Critical behavior of megabase-size DNA toward the transition into a compact state.
We studied the changes in the higher-order structure of a megabase-size DNA (S120-1 DNA) under different spermidine (SPD) concentrations through single-molecule observations using fluorescence microscopy (FM) and atomic force microscopy (AFM). We examined the difference between the folding transitions in S120-1 DNA and sub-megabase-size DNA, T4 DNA (166 kbp). From FM observations, it is found that S120-1 DNA exhibits intra-chain segregation as the intermediate state of transition, in contrast to the all-or-none nature of the transition on T4 DNA. Large S120-1 DNA exhibits a folding transition at lower concentrations of SPD than T4 DNA. AFM observations showed that DNA segments become aligned in parallel on a two-dimensional surface as the SPD concentration increases and that highly intense parallel alignment is achieved just before the compaction. S120-1 DNA requires one-tenth the SPD concentration as that required by T4 DNA to achieve the same degree of parallel ordering. We theoretically discuss the cause of the parallel ordering near the transition into a fully compact state on a two-dimensional surface, and argue that such parallel ordering disappears in bulk solution.


Basilar invagination.
Basilar invagination is a developmental anomaly of the craniovertebral junction in which the odontoid abnormally prolapses into the foramen magnum. It is often associated with other osseous anomalies of the craniovertebral junction, including atlanto-occipital assimilation, incomplete ring of C1, and hypoplasia of the basiocciput, occipital condyles, and atlas. Basilar invagination is also associated with neural axis abnormalities, including Chiari malformation, syringomyelia, syringobulbia, and hydrocephalus. Patients frequently present with neurologic symptoms and deficits and warrant surgical treatment to prevent progression. To review the management of basilar invagination. The literature was reviewed in reference to the evaluation and management of basilar invagination, with particular emphasis on the surgical treatment. Reducible basilar invagination may be treated with posterior decompression and stabilization. Ventral decompression may be necessary for basilar invagination with neural compression that is not reducible with axial cervical traction. Posterior cervical stabilization is necessary after ventral decompression. Modern rod and screw systems combined with autogenous bone graft enable correction of deformity, immediate stabilization, and high fusion rates. Basilar invagination is a developmental anomaly and commonly presents with neurologic findings. Treatment is typically surgical and involves anterior decompression followed by posterior stabilization for irreducible invagination and posterior decompression and stabilization for reducible invagination.


[Under what conditions does G.C Watson-Crick DNA base pair acquire all four configurations characteristic for A.T Watson-Crick DNA base pair?].
At the MP2/6-311++G(2df,pd)//B3LYP/6-311++G(d,p) level of theory it was established for the first time, that the Löwdin's G*.C* DNA base pair formed by the mutagenic tautomers can acquire, as the A-T Watson-Crick DNA base pair, four biologically important configurations, namely: Watson-Crick, reverse Watson-Crick, Hoogsteen and reverse Hoogsteen. This fact demonstrates rather unexpected role of the tautomerisation of the one of the Watson-Crick DNA base pairs, in particular, via double proton transfer: exactly the G.C-->G*.C* tautomerisation allows to overcome steric hindrances for the implementation of the above mentioned configurations. Geometric, electron-topological and energetic properties of the H-bonds that stabilise the studied pairs, as well as the energetic characteristics of the latters are presented.


Identification of a tissue-specific putative transcription factor in breast tissue by serological screening of a breast cancer library.
Application of SEREX (serological analysis of recombinant tumor cDNA expression libraries) to different tumor types has led to the identification of several categories of human tumor antigens. In this study, the analysis of a breast cancer library with autologous patient serum led to the isolation of seven genes, designated NY-BR-1 through NY-BR-7. NY-BR-1, representing 6 of 14 clones isolated, showed tissue-restricted mRNA expression in breast and testis but not in 13 other normal tissues tested. Among tumor specimens, NY-BR-1 mRNA expression was found in 21 of 25 breast cancers but in only 2 of 82 nonmammary tumors. Structural analysis of NY-BR-1 cDNA and the corresponding genomic sequences in the recently released working draft of human genome indicated that NY-BR-1 is composed of 37 exons and has an open reading frame of 4.0-4.2 kb, encoding a peptide of Mr 150,000-160,000. A bipartite nuclear localization signal motif indicates a nuclear site for NY-BR-1, and the presence of a bZIP site (DNA-binding site followed by leucine zipper motif) suggests that NY-BR-1 is a transcription factor. Additional structural features include five tandem ankyrin repeats, implying a role for NY-BR-1 in protein-protein interactions. NY-BR-1 thus represents a breast tissue-specific putative transcription factor with autoimmunogenicity in breast cancer patients. In addition to NY-BR-1, a homologous gene, NY-BR-1.1, was identified in this study. NY-BR-1.1 shares 54% amino acid homology with NY-BR-1 and also shows tissue-restricted mRNA expression. However, unlike NY-BR-1, NY-BR-1.1 mRNA is expressed in brain, in addition to breast and testis. The exon structure of NY-BR-1.1 remains to be defined. Using human genome database, NY-BR-1 was localized to chromosome 10p11-p12, and NY-BR-1.1 was tentatively localized to chromosome 9.


Data needed for assessing water footprint of steel production.
The data presented in this paper offer the information needed for assessing the water footprint of steel production. The data provided here are related to the research paper, "An Improved Water Footprint Model of Steel Production Concerning Virtual Water of Personnel: The Case of Iran" [1]. The data were collected form analysing a case study and reviewing the relevant literature. The case study data were collected from a large steel plant in Iran. All information received from this plant is related to 2017. The primary data were collected by interviewing the head of the research and development of the plant. All relevant formal documents of the plant and information on its web site were also reviewed. For data related to the water footprint of energy and raw materials, used for steel production, the relevant studies were reviewed.


Poly(ADP-Ribose) polymerase inhibition synergizes with 5-fluorodeoxyuridine but not 5-fluorouracil in ovarian cancer cells.
5-Fluorouracil (5-FU) and 5-fluorodeoxyuridine (FdUrd, floxuridine) have activity in multiple tumors, and both agents undergo intracellular processing to active metabolites that disrupt RNA and DNA metabolism. These agents cause imbalances in deoxynucleotide triphosphate levels and the accumulation of uracil and 5-FU in the genome, events that activate the ATR- and ATM-dependent checkpoint signaling pathways and the base excision repair (BER) pathway. Here, we assessed which DNA damage response and repair processes influence 5-FU and FdUrd toxicity in ovarian cancer cells. These studies revealed that disabling the ATM, ATR, or BER pathways using small inhibitory RNAs did not affect 5-FU cytotoxicity. In stark contrast, ATR and a functional BER pathway protected FdUrd-treated cells. Consistent with a role for the BER pathway, the poly(ADP-ribose) polymerase (PARP) inhibitors ABT-888 (veliparib) and AZD2281 (olaparib) markedly synergized with FdUrd but not with 5-FU in ovarian cancer cell lines. Furthermore, ABT-888 synergized with FdUrd far more effectively than other agents commonly used to treat ovarian cancer. These findings underscore differences in the cytotoxic mechanisms of 5-FU and FdUrd and suggest that combining FdUrd and PARP inhibitors may be an innovative therapeutic strategy for ovarian tumors.


Phytophthora borealis and Phytophthora riparia, new species in Phytophthora ITS Clade 6.
Phytophthora borealis and Phytophthora riparia, identified in recent Phytophthora surveys of forest streams in Oregon, California and Alaska, are described as new species in Phytophthora ITS Clade 6. They are similar in growth form and morphology to P. gonapodyides and are predominantly sterile. They present unique DNA sequences, however, and differ in temperature/growth relations and geographic distribution.


Further spread of perch rhabdovirus on European percid farms.
Variants of perch rhabdovirus (PRV) circulate across European percid farms via the fish trade. To trace their circulation, they are usually isolated by cell culture and subsequently identified genetically by sequencing partial or complete genes. Here, a newly developed nested PCR-based method was used to amplify and sequence the complete N and P genes directly from clinical samples obtained during an outbreak on a farm as well as from four batches of fish sampled from two other farms in another country. In an attempt to trace the origin of the five detected viruses, their N and P sequences were concatenated and compared with related viruses. One virus found in pike-perch was highly related to a virus isolated in 2016 in Belgium. Two other viruses detected on a single farm were distinct from one another, with one being almost identical to another virus isolated in 2016 in Belgium and the other being more closely related to a subgroup with different origins, France and Belgium. Two other viruses found in perch from a third farm were identical and were more related to a subgroup of viruses isolated in France. Identifying variants by a direct PCR approach will help to prevent further dissemination in farms.


Recursive training of neural networks for classification.
A method for recursive training of neural networks for classification is proposed. It searches for the discriminant functions corresponding to several small local minima of the error function. The novelty of the proposed method lies in the transformation of the data into new training data with a deflated minimum of the error function and iteration to obtain the next solution. A simulation study and a character recognition application indicate that the proposed method has the potential to escape from local minima and to direct the local optimizer to new solutions.


Two-phase Bayesian latent class analysis to assess diagnostic test performance in the absence of a gold standard: COVID-19 serological assays as a proof of concept.
In this proof-of-concept study, which included blood donor samples, we aimed to demonstrate how Bayesian latent class models (BLCMs) could be used to estimate SARS-CoV-2 seroprevalence in the absence of a gold standard assay under a two-phase sampling design. To this end, 6810 plasma samples from blood donors who resided in Québec (Canada) were collected from May to July 2020 and tested for anti-SARS-CoV-2 antibodies using seven serological assays (five commercial and two non-commercial). SARS-CoV-2 seroprevalence was estimated at 0.71% (95% credible interval [CrI] = 0.53%-0.92%). The cPass assay had the lowest sensitivity estimate (88.7%; 95% CrI = 80.6%-94.7%), while the Héma-Québec assay had the highest (98.7%; 95% CrI = 97.0%-99.6%). The estimated low seroprevalence (which indicates a relatively limited spread of SARS-CoV-2 in Quebec) might change rapidly-and this tool, developed using blood donors, could enable a rapid update of the prevalence estimate in the absence of a gold standard. Further, the present analysis illustrates how a two-stage BLCM sampling design, along with blood donor samples, can be used to estimate the performance of new diagnostic tests and inform public health decisions regarding a new or emerging disease for which a perfect reference standard does not exist.


