respectively. No resting block was apparent in either tissue at normal resting membrane potential. Indecainide had only minimal effects on automaticity arising from normal or depolarized (barium) membrane potentials. Thus, indecainide is a potent class I local anesthetic antiarrhythmic agent that depresses Vmax and conduction in cardiac tissues. The depressant effects of indecainide are completely dependent on prior activation of the tissue, but because of its slow kinetics for recovery from sodium channel block, little additional change in Vmax occurs within physiologically relevant heart rates and prematurity intervals.


Correlation between posterior tibial slope and sagittal alignment under weight-bearing conditions in osteoarthritic knees.
Posterior tibial slope (PTS) and sagittal alignment are important factors in the etiology of knee osteoarthritis and knee surgery. Clinically, sagittal alignment, which indicates flexion contracture of the knee, contributes to knee function in weight-bearing (WB) conditions. PTS and sagittal alignment under WB conditions in varus osteoarthritic knees are presumed to affect each other, but their association remains unclear. In this study, we aimed to clarify the association. In total, 140 osteoarthritic varus knees were investigated. Under WB conditions, a three-dimensional (3D) alignment assessment system was applied via biplanar long-leg X-rays, using 3D-to-2D image registration technique. The evaluation parameters were as follows: 1) 3D mechanical flexion angle (3DMFA) in regards to sagittal alignment, 2) passing point in the WB line (PP), and 3) medial and lateral PTS. The medial and lateral PTS showed a positive correlation with 3DMFA and PP, respectively (medial PTS-3DMFA, p = 0.001; medial PTS-PP, p < 0.0001; lateral PTS-3DMFA, p < 0.0001; lateral PTS-PP, p = 0.002). The flexion contracture group with 3DMFA >5° demonstrated greater PTS than non-flexion contracture group (medial PTS, p = 0.006; lateral PTS, p = 0.006). Both medial and lateral PTS were correlated with sagittal alignment under WB conditions and were larger in the flexion contracture group. This finding can explain the function to take the load articular surface parallel to the ground for holding the balance in WB conditions in the sagittal plane for osteoarthritic knees. Moreover, surgeons may be required to decrease the PTS during knee arthroplasty to restore full extension in knees of patients with fixed flexion contracture.


Risk of serious toxicity in 1181 patients treated in phase I clinical trials of predominantly targeted anticancer drugs: the M. D. Anderson Cancer Center experience.
This study assessed toxicity in advanced cancer patients treated in a phase I clinic that focuses on targeted agents. An analysis of database records of 1181 consecutive patients with advanced cancer who were treated in the phase I program starting 1 January 2006 was carried out. All patients were treated on at least 1 of the 82 phase I clinical trials. Overall, 56 trials (68.3%) had only targeted agents, 13 (15.9%) only cytotoxics, and 13 (15.9%) targeted and cytotoxic agents. Rates of grade 3 and 4 toxicity that were at least possibly drug related were 7.1% and 3.2%, respectively, and 5 of the 1181 patients (0.4%) died from toxicity that was at least possibly drug related. The most common grade 3 or more toxic effects were neutropenia, thrombocytopenia, anemia, dehydration, infection, altered mental status, bleeding, vomiting, nausea, and diarrhea. Eastern Cooperative Oncology Group (ECOG) performance status greater than zero and use of a cytotoxic agent were selected as independent factors associated with serious toxicity. Phase I trials of primarily targeted agents showed low rates of toxicity, with 10.3% of patients experiencing grade 3 or 4 toxicity and a 0.4% rate of death, at least possibly drug related.


Confrontment and solution to gonadotropin resistance and low oocyte retrieval in in vitro fertilization for type I BPES: a case series with review of literature.
FOXL2 mutations in human cause Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES). While type II BPES solely features eyelid abnormality, type I BPES involves not only eyelid but also ovary, leading to primary ovarian insufficiency (POI) and female infertility. Current mainstream reproductive option for type I BPES is embryo or oocyte donation. Attempts on assisted reproductive technology (ART) aiming biological parenthood in this population were sparse and mostly unsuccessful. Two Chinese type I BPES patients with low anti-müllerian hormone (AMH) and elevated follicle stimulating hormone (FSH) presented with primary infertility in their early 30s. Genetic studies confirmed two heterozygous duplication mutations that were never reported previously in East Asian populations. They received in vitro fertilization (IVF) treatment and both exhibited resistance to gonadotropin and difficulty in retrieving oocytes in repeated cycles. Doubled to quadrupled total gonadotropin doses were required to awaken follicular response. Patient 1 delivered a baby girl with the same eyelid phenotype and patient 2 had ongoing live intrauterine pregnancy at the time of manuscript submission. This is the second reported live birth of biological offspring in type I BPES patients, and first success using IVF techniques. It confirmed that ART is difficult but feasible in type I BPES. It further alerts clinicians and genetic counsellors to type female BPES patients with caution in view of the precious and potentially narrowed reproductive window.


