A Bibliometric Analysis of the Literature on Norovirus Disease from 1991-2021.
Norovirus (NoV) is one of the oldest recognized diseases and the leading causal pathogen for acute gastroenteritis (AGE) worldwide. Though numerous studies have been reported on NoV disease, limited research has explored the publication trends in this area. As a result, the objective of this work was to fill the void by conducting a bibliometric study in publication trends on NoV studies as well as discovering the hotspots. The Web of Science central assemblage database was hunted for publications from 1991 to 2021 with "norovirus" in the heading. Microsoft Excel 2016, VOSviewer, R Bibliometrix, and Biblioshiny packages were deployed for the statistical analysis of published research articles. A total of 6021 published documents were identified in the Web of Science database for this thirty-year study period (1991-2021). The analyses disclosed that the Journal of Medical Virology was the leading journal in publications on norovirus studies with a total of 215 published articles, the Journal of Virology was the most cited document with 11,185 total citations. The United States of America (USA) has the most significant productivity in norovirus publications and is the leading country with the highest international collaboration. Analysis of top germane authors discovered that X. Jiang (135) and J. Vinje (119) were the two top relevant authors of norovirus publications. The commonly recognized funders were US and EU-based, with the US emerging as a top funder. This study reveals trends in scientific findings and academic collaborations and serves as a leading-edge model to reveal trends in global research in the field of norovirus research. This study points out the progress status and trends on NoV research. It can help researchers in the medical profession obtain a comprehensive understanding of the state of the art of NoV. It also has reference values for the research and application of the NoV visualization methods. Further, the research map on AGE obtained by our analysis is expected to help researchers efficiently and effectively explore the NoV field.


Was the "nervous illness" of Schreber a case of affective disorder?
The available historical information concerning Freud's subject Daniel Paul Schreber's life, family, and the phenomenology of his illness is reviewed. The author challenges the traditional diagnosis of paranoid schizophrenia in favor of a diagnosis of affective disorder.


Intracranial infections: lessons learned from 52 surgically treated cases.
Intracranial infections are serious and life-threatening health problems. They may present as subdural empyemas or intracerebral abscesses. Surgical drainage and subsequent antibiotic treatment is the main technique for a satisfactory clinical outcome. The aims of this study were to present a 10-year intracranial infection series and discuss the surgical characteristics in the light of literature. Fifty-two patients with intracranial infection underwent surgical treatment between 2008 and 2018. Eleven patients were female and 41 patients were male. The mean age was 40.46 years (range 10-75 years). Eighteen patients had intracerebral abscesses, and 34 had subdural empyemas. All patients underwent surgical treatment as well as an antibiotic regimen. No etiological agent was isolated in 29 (56%) cases. Bacterial agents were detected in 20 cases, while fungi were observed in 3 cases. Staphylococci species were the most common agents and were isolated in 8 (15%) cases. Endoscopic aspiration was performed in 3 cases, while surgical drainage and capsule resection via craniotomy was performed in 49 cases. An associated intracranial tumor was diagnosed in 2 patients with brain abscesses. Four (8%) patients died despite surgical and medical treatments. Surgical treatment via craniotomy is an older method, but it is still the best to treat the intracranial infections not only for decompression of the brain but also to attain an accurate diagnosis. The abscess wall should always be histologically examined after surgery to rule out any intracranial tumor.


[Neurophysiologic and clinical aspects of intranatal fetal hibernation].
On the basis the results of the study on the state of the fetus in 96 physiological parturitions (using a number of clinical and physiological techniques) and analysis of the literature data concerning changes in the parturient-placenta-fetus system and especially of the levels of a number of biologically active substances and the investigation of their physiological properties, the proposition is substantiated that in parturition, particularly at its second stage, the fetus is in the state of profound hybernation. The question is discussed concerning differential diagnosis of the status of intranatal hybernation of the fetus and other conditions (asphyxia, shock of the newborn, etc.). The study is of importance for perinatology, clinical neurology of the neonatal period, obstetrics and evolutional physiology.


How Do People Perform an Inspection Time Task? An Examination of Visual Illusions, Task Experience, and Blinking.
In the inspection time (IT) paradigm, participants view two lines of unequal length (called the Pi-figure) for a short exposure time, and then judge which of the two lines was longer. Early research has interpreted IT as a simple index of mental speed, which does not involve motor activity. However, more recent studies have associated IT with higher-level cognitive mechanisms, including focused attention, task experience, and the strategic use of visual illusions. The extent to which these factors affect IT is still a source of debate. We used an eye-tracker to capture participants' (N = 147) visual attention while performing IT trials. Results showed that blinking was time-dependent, with participants blinking less when the Pi-figure was visible as compared to before and after. Blinking during the presentation of the Pi-figure correlated negatively with response accuracy. Also, participants who reported seeing a brightness illusion had a higher response accuracy than those who did not. The first experiment was repeated with new participants (N = 159), enhanced task instructions, and the inclusion of practice trials. Results showed substantially improved response accuracy compared to the first experiment, and no significant difference in response accuracy between those who did and did not report illusions. IT response accuracy correlated modestly (r = 0.18) with performance on a short Raven's advanced progressive matrices task. In conclusion, performance at the IT task is affected by task familiarity and involves motor activity in the form of blinking. Visual illusions may be an epiphenomenon of understanding the IT task.