Hesperidin ameliorates bleomycin-induced experimental pulmonary fibrosis via inhibition of TGF-beta1/Smad3/AMPK and IkappaBalpha/NF-kappaB pathways.
Bleomycin (BLM) is a chemotherapeutic agent which is associated with Idiopathic pulmonary fibrosis (IPF) due to its chronic administration. Hesperidin, a bioflavonoid has been reported to possess antioxidant, anti-inflammatory, wound healing, and antiapoptotic potential. To evaluate the therapeutic potential of hesperidin against BLM-induced pulmonary fibrosis and decipher its possible mechanism of action. Intraperitoneal administration of BLM (6 IU/kg) caused induction of IPF in Sprague-Dawley rats. Rats were treated with hesperidin (25, 50, and 100 mg/kg, p.o.) for 28 days, followed by estimation of various parameters in bronchoalveolar lavage fluid (BALF) and lung. Hesperidin (50 and 100 mg/kg) administration significantly ameliorated (p < 0.05) alterations induced by BLM in lung index, percent oxygen saturation, serum ALP and LDH levels, BALF differential cell count, and lung function test. Elevated levels of oxido-nitrosative stress, hydroxyproline, and myeloperoxidase levels in BALF and lung were significantly decreased by hesperidin on day 14. Hesperidin significantly inhibited BLM-induced down-regulated lung Nrf2 and HO-1 as well as up-regulated TNF-α, IL-1β, IL-6, collagen-1, TGF-β, and Smad-3 mRNA expressions. Western blot analysis showed that alteration in lung NF-κB, IκBα, AMPK, and PP2C-α protein expressions were ameliorated by hesperidin on day 28. Furthermore, BLM induced histological and ultrastructural aberrations in the lung which were attenuated by hesperidin treatment. Hesperidin alleviates BLM-induced IPF via inhibition of TGF-β1/Smad3/AMPK and IκBα/NF-κB pathways which in turn ameliorate the modulation of oxido-inflammatory markers (Nrf2 and HO-1) and pro-inflammatory markers (TNF-α, IL-1β, and IL-6) to reduce collagen deposition during pulmonary fibrosis. See also Figure 1(Fig. 1).


Comparative 16S rRNA gene surveys of granular sludge from three upflow anaerobic bioreactors treating purified terephthalic acid (PTA) wastewater.
The microbial communities from three upflow anaerobic bioreactors treating purified terephthalic acid (PTA) wastewater were characterized with 16S ribosomal RNA gene sequencing surveys. Universal bacterial and archaeal primers were used to compare the bioreactor communities to each other. A total of 1,733 bacterial sequences and 383 archaeal sequences were characterized. The high number of Syntrophus spp. and Pelotomaculum spp. found within these reactors indicates efficient removal of benzoate and terephthalate. Under anaerobic conditions benzoate can be degraded through syntrophic associations between these bacteria and hydrogen-scavenging microbes, such as Desulfovibrio spp. and hydrogenotrophic methanogens, which remove H(2) to force the thermodynamically unfavourable reactions to take place. The authors did not observe a relatively high percentage of hydrogenotrophic methanogens with the archaeal gene survey because of a high acetate flux (acetate is a main component in PTA wastewater and is the main degradation product of terephthalate/benzoate fermentation), and because of the presence of Desulfovibrio spp. (a sulfate reducer that scavenges hydrogen). The high acetate flux also explains the high percentage of acetoclastic methanogens from the genus Methanosaeta among the archaeal sequences. A group of uncultured bacteria (OD1) may be involved in the degradation of p-toluate (4-methyl benzoate), which is a component of PTA wastewater.


Implantation of the Auditory Nerve via the Middle Ear Cavity in Rats with Partial Hearing Preservation.
The aim of this study was to evaluate the residual hearing function and cochlear morphology after auditory nerve implantation via middle ear spaces in rats. A titanium rod (1.5 mm long and 0.3 mm thick) coated with Parylene was inserted in the cochlear apex in the direction of the modiolus in 9 Wistar rats. Auditory brainstem-evoked responses to tone bursts at 2, 8, 12 and 32 kHz were recorded before surgery and on postoperative days 0, 2, 15 and 30. Eight cochleas were examined microscopically. The rod was inside the modiolus in 4, and partly or totally outside the modiolus in 4 animals. Residual hearing was present in all cases. The average threshold shift in cochleas with modiolar implant was 39 ± 11.2, 54 ± 9.7, 48 ± 20.3 and 43 ± 21.3 dB SPL on postoperative days 0, 2, 15 and 30, respectively. The transmodiolar approach allows a minimally invasive cochlear implantation and a partial hearing preservation.


Imaging in Type 1 Diabetes, Current Perspectives and Directions.
Type 1 diabetes (T1D) is characterized by the autoimmune-mediated attack of insulin-producing beta cells in the pancreas, leading to reliance on exogenous insulin to control a patient's blood glucose levels. As progress is being made in understanding the pathophysiology of the disease and how to better develop therapies to treat it, there is an increasing need for monitoring technologies to quantify beta cell mass and function throughout T1D progression and beta cell replacement therapy. Molecular imaging techniques offer a possible solution through both radiologic and non-radiologic means including positron emission tomography, magnetic resonance imaging, electron paramagnetic resonance imaging, and spatial omics. This commentary piece outlines the role of molecular imaging in T1D research and highlights the need for further applications of such methodologies in T1D.


RNase-like domain in DNA-directed RNA polymerase II.
DNA-directed RNA polymerase is responsible for gene expression. Despite its importance, many details of its function and higher-order structure still remain unknown. We report here a local sequence similarity between the second largest subunit of RNA polymerase II and bacterial RNases Ba (barnase), Bi, and St. The most remarkable similarity is that the catalytic sites of the RNases are shared with the eukaryotic RNA polymerase II subunits of Drosophila melanogaster and Saccharomyces cerevisiae. Several amino acids conserved among the RNases and the RNase-like domains of the RNA polymerase subunits are located in the neighborhood of the catalytic sites of barnase, whose three-dimensional structure has been resolved. This observation suggests the functional importance of the RNase-like domain of the RNA polymerase subunits and indicates that the RNase-like domain may have RNase activity. The location of the RNase-like domain relative to the region necessary for RNA polymerization is similar to the relative proximity of 5'----3' or 3'----5' exonuclease and the region of polymerase activity of DNA polymerase I. The RNase-like domain might work in proofreading, as in RNA-directed RNA polymerase of influenza virus, or it may contribute to RNA binding through an unknown function.


[Mechanism of transport of secreted organic substances through kidney tubule cells].
Vinblastin or copper chloride inhibiting the microtubules, decrease tubular excretion of cardiotrast in rats. After incubation of the kidney tissue homogenat at pH 9.0 the augmentation of inorganic phosphate was more obvious in rats preliminarily injected with cardiotrast. The data obtained indicate the possible role of microtubules in the tubular secretion of organic substances and the participation of phosphorylation in this process.


Comparative analysis on wavelet-based detection of finite duration low-amplitude signals related to ventricular late potentials.
Ventricular late potentials (VLPs) are considered as a noninvasive marker of patients with myocardial infarction, who are prone to the development of ventricular tachycardia. This paper investigates the effects of variations in physical properties of myocardial infarcts in terms of their effects on the parametric variations in VLP analysis. A sufficiently large set of signals underlining the behavior of physical parameters was employed to represent the effect of physical size, position, orientation and type of infarct. The approximated signals are variations from real electrocardiography signals by adding potentials representing late potentials based on duration, frequency, amplitude and position. The aim is not to exactly model VLP but rather to generate an approximate set of signals to examine the performance of the standard methods for different possibilities in infarct dynamics. We investigate some of the detection approaches together with their related assumptions, and try to pinpoint the drawbacks and inaccuracies of these methods and also their assumptions. The three widely accepted criteria--QRS duration, root-mean-square and duration of the signal at the end of QRS for VLP detection--were used in the investigation. Results from the application of these parameters to the set of signals are presented. In addition we investigate the physical nature of an infarct and list a number of possible reasons that might be the cause of a low success rate for the detection of additive potentials. To improve the performance of the common methods, two more wavelet transform parameters are added to those of the standard methods. The method derived from this analysis is presented as an alternative means for the detection of late signals named as delayed potentials, a more general class that includes VLP as a subset.


Visual attention abnormalities in autism: delayed orienting to location.
These studies provide evidence for slowed spatial orienting of attention in autism. A group of well-defined adult autistic subjects and age-matched normal controls performed a traditional spatial cueing task in which attention-related response facilitation is indexed by speed of target detection. To address the concern that motor impairment may interfere with interpretation of response time measures in those with neurologic abnormality, we also used a new adaptation of the traditional task that depended on accuracy of response (target discrimination) rather than speed of response. This design allowed separation of time to process and respond to target information from the time to move and engage (orient) attention. Results from both tasks were strikingly similar. Normal subjects oriented attention very quickly, and showed maximal performance facilitation at a cued location within 100 ms. Autistic subjects oriented attention much more slowly and showed increasing benefits of a spatial cue with increasing cue-to-target delays. These results are consistent with previous reports that patients with autism, the majority of whom have developmental abnormalities of the cerebellum, as well as those with acquired damage to the cerebellum, are slow to shift attention between and within modalities. This paper also addresses the variability in behavioral findings in autism, and suggests that many of the apparently contradictory findings may actually reflect sampling differences in patterns of brain pathology.


Influence of aspirin and cigarette smoke extract on the expression of cyclin D1 and effects of cell cycle in esophageal squamous cell carcinoma cell line.
The relationship between smoking and esophageal squamous cell carcinoma (ESCC) has been confirmed by epidemiology. Cyclin D(1) plays a critical role in regulating the cell cycle; it is an important regulator of cell cycle and can function as a transcriptional co-regulator. The importance of cyclin D(1) makes it an attractive target for anticancer therapy. Human ESCC cell line EC109 was cultured with aspirin and cigarette smoke extract (CSE) at different concentrations for 48 h. Cell growth was tested with 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide reduction assay; cyclin D(1) mRNA level was detected by reverse transcription-polymerase chain reaction assays; protein level of cyclin D(1) was detected by Western blot; the cell cycle change was monitored by flow cytometry detection assays. CSE stimulated cell proliferation, increased the protein level of cyclin D(1) in a dose-dependent manner (P < 0.01), and decreased the proportion of G(0)/G(1) phase cell of cell cycle. However, aspirin can inhibit the cell growth and suppress the protein level of cyclin D(1) after CSE affected the EC109 cell line in a dose-dependent manner (P < 0.01). Meanwhile, aspirin increased the proportion of G(0)/G(1) phase cell, while that of S and G(2)/M phases decreased. Aspirin can inhibit the cell growth and suppress the protein level of cyclin D(1) after CSE affected EC109 cell line. The probable mechanism is through decreasing the expression of cyclin D(1), thus stopping the transition of cell cycle from G(0)/G(1) to S phase.