Continuity of the dsRNA genome of bluetongue virus.
The duplex RNA genome of bluetongue virus, extracted under acidic conditions with sodium dodecyl sulfate and phenol, is an unfragmented continuous structure. Most genomes appeared as a rosette with 10 loops (genes) emanating from a central crescent- or doughnutshaped area. The genome has a mean length of ca. 10 μm which corresponds to a molecular weight of ca. 23 million.


Selection and evolution in macromolecular systems.
The notion of a quasi-species represents the ensemble of macromolecular sequences derived by the mechanism of mutation and replication from a single wild type. In Eigen (1971) and Eigen & Schuster (1979), the deterministic evolution of this ensemble under constant environmental conditions is given in terms of continuous models which describe the dynamics of the distribution of polynucleotides. This paper starts from a discrete model of macromolecular evolution and introduces the notion of a genealogy in order to study the dynamics of the quasi-species in constant and variable environments. We introduce, in terms of these genealogies, the notions of entropy and adaptive value of a quasi-species and the notion of capacity of the environment. We discuss the significance of these indices as measures of selective value and we analyse the conditions under which these measures coincide with the growth rate of the quasi-species.


Physical symptoms, posttraumatic stress disorder, and healthcare utilization of women with and without childhood physical and sexual abuse.
For four groups of women: no abuse, physical abuse alone, combined sexual and physical abuse, and unclear about memories of abuse, we examined the associations between childhood sexual and physical abuse, chronic physical symptoms in adulthood, PTSD, and health care utilization. Of a randomly selected sample of 600 adult femalc members of a health maintenance organization, 86 (14%) chose to participate. Women with a history of physical and sexual abuse in childhood reported significantly more cardiovascular, immune, musculoskeletal, neurologic, and reproductive symptoms than those without this history. While the Sexual/Physical Abuse group had the most chronic physical symptoms, medical visits, emergency room visits, prescriptions, and severe PTSD, the Unclear Memory group consistently ranked second on these same measures--higher than either Controls or the Physical Abuse group. Findings underscore the importance of screening for trauma history among patients seen in medical clinics, and the importance for psychotherapists of attending to patients' physical as well as psychological symptoms of childhood trauma.


The caffeine contents of non-alcoholic beverages.
The caffeine content of a number of non-alcoholic beverages was determined using HPLC. It was found that Diet Coke had a greater caffeine content than Coke (4.15 compared with 3.13 mg/fl oz), Tab is virtually caffeine free, and Lucozade, sold as a tonic, contains more caffeine than any of the other carbonated beverages tested (5.17 mg/fl oz). The pure instant coffee tested contained much more caffeine than the coffee/chicory mixtures (12.61 compared with 3.18 mg/fl oz). The caffeine content of Ceylon tea blends increases with the time the tea is allowed to draw (from about 8 mg/fl oz after 1 min to about 12 mg/fl oz after 20 min). Tea that has been allowed to draw for 20 min has a caffeine content similar to that of pure coffee.


Forest savanna ecotone dynamics in India as revealed by carbon isotope ratios of soil organic matter.
In India, the stability of the forest savanna boundary (ecotone) has been questioned. To investigate the possibility of vegetation change at this boundary, we used the natural difference in the stable carbon isotope ratio (13C/12C, expressed as δ13C) of C3 (forest) and C4 (savanna) plants, which is preserved in the isotopic composition of soil organic carbon. Past changes in the position of the ecotone can thus be documented by 13C/12C analysis of soil organic matter (SOM). Measurements were made on soil samples taken along a transect across the forest savanna boundary. In both ecosystems, δ13C values of SOM in upper soil layers appeared to be in equilibrium with the current plant community: SOM was near-14‰ under savanna cover, and near-28‰ under forest. By contrast, δ13C values of SOM from deep layers of soil profiles under forest cover near the ecotone, were less negative than would be expected for a C3-dominated community. These results indicate that a change in ecosystem dominance occurred recently, and that forest has invaded an area occupied previously by a C4 plant community (savanna and cultivated grassland).


Interaction of chemical cues from fish tissues and organophosphorous pesticides on Ceriodaphnia dubia survival.
Cladocera are frequently used as test organisms for assessing chemical and effluent toxicity and have been shown to respond to stimuli and cues from potential predators. In this study, the interactive effects of visual and chemical cues of fish and two organophosphorous pesticides on survival of Ceriodaphnia dubia were examined. A significant chemical cue (homogenized Pimephales promelas) and malathion interaction was observed on C. dubia survival (P = 0.006). Chemical cue and 2.82 microg/L malathion resulted in a 76.0% reduction in survival compared to malathion alone (P < 0.01). Furthermore, potentiation of malathion toxicity varied based on the source of chemical cues (i.e., epithelial or whole body). It is unclear in this study whether these chemical cues elicited a predation-related stress in C. dubia. Future research should examine the mechanism of this interaction and determine what role, if any, stress responses by C. dubia might play in the interaction.