[Classical conditioning of agonistic behavior in the Syrian golden hamster (Mesocricetus auratus Waterhouse)].
Nine different reactions of unconditioned agonistic behavior of golden hamsters (Mesocricetus auratus Waterhouse) which could be elicited by an air blow (UCS) were classically conditioned at a sound of a xylophone (tone g), a previously neutral stimulus. Tone g (CS) was paired with UCS for a different number of trials/day. In all animals exposed to over 20 pairings/day components of the agonistic behavior were brought under the control of CS, but it was not possible to predict which one of the agonistic reactions would appear. Most of the animals generalized and also showed conditioned reactions (CR) when presenting tone c' instead of tone g. When utilizing a differential conditioning procedure the animals learned to discriminate between the different tones. Extinction of CR at tone g was reached after an individually different number of trials.


4-Hydroxyphenylpyruvate Dioxygenase Thermolability Is Responsible for Temperature-Dependent Melanogenesis in Aeromonas salmonicida subsp. salmonicida.
Aeromonas salmonicida subsp. salmonicida is a major pathogen affecting fisheries worldwide and is a well-known pigmented member of the Aeromonas genus. This subspecies produces melanin at ≤22°C. However, melanogenesis decreases as the culture temperature increases and is completely suppressed at 30°C to 35°C, while bacterial growth is unaffected. The mechanism and biological significance of this temperature-dependent melanogenesis remain unclear. Heterologous expression of an A. salmonicida subsp. salmonicida 4-hydroxyphenylpyruvate dioxygenase (HppD), the most critical enzyme in the homogentisic acid (HGA)-melanin synthesis pathway, results in thermosensitive pigmentation in Escherichia coli, suggesting that HppD plays a key role in this process. In this study, we demonstrated that the thermolability of HppD is responsible for the temperature-dependent melanization of A. salmonicida subsp. salmonicida Substitutions of three residues, S18T, P103Q, and L119P, in A. salmonicida subsp. salmonicida HppD increased the thermostability of this enzyme and resulted in temperature-independent melanogenesis. Moreover, the replacement of the corresponding residues in HppD from Aeromonas media strain WS, which forms pigment independent of temperature, with those of A. salmonicida subsp. salmonicida HppD resulted in thermosensitive melanogenesis. A structural analysis suggested that mutations at these sites, especially at position P103, strengthen the secondary structure of HppD and greatly improve its thermal stability. Additionally, we found that the HppD sequences of all A. salmonicida subsp. salmonicida isolates were identical and that two of the three residues were clearly distinct from those of other Aeromonas strains.IMPORTANCEAeromonas salmonicida subsp. salmonicida is the causative agent of furunculosis, a bacterial septicemia of cold-water fish of the Salmonidae family. Although other Aeromonas species can produce melanin, A. salmonicida subsp. salmonicida is the only member of this genus that has been reported to exhibit temperature-dependent melanization. Here, we demonstrated that thermosensitive melanogenesis in A. salmonicida subsp. salmonicida strains is due to the thermolability of 4-hydroxyphenylpyruvate dioxygenase (HppD). Additionally, we confirmed that this thermolabile HppD exhibited higher activity at low temperatures than its mesophilic homologues, suggesting this as an adaptive strategy of this enzyme to the psychrophilic lifestyle of A. salmonicida subsp. salmonicida The strictly conserved hppD sequences among A. salmonicida subsp. salmonicida isolates and the specific possession of P103 and L119 residues could be used as a reference for the identification of A. salmonicida subsp. salmonicida isolates.


Inhibitory effect of angiogenesis inhibitor TNP-470 on tumor growth and metastasis of human cell lines in vitro and in vivo.
Antitumor activity of angiogenesis inhibitor TNP-470 was evaluated in eight human cultured cell lines derived from choriocarcinoma: SCH, NUC-1, and GCH-1(m); ovarian cancer; TYK and Nakajima; and uterine endometrial cancer: HEC-6, HEC-50, and HEC-1-A. After 7-day culture with TNP-470, in medium at the concentration of 10(1) to 10(-2) micrograms/ml, the inhibition of growth was observed in all of the eight cell lines. The 50% inhibitory concentration of choriocarcinona cell lines was at an extremely low level compared to that of epithelial ovarian cancer and uterine endometrial cancer. In addition, the antitumor effect of this compound was studied in in vivo experiments using nude mice with tumors of GCH-1(m), NUC-1, or Nakajima cells. When the size of the transplanted tumor reached 100-200 mm3 in volume, 3, 10, or 30 mg/kg of TNP-470 was injected s.c. every other day. The inhibitory effect of TNP-470 was obtained by the administration of 10 and 30 mg/kg in GCH-1(m) and NUC-1 cells, respectively, while in Nakajima cells no significant effect was observed. In nude mice treated with 30 mg/kg of TNP-470, lung metastasis of GCH-1(m) cells was strongly inhibited both in the number and in the size of tumor nodules, indicating that the capillary growth in the originally developed tumor was also significantly reduced. These results suggest that the clinical setting using TNP-470 may be one of the promising treatments for the metastasis of tumor cells.