Shortening the 4-hour gastric-emptying protocol.
A standardized 4-hour gastric-emptying protocol has been recommended by a consensus panel. However, a study length of 4 hours may be inconvenient. The purpose of this investigation was to determine if the percent emptying at 2 hours could predict abnormal or normal results at 4 hours. Our data consist of 2 distinct patient groups, containing 174 and 158 patients, respectively. All patients were given a standardized meal according to the Tougas et al protocol. Percent gastric emptying was measured at 1, 2, 3, and 4 hours (or until gastric emptying was equal to or more than 90%). The sensitivity, specificity, and the likelihood ratios of the 2-hour cutoffs were determined using the 4-hour data as the standard. We have estimated the accuracy and percent of studies stopped at 2 hours, resulting from various "definitely normal" and "definitely abnormal" threshold combinations. Using gastric emptying of less than 35% at 2 hours for diagnosis of delayed gastric emptying, and emptying at 2 hours greater than 55% for a diagnosis of normal gastric emptying yielded accuracies of 0.966 and 0.949 in the 2 datasets, respectively, compared with the Tougas standard values. The observed 2-hour gastric-emptying values would have allowed early termination in 79% and 78% of the studies, respectively. Adopting criteria for the termination of gastric-emptying study at 2 hours in selected patients yields significant reductions in the average length of a gastric-emptying study, while maintaining study accuracy.


Stem Cells in Orthopedic Web Information: An Assessment with the DISCERN Tool.
Regenerative medicine is experiencing a strong expansion worldwide, including the treatment of some common orthopedic pathologies, with an increase in physicians adopting these technologies. This growing interest has been associated with an equally significant spread of websites dedicated to public information on this topic, often lacking scientific bases. This study aims to evaluate the quality of information on the World Wide Web about stem cells for cartilage disorders in orthopedic practice. On February 19, 2021 we performed a search on Google using as keywords "cartilage stem cells," considering only the freely accessible sites in Italian, English, French, and Spanish. We selected the first 50 valid results for each language and evaluated them using the DISCERN scale. A total of 249 sites were observed, of which 49 were discarded as duplicates (8) or not relevant to the topic (41). Of the 200 sites surveyed, 47 were affiliated to a singular surgeon (23.5%), 31 to private stakeholders (15.5%), 73 to information sites (36.5%), 8 to public hospitals (4%), 13 to universities (6.5%), and 28 referred to international scientific journals (14%). Only 76 sites (38%) were rated as fair or better, while the remaining 124 (62%) were classified as poor or very poor. The quality of the information promoted for stem cells in orthopedics is generally low, although a significant minority of the sites offers good quality information. A greater commitment on the part of surgeons and other stakeholders is desirable to promote information on regenerative medicine through scientific criteria supported by adequate literature.


Internet of Robotic Things Intelligent Connectivity and Platforms.
The Internet of Things (IoT) and Industrial IoT (IIoT) have developed rapidly in the past few years, as both the Internet and "things" have evolved significantly. "Things" now range from simple Radio Frequency Identification (RFID) devices to smart wireless sensors, intelligent wireless sensors and actuators, robotic things, and autonomous vehicles operating in consumer, business, and industrial environments. The emergence of "intelligent things" (static or mobile) in collaborative autonomous fleets requires new architectures, connectivity paradigms, trustworthiness frameworks, and platforms for the integration of applications across different business and industrial domains. These new applications accelerate the development of autonomous system design paradigms and the proliferation of the Internet of Robotic Things (IoRT). In IoRT, collaborative robotic things can communicate with other things, learn autonomously, interact safely with the environment, humans and other things, and gain qualities like self-maintenance, self-awareness, self-healing, and fail-operational behavior. IoRT applications can make use of the individual, collaborative, and collective intelligence of robotic things, as well as information from the infrastructure and operating context to plan, implement and accomplish tasks under different environmental conditions and uncertainties. The continuous, real-time interaction with the environment makes perception, location, communication, cognition, computation, connectivity, propulsion, and integration of federated IoRT and digital platforms important components of new-generation IoRT applications. This paper reviews the taxonomy of the IoRT, emphasizing the IoRT intelligent connectivity, architectures, interoperability, and trustworthiness framework, and surveys the technologies that enable the application of the IoRT across different domains to perform missions more efficiently, productively, and completely. The aim is to provide a novel perspective on the IoRT that involves communication among robotic things and humans and highlights the convergence of several technologies and interactions between different taxonomies used in the literature.


Analysis of GWAS-linked loci in Parkinson disease reaffirms PARK16 as a susceptibility locus.
A genome-wide association study (GWAS) in the Japanese population identified 2 new Parkinson disease (PD) susceptibility loci on 1q32 (PARK16) (OMIM 613164) and BST1. We analyzed single nucleotide polymorphism (SNPs) located at the GWAS-linked loci (PARK16, PARK8, PARK1, and BST1) in a Chinese population and also conducted a meta-analysis in Asians by pooling 2 independent replication studies from Japan. We conducted an analysis of 13 SNPs associated with PD GWAS-linked loci in 2 case-control cohorts comprised of 1,349 ethnic Chinese subjects. PARK16, PARK8, and PARK1 loci but not BST1 were found to be associated with PD. PARK16 SNPs were associated with a decreased risk while PARK1 and PARK8 SNPs were associated with an increased risk of PD. A pooled analysis of our Chinese cohorts and 2 Japanese replication cohorts involving 1,366 subjects with PD and 16,669 controls revealed robust association with these 3 loci and also BST1. There was a trend toward a stronger protective effect of SNPs at the PARK16 locus in sporadic PD compared to familial cases and in older compared to younger subjects. Our study reaffirms the role of GWAS-linked loci in PD in Asian subjects and the strength of association is similar between Chinese and Japanese subjects. Efforts to elucidate the associated gene within PARK16 locus are warranted.


Millennial processes of population decline, range contraction and near extinction of the European bison.
European bison (Bison bonasus) were widespread throughout Europe during the late Pleistocene. However, the contributions of environmental change and humans to their near extinction have never been resolved. Using process-explicit models, fossils and ancient DNA, we disentangle the combinations of threatening processes that drove population declines and regional extinctions of European bison through space and across time. We show that the population size of European bison declined abruptly at the termination of the Pleistocene in response to rapid environmental change, hunting by humans and their interaction. Human activities prevented populations of European bison from rebounding in the Holocene, despite improved environmental conditions. Hunting caused range loss in the north and east of its distribution, while land use change was responsible for losses in the west and south. Advances in hunting technologies from 1500 CE were needed to simulate low abundances observed in 1870 CE. While our findings show that humans were an important driver of the extinction of the European bison in the wild, vast areas of its range vanished during the Pleistocene-Holocene transition because of post-glacial environmental change. These areas of its former range have been climatically unsuitable for millennia and should not be considered in reintroduction efforts.


Temporal trends in the use of high-dose potent statins following acute coronary syndrome in Israel.
This study aimed to evaluate factors associated with the prescription of high-dose potent statin (HDPS) therapy following hospitalization for acute coronary events. Sub-analysis was made using the data of 3,525 patients enrolled in the 2008 and 2010 Acute Coronary Syndrome Israeli Surveys (ACSIS). Analyses were carried out to identify demographic and clinical factors associated with the prescription of HDPS therapy (atorvastatin 40-80 mg/day or rosuvastatin 20-40 mg/day) at discharge compared with the prescription of lower-dose statins. Among the study patients, 1,387 (39%) were discharged on HDPS, 1,860 (53%) with lower-dose statin regimens and 278 (8%) with no recommendation for statin therapy. Multivariate logistic regression analysis showed that pre-admission usage of HDPS and participation in the more recent (2010) ACSIS survey were independently associated with a higher likelihood of HDPS prescription at discharge from the index event (odds ratio, OR, 21.07, p < 0.001, and 5.61, p < 0.001, respectively), whereas factors independently associated with a lack of HDPS prescription included age >75 years (OR 0.76, p = 0.03), low-density lipoprotein-cholesterol levels <100 mg/dl on admission (OR 0.67, p < 0.001) and a history of heart failure prior to the index hospitalization (OR 0.54, p = 0.0018). The 30-day compliance with the HDPS regimen was 98%. The findings show increased use of HDPS therapy in acute coronary syndrome (ACS) patients, although this mode of medical therapy is still underutilized in the important subset of high-risk ACS patients.


Programmed death one homolog maintains the pool size of regulatory T cells by promoting their differentiation and stability.
Programmed death one homolog (PD-1H) is an immunoglobulin superfamily molecule and primarily acts as a coinhibitor in the initiation of T cell response to antigens. Here, we report that genetic ablation of PD-1H in mice blocks the differentiation of naive T cells to Foxp3+ inducible Treg cells (iTreg) with a significant decrease of iTreg in lymphoid organs. This effect of PD-1H is highly specific for iTreg because both naturally generated iTreg in gut-related tissues and in vitro induced iTreg by TGF-β were decreased whereas the genesis of natural Treg (nTreg) remains normal. The suppressive function of both iTreg and nTreg, however, is not affected by the loss of PD-1H. In addition to decreased production, PD-1H deficient iTreg could also rapidly convert to CD4+ T helper 1 or T helper 17 cells in an inflammatory environment. Our results indicate that PD-1H is required for maintenance of iTreg pool size by promoting its differentiation and preventing its conversion to other CD4+ T cell subsets. These findings may have important implications for manipulating Tregs to control inflammation.