Treatment of nonalcoholic fatty liver disease with dapagliflozin in non-diabetic patients.
Steatosis, a condition characterized by excessive lipid deposition. Although usually a benign condition, steatosis mays progress to cirrhosis or hepatocellular carcinoma. Recent evidence suggests that SGLT2 inhibitors suppress the development of nonalcoholic steatohepatitis in humans, as well as in rodent models and that SGLT2 inhibitors alleviate hepatic steatosis or steatohepatitis in obese type 2 diabetic rats or mice. 14 Patients with nonalcoholic fatty liver disease used a fixed dose of 10 mg of dapagliflozin for an average of 75 days. ALT, AST, GGT, insulin, HOMA-IR, and weight levels were significantly lower after treatment. There was no significant correlation between the reduction in HOMA and the reduction in ALT values or weight reduction obtained during treatment and ALT values.


Cystic intracerebellar epidermoids with rim enhancement. A case report.
A case of two infected cystic epidermoids of the right cerebellar hemisphere is reported. One of the cysts showed peripheral contrast enhancement on CT. Relevant literature regarding the pathogenesis and CT diagnosis is reviewed.


Experience to date with CFTR modulators during pregnancy and breastfeeding in the British Columbia Cystic Fibrosis clinic.
The introduction and rapid uptake of CFTR modulator therapy, in addition to other treatments, has significantly increased life expectancy in CF and provided more women the opportunity to consider and successfully be managed throughout pregnancy. There is however limited evidence to guide patient management and enable informed decision making. Here we report the experience to date from a large multidisciplinary Cystic Fibrosis quaternary referral center in managing patients on CFTR modulators in the peri- and post-partum periods. While women in this case series were advised to discontinue CFTR modulators during pregnancy, they would likely receive a very different message today.


Cold-induced activation of brown adipose tissue and adipose angiogenesis in mice.
Exposure of humans and rodents to cold activates thermogenic activity in brown adipose tissue (BAT). This protocol describes a mouse model to study the activation of BAT and angiogenesis in adipose tissues by cold acclimation. After a 1-week exposure to 4 °C, adult C57BL/6 mice show an obvious transition from subcutaneous white adipose tissue (WAT) into brown-like adipose tissue (BRITE). The BRITE phenotype persists after continuous cold exposure, and by the end of week 5 BRITE contains a high number of uncoupling protein-1-positive mitochondria, a characteristic feature of BAT. During the transition from WAT into BRITE, the vascular density is markedly increased owing to the activation of angiogenesis. In BAT, cold exposure stimulates thermogenesis by increasing the mitochondrial content and metabolic rate. BAT and the increased metabolic rate result in a lean phenotype. This protocol provides an outstanding opportunity to study the molecular mechanisms that control adipose mass.


De novo expression of calretinin in trimethyltin-induced degeneration of developing rat hippocampus.
In the model of trimethyltin (TMT)-induced neurodegeneration in developing rat hippocampus, calretinin (CR)-immunoreactive neurons are selectively spared and even more numerous than in controls. We investigated the possibility of an additional synthesis of CR using RT-PCR. The amount of CR mRNA increased significantly after TMT treatment. CR mRNA production after TMT treatment could hypothetically be regarded as a compensatory phenomenon in developing rats.


Synthesis and characterization of π-extended "earring" subporphyrins.
A π-extended "earring" subporphyrin 3 was synthesized from β,β'-diiodosubporphyrin and diboryltripyrrane via a Suzuki-Miyaura coupling and following oxidation. Its Pd complex 3Pd was also synthesized and both of the compounds were fully characterized by 1H NMR, MS and X-ray single crystal diffraction. The 1H NMR spectra and single crystal structures revealed that aromatic ring current did not extend to the "ear" in both of the two compounds. Their UV-vis/NIR spectra were recorded and the absorption of both compounds is extended to the NIR region and that the absorption of 3Pd is further red-shifted and more intense.