Host microbiome-pathogen interactions in pediatric infections.
In this review, we discuss recent research that has furthered our understanding of microbiome development during childhood, the role of the microbiome in infections during this life stage, and emerging opportunities for microbiome-based therapies for infection prevention or treatment in children. The microbiome is highly dynamic during childhood and shaped by a variety of host and environmental factors. In turn, the microbiome influences risk and severity of a broad range of infections during childhood, with recent studies highlighting potential roles in respiratory, gastrointestinal, and systemic infections. The microbiome exerts this influence through both direct interactions with potential pathogens and indirectly through modulation of host immune responses. The elucidation of some of these mechanisms by recent studies and the development of effective microbiome-based therapies for adults with recurrent Clostridioides difficile infection highlight the enormous promise that targeting the microbiome has for reducing the burden of infectious diseases during childhood. The microbiome has emerged as a key modifier of infection susceptibility and severity among children. Further research is needed to define the roles of microbes other than bacteria and to elucidate the mechanisms underlying microbiome-host and microbiome-pathogen interactions of importance to infectious diseases in children.


Evaluation of the online learning of veterinary anatomy education during the Covid-19 pandemic lockdown in Egypt: Students' perceptions.
The sudden shift of veterinary anatomy teaching from traditional to online mode during the coronavirus disease 2019 (Covid-19) pandemic lockdown was a major challenge used for the first time in Egyptian veterinary medical schools. This study aimed to evaluate the students' perspectives regarding the shift of veterinary anatomy teaching to online mode during the lockdown in Egypt. A total of 502 students from all veterinary medical schools in Egypt (n = 17) answered the questionnaire. The results revealed that nearly two-thirds of students felt enthusiastic about studying anatomy online during the pandemic. Moreover, approximately 63% of students were satisfied with the provided learning materials, 66% were able to understand anatomy using the online learning system during the lockdown period, 67% were comfortable with technological skills during their online study, and 47% believed that online learning of anatomy could replace face-to-face teaching. Therefore, despite the problems associated with the emergency switch to remote teaching, it appears to be a suitable alternative in teaching veterinary anatomy in Egyptian universities during this pandemic crisis in Egyptian universities. Moreover, the study provided several measurements to overcome the common problems associated with this challenging method for future application, such as providing three-dimensional virtual tools and electronic devices with either free or low-priced Internet packages, and measuring students' understanding before and after each lecture. This is the first study to solicit the early students' feedback regarding the emergency shift to online veterinary anatomy teaching which might help decision-makers in Egypt for future implementation of online learning of veterinary anatomy.


Chrysotile asbestos in a California recreational area.
Dustfall along roads and trails being used recreationally in the Clear Creek area of San Benito County, California, located in the New Idria serpentinite, was found to be 90 percent or more chrysotile asbestos. Personal samplers worn by motorcyclists using one of the trails showed concentrations of airborne fibers ranging from 0.3 to 5.3 fibers per milliliter, according to methods prescribed for monitoring occupational exposures. The present workplace standard for brief exposures to asbestos is 10 fibers per milliliter; 5 fibers per milliliter is the proposed standard. The average total dust concentration estimated from personal samplers was approximately 20 milligrams per cubic meter of roughly 90 percent chrysotile. To our knowledge, this is the first demonstration of asbestos exposures of this magnitude, in size ranges known to be pathogenic, resulting from natural deposits not associated with mining, milling, or industrial use.


High-Fidelity Anthropometric Facial Measurements Can Be Obtained From a Single Stereophotograph From the Vectra H1 3-Dimensional Camera.
Anthropometry is a well-established means of measuring facial morphology. Although reliable, direct anthropometry can be time-consuming and not conducive to a busy clinical practice. The Vectra H1 handheld stereophotogrammetric system requires 3 stereophotographs taken from different perspectives to generate a three-dimensional (3D) surface. The time needed to take the 3 stereophotographs can increase the possibility of involuntary movements, precluding its use to assess young patients. To overcome this limitation, we evaluated if accurate linear facial measurements can be obtained from a single stereophotograph and compare these to the measurements taken by direct anthropometry. Twenty pediatric patients, aged 0 to 10 years, who were undergoing minor surgical procedures at Johns Hopkins All Children's Hospital were recruited. Fourteen linear facial distances were obtained from each participant using direct anthropometry under general anesthesia. These same distances were measured using Mirror 3D analysis. Intraclass correlation was used to determine intrarater reliability on duplicate 3D images. Correlation coefficients between 3D imaging in frontal view and direct anthropometric measurements were excellent for 13 measures taken, ranging from 0.8 (subnasale to columella and subnasale to stomion superius) to 0.98 (nasion to subnasale and subnasale to labiale superius). Correlation coefficients between submental view and direct anthropometric measurements were excellent for 13 measures as well, ranging from 0.77 (subnasale to columella) to 0.98 (nasion to subnasale). Linear anthropometric measurements taken from 3D surfaces generated from a single stereophotograph correlate closely with direct anthropometric measures. This improves workflow and applicability of anthropometric studies to our youngest patients.