Emotional barriers and facilitators of deprescribing for older adults with cancer and polypharmacy: a qualitative study.
To describe emotional barriers and facilitators to deprescribing (the planned reduction or discontinuation of medications) in older adults with cancer and polypharmacy. Virtual focus groups were conducted over Zoom with 5 key informant groups: oncologists, oncology nurses, primary care physicians, pharmacists, and patients. All groups were video- and audio-recorded and transcribed verbatim. Focus group transcripts were analyzed using inductive content analysis, and open coding was performed by two coders. A codebook was generated based on the initial round of open coding and updated throughout the analytic process. Codes and themes were discussed for each transcript until consensus was reached. Emotion coding (identifying text segments expressing emotion, naming the emotion, and assigning a label of positive or negative) was performed by both coders to validate the open coding findings. All groups agreed that polypharmacy is a significant problem. For clinicians, emotional barriers to deprescribing include fear of moral judgment from patients and colleagues, frustration toward patients, and feelings of incompetence. Oncologists and patients expressed ambivalence about deprescribing due to role expectations that physicians "heal with med[ication]s." Emotional facilitators of deprescribing included the involvement of pharmacists, who were perceived to be neutral, discerning experts. Pharmacists described emotionally aware communication strategies when discussing deprescribing with other clinicians and expressed increased awareness of patient context. Deprescribing can elicit strong and predominantly negative emotions among clinicians and patients which could inhibit deprescribing interventions. The involvement of pharmacists in deprescribing interventions could mitigate these emotional barriers. ClinicalTrials.gov Identifier: NCT05046171 . Date of registration: September 16, 2021.


Simple PbII fluorescent probe based on PbII-catalyzed hydrolysis of phosphodiester.
A new fluorescent probe for PbII, p-nitrophenyl 3H-phenoxazin-3-one-7-yl phosphoric acid (NPPA), was designed and synthesized by linking resorufin (serving as a fluorophore and electron acceptor) to p-nitrophenol (serving as a fluorescence quencher and electron donor) through phosphodiester bonds. When NPPA was irradiated with light, intramolecular fluorescence self-quenching took place because of the photoinduced electron transfer from the donor to the acceptor. However, upon the addition of PbII, the phosphate ester bonds in the probe were cleaved and the fluorophore was released, accompanying the retrievement of fluorescence.


Methods to improve diagnostic accuracy in a community mental health setting.
This study determined the extent to which adding structured procedures improved diagnostic accuracy for outpatients with severe mental illness in a community mental health setting. The Structured Clinical Interview for DSM-III-R (SCID) was used to interview 200 psychiatric outpatients. A research nurse reviewed medical records and amended the SCID diagnoses accordingly. A research psychiatrist or psychologist reviewed the diagnostic data and interviewed each patient to verify or further modify the previous findings. Diagnostic outcomes at each step of the procedure were compared to determine whether adding additional data improved diagnostic accuracy. The additional time required for each element of the diagnostic procedure was also assessed. Kappa comparisons of the different diagnostic levels showed that adding additional data significantly improved accuracy. Diagnoses rendered by combining the SCID and review of the medical record were the most accurate, followed by the SCID alone, and then diagnoses made by psychiatrists during routine care. In addition, the SCID alone identified five times as many current and past secondary diagnoses as were documented routinely in patients' charts. Combining structured interviewing with a review of the medical record appears to produce more accurate primary diagnoses and to identify more secondary diagnoses than routine clinical methods. The patients' knowledge of their diagnoses was limited, suggesting a need for patient education in this setting. Whether use of structured interviewing in routine practice improves patient outcomes deserves further study.


Transcriptome and cytogenetic profiling analysis of matched in situ/invasive cutaneous squamous cell carcinomas from immunocompetent patients.
Although most cutaneous squamous cell carcinomas (cSCCs) develop from actinic keratoses (AKs), the key events in this evolution remain unclear. We have combined the results of different genomic and expression array platforms on matched concomitant samples of sun-exposed skin (SES), AK, and cSCC from 10 immunocompetent patients. Gene expression analysis and copy number alterations were assessed using GeneChip Human Gene 2.0 ST Array (Affymetrix, Santa Clara, CA) and CytoScan HD Cytogenetics Solution (Affymetrix) platforms, respectively. Integration of transcriptome and genome results was evaluated using the DR-Integrator tool. Additional studies (qPCR, immunohistochemistry, and Western blot) were performed for selected genes. FOSL1 and BNC1 encode transcription factors whose expression was increased in cSCC in the expression array and the qPCR. By immunohistochemistry, FOSL1 showed an intense staining at the invasive front of cSCC samples and BNC1 expression varied from a nuclear (SES) to a cytoplasmic location (cSCC). Western blot analyses confirmed the enhancement of FOSL1 and BNC1. In addition, the smallest overlapping regions (SORIs) of genomic imbalance involving at least three of the samples were selected. One of the SORIs was a deletion in the p24.1 band of chromosome 3, shared by seven of the cSCCs. A strong correlation in the integration analysis was found for NEK10, a gene contained in the previously mentioned SORI. Loss of NEK10 expression in cSCC was confirmed by immunohistochemistry and Western blot analyses. In addition, functional studies in NEK10 depleted cells were performed. In conclusion, we identified FOSL1 and BNC1, which could act as tumor drivers, and NEK10, which could function as a tumor suppressor, to be differentially expressed during cSCC development.


Critique of current therapies of noninsulin-dependent diabetes mellitus.
In summary, there are a number of therapeutic modalities, including life-style modifications and pharmacological intervention, available and useful in the treatment of NIDDM patients. Nonetheless, therapeutic success in the management of NIDDM remains highly dependent upon patient motivation, cooperation, and ability to comply on a regular basis with measures that are inconvenient and of modest efficacy in reversing the physiologic abnormalities of the NIDDM state. There remains considerable need for therapeutic tools of greater efficacy and of greater ease of application than the ones we currently have.


Structural basis for ATP-dependent DnaA assembly and replication-origin remodeling.
In bacteria, the initiation of replication is controlled by DnaA, a member of the ATPases associated with various cellular activities (AAA+) protein superfamily. ATP binding allows DnaA to transition from a monomeric state into a large oligomeric complex that remodels replication origins, triggers duplex melting and facilitates replisome assembly. The crystal structure of AMP-PCP-bound DnaA reveals a right-handed superhelix defined by specific protein-ATP interactions. The observed quaternary structure of DnaA, along with topology footprint assays, indicates that a right-handed DNA wrap is formed around the initiation nucleoprotein complex. This model clarifies how DnaA engages and unwinds bacterial origins and suggests that additional, regulatory AAA+ proteins engage DnaA at filament ends. Eukaryotic and archaeal initiators also have the structural elements that promote open-helix formation, indicating that a spiral, open-ring AAA+ assembly forms the core element of initiators in all domains of life.


Chronic rhinosinusitis with nasal polyps: eosinophils versus B lymphocytes in disease pathogenesis.
To highlight the current evidence that supports the view that eosinophils may not drive disease in chronic rhinosinusitis with nasal polyps (CRSwNP) and the emerging evidence for B cells as an important player in this disease. Eosinophil depletion studies in CRSwNP do not fully support a critical role for eosinophils in CRSwNP. Almost complete eosinophil depletion with dexpramipexole had no impact on polyp size reduction or clinical improvement. Anti-interleukin (IL)-5 and IL-5Rα inhibition were more effective though with less clinical impact when compared to anti-immunoglobulin E (IgE) or IL-4Rα inhibition strategies. As IL-5Rα is also expressed on CRSwNP derived IgE+ and IgG4+ plasma cells to the same extent as eosinophils, improvements in CRSwNP with IL-5 inhibition may suggest a role for B cells over eosinophils in CRSwNP. We review both eosinophils and B cells in the context of CRSwNP and highlight the current evidence that supports an emerging role for B cells. Despite many aspects of immunopathology in CRSwNP explainable by B cell dysfunction, B cells have so far been ignored in CRSwNP. Further work is needed, as targeting B cells may offer an exciting new therapeutic option in the future.


Bioavailability and possible benefits of wheat intake naturally enriched with selenium and its products.
Bioavailability and possible benefits of wheat intake naturally enriched with selenium and its products was tested. Wheat obtained by application of an original combination and procedure for foliar supplementation of plants with Se was characterized on the average by five times higher content of Se, the main form being L-(+)-selenomethionine (SeMet). Substitution of Se-deficient wheat by wheat naturally enriched with Se and its products contributed to the increase of daily intake on the average by 18 microg (12-35 microg) in volunteers, which is more than 50% of the average daily intake. Six weeks after the beginning of its application, increased daily intake of Se brought about the increase of its concentration in the plasma of the examined persons by 53%, in their erythrocytes by 37%, in their hair by 44%, and in their urine by 54%. This result was comparable to the effect obtained in the course of an 8-wk daily intake of supplements with 100 microg Se in the form of enriched bakery yeast. Analysis of glutathione peroxidase (GSH-Px) activity in blood, thiobarbituric acid reactive substances (TBARS) in plasma, lipid parameters (total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides), and glucose in serum of volunteers showed that the increased Se intake induced increased GSH-Px activity in blood and decreased concentrations of TBARS, lipid parameters, and glucose in blood. Using only one crop (wheat enriched with Se), the existing deficiency of Se in our population can be alleviated. In this way, one-fourth of our population with lower Se intake than 21 microg/d will satisfy basal requirements, whereas one-half will become moderately deficient in Se instead of distinctly deficient in Se.


Quantum state cloning using Deutschian closed timelike curves.
We show that it is possible to clone quantum states to arbitrary accuracy in the presence of a Deutschian closed timelike curve (D-CTC), with a fidelity converging to one in the limit as the dimension of the CTC system becomes large--thus resolving an open conjecture [Brun et al., Phys. Rev. Lett. 102, 210402 (2009)]. This result follows from a D-CTC-assisted scheme for producing perfect clones of a quantum state prepared in a known eigenbasis, and the fact that one can reconstruct an approximation of a quantum state from empirical estimates of the probabilities of an informationally complete measurement. Our results imply more generally that every continuous, but otherwise arbitrarily nonlinear map from states to states, can be implemented to arbitrary accuracy with D-CTCs. Furthermore, our results show that Deutsch's model for closed timelike curves is in fact a classical model, in the sense that two arbitrary, distinct density operators are perfectly distinguishable (in the limit of a large closed timelike curve system); hence, in this model quantum mechanics becomes a classical theory in which each density operator is a distinct point in a classical phase space.