The Gamma Gap and All-Cause Mortality.
The difference between total serum protein and albumin, i.e. the gamma gap, is a frequently used clinical screening measure for both latent infection and malignancy. However, there are no studies defining a positive gamma gap. Further, whether it is an independent risk factor of mortality is unknown. This study examined the association between gamma gap, all-cause mortality, and specific causes of death (cardiovascular, cancer, pulmonary, or other) in 12,260 participants of the National Health and Nutrition Examination Survey (NHANES) from 1999-2004. Participants had a comprehensive metabolic panel measured, which was linked with vital status data from the National Death Index. Cause of death was based on ICD10 codes from death certificates. Analyses were performed with Cox proportional hazards models adjusted for mortality risk factors. The mean (SE) age was 46 (0.3) years and the mean gamma gap was 3.0 (0.01) g/dl. The population was 52% women and 10% black. During a median follow-up period of 4.8 years (IQR: 3.3 to 6.2 years), there were 723 deaths. The unadjusted 5-year cumulative incidences across quartiles of the gamma gap (1.7-2.7, 2.8-3.0, 3.1-3.2, and 3.3-7.9 g/dl) were 5.7%, 4.2%, 5.5%, and 7.8%. After adjustment for risk factors, participants with a gamma gap of ≥3.1 g/dl had a 30% higher risk of death compared to participants with a gamma gap <3.1 g/dl (HR: 1.30; 95%CI: 1.08, 1.55; P = 0.006). Gamma gap (per 1.0 g/dl) was most strongly associated with death from pulmonary causes (HR 2.22; 95%CI: 1.19, 4.17; P = 0.01). The gamma gap is an independent risk factor for all-cause mortality at values as low as 3.1 g/dl (in contrast to the traditional definition of 4.0 g/dl), and is strongly associated with death from pulmonary causes. Future studies should examine the biologic pathways underlying these associations.


Cellular and molecular determinants of cisplatin resistance.
Cisplatin and carboplatin are among the most active and widely used cytotoxic anticancer drugs. However, the acquisition or presence of resistance significantly undermines the curative potential of these drugs against many malignancies. Multiple potential mechanisms of resistance have been identified at the cellular and molecular levels. Alterations in cellular pharmacology, including decreased drug accumulation, increased cellular thiol levels and increased repair of platinum-DNA damage, have been observed in numerous model systems. More recently, it has become apparent that an enhanced capacity to tolerate cisplatin-induced damage may also contribute to resistance. Alterations in proteins that recognise cisplatin-DNA damage (mismatch repair and high-mobility group (HMG) family proteins) and in pathways that determine sensitivity to apoptosis may contribute to damage tolerance. It remains to be determined whether any of these mechanisms contribute significantly to resistance in the clinical setting. Ongoing biochemical modulation and translational correlative trials should clarify which specific mechanisms are most relevant to clinical cisplatin resistance. Such investigations have the potential to improve the ability to predict likelihood of response and should identify potential targets for pharmacological or molecular intervention.


A ruptured renal lymphangiectasia in the retroperitoneum: A rare complication of a rare condition.
Renal lymphangiectasia is a rare and benign renal lymphatics disorder. It is usually asymptomatic, and rarely revealed by lumbar pain, arterial hypertension or retroperitoneal fluid collection. Radiological diagnostic is challenging and can be done if radiologists are aware of the imaging findings. Here in, we report a case of a young woman admitted for the management of a blunt abdominal trauma. Computed tomography showed a huge right retroperitoneal fluid collection, communicating with a perirenal cyst. This perirenal collection was bilateral and symmetrical. The diagnostic of a ruptured perirenal lymphangiectasia was suspected and confirmed by needle puncture. We managed the case using percutaneous drainage. Reassessment at subsequent follow-up visits showed a total regression of the collection improvement in the patient's clinical.


The Utility of High-Definition 2-Dimensional Stereotactic Exoscope in Cranial and Spinal Procedures.
The use of an exoscope in neurosurgical procedures has been proposed to improve ergonomics and to overcome the limitations faced with the microscope and endoscope. However, there remains scarcity of data regarding its surgical utility and outcomes. The authors report their experience and evaluate the surgical outcomes using a high-definition 2-dimensional (HD-2D) stereotactic exoscope in the management of various cranial and spinal pathologies. We retrospectively identified patients who underwent neurosurgical procedures using the HD-2D stereotactic exoscope over a 2-year period. Demographic and surgical characteristics were analyzed. Twenty-nine patients (70.7%) underwent cranial surgery, and 12 patients (29.3%) underwent spine surgery. In patients having brain tumor removal, gross total resection was achieved in 18 patients (62.1%), with an overall average pathology size of 4.2 ± 1.6 cm. Adjuvant utilization of the microscope was required in 4 cranial cases (13.8%) to ensure optimal resection rate. Three complications and 2 mortalities were encountered in the cranial group during a mean follow-up of 4.6 ± 3.3 months. In the spinal cohort, the HD-2D stereotactic exoscope was used for anterior decompression and fusion (n = 5), posterior decompression and fusion (n = 5), and microdiskectomy and foraminotomy (n = 2). No complications were encountered in the spinal group during a mean follow-up of 3.8 ± 2.7 months. The HD-2D stereotactic exoscope offers a wider field of view, greater mean focal distance, enhanced ergonomics, and immersive stereotactic visual experience. The lack of stereopsis remains the principal limitation of its use, and further optimization of surgical outcomes might be achieved with newer 3-dimensional models.


Photoswitching of halide-binding affinity and selectivity in dithienylethene-strapped calix[4]pyrrole.
Dithienylethene-strapped calix[4]pyrrole is isomerized by 300/630 nm light between ring-open and -closed isomers, which affects the size of the anion binding site. Where for chloride this results in only a small change in affinity, that of the larger bromide and iodide ions is majorly affected, resulting in altered selectivity.