The definition of rare disease in China and its prospects.
The latest definition of rare disease in China was released on September 11, 2021 at the third multidisciplinary expert seminar on the definition of rare diseases/orphan drugs in China. A rare disease is defined as a condition satisfying at least one of the following three criteria: an incidence among newborns of less than 1/10,000, a prevalence of less than 1/10,000, and an affected population of less than 140,000. Before this new definition, rare diseases were defined by different agencies with different parameters in China. The 2021 definition is a milestone, it could further spur the development of rare diseases beyond China's First List of Rare Disease in May 2018. This definition also provides a reference for the total number of rare diseases in China.


[The effect of maternal IGF-I on fetal and placental growth in mice].
Insulin-like growth factor-I (IGF-I) is a polypeptide that mediates growth-promoting actions of GH and has insulin-like activity. Increase in the levels of IGF-I in the maternal and fetal circulation during pregnancy and the identification of the specific receptors for IGF-I in a variety of fetal tissues suggest that IGF-I may play a significant role in the regulation of fetal growth. The present study was undertaken to determine the significance of maternal IGF-I on fetal and placental growth by administering the specific antiserum for IGF-I to pregnant mice. The antiserum was produced by repeatedly injecting recombinant IGF-I into rabbits. The antiserum obtained showed 30% binding to 125I-IGF-I at a dilution of 1:240,000, and crossreactivity with IGF-II was 0.012%. In the first set of experiments, pregnant mice were given a daily dose of 50 microliters of the original antiserum (E-1) or normal rabbit serum (C-1) into the peritoneal cavity between Day 3 and 10. In the second set of experiments, antiserum (E-2) or normal rabbit serum (C-2) was administered between Day 11 and 18. On Day 18, all mice were killed, blood was collected for measurement of levels of IGF-I by RIA, and the weights of fetuses and placentas in individual mice were recorded. The maternal levels of IGF-I in group E-1 and E-2 were extremely low compared to those in group C-1 and C-2. The number of fetuses and rate of abortion among each group were not significant.(ABSTRACT TRUNCATED AT 250 WORDS)


Hoxb1 controls cell fate specification and proliferative capacity of neural stem and progenitor cells.
The directed differentiation of embryonic stem cells (ESCs) into neural stem cells (NSCs) of specific identities and the identification of endogenous pathways that may mediate expansion of NSCs are fundamental goals for the treatment of degenerative disorders and trauma of the nervous system. We report that timely induction of a Hoxb1 transgene in ESC-derived NSCs resulted in the specification of NSCs toward a hindbrain-specific identity through the activation of a rhombomere 4-specific genetic program and the repression of anterior neural identity. This change was accompanied by changes in signaling pathways that pattern the dorsoventral (DV) axis of the nervous system and concomitant changes in the expression of DV neural progenitor markers. Furthermore, Hoxb1 mediated the maintenance and expansion of posterior neural progenitor cells. Hoxb1(+) cells kept proliferating upon mitogen withdrawal and became transiently amplifying progenitors instead of terminally differentiating. This was partially attributed to Hoxb1-dependent activation of the Notch signaling pathway and Notch-dependent STAT3 phosphorylation at Ser 727, thus linking Hox gene function with maintenance of active Notch signaling and the JAK/STAT pathway. Thus, timely expression of specific Hox genes could be used to establish NSCs and neural progenitors of distinct posterior identities. ESC-derived NSCs have a mixed DV identity that is subject to regulation by Hox genes. Finally, these findings set the stage for the elucidation of molecular pathways involved in the expansion of posterior NSCs and neural progenitors. Disclosure of potential conflicts of interest is found at the end of this article.


[Equivalence of combined decoction and mixed single decoctions of Gegen Qinlian Decoction in alleviating chemotherapy-associated diarrhea].
This study compared the chemical profiles, component content, dry paste yield, and pharmacological effects of samples obtained from the mixed single decoctions and the combined decoction of Gegen Qinlian Decoction(GQD), aiming to provide an experimental foundation for evaluating the equivalence of the two decocting methods and the suitability of TCM formula granules in clinical application. The same decoction process was used to prepare the combined decoction and mixed single decoctions of GQD. Ultra-performance liquid chromatography coupled with Q-Exactive Orbitrap mass spectrometry(UPLC-Q-Exactive Orbitrap MS) was employed to compare the chemical profiles between the two groups. High-performance liquid chromatography(HPLC) was used to compare the content of nine characteristic components between the two groups. Then, a delayed diarrhea mouse model induced by irinotecan was established to compare the pharmacological effects of the two groups on chemotherapy-induced diarrhea. The UPLC-Q-Exactive Orbitrap MS in ESI~+ and ESI~- modes identified 59 chemical components in the compound decoction and mixed single decoctions, which showed no obvious differences in component species. The content of baicalin and wogonoside was higher in the compound decoction, while that of puerarin, daidzein-8-C-apiosylglucoside, berberine, epiberberine, wogonin, glycyrrhizic acid, and daidzein was higher in the mixed single decoctions. Further statistical analysis revealed no significant difference in the content of the nine characteristic components between the compound decoction and the mixed single decoctions. The dry paste yield had no significant difference between the two groups. Compared with the model group, both compound decoction and mixed single decoctions alleviated the weight loss and reduced diarrhea index in mice. Both of them lowered the levels of tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), cyclooxygenase-2(COX-2), intercellular adhesion molecule-1(ICAM-1), interleukin-10(IL-10), malondialdehyde(MDA), and nitric oxide(NO) in the colon tissue. Furthermore, they significantly increased the levels of glutathione peroxidase(GSH-Px) and superoxide dismutase(SOD). Hematoxylin-eosin(HE) staining showed that colon tissue cells were tightly arranged with clear nuclei in both groups without obvious difference. The compound decoction and mixed single decoctions showed no significant differences in chemical component species, content of nine characteristic components, dry paste yield, or the pharmacological effects on alleviating chemotherapy-induced diarrhea. The findings provide a reference for evaluating the flexibility and superiority of combined or single decocting method in the preparation of TCM decoctions or formula granules.