Understanding the Complexity of Teacher Emotions From Online Forums: A Computational Text Analysis Approach.
Teacher emotions are complex as emotions are unique to individuals, situated within specific contexts, and vary over time. This study contributed in synthesizing theories of the complexity in two characteristics of multi-dimensionality and dynamics. Further, we provided large-scale empirical evidence by employing big data and computational text analysis. The data contained around one million teachers' online posts from 2007 to 2018. It was scraped from three representative forums of teachers' workplace events and personal life occasions in a popular American teacher website. By conducting thread-level sentiment analysis in forums, we computed word-frequency-based eight discrete emotions ratios (i.e., anger, anticipation, disgust, fear, joy, sadness, surprise, and trust) and the degrees of sentiment polarity (i.e., positive, negative, and neutral). We then used latent Dirichlet allocation for topic classifications. These topics, proxies of contexts, covered a holistic range of teachers' real-life events. Some topics are in the main interest of scholars, such as teachers' professional development and students' behavioral management. This paper is also the first to include the less scholarly studied contexts like professional dressing advice and holiday choices. Then, we examined and visualized variations of emotions and sentiments across 30 topics along with three scales of time (i.e., calendar year, calendar month, and academic semesters). The results showed that teachers tended to have positive sentiments in the online professional community across the past decade, but all eight discrete emotions were presented. The compositions of the specific emotion types varied across topics and time. Regarding the topics of students' behavior issues, teachers' negative emotions' ratios were higher compared when it was presented in other topics. Their negative emotions also peaked during semesters. The forum of teachers' personal lives had positive emotions pronounced across topics and peaked during the wintertime. This paper summarized the evidenced multi-dimensionality characteristic with the multiple types of emotions as compositions and varying degrees of sentiment polarity of teachers. The dynamics characteristic is that teachers' emotions vary across contexts from their workplace to their personal lives and over time. These two characteristics of complexity also suggested potential interplay effects among emotions and across contexts over time.


Direct measurement of free radical generation following reperfusion of ischemic myocardium.
Electron paramagnetic resonance spectroscopy was used to directly measure free radical generation in perfused rabbit hearts. Hearts were freeze-clamped at 77 degrees K during control perfusion, after 10 min of normothermic global ischemia (no coronary flow), or following post-ischemic reperfusion with oxygenated perfusate. The spectra of these hearts exhibited three different signals with different power saturation and temperature stability: signal A was isotropic with g = 2.004; signal B was anisotropic with axial symmetry with g parallel = 2.033 and g perpendicular = 2.005; signal C was an isotropic triplet with g = 2.000 and hyperfine splitting an = 24 G (1 G = 0.1 mT). The g values, linewidth, power saturation, and temperature stability of signal A are identical to those of a carbon-centered semiquinone, whereas those of signal B are similar to alkyl peroxyl or superoxide oxygen-centered free radicals; signal C is most likely a nitrogen-centered free radical. In the control heart samples signal A predominated, whereas in ischemic hearts signal A decreased in intensity, and signals B and C became more intense; with reperfusion all three signals markedly increased. Free radical concentrations derived from the intensities of the B and C signals peaked 10 sec after initiation of reflow. At this time the oxygen-centered free radical concentration derived from the intensity of signal B was increased over six times the concentration measured in control hearts and over two times the concentration measured in ischemic hearts. Hypoxic reperfusion did not increase any of the free radical signals over the levels observed during ischemia. These experiments directly demonstrate that reactive oxygen-centered free radicals are generated in hearts during ischemia and that a burst of oxygen radical generation occurs within moments of reperfusion.


Genetic analysis of common variants in the ZNF804A gene with schizophrenia and major depressive disorder.
ZNF804A has been investigated widely as a candidate susceptibility gene for mental disorders in individuals of different ethnicities. However, in the Han Chinese population, most studies of this gene have focused on associations of the common single nucleotide polymorphism (SNP) rs1344706. To investigate additional common variants within ZNF804A, we carried out a case-control study of 13 SNPs distributed across the whole gene, in 1330 schizophrenic patients, 1045 major depressive disorder patients, and 1235 normal controls. We found that rs12476147 (P=0.0078) was associated significantly with schizophrenia, but no SNPs showed statistically significant associations with major depressive disorder after Bonferroni correction. Moreover, we also found that haplotype block 2, which included rs12476147 and rs1344706, was associated significantly with schizophrenia and major depressive disorder. Nevertheless, we could not replicate the association of rs1344706 with schizophrenia. In conclusion, the common variant rs12476147 and the related haplotype block in ZNF804A were associated significantly with schizophrenia in the Han Chinese population.


High selectivity of sulfur-doped SnO2 in NO2 detection at lower operating temperatures.
Resistive gas sensors based on metal oxides have aroused great interest in the sensing of NO2 gas due to their low cost, good stability, and easy fabrication. However, drawbacks such as low sensitivity and a lack of selectivity, which originate from the limited kinds of intrinsic active centers on the surface of the metal oxides that could be involved in the gas-sensing reaction, remain great challenges to overcome. To solve these problems, surface modification of SnO2 by S-doping was carried out by the sintering of flower-like SnS2. Gas-sensing tests revealed that the S-doped SnO2 showed ultra-high sensitivity to NO2 (Rg/Ra = 600 toward 5 ppm) with low optimal operating temperature (50 °C). The detection limit of the sensor was as low as 50 ppb (Rg/Ra = 11). Notably, the S-doped SnO2 showed negligible cross-responses to alcohol, acetone, HCHO, SO2, H2S, and xylene. The ultra-high sensitivity and selectivity toward NO2 were closely related to the content of the S-dopant. This phenomenon is attributed to the active role of S-dopant during the surface reactions with NO2, which was substantiated by in situ Raman characterization and DFT-based calculations. This study offers an important guide for surface modification by doping to improve the sensitivity and selectivity of metal oxides and sheds new light on material design to develop resistive gas sensors for NO2 detection.


Emergency department resource utilization during Ramadan: distinct and reproducible patterns over a 4-year period in Abu Dhabi.
Emergency Department (ED) patient arrivals vary daily and change considerably during holidays, posing challenges to resource allocation. Ramadan, during which observant Muslims follow a daily fasting period for ∼30 days, could represent a unique annual circumstance that predictably alters ED arrivals in predominantly Muslim populations. Our study examined an adult and pediatric ED in the United Arab Emirates to determine whether arrival patterns and patient characteristics differed during Ramadan. Hourly arrivals, census (number of patients in ED at any given time), and visit characteristics were retrospectively compared for Ramadan versus non-Ramadan periods over 4 years (2010-2013). Hourly arrivals and census were plotted using two-way repeated-measures analysis of variance. Differences in characteristics were examined using the χ-test and Wilcoxon rank sum tests. Ramadan adult and pediatric ED arrival patterns differed significantly (P<0.001) from non-Ramadan days, with sharp decreases after the fast was broken around 6 p.m. (sunset), followed by steep increases by 8:30 pm. The median daily adult arrivals were similar [143 (Ramadan) vs. 148 (non-Ramadan); P=0.060], with slightly decreased length-of-stay (7%; P<0.001) during Ramadan. The median daily pediatric arrivals were lower during Ramadan (43 vs. 57; P<0.001), with decreased length-of-stay (20%; P<0.001). Arrival pattern shifts led to significant census redistribution to evening hours. Patient characteristics were similar during both periods. A distinct, predictable pattern of arrivals emerged during Ramadan. EDs serving predominantly Muslim populations or anticipating increases in Muslim patients in their catchment region may benefit from advanced planning for efficient distribution of provider hours during Ramadan.


On the effects of a plant extract of Orthosiphon stamineus on sebum-related skin imperfections.
Overproduction of sebum is very common and results in an undesirable oily, shiny complexion with enlarged pores. Sebum secretion is basically under the control of 5-α reductase, and more particularly under that of type 1 isozyme. But it is also highly sensitive to environmental factors such as temperature, humidity and food. Moreover, in Asia, the edicts of a flawless facial skin turn oily skin into a major concern for Asian women. We identified Orthosiphon stamineus leaf extract as an interesting ingredient for reducing the oily appearance of skin thanks to its ability to reduce 5-α reductase type 1 expression in normal human epidermal keratinocytes in vitro. This was confirmed ex vivo, where Orthosiphon stamineus leaf extract was shown to reduce 5-α reductase activity as well as the production of squalene, one of the main components of sebum that was used as a tracer of sebum. To evaluate the efficacy of Orthosiphon stamineus leaf extract at reducing sebum-related skin imperfections in vivo, we performed two different clinical studies, one in France on a panel of Caucasian volunteers and the other one in Thailand on a panel of Asian volunteers. Using instrumental techniques as well as clinical evaluation and self-evaluation, we could highlight that an O/W cosmetic formula containing 2% of Orthosiphon stamineus leaf extract could visibly reduce the oily appearance of skin as well as the size of pores, thus leading to a significant improvement of complexion evenness and radiance. Overall, the results obtained were better than those observed with the same formula containing 1% of zinc gluconate, an ingredient frequently used in oily skin care products.


Metal Oxide Gas Sensors, a Survey of Selectivity Issues Addressed at the SENSOR Lab, Brescia (Italy).
This work reports the recent results achieved at the SENSOR Lab, Brescia (Italy) to address the selectivity of metal oxide based gas sensors. In particular, two main strategies are being developed for this purpose: (i) investigating different sensing mechanisms featuring different response spectra that may be potentially integrated in a single device; (ii) exploiting the electronic nose (EN) approach. The former has been addressed only recently and activities are mainly focused on determining the most suitable configuration and measurements to exploit the novel mechanism. Devices suitable to exploit optical (photoluminescence), magnetic (magneto-optical Kerr effect) and surface ionization in addition to the traditional chemiresistor device are here discussed together with the sensing performance measured so far. The electronic nose is a much more consolidated technology, and results are shown concerning its suitability to respond to industrial and societal needs in the fields of food quality control and detection of microbial activity in human sweat.