Considerations for Peripheral Blood Stem Cell Apheresis in a Low Body Weight Infant.
Peripheral blood stem cell (PBSC) apheresis in infants (<10 kg body weight) requires specific precautions to prevent periprocedural complications. A 9 month old child was diagnosed with high-risk neuroblastoma and planned for autologous stem cell transplantation after induction chemotherapy. We illustrate the precautions and technical details observed while performing PBSC collection in this patient. Use of continuous flow devices, priming of apheresis circuits, appropriate flow rates and continuous monitoring can help to mitigate several procedure related complications. PBSC apheresis in infants (<10 Kg) is safe and feasible with appropriate precautions detailed above.


Enhanced toileting program decreases incontinence in long term care.
Incontinence is a common problem in long term care. In March 2003, in reviewing its performance on the Minimum Data Set (MDS 3.0) quality indicators, Sea View Hospital Rehabilitation Center and Home, a 304-bed long term care facility in Staten Island, New York, discovered it was 39% above the average of the state and national means for the incontinence indicators. In response, it initiated a facilitywide performance improvement project. Processes identified in the action plan for the project, "Residents who trigger for occasional or frequent bowel and bladder incontinence on MDS will be assessed for an individualized toileting schedule," included (1) revision of assessment documentation, which improved the initial assessment of continence, with an added reassessment process; (2) documentation of the toileting plan on the Patient Care Technician Assignment Card and the Activity of Daily Living Accountability Sheet; (3) adoption of toilet-assist devices; (4) hospitalwide in-service on incontinence and toileting; and (5) revision of the bowel and bladder incontinence policy. After implementation of the revised bowel and bladder incontinence assessment tool, the rate of incontinence without a toileting plan decreased--from 79% to 38%--and remained below the yearly mean. The new assessment processes made individualized planning possible and accurate. This initiative could be easily replicated because it requires resources that are basic to most long term care facilities.


Interpreting the Relationship Among Itch, Sleep, and Work Productivity in Patients with Moderate-to-Severe Atopic Dermatitis: A Post Hoc Analysis of JADE MONO-2.
Abrocitinib, an oral, once-daily Janus kinase 1-selective inhibitor, improved itch severity, sleep, and work productivity versus placebo in patients with moderate-to-severe atopic dermatitis. The aim of this study was to investigate relationships among itch, sleep, and work productivity in the phase III JADE MONO-2 clinical trial. A repeated-measures longitudinal model was used to examine relationships between itch (using the Peak Pruritus Numerical Rating Scale [PP-NRS] or Nighttime Itch Scale [NTIS]) and sleep disturbance/loss (using the Patient-Oriented Eczema Measure sleep item and SCORing AD Sleep Loss Visual Analog Scale) and, separately, between itch and work productivity (using the Work Productivity and Activity Impairment-Atopic Dermatitis Version 2.0 questionnaire). Mediation modelling was used to investigate the effect of treatment (abrocitinib vs placebo) on work impairment via improvements in itch and sleep. The relationships between itch/sleep and itch/work productivity were approximately linear. PP-NRS scores of 0, 4-6, and 10 were associated with 0 days, 3-4 days, and 7 days per week of disturbed sleep, respectively. PP-NRS or NTIS scores of 0-1, 4-5, and 10 were associated with 0-10%, 20-30%, and >50% overall work impairment, respectively. Seventy-five percent of the effect of abrocitinib on reducing work impairment was indirectly mediated by improvement in itch, followed by sleep. These results quantitatively demonstrate that reducing itch severity is associated with improvements in sleep and work productivity. Empirical evidence for the mechanism of action of abrocitinib showed that itch severity is improved, which reduces sleep loss/sleep disruption and, in turn, improves work productivity. NCT03575871.


Synthesis and antibacterial activity of novel 7-(3-substituted-3 or 4-trifluoromethyl-1-pyrrolidinyl)-8-methoxyfluoroquinolones.
The titled compounds were synthesized and evaluated for in vitro antibacterial activity. The (3R, 4S)-3-aminomethyl-4-trifluoromethyl derivative (S-34109) was confirmed to be optimal because of its superior activity against quinolone and methicillin-resistant Staphylococcus aureus and low side effect potential.