Expression of the Yeast Delta-9 Fatty Acid Desaturase in Nicotiana tabacum.
To examine the processes of plant cytoplasmic fatty acid desaturation and glycerolipid biosynthesis, the protein coding sequence of the endoplasmic reticulum cytochrome b(5)-dependent, Delta-9 fatty acid desaturase gene from Saccharomyces cerevisiae was introduced into Nicotiana tabacum via Agrobacterium transformation. All transformed plants expressing the yeast gene at the mRNA level exhibited an approximately 10-fold increase in the levels of palmitoleic acid (16:1) in leaf tissue. This fatty acid species is found in very low levels (less than 2%) in wild-type plants. These results indicate that the yeast desaturase can function in plants, presumably by using a leaf microsomal cytochrome b(5)-mediated electron transport system. Lipid analysis demonstrated that the overproduced 16:1 is incorporated into most of the major polar lipid classes, including the cytoplasmically produced "eukaryotic" fraction of the chloroplast galactolipids. 16:1 was not found, however, in phosphatidyl glycerol, which is considered to be produced almost exclusively in the chloroplast. Despite these changes in membrane lipid composition, no obvious phenotypic differences were apparent in the transformed plants. Positional analysis shows that the cytoplasmically produced 16:1 is found primarily in the sn-2 position of phosphatidylcholine, phosphatidylethanolamine, monogalactosyldiacylglycerol, and digalactosyldiacylglycerol. The positional data suggest that the sn-2 acyltransferases responsible for the "eukaryotic" arrangement of 16- and 18- carbon fatty acids in glycerolipids are selective for unsaturated fatty acids rather than chain length.


Adult children of alcoholics--a treatable entity: an aviation case report.
This is a case report of a male naval aviator, raised in an alcoholic environment, and the impact of that environment on his development and adult functioning. A review of the adult children of alcoholics syndrome is presented to help familiarize the reader with this evolving entity and its probable impact on aviation personnel. In the United States, current estimates indicate that parental alcoholism affects 27 million children. Only about 5% of these children are receiving any evaluation, supportive care, or treatment. This case of a naval aviator affected by this syndrome illustrates the need for its recognition and potential for treatment and modification of maladaptive behavior. As a treatment entity, recognition of the adult children of alcoholics syndrome will hopefully have a positive effect upon aviation safety and will help save a valuable national asset, our trained aviation personnel.


Effects of a cognitive training program and sleep hygiene for executive functions and sleep quality in healthy elderly.
The aging process causes changes in the sleep-wake cycle and cognition, especially executive functions. Interventions are required to minimize the impact of the losses caused by the aging process. To evaluate the effects of a cognitive training program and psychoeducation on sleep hygiene techniques for executive functions and sleep quality in healthy elderly. The participants were 41 healthy elderly randomized into four groups ([CG] control group, cognitive training group [CTG], sleep hygiene group [SHG] and cognitive training and hygiene group [THG]). The study was conducted in three stages:1st - assessment of cognition and sleep;2nd - specific intervention for each group;3rd - post-intervention assessment. The results showed that the CTG had significant improvements in cognitive flexibility tasks, planning, verbal fluency and episodic memory, gains in sleep quality and decreased excessive daytime sleepiness. The SHG also had improved sleep quality, excessive daytime sleepiness and significant improvements in insights, planning, attention and episodic memory. The THG had significant gains in cognitive flexibility, problem solving, verbal fluency, attention and episodic memory. Cognitive training and sleep hygiene interventions were useful strategies for improving cognitive performance and sleep quality of healthy elderly, but there was no evidence that sessions combining cognitive training and psychoeducation on sleep hygiene enhanced the gains provided by these interventions applied individually.