Lack of AcrB Efflux Function Confers Loss of Virulence on Salmonella enterica Serovar Typhimurium.
AcrAB-TolC is the paradigm resistance-nodulation-division (RND) multidrug resistance efflux system in Gram-negative bacteria, with AcrB being the pump protein in this complex. We constructed a nonfunctional AcrB mutant by replacing D408, a highly conserved residue essential for proton translocation. Western blotting confirmed that the AcrB D408A mutant had the same native level of expression of AcrB as the parental strain. The mutant had no growth deficiencies in rich or minimal medium. However, compared with wild-type SL1344, the mutant had increased accumulation of Hoechst 33342 dye and decreased efflux of ethidium bromide and was multidrug hypersusceptible. The D408A mutant was attenuated in vivo in mouse and Galleria mellonella models and showed significantly reduced invasion into intestinal epithelial cells and macrophages in vitro A dose-dependent inhibition of invasion was also observed when two different efflux pump inhibitors were added to the wild-type strain during infection of epithelial cells. RNA sequencing (RNA-seq) revealed downregulation of bacterial factors necessary for infection, including those in the Salmonella pathogenicity islands 1, 2, and 4; quorum sensing genes; and phoPQ Several general stress response genes were upregulated, probably due to retention of noxious molecules inside the bacterium. Unlike loss of AcrB protein, loss of efflux function did not induce overexpression of other RND efflux pumps. Our data suggest that gene deletion mutants are unsuitable for studying membrane transporters and, importantly, that inhibitors of AcrB efflux function will not induce expression of other RND pumps.IMPORTANCE Antibiotic resistance is a major public health concern. In Gram-negative bacteria, overexpression of the AcrAB-TolC multidrug efflux system confers resistance to clinically useful drugs. Here, we show that loss of AcrB efflux function causes loss of virulence in Salmonella enterica serovar Typhimurium. This is due to the reduction of bacterial factors necessary for infection, which is likely to be caused by the retention of noxious molecules inside the bacterium. We also show that, in contrast to loss of AcrB protein, loss of efflux does not induce overexpression of other efflux pumps from the same family. This indicates that there are differences between loss of efflux protein and loss of efflux that make gene deletion mutants unsuitable for studying the biological function of membrane transporters. Understanding the biological role of AcrB will help to assess the risks of targeting efflux pumps as a strategy to combat antibiotic resistance.


Control of antiviral innate immune response by protein geranylgeranylation.
The mitochondrial antiviral signaling protein (MAVS) orchestrates host antiviral innate immune response to RNA virus infection. However, how MAVS signaling is controlled to eradicate virus while preventing self-destructive inflammation remains obscure. Here, we show that protein geranylgeranylation, a posttranslational lipid modification of proteins, limits MAVS-mediated immune signaling by targeting Rho family small guanosine triphosphatase Rac1 into the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) at the mitochondria-ER junction. Protein geranylgeranylation and subsequent palmitoylation promote Rac1 translocation into MAMs upon viral infection. MAM-localized Rac1 limits MAVS' interaction with E3 ligase Trim31 and hence inhibits MAVS ubiquitination, aggregation, and activation. Rac1 also facilitates the recruitment of caspase-8 and cFLIPL to the MAVS signalosome and the subsequent cleavage of Ripk1 that terminates MAVS signaling. Consistently, mice with myeloid deficiency of protein geranylgeranylation showed improved survival upon influenza A virus infection. Our work revealed a critical role of protein geranylgeranylation in regulating antiviral innate immune response.


Sequence variability of FrpB, a major iron-regulated outer-membrane protein in the pathogenic neisseriae.
The FrpB protein from pathogenic neisseriae is a 77 kDa iron-regulated outer-membrane protein that belongs to the family of TonB-dependent receptors and may have potential as a vaccine component. Comparison between the frpB gene from three different meningococcal strains and a published gonococcal one revealed that the region from residues 350 to 390 displays pronounced sequence variability. In a model for the topology of FrpB in the outer membrane, this region corresponds to loop 7, the longest of the predicted 13 surface-exposed loops. Binding of four out of a total of eight bactericidal monoclonal antibodies to synthetic peptides corresponding to loop 7 showed that their epitopes are located here. The frpB genes from five additional meningococcal strains were cloned and sequenced in this region. Pairwise comparisons showed different degrees of similarity.


Upregulated expression and function of integrin adhesive receptors in systemic lupus erythematosus patients with vasculitis.
Upregulation of integrin adhesive receptors has been implicated in various pathological conditions. We examined expression and function of integrin adhesive receptors on peripheral blood lymphocytes from patients with systemic lupus erythematosus (SLE), particularly those with the complication of vasculitis, and found that VLA-4 and LFA-1 expression was increased in SLE patients with vasculitis, while LFA-1 but not VLA-4 expression was increased in those without vasculitis. These results suggested a role of VLA-4 in the pathogenesis of vasculitis in SLE. Functional studies further demonstrated that adhesion to cytokine-activated human umbilical cord vein endothelial cells and to the CS-1 alternatively spliced domain of fibronectin was significantly increased in SLE patients with vasculitis. Analysis of the functional epitopes on the alpha 4 chain demonstrated that antigen densities of all the functional epitopes were increased in those with vasculitis, indicating that the increased expression of VLA-4 resulted from the increased number of VLA-4 molecules, and was not secondary to an increase in one particular functional epitope. Immunoprecipitation studies further support these results. Interestingly, high molecular weight bands associated with VLA-4 were observed in about half of the SLE patients with vasculitis. These results introduce a possibility that upregulation of integrin adhesive receptors has a potential role in the pathogenesis of vasculitis in SLE.


[Mechanisms of development of neurodegenerative processes in multiple sclerosis: neuroprotective influence of beta-interferons today and neurotrophic factors -- tomorrow].
The review addresses an analysis of the causes of neurodegenerative process development in multiple sclerosis (MS) as well as the modern approaches to the treatment of the disease. The best-studied mechanisms of degenerative alterations and clinical and experimental evidence supported the protective influence of beta-interferons treatment in MS are discussed. Neuroprotection is highlighted among the future directions. The main features of the various groups of neurotrophic factors and the possible ways of their therapy-targeted transport into brain tissues are analyzed.


The rate of acute gastrointestinal illness in developed countries.
This paper reviews estimates of the incidence and prevalence of acute gastrointestinal illness (AGI) from 33 studies. These studies include prospective cohort studies, retrospective cross-sectional population-based surveys, and intervention trials from the United States and six other developed countries published since 1953. The incidence and prevalence estimates for AGI reported in these studies range from 0.1 to 3.5 episodes per person-year. However, comparisons of these rates are problematic owing to significant variation in study design, sampling methodology, and case definitions and should be made with caution. In the United States, the Centers for Disease Control and Prevention's (CDC) Foodborne Diseases Active Surveillance Network (FoodNet) estimates a rate of 0.65 episodes of AGI per person-year. This estimate includes diarrhea and/or vomiting of infectious or non-infectious origin, with a measure of severity (impairment of daily activities or diarrhea duration greater than 1 day), and has been adjusted for combined respiratory-gastrointestinal illnesses. However, it excludes episodes of diarrhea or vomiting due to any long-lasting or chronic illness or condition. Limitations in study design result in an unknown degree of uncertainty around this point estimate.


The patatin-like phospholipase PfPNPLA2 is involved in the mitochondrial degradation of phosphatidylglycerol during Plasmodium falciparum blood stage development.
Plasmodium falciparum is an Apicomplexa responsible for human malaria, a major disease causing more than ½ million deaths every year, against which there is no fully efficient vaccine. The current rapid emergence of drug resistances emphasizes the need to identify novel drug targets. Increasing evidences show that lipid synthesis and trafficking are essential for parasite survival and pathogenesis, and that these pathways represent potential points of attack. Large amounts of phospholipids are needed for the generation of membrane compartments for newly divided parasites in the host cell. Parasite membrane homeostasis is achieved by an essential combination of parasite de novo lipid synthesis/recycling and massive host lipid scavenging. Latest data suggest that the mobilization and channeling of lipid resources is key for asexual parasite survival within the host red blood cell, but the molecular actors allowing lipid acquisition are poorly characterized. Enzymes remodeling lipids such as phospholipases are likely involved in these mechanisms. P. falciparum possesses an unusually large set of phospholipases, whose functions are largely unknown. Here we focused on the putative patatin-like phospholipase PfPNPLA2, for which we generated an glmS-inducible knockdown line and investigated its role during blood stages malaria. Disruption of the mitochondrial PfPNPLA2 in the asexual blood stages affected mitochondrial morphology and further induced a significant defect in parasite replication and survival, in particular under low host lipid availability. Lipidomic analyses revealed that PfPNPLA2 specifically degrades the parasite membrane lipid phosphatidylglycerol to generate lysobisphosphatidic acid. PfPNPLA2 knockdown further resulted in an increased host lipid scavenging accumulating in the form of storage lipids and free fatty acids. These results suggest that PfPNPLA2 is involved in the recycling of parasite phosphatidylglycerol to sustain optimal intraerythrocytic development when the host resources are scarce. This work strengthens our understanding of the complex lipid homeostasis pathways to acquire lipids and allow asexual parasite survival.


How Interpersonal Psychotherapy Changes the Brain: A Study of fMRI in Borderline Personality Disorder.
Background: Recent guidelines and systematic reviews suggest that disorder-specific psychotherapeutic interventions are the first choice in the treatment of borderline personality disorder (BPD). The aim of this study is to examine brain activity changes in BPD patients (DSM-5) who received a revised BPD-adapted interpersonal psychotherapy (IPT-BPD-R) compared with patients on the waiting list. Methods: Forty-three patients with a BPD diagnosis (DSM-5) were randomly assigned to IPT-BPD-R (n = 22 patients) or the waiting list with clinical management (n = 21 patients) for 10 months. Both groups were tested before and after treatment with the Social and Occupational Functioning Assessment Scale (SOFAS), the Clinical Global Impressions-Severity of Illness scale (CGI-S), the Borderline Personality Disorder Severity Index (BPDSI), the Barratt Impulsiveness Scale-version 11 (BIS-11), and the Autobiographical Interview. Both groups underwent pre- and posttreatment functional magnetic resonance imaging (fMRI) testing. The fMRI task consisted of the presentation of resolved and unresolved life events compared to a neutral condition. All structural and functional images were analyzed using Statistical Parametric Mapping 12 software, which interfaces with MATLAB. Clinical data were analyzed using analysis of variance for repeated measures. Patients were recruited between September 2017 and April 2019. Results: In clinical results, for the 4 rating scales, a significant between-subject effect was found in favor of the IPT-BPD-R-treated group (CGI-S: P = .011; BPDSI: P = .009; BIS-11: P = .033; SOFAS: P = .022). In fMRI results, posttreatment versus pretreatment for the contrast unresolved life event versus neutral condition showed significantly decreased right temporoparietal junction (rTPJ: x = 45, y = -51, z = 36) (P = .043) and right anterior cingulate cortex (rACC: x = -4, y = 37, z = 8) activity (P = .021). Conclusions: IPT-BPD-R appears to be effective in treating BPD symptoms, and these clinical effects are reflected in the functional changes observed with fMRI. Brain areas that showed modulation of their activity are the rTPJ and rACC, which are involved in mentalization processes that are fundamental to BPD pathology. Trial Registration: Australian New Zealand Clinical Trials Registry (ANZCTR) code: ACTRN12619000078156.