Effect of Concomitant Therapy With Steroids and Tumor Necrosis Factor Antagonists for Induction of Remission in Patients With Crohn's Disease: A Systematic Review and Pooled Meta-analysis.
It is not clear whether concomitant therapy with corticosteroids and anti-tumor necrosis factor (TNF) agents is more effective at inducing remission in patients with Crohn's disease (CD) than anti-TNF monotherapy. We aimed to determine whether patients with active CD receiving corticosteroids during induction therapy with anti-TNF agents had higher rates of clinical improvement than patients not receiving corticosteroids during induction therapy. We systematically searched the MEDLINE, Embase, and CENTRAL databases, through January 20, 2016, for randomized trials of anti-TNF agents approved for treatment of CD and identified 14 trials (5 of adalimumab, 5 of certolizumab, and 4 of infliximab). We conducted a pooled meta-analysis of individual patient and aggregated data from these trials. We compared data from participants who continued oral corticosteroids during induction with anti-TNF therapy to those treated with anti-TNF agents alone. The endpoints were clinical remission (CD activity index [CDAI] scores <150) and clinical response (a decrease in CDAI of 100 points) at the end of induction (weeks 4-14 of treatment). We included 4354 patients who received induction therapy with anti-TNF agents, including 1653 [38.0%] who were receiving corticosteroids. The combination of corticosteroids and an anti-TNF agent induced clinical remission in 32.0% of patients, whereas anti-TNF monotherapy induced clinical remission in 35.5% of patients (odds ratio [OR], 0.93; 95% CI, 0.74-1.17). The combination of corticosteroids and an anti-TNF agent induced a clinical response in 42.7% of patients, whereas anti-TNF monotherapy induced a clinical response in 46.8% (OR 0.84; 95% CI, 0.73-0.96). These findings did not change with adjustment for baseline CDAI scores and concurrent use of immunomodulators. Based on a meta-analysis of data from randomized trials of anti-TNF therapies in patients with active CD, patients receiving corticosteroids during induction therapy with anti-TNF agents did not have higher rates of clinical improvement compared with patients not receiving corticosteroids during induction therapy. Given these findings and the risks of corticosteroid use, clinicians should consider early weaning of corticosteroids during induction therapy with anti-TNF agents for patients with corticosteroid-refractory CD.


Effects of dietary cyanidin-3-diglucoside-5-glucoside complexes with rutin/Mg(II) against H2O2-induced cellular oxidative stress.
Anthocyanins exist likely as complexes with flavones/metal ions in some plants. However, few studies indicate the complexation effects on bioactivities, i.e. antioxidant activities. The aim of this study was to evaluate effects of complexes of cyanidin-3-diglucoside-5-glucoside (CY3D5G) with rutin/Mg(II) on intrinsic antioxidant enzymes and mRNA expressions. All complexes exhibited cellular antioxidant activity in RAW264.7 cells, whereas half maximal effective concentration (EC50) values of CY3D5G complexes were significantly lower than its alone. Combination indexes of CY3D5G-rutin, CY3D5G-Mg(II), and CY3D5G-rutin-Mg(II) complexes were < 1 (p < .05), indicating of synergistic effects. Additionally, CY3D5G-Mg(II) rather than others significantly enhanced total antioxidant capacity, superoxide dismutase activity, and glutathione peroxidase activity while reducing malonic dialdehyde contents in H2O2-induced RAW264.7 cell model (p < 0.05), which were further confirmed with the up-regulated mRNA expression of nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), and the down-regulated p21 (p < 0.05). Our results demonstrated that CY3D5G and its complexes might enhance cellular antioxidant activities via the Nrf2/HO-1 signaling pathway. Additionally, a synergistic antioxidant effect of CY3D5G in the present of rutin/ Mg(II) as regular food components was evident, suggesting anthocyanin might interact with dietary components such as Mg(II) or rutin in food matrix or biological systems and exhibit a stronger antioxidant activity than it alone. The Mg (II) that exhibited no antioxidant activities alone shows potential as a co-adjuvant for the anthocyanin antioxidant activity.


Autoreactive B-cell repertoire in mice with chronic graft versus host disease.
A quantitative analysis of the frequencies of autoantibody producing B-cells has been undertaken by producing and analyzing random hybridoma collections generated in fusions with activated B-cells. Activated B-cells were derived from mice injected with LPS and SRBC and normal mice. They were compared to those derived from mice undergoing chronic GVHD. The frequencies of successful fusion events correlate well with the number of activated B-cells used in the fusions, so that it is reasonable to conclude that the hybridoma collections reflect the activated B-cell repertoires in the different animals. The frequencies of hybridomas producing autoantibodies as well as their specificities for self-antigens, were not significantly different between the different collections of hybridomas. Moreover, no difference in VH gene family expression was found in the different collections of autoantibody producing hybridomas. So, the activated autoreactive B-cell repertoires in GVHF1 mice and in normal mice is similar. In contrast to the normal activated autoreactive B-cell repertoires, which make predominantly IgM antibodies, the GVH-activated autoreactive B-cells make predominantly antibodies of the IgG class. Therefore, we conclude that T-cell mediated graft versus host activation does not generally lead to selective expansion of autoreactive B-cells, but appears to play a crucial role in the switch from IgM to IgG production.