Ultrafast X-ray Transient Absorption Spectroscopy of Gas-Phase Photochemical Reactions: A New Universal Probe of Photoinduced Molecular Dynamics.
Time-resolved spectroscopic investigations of light-induced chemical reactions with universal detection capitalize recently on single-photon molecular probing using laser pulses in the extreme ultraviolet or X-ray regimes. Direct and simultaneous mappings of the time-evolving populations of ground-state reactants, Franck-Condon (FC) and transition state regions, excited-state intermediates and conical intersections (CI), and photoproducts in photochemical reactions utilize probe pulses that are broadband and energy-tunable. The limits on temporal resolution are set by the transit- or dwell-time of the photoexcited molecules at specific locations on the potential energy surface, typically ranging from a few femtoseconds to several hundred picoseconds. Femtosecond high-harmonic generation (HHG) meets the stringent demands for a universal spectroscopic probe of large regions of the intramolecular phase-space in unimolecular photochemical reactions. Extreme-ultraviolet and soft X-ray pulses generated in this manner with few-femtosecond or sub-femtosecond durations have enormous bandwidths, allowing the probing of many elements simultaneously through excitation or ionization of core-electrons, creating molecular movies that shed light on entire photochemical pathways. At free electron lasers (FELs), powerful investigations are also possible, recognizing their higher flux and tunability but more limited bandwidths. Femtosecond time-resolved X-ray transient absorption spectroscopy, in particular, is a valuable universal probe of reaction pathways that maps changes via the fingerprint core-to-valence resonances. The particular power of this method over valence-ionization probes lies in its unmatched element and chemical-site specificities. The elements carbon, nitrogen, and oxygen constitute the fundamental building blocks of life; photochemical reactions involving these elements are ubiquitous, diverse, and manifold. However, table-top HHG sources in the "water-window" region (280-550 eV), which encompasses the 1s-absorption edges of carbon (284 eV), nitrogen (410 eV), and oxygen (543 eV), are far from abundant or trivial. Recent breakthroughs in the laboratory have embraced this region by using long driving-wavelength optical parametric amplifiers coupled with differentially pumped high-pressure gas source cells. This has opened avenues to study a host of photochemical reactions in organic molecules using femtosecond time-resolved transient absorption at the carbon K-edge. In this Account, we summarize recent efforts to deploy a table-top carbon K-edge source to obtain crucial chemical insights into ultrafast, ultraviolet-induced chemical reactions involving ring-opening, nonadiabatic excited-state relaxation, bond dissociation and radical formation. The X-ray probe provides a direct spectroscopic viewport into the electronic characters and configurations of the valence electronic states through spectroscopic core-level transitions into the frontier molecular orbitals of the photoexcited molecules, laying fertile ground for the real-time mapping of the evolving valence electronic structure. The profound detail and mechanistic insights emerging from the pioneering experiments at the carbon K-edge are outlined here. Comparisons of the experimental methodology with other techniques employed to study similar reactions are drawn, where applicable and relevant. We show that femtosecond time-resolved X-ray transient absorption spectroscopy blazes a new trail in the study of nonadiabatic molecular dynamics. Despite table-top implementations being largely in their infancy, future chemical applications of the technique will set the stage for widely applicable, universal probes of photoinduced molecular dynamics with unprecedented temporal resolution.


Common goals, different stages: the state of the ARTs for reptile and amphibian conservation.
Amphibians and reptiles are highly threatened vertebrate taxa with large numbers of species threatened with extinction. With so many species at risk, conservation requires the efficient and cost-effective application of all the tools available so that as many species as possible are assisted. Biobanking of genetic material in genetic resource banks (GRBs) in combination with assisted reproductive technologies (ARTs) to retrieve live animals from stored materials are two powerful, complementary tools in the conservation toolbox for arresting and reversing biodiversity decline for both amphibians and reptiles. However, the degree of development of the ARTs and cryopreservation technologies differ markedly between these two groups. These differences are explained in part by different perceptions of the taxa, but also to differing reproductive anatomy and biology between the amphibians and reptiles. Artificial fertilisation with cryopreserved sperm is becoming a more widely developed and utilised technology for amphibians. However, in contrast, artificial insemination with production of live progeny has been reported in few reptiles, and while sperm have been successfully cryopreserved, there are still no reports of the production of live offspring generated from cryopreserved sperm. In both amphibians and reptiles, a focus on sperm cryopreservation and artificial fertilisation or artificial insemination has been at the expense of the development and application of more advanced technologies such as cryopreservation of the female germline and embryonic genome, or the use of sophisticated stem cell/primordial germ cell cryopreservation and transplantation approaches. This review accompanies the publication of ten papers on amphibians and twelve papers on reptiles reporting advances in ARTs and biobanking for the herpetological taxa.


Dawn simulation light impacts on different cognitive domains under sleep restriction.
Chronic sleep restriction (SR) has deleterious effects on cognitive performance that can be counteracted by light exposure. However, it is still unknown if naturalistic light settings (dawn simulating light) can enhance daytime cognitive performance in a sustainable matter. Seventeen participants were enrolled in a 24-h balanced cross-over study, subsequent to SR (6-h of sleep). Two different light settings were administered each morning: a) dawn simulating light (DsL; polychromatic light gradually increasing from 0 to 250 lx during 30 min before wake-up time, with light around 250 lx for 20 min after wake-up time) and b) control dim light (DL; <8 lx). Cognitive tests were performed every 2 h during scheduled wakefulness and questionnaires were completed hourly to assess subjective mood. The analyses yielded a main effect of "light condition" for the motor tracking task, sustained attention to response task and a working memory task (visual 1 and 3-back task), as well as for the Simple Reaction Time Task, such that participants showed better task performance throughout the day after morning DsL exposure compared to DL. Furthermore, low performers benefited more from the light effects compared to high performers. Conversely, no significant influences from the DsL were found for the Psychomotor Vigilance Task and a contrary effect was observed for the digit symbol substitution test. No light effects were observed for subjective perception of sleepiness, mental effort, concentration and motivation. Our data indicate that short exposure to artificial morning light may significantly enhance cognitive performance in a domain-specific manner under conditions of mild SR.