The SMAD3 transcription factor binds complex RNA structures with high affinity.
Several members of the SMAD family of transcription factors have been reported to bind RNA in addition to their canonical double-stranded DNA (dsDNA) ligand. RNA binding by SMAD has the potential to affect numerous cellular functions that involve RNA. However, the affinity and specificity of this RNA binding activity has not been well characterized, which limits the ability to validate and extrapolate functional implications of this activity. Here we perform quantitative binding experiments in vitro to determine the ligand requirements for RNA binding by SMAD3. We find that SMAD3 binds poorly to single- and double-stranded RNA, regardless of sequence. However, SMAD3 binds RNA with large internal loops or bulges with high apparent affinity. This apparent affinity matches that for its canonical dsDNA ligand, suggesting a biological role for RNA binding by SMAD3.


The political economy of early COVID-19 interventions in US states.
We investigate how politico-economic factors shaped government responses to the spread of COVID-19. Our simple framework uses epidemiological, economic and politico-economic arguments. Confronting the theory with US state level data we find strong evidence for partisanship even when we control for fundamentals including the electorate's political views. Moreover, we detect an important role for the proximity of elections which we interpret as indicative of career concerns. Finally, we find suggestive evidence for complementarities between voluntary activity reductions and government imposed restrictions.


The mechanistic basis for the rapid antidepressant-like effects of ketamine: From neural circuits to molecular pathways.
Conventional antidepressants that target monoaminergic receptors require several weeks to be efficacious. This lag represents a significant problem in the currently available treatments for serious depression. Ketamine, acting as an N-methyl-d-aspartate receptor antagonist, was shown to have rapid antidepressant-like effects, marking a significant advancement in the study of mood disorders. However, serious side effects and adverse reactions limit its clinical use. Considering the limitations of ketamine, it is crucial to further define the network targets of ketamine. The rapid action of ketamine an as antidepressant is thought to be mediated by the glutamate system. It is believed that synaptic plasticity is essential for the rapid effects of ketamine as an antidepressant. Other mechanisms include the involvement of the γ-aminobutyric acidergic (GABAergic), 5-HTergic systems, and recent studies have linked astrocytes to ketamine's rapid antidepressant-like effects. The interactions between these systems exert a synergistic rapid antidepressant effect through neural circuits and molecular mechanisms. Here, we discuss the neural circuits and molecular mechanisms underlying the action of ketamine. This work will help explain how molecular and neural targets are responsible for the effects of rapidly acting antidepressants and will aid in the discovery of new therapeutic approaches for major depressive disorder.


A Comparative Health Risk Assessment of Electronic Cigarettes and Conventional Cigarettes.
Background: Although some studies have identified hazardous substances in electronic cigarette (EC) liquids and emissions, there is limited information about the health risks of using ECs. Methods: In this study, the U.S. Environmental Protection Agency (EPA) health risk assessment model and findings of a literature review were used to determine and profile hazards. Focus was put on the toxicants reported in the literature on conventional cigarette (CC) smoke that most strongly associated with adverse health effects. To evaluate their health risks, dose-response relationships and standard-use conditions were used to estimate average hazard exposures and to calculate the overall health risks of ECs and CCs, benchmarked against international guideline levels for each hazard. Results: Four hazards (acrolein, diethylene glycol, propylene glycol and cadmium) reported in EC emissions and seven hazards (acetaldehyde, acrolein, formaldehyde, cadmium, CO, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), N'-nitrosonornicotine (NNN)) reported in CC emissions had maximum exposure levels higher than the guideline levels. Two hazards (acrolein, propylene glycol) in EC emissions and five hazards (acetaldehyde, acrolein, formaldehyde, cadmium, NNN) in CC emissions had average exposure levels higher than the guideline levels. Conclusions: Based on the conditions of use, ECs should be a safer nicotine-delivery product than CCs.


Hemoglobin switching in sheep. Cloning and characterization of the beta A and beta-like embryonic globin genes from genomic DNA.
Genomic DNA from a fetal sheep homozygous for the beta A gene was used to construct a library of one million cloned DNA fragments using the bacteriophage vector, Charon 4A. Screening of 150,000 plaques from this library using radioactive beta-globin gene sequences resulted in the isolation of two recombinant bacteriophage containing globin genes. One of these, S beta AG-21, contains the complete adult beta A-globin gene as demonstrated by hybridization and restriction endonuclease analysis. In common with adult globin genes from other species, the beta A gene contains small (105 base pairs) and large (900 base pairs) intervening sequences. The second recombinant bacteriophage, SG-4, contains a complete embryonic beta-like globin gene which is expressed in the sheep embryo as demonstrated by hybridization analysis with cDNA made from sheep embryonic globin mRNA. Although differing in its restriction endonuclease map from the adult beta-globin genes, SG-4 appears to contain a large intervening sequence of at least 750 base pairs in length. Finally, preliminary evidence is discussed which indicates that a Pvu II site just 5' to the Cap site may be a common feature of sheep globin genes.


Incidence of and risk factors associated with nedaplatin-related hypersensitivity reactions.
Nedaplatin (NDP)-related hypersensitivity reactions (HSRs) trigger adverse clinical events. Prediction and prevention of NDP-HSRs are thus essential to minimize the risk and maximize the benefit of NDP therapy. However, the incidence of NDP-HSRs and the associated risk factors remain unclear. We retrospectively examined patients who received NDP monotherapy between April 2011 and July 2015 in Nagoya University Hospital. HSRs severity was defined according to the Common Terminology Criteria for Adverse Events version 4 (CTCAE ver.4). Risk factors for NDP-HSRs were determined using multivariate logistic regression. Of 111 patients who received NDP monotherapy, 90 (81%) were female; median age was 59 years (range, 29-78 years). Eighty-eight patients had gynecological cancer and 20 suffered from head and neck cancer. Eight of 111 patients (7.2%) experienced NDP-HSRs, six of which developed in the second NDP cycle. However, all patients with NDP-HSRs were treated with carboplatin (CBDCA) for more than three cycles. Grade 3 and 4 HSRs developed in 2 patients. NDP-HSRs were significantly associated with a history of CBDCA-HSRs (odds ratio 37.5, 95% confidence interval 5.38-262, p < 0.001) and with the interval between NDP administration and the previous platinum treatment (odds ratio 13.9, 95% confidence interval 1.23-158, p = 0.034). The risk of NDP-HSRs increases in patients with a history of CBDCA-HSRs and in those administered NDP for more than 6 months after previous platinum treatment. Such individuals must be closely monitored if given NDP, even if they are expected to benefit from the treatment.


Predictor factors for choledocholithiasis.
The choledocolithiasis has an incidence of 8-20% in patients with cholecystolithiasis. The preoperative diagnosis guides the interventional treatment on the bile duct To evaluate the sensitivity and specificity of the laboratory markers and imaging studies for choledocholithiasis preoperatively. The study comprised 254 patients divided into two groups: the control group (207 patients), patients without choledocholithiasis intraoperatively and cases group (47 patients), that enrolled the patients with choledocholithiasis intra-operatively. Were evaluated the laboratory markers, image exams and intra-operative diagnostic aspects. The sample was homogeneous for age and gender. It was observed that 47% of the cases the patients did not show comorbidities. Hospitalization showes in cases group acute pancreatitis in12.8%, jaundice in 30%, fever in 30% and pain in the right hypochondrium in 95%. By comparing them, was observed that fever and jaundice were the signs and symptoms with statistical significance. Patients with choledocholithiasis had transaminases, alkaline phosphatase, gamma-glutamyl transferase and higher bilirubin with statistical significance (p<0.001). In regard to imaging studies, ultrasound was fairly accurate for cholelithiasis and choledocholithiasis (p<0.001). Changes in canalicular and transaminase enzymes are suggestive for preoperative choledocholithiasis; GGT showed better sensitivity and alkaline phosphatase greater specificity; ultrasonography and nuclear magnetic resonance cholangiopancreatography showed high specificity.


Nanocrystalline carbonate-apatites: role of Ca/P ratio on the upload and release of anticancer platinum bisphosphonates.
In the present study two nanocrystalline apatites have been investigated as bone-specific drug delivery devices to be used for treatment of bone tumors either by local implantation or by injection. In order to assess how the Ca/P ratio can influence the adsorption and release of anticancer platinum-bisphosphonate complexes, two kinds of apatite nanocrystals having different Ca/P ratios but similar morphologies, degree of crystallinity, and surface areas have been synthesized and characterized. The two platinum-bisphosphonate complexes considered were the bis-{ethylenediamineplatinum(ii)}-2-amino-1-hydroxyethane-1,1-diyl-bisphosphonate and the bis-{ethylenediamineplatinum(ii)}medronate. The Ca/P ratio plays an important role in the adsorption as well as in the release of the two drugs. In fact, the apatite with a higher Ca/P ratio showed greater affinity for both platinum complexes. Also the chemical structure of the two Pt complexes appreciably affects their affinity towards as well as their release from the two kinds of apatites. In particular, the platinum complex whose bisphosphonate contains a free aminic group showed greater upload and smaller release. The cytotoxicity of the Pt complexes released from the apatite was tested against human cervical, colon, and lung cancer cells as well as against osteosarcoma cells. In agreement with previous work, the Pt complexes released were found to be more cytotoxic than the unmodified complexes.