Structural study of medium-long chain fatty acyl-CoA ligase FadD8 from Mycobacterium tuberculosis.
In mycobacteria, lipids are important components of the cell wall and play a critical role for pathogenic activities. Lipids need to be activated before participating in many biological pathways. FadD proteins are members of the adenylate-forming superfamily, catalyzing activation of fatty acids. FadD8 is one of the 34 Mycobacterium tuberculosis FadD proteins, which was reported to be a putative medium-long chain fatty acyl-CoA ligase. Previous studies showed FadD8 from Mycobacterium smegmatis exhibited higher activity with oxidized cholesterol than fatty acids. However, the catalytic mechanism of the FadD8 is still exclusive. Here, we reported the crystal structure of FadD8 from Mycobacterium tuberculosis, which forms homodimer. Structural analysis revealed presence of a relatively narrow pocket compared to other FadD proteins and a novel alternative pocket, implying distinct substrate binding preference. We propose that FadD8 plays a vital role in cholesterol utilization and metabolism by catalyzing activation of cholesterol. Collectively, our findings provide novel information for the further studies of the inhibitor and drug development.


Increased susceptibility to SARS-CoV-2 infection in patients with reduced left ventricular ejection fraction.
Cardiovascular disease has been recognized as a major determinant of coronavirus disease 2019 (COVID-19) vulnerability and severity. Angiotensin-converting enzyme (ACE) 2 is a functional receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is up-regulated in patients with heart failure. We sought to examine the potential association between reduced left ventricular ejection fraction (LVEF) and the susceptibility to SARS-CoV-2 infection. Of the 1162 patients with acute coronary syndrome (ACS) who underwent percutaneous coronary intervention between February 2014 and October 2018, we enrolled 889 patients with available clinical follow-up data. Follow-up was conducted by telephone interviews 1 month after the start of the French lockdown which began on 17 March 2020. Patients were divided into two groups according to LVEF <40% (reduced LVEF) (n = 91) or ≥40% (moderately reduced + preserved LVEF) (n = 798). The incidence of COVID-19-related hospitalization or death was significantly higher in the reduced LVEF group as compared with the moderately reduced + preserved LVEF group (9% vs. 1%, P < 0.001). No association was found between discontinuation of ACE-inhibitor or angiotensin-receptor blockers and COVID-19 test positivity. By multivariate logistic regression analysis, reduced LVEF was an independent predictor of COVID-19 hospitalization or death (odds ratio: 6.91, 95% confidence interval: 2.60 to 18.35, P < 0.001). In a large cohort of patients with previous ACS, reduced LVEF was associated with increased susceptibility to COVID-19. Aggressive COVID-19 testing and therapeutic strategies may be considered for patient with impaired heart function.


Long non-coding RNA CCAT1/miR-148a/PKCζ prevents cell migration of prostate cancer by altering macrophage polarization.
Macrophage polarization plays an important role in tumor microenvironment, which regulated the prognosis of prostate cancer. However, the potential role of it is still need further identification. The M1 Macrophages were inducted using 100 ng/mL LPS and 100 ng/mL IFN-γ, the M1 Macrophages were inducted using 20 ng/mL IL-4. TAMs were obtained by culturing monocytes for 7 days in RPMI 1640 10% FBS with 50% of conditioned medium from PC-3 cells real-time PCR was performed to determine the expression of miR-148a, CCAT1, and PKCζ. Western blot was used to measure the level of PKCζ. The cytokine IL-10 was determined using ELISA. Transwell chamber was carried out to determine cell migration. Luciferase reporter assay was used to determine the relationship between miR-148a and PKCζ. The expression of miR-148a was highest in TAMs, while CCAT1 and PKCζ were highest in M1 Macrophages. Overexpressed miR-148a promoted the level of IL-10 and cell migration. Down-regulated CCAT1 promoted the level of IL-10 and cell migration, while this effects were abolished by co-transfection of si-CCAT1 and miR-148a inhibitor. PKCζ is the target gene of miR-148a. The effects of overexpressed miR-148a on the level of IL-10, genes expression, and cell migration were abolished by miR-148a mimic and pcDNA-PKCζ. In vivo experiments verified the effects of CCAT1 and miR-148a on tumor growth. CCAT1 knockdown promoted M2 macrophages polarization by up-regulating miR-148a, while miR-148a up-regulation promoted M2 macrophages polarization by down-regulating the expression of PKCζ.