Sex-specific incidence of hepatitis B virus flares among Bcr-Abl tyrosine kinase inhibitor users in Taiwan.
The use of Bcr-Abl TKI was found to be associated with hepatitis B (HBV) flares, with a more profound risk observed in females. This study was conducted to characterize the clinical features of patients with HBV flare among Bcr-Abl TKI users, to estimate sex-specific incidence rates of HBV flare, and to evaluate potential cumulative effect of Bcr-Abl TKI. Bcr-Abl TKI users with chronic HBV infection were identified from Taiwan's National Health Insurance database. The HBV flare cases were identified within the cohort. Incidence rates of HBV flare between men and women were assessed. Nested case-control analysis was used to evaluate the cumulative effect of Bcr-Abl TKI use on HBV flare. Among 415 patients with chronic HBV infection treated with Bcr-Abl TKI from 2005 through 2018, 45 flare cases (28 males and 17 females) were identified. Days between Bcr-Abl TKI initiation and HBV flare was 319 days in women compared to 610 days in men. 66.7% of the flares occurred during TKI therapy. Twelve of the 45 patients died, half of them died around 6 months after hepatitis B flare. Incidence rates of HBV flare were 2.34 and 3.33 per 100 person-years in males and females, respectively. Higher incidence was observed among patients with chronic myeloid leukemia. Cumulative effect of Bcr-Abl TKI on HBV flare was not observed. Approximately 10% of HBV carriers who used Bcr-Abl TKI experienced HBV flare in Taiwan. The risk was higher in women and among patients with chronic myeloid leukemia.


Sti1 is a novel activator of the Ssa proteins.
The molecular chaperones Hsp70 and Hsp90 are involved in the folding and maturation of key regulatory proteins in eukaryotes. Of specific importance in this context is a ternary multichaperone complex in which Hsp70 and Hsp90 are connected by Hop. In Saccharomyces cerevisiae two components of the complex, yeast Hsp90 (yHsp90) and Sti1, the yeast homologue of Hop, had already been identified, but it remained to be shown which of the 14 different yeast Hsp70s are part of the Sti1 complex and what were the functional consequences resulting from this interaction. With a two-hybrid approach and co-immunoprecipitations, we show here that Sti1 specifically interacts with the Ssa group of the cytosolic yeast Hsp70 proteins. Using purified components, we reconstituted the dimeric Ssa1-Sti1 complex and the ternary Ssa1-Sti1-yHsp90 complex in vitro. The dissociation constant between Sti1 and Ssa1 was determined to be 2 orders of magnitude weaker than the affinity of Sti1 for yHsp90. Surprisingly, binding of Sti1 activates the ATPase of Ssa1 by a factor of about 200, which is in contrast to the behavior of Hop in the mammalian Hsp70 system. Analysis of the underlying activation mechanism revealed that ATP hydrolysis is rate-limiting in the Ssa1 ATPase cycle and that this step is accelerated by Sti1. Thus, Sti1 is a potent novel effector for the Hsp70 ATPase.


Intrathymic elimination of Mlsa-reactive (V beta 6+) cells during neonatal tolerance induction to Mlsa-encoded antigens.
The cellular basis of neonatally induced T cell tolerance has been investigated in a model system in which usage of a particular TCR V beta segment (V beta 6) is strongly correlated with reactivity to antigens encoded by the Mlsa genetic locus. Expression of V beta 6 by peripheral T cells was virtually abolished in BALB/c (H-2d, Mlsb) mice rendered neonatally tolerant to DBA/2 (H-2d, Mlsa) lymphoid cells, whereas control V beta 8-bearing T cells remained at near normal levels. Further analysis revealed that elimination of V beta 6+ T cells occurred in the thymus of neonatally tolerant mice and could not be explained by receptor modulation or T cell chimerism. These data thus support the clonal deletion model of tolerance induction.


Patient misidentification in nursing care.
The goal of the study was to assess the opinions of nurses regarding patient safety associated with patient misidentification. The investigation was focused on actual patient misidentification as well as loss of patient materials (e.g., blood samples, X-rays, etc.). These are problems often associated with patient identification methods and/or confusing patients with the same surname assigned to the same ward. The risks of misidentification incidents pose a considerable threat to patient health especially when the confusion extends to the operating room. Our objective was to identify the potential causes of patient misidentification and offers solutions to correct the issue. A survey as part of a sociological investigation was carried out through the use of questionnaires. The selected sample included, in accordance with the needs of the project and methodology of the Institute for Health Care Information and Statistics of the Czech Republic, registered nurses working shifts on inpatient wards. The study took place across the Czech Republic between Sept. 15 and 30, 2013. The sample consisted of 772 registered nurses. The potential for patient misidentification (PM) was described as negligible by 73.8% of respondents. Only 9.1% of nurses admitted problems associated with patient misidentification. Respondents reported that the greatest potential for patient misidentification was associated with patients having the same surname staying on the same ward. An absolute majority of nurses responded that patient identification wristbands were the most frequently used method to prevent PM. Over 90% (90.6%) of nurses reported that patient ID wristbands were used for all patients. Almost 80% (77.4%) reported the use of positive verbal identification in addition to ID wrist bands. Respondents reported (76.2%) that the most frequently used method to avoid PM in the operating room involved a review of patient documentation. Almost the same number of repondents (74.1%) reported the use of verbal confirmation as a method to avoid PM. Another mechanism included verification of the surgical procedure. ID wristbands and completion of an 'identification protocol' rank among other options mentioned most frequently by respondents. The study shows that registered nurses regard patient misidentification as a very rare and unlikely event. Nonetheless, statistics suggest otherwise and education, changes in protocols, and new technologies are needed to improve the precision of patient identification.