Shedding of RANKL by tumor-associated MT1-MMP activates Src-dependent prostate cancer cell migration.
Membrane type 1 matrix metalloproteinase (MT1-MMP) plays an essential role in protease-mediated extracellular matrix (ECM) degradation, but it also functions as a sheddase releasing non-ECM substrates such as receptor activator of NF-kappaB ligand (RANKL), an osteoclastogenic factor typically confined to the surface of osteoblasts. We previously found high expression of MT1-MMP in skeletal metastasis of prostate cancer patients, in a pattern similar to RANKL expression. We also showed that overexpression of MT1-MMP in prostate cancer cells increases tumor growth and osteolysis in an intratibial mouse model of bone metastasis, and that soluble factor(s) shed by tumor-derived MT1-MMP enhance osteoclast differentiation in a RANKL-dependent manner. Recent evidence indicates that the cognate receptor for RANKL, RANK, is expressed in prostate cancer cells, suggesting the presence of an autocrine pathway. In this study, we show that MT1-MMP-expressing LNCaP prostate cancer cells display enhanced migration. Moreover, conditioned medium from LNCaP cells expressing both RANKL and MT1-MMP stimulates the migration of MT1-MMP-deficient C42b prostate cancer cells. This enhanced chemotaxis can be abrogated by osteoprotegerin (soluble decoy receptor of RANKL), MIK-G2 (a selective inhibitor for MT1-MMP), and PP2 (a Src inhibitor). These findings indicate that tumor-derived MT1-MMP enhances tumor cell migration through initiation of an autocrine loop requiring ectodomain shedding of membrane-bound RANKL in prostate cancer cells, and that Src is a key downstream mediator of RANKL-induced migration of prostate cancer cells.


Absorption, refraction and scattering in analyzer-based imaging: comparison of different algorithms.
Many mathematical methods have been so far proposed in order to separate absorption, refraction and ultra-small angle scattering information in phase-contrast analyzer-based images. These algorithms all combine a given number of images acquired at different positions of the crystal analyzer along its rocking curve. In this paper a comprehensive quantitative comparison between five of the most widely used phase extraction algorithms based on the geometrical optics approximation is presented: the diffraction-enhanced imaging (DEI), the extended diffraction-enhanced imaging (E-DEI), the generalized diffraction-enhanced (G-DEI), the multiple-image radiography (MIR) and the Gaussian curve fitting (GCF). The algorithms are theoretically analyzed in terms of their validity conditions and experimentally compared by using geometrical phantoms providing various amounts of absorption, refraction and scattering. The presented work shows that, due to their specific validity conditions, the considered algorithms produce results that may greatly differ, especially in the case of highly refracting and/or highly scattering materials. The various extraction algorithms are also applied to images of a human bone-cartilage sample. The aim is to validate the results obtained on geometrical phantoms and prove the efficiency of the different algorithms for applications on biological samples.


Spliced leader trapping reveals widespread alternative splicing patterns in the highly dynamic transcriptome of Trypanosoma brucei.
Trans-splicing of leader sequences onto the 5'ends of mRNAs is a widespread phenomenon in protozoa, nematodes and some chordates. Using parallel sequencing we have developed a method to simultaneously map 5'splice sites and analyze the corresponding gene expression profile, that we term spliced leader trapping (SLT). The method can be applied to any organism with a sequenced genome and trans-splicing of a conserved leader sequence. We analyzed the expression profiles and splicing patterns of bloodstream and insect forms of the parasite Trypanosoma brucei. We detected the 5' splice sites of 85% of the annotated protein-coding genes and, contrary to previous reports, found up to 40% of transcripts to be differentially expressed. Furthermore, we discovered more than 2500 alternative splicing events, many of which appear to be stage-regulated. Based on our findings we hypothesize that alternatively spliced transcripts present a new means of regulating gene expression and could potentially contribute to protein diversity in the parasite. The entire dataset can be accessed online at TriTrypDB or through: http://splicer.unibe.ch/.


Mechanosensitive recruitment of stator units promotes binding of the response regulator CheY-P to the flagellar motor.
Reversible switching of the bacterial flagellar motor between clockwise (CW) and counterclockwise (CCW) rotation is necessary for chemotaxis, which enables cells to swim towards favorable chemical habitats. Increase in the viscous resistance to the rotation of the motor (mechanical load) inhibits switching. However, cells must maintain homeostasis in switching to navigate within environments of different viscosities. The mechanism by which the cell maintains optimal chemotactic function under varying loads is not understood. Here, we show that the flagellar motor allosterically controls the binding affinity of the chemotaxis response regulator, CheY-P, to the flagellar switch complex by modulating the mechanical forces acting on the rotor. Mechanosensitive CheY-P binding compensates for the load-induced loss of switching by precisely adapting the switch response to a mechanical stimulus. The interplay between mechanical forces and CheY-P binding tunes the chemotactic function to match the load. This adaptive response of the chemotaxis output to mechanical stimuli resembles the proprioceptive feedback in the neuromuscular systems of insects and vertebrates.


Effects of Hibiscus sabdariffa extract powder and preventive treatment (diet) on the lipid profiles of patients with metabolic syndrome (MeSy).
Insulin resistance, obesity, hypertension, and dyslipidemia are strongly associated with metabolic syndrome (MeSy), which is considered to be a reversible clinical stage before its evolution to coronary heart disease and diabetes. Currently, the antihypertensive and hypolipidemic properties of aqueous Hibiscus sabdariffa extracts (HSE) have been demonstrated in clinical trials and in vivo experiments. The aim of the present study was to evaluate the effects of a Hibiscus sabdariffa extract powder (HSEP) and a recognized preventive treatment (diet) on the lipid profiles of individuals with and without MeSy according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) criteria. The protocol was a follow-up study carried out in a factorial, randomized design (T1=preventive treatment comprises Diet, T2=HSEP, T3=HSEP+preventive treatment (Diet) X MeSy, non-MeSy individuals). A total daily dose of 100 mg HSEP was orally administered in capsules for one month. The preventive treatment (diet) was selected according to NCEP-ATP III recommendations and adjusted individually. Total cholesterol, LDL-c, HDL-c, VLDL-c, triglycerides, glucose, urea, creatinine, AST, and ALT levels in the blood were determined in all individuals pre- and post-treatment. The MeSy patients treated with HSEP had significantly reduced glucose and total cholesterol levels, increased HDL-c levels, and an improved TAG/HDL-c ratio, a marker of insulin resistance (t-test p<0.05). Additionally, a triglyceride-lowering effect was observed in MeSy patients treated with HSEP plus diet, and in individuals without MeSy treated with HSEP. Significant differences in total cholesterol, HDL-c, and the TAG/HDL-c ratio were found when the means of absolute differences among treatments were compared (ANOVA p<0.02). Therefore, in addition to the well documented hypotensive effects of Hibiscus sabdariffa, we suggest the use of HSEP in individuals with dyslipidemia associated with MeSy.


Micromorphology and Histology of the Secretory Apparatus of Diospyros villosa (L.) de Winter Leaves and Stem Bark.
Diospyros villosa is a perennial species prominently acknowledged for its local medicinal applications. The native utilisation of this species in traditional medicine may be ascribed to the presence of secretory structures and their exudate (comprised of phytochemicals). However, the morphological nature and optical features of the secretory structures in D. villosa remain largely unclear. This study was directed to ascertain the occurrence and adaptive features of structures found within the leaves and stem bark of D. villosa using light and electron microscopy techniques. The current study notes the existence of trichomes, and other secretory structures were noted. SEM indicated the presence of non-glandular hirsute trichomes with bulky stalk on both leaves and stem surfaces. Transverse stem sections revealed the existence of crystal idioblasts. Moreover, the presence of the main phytochemical groups and their localisation within the foliage and stem bark was elucidated through various histochemical tests. The trichomal length and density were also assessed in leaves at different stages of development. The results indicated that the trichomal density at different stages of development of the D. villosa leaves and stem bark was not significantly different from one another, F(3,39) = 1.183, p = 0.3297. The average length of the non-glandular trichomes in the emergent, young and mature leaves, as well as in the stem, was recorded to be 230 ± 30.6 µm, 246 ± 40.32 μm, 193 ± 27.55 µm and 164 ± 18.62 µm, respectively. The perimeter and circumference of the observed trichomes in the developmental stages of D. villosa leaf and the stem bark were not statistically different, F(3,39) = 1.092, p = 0.3615. The results of histochemical tests showed the existence of phenols alkaloids, which are medicinally important and beneficial for treatment of diseases. The findings of this study, being reported for the first time may be considered in establishing microscopic and pharmacognostic measure for future identification and verification of natural herbal plant. Trichomal micromorphology and histological evaluations could be utilised as a tool for appropriate description for the assessment of this species.


Novel antimicrobial peptides derived from human immunodeficiency virus type 1 and other lentivirus transmembrane proteins.
We have previously described a conserved set of peptides derived from lentiviral envelope transmembrane proteins that are similar to the natural antimicrobial peptides cecropins and magainins in overall structure but bear no sequence homology to them or other members of their class. We describe here an evaluation of the antimicrobial properties of these virally derived peptides, designated lentivirus lytic peptides (LLPs). The results of this study demonstrate that they are potent and selective antibacterial peptides: the prototype sequence, LLP1, is bactericidal to both gram-positive and gram-negative organisms at micromolar concentrations in 10 mM phosphate buffer. Furthermore, LLP1 kills bacteria quite rapidly, causing a 1,000-fold reduction in viable organisms within 50 s. Peptides corresponding to sequences from three lentivirus envelope proteins were synthesized and characterized. Several of these peptides are selective, killing bacteria at concentrations 50- to 100-fold lower than those required to lyse erythrocytes. Development of antimicrobial agents based on these peptides may lead to improved therapeutics for the management of a variety of infectious diseases.


Standards for sequencing viral genomes in the era of high-throughput sequencing.
Thanks to high-throughput sequencing technologies, genome sequencing has become a common component in nearly all aspects of viral research; thus, we are experiencing an explosion in both the number of available genome sequences and the number of institutions producing such data. However, there are currently no common standards used to convey the quality, and therefore utility, of these various genome sequences. Here, we propose five "standard" categories that encompass all stages of viral genome finishing, and we define them using simple criteria that are agnostic to the technology used for sequencing. We also provide genome finishing recommendations for various downstream applications, keeping in mind the cost-benefit trade-offs associated with different levels of finishing. Our goal is to define a common vocabulary that will allow comparison of genome quality across different research groups, sequencing platforms, and assembly techniques.