Novel phage peptides attenuate beta amyloid-42 catalysed hydrogen peroxide production and associated neurotoxicity.
Amyloid-beta (Abeta) peptides play a central role in the pathogenesis of Alzheimer's disease. There is accumulating evidence that supports the notion that the toxicity associated with human Abeta (both 40 and 42) is dependent on its superoxide dismutase (SOD)-like activity. We developed a novel screening method involving phage display technology to identify novel peptides capable of inhibiting Abeta's neurotoxicity. Two random peptide libraries containing 6-mer and 15-mer peptide inserts were used and resulted in the identification of 25 peptides that bound human Abeta (40 or 42). Here, we show that two of the three most enriched peptides obtained significantly reduced Abeta42's SOD-like activity. A 15-mer peptide reduced Abeta42 neurotoxicity in a dose-dependent manner as evidenced by a reduction in LDH release. These findings were confirmed in the independent MTT assay. Furthermore, comparative analysis of the 15-mer peptide with Clioquinol, a known inhibitor of Abeta's metal-mediated redox activity, showed the 15-mer peptide to be equipotent to this metal chelator, under the same experimental conditions. These agents represent novel peptides that selectively target and neutralise Abeta-induced neurotoxicity and thus provide promising leads for rational drug development.


Erythropoietin protects the developing brain against N-methyl-D-aspartate receptor antagonist neurotoxicity.
Pharmacological blockade of NMDA receptor function induces apoptotic neurodegeneration in the developing rat brain. However, the use of NMDA receptor antagonists as anesthetics and sedatives represents a difficult-to-avoid clinical practice in pediatrics. This warrants the search for adjunctive neuroprotective measures that will prevent or ameliorate neurotoxicity of NMDA receptor antagonists. The NMDA receptor antagonist MK801 triggered apoptosis in the neonatal rat forebrain, most notably in cortex and thalamus. MK801 exposure reduced mRNA levels of erythropoietin (EPO) and the EPO receptor, suggesting that loss of endogenous EPO activity may contribute to MK801-induced apoptosis. Coadministration of recombinant EPO (rEPO) conferred 50% neuroprotection, partially restored MK801-induced reduction of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) mRNA, and prevented decreased phosphorylation levels of extracellular signal-regulated protein kinase-1/2 (ERK1/2) and Akt. These observations indicate that rEPO partly rescues newborn rats from MK801-mediated brain damage by enhancing neurotrophin-associated signaling pathways.


Regulation of deubiquitinase proteolytic activity.
Deubiquitinases (DUBs) are proteolytic enzymes whose function is to oppose the process of the conjugation of ubiquitin to a specific substrate. This task is accomplished through an enzymatic cascade involving E1, E2, and E3 enzymes, which collectively produce a product that is either monoubiquitinated, or polyubiquitinated with multiple single ubiquitins or with ubiquitin chains. The resulting modifications may impact protein function or may lead to the degradation of the ubiquitinated species, so the removal of such modifications must be tightly regulated. On the basis of recent work featuring crystal structures and detailed biochemical or biophysical studies of DUBs, we will discuss here how posttranslational modifications, protein binding partners, and reactive oxygen species regulate their catalytic activity.


Bioinspired Quasi-3D Multiplexed Anti-Counterfeit Imaging via Self-Assembled and Nanoimprinted Photonic Architectures.
Innovative multiplexing technologies based on nano-optics for anti-counterfeiting have been proposed as overt and covert technologies to secure products and make them difficult to counterfeit. However, most of these nano-optical anti-counterfeiting materials are metasurfaces and metamaterials with complex and expensive fabrication process, often resulting in materials that are not damage tolerant. Highly efficient anti-counterfeiting technologies with easy fabrication process are targeted for intuitive and effective authentication of banknotes, secure documents, and goods packing. Here, a simple strategy exploiting self-assembling and nanoimprinting technique to fabricate a composite lattice photonic crystal architecture featuring full spatial control of light, multiplexed full-pixel imaging, and multichannel cryptography combined with customized algorithms is reported. In particular, the real-time encryption/recognition of mobile quick response codes and anti-counterfeiting labels on a postage stamp, encoded by the proposed photonic architecture, are both demonstrated. The wave optics of scattering, diffraction, and polarization process involved are also described, validated with numerical simulations and experiments. By introducing a new degree of freedom in the 3D space, the multichannel image switching exhibits unprecedented variability of encryption, providing a promising roadmap to achieve larger information capacity, better security, and higher definition for the benefit of modern anti-counterfeiting security.


Further support for aneuploidy tolerance in wild yeast and effects of dosage compensation on gene copy-number evolution.
In our prior work by Hose et al., we performed a genome-sequencing survey and reported that aneuploidy was frequently observed in wild strains of S. cerevisiae. We also profiled transcriptome abundance in naturally aneuploid isolates compared to isogenic euploid controls and found that 10-30% of amplified genes, depending on the strain and affected chromosome, show lower-than-expected expression compared to gene copy number. In Hose et al., we argued that this gene group is enriched for genes subject to one or more modes of dosage compensation, where mRNA abundance is decreased in response to higher dosage of that gene. A recent manuscript by Torres et al. refutes our prior work. Here, we provide a response to Torres et al., along with additional analysis and controls to support our original conclusions. We maintain that aneuploidy is well tolerated in the wild strains of S. cerevisiae that we studied and that the group of genes enriched for those subject to dosage compensation show unique evolutionary signatures.