Histochemical studies on the effect of propoxur on yolk synthesis in the ovarioles of the blow fly, Chrysomyia albiceps (Wiedemann) (Diptera: Calliphoridae).
The effect of the carbamate insecticide, propoxur, on yolk synthesis in the ovarioles of the blow fly, Chrysomyia albiceps (Wiedemann) was studied. Histochemical studies showed that DNA, RNA, protein and lipid synthesis in propoxur--treated ovarioles decreased as compared to that in non-treated ovarioles, with some deteriorations in the chromatin materials in the nuclei of some nurse cells. On the other hand, the synthesis of carbohydrate is more or less not affected.


Aerosolized acetaldehyde induces histamine-mediated bronchoconstriction in asthmatics.
It has been reported that acetaldehyde may be a main factor of alcohol-induced bronchoconstriction in Japanese patients with asthma. The purpose of this study was to investigate the direct action of acetaldehyde on the airway in asthmatic and healthy nonasthmatic subjects. We investigated the bronchial response to inhalation of ascending doses (5, 10, 20, and 40 mg/ml) of acetaldehyde in nine asthmatic subjects, who were treated with placebo or terfenadine for 4 days in a double-blind, randomized, placebo-controlled, crossover fashion, and in nine age- and sex-matched healthy subjects. The bronchial responsiveness to inhaled methacholine was also measured in the same asthmatics on a separate day. Inhaled acetaldehyde caused marked (more than 20%) significant decrease in FEV1 in asthmatics after placebo, which was larger than that in asthmatics after terfenadine and in healthy subjects. There was no significant difference in the decrease in FEV1 between asthmatics treated with terfenadine and healthy subjects. There was a significant correlation between the methacholine and acetaldehyde concentrations producing a 20% fall in FEV1 in asthmatics. We conclude that acetaldehyde causes bronchoconstriction indirectly via histamine release in asthmatics, and that nonspecific bronchial hyperresponsiveness is a necessary precondition for the expression of acetaldehyde-produced bronchoconstriction.


Catalytic reductive aminations using molecular hydrogen for synthesis of different kinds of amines.
Reductive aminations constitute an important class of reactions widely applied in research laboratories and industries for the synthesis of amines as well as pharmaceuticals, agrochemicals and biomolecules. In particular, catalytic reductive aminations using molecular hydrogen are highly valued and essential for the cost-effective and sustainable production of different kinds of amines and their functionalization. These reactions couple easily accessible carbonyl compounds (aldehydes or ketones) with ammonia, amines or nitro compounds in the presence of suitable catalysts and hydrogen that enable the preparation of linear and branched primary, secondary and tertiary amines including N-methylamines and molecules used in life science applications. In general, amines represent valuable fine and bulk chemicals, which serve as key precursors and central intermediates for the synthesis of advanced chemicals, life science molecules, dyes and polymers. Noteworthily, amine functionalities are present in a large number of pharmaceuticals, agrochemicals and biomolecules, and play vital roles in the function of these active compounds. In general, reductive aminations are challenging processes, especially for the syntheses of primary amines, which often are non-selective and suffer from over-alkylation and reduction of carbonyl compounds to the corresponding alcohols. Hence, the development of suitable catalysts to perform these reactions in a highly efficient and selective manner is crucial and continues to be important and attracts scientific interest. In this regard, both homogeneous and heterogeneous catalysts have successfully been developed for these reactions to access various amines. There is a need for a comprehensive review on catalytic reductive aminations to discuss the potential catalysts used and applicability of this methodology in the preparation of different kinds of amines, which are of commercial, industrial and medicinal importance. Consequently, in this review we discuss catalytic reductive aminations using molecular hydrogen and their applications in the synthesis of functionalized and structurally diverse benzylic, heterocyclic and aliphatic primary, secondary and tertiary amines as well as N-methylamines and more complex drug targets. In addition, mechanisms of reductive aminations including selective formation of desired amine products as well as possible side reactions are emphasized. This review aims at the scientific communities working in the fields of organic synthesis, catalysis, and medicinal and biological chemistry.


Infectious disease prevalence in a feral cat population on Prince Edward Island, Canada.
Ninety-six feral cats from Prince Edward Island were used to determine the prevalence of selected infectious agents. The prevalence rates were 5.2% for feline immunodeficiency virus, 3.1% for feline leukemia virus, 3.1% for Mycoplasma haemofelis, 8.4% for Candidatus Mycoplasma haemominutum, 2.1% for Bartonella spp. and 29.8% for exposure to Toxoplasma gondii. Oocysts of T. gondii were detected in 1.3% of the fecal samples that were collected. Gender and retroviral status of the cats were significantly correlated with hemoplasma infections. Use of a flea comb showed that 9.6% of the cats had fleas; however, flea infestation was not associated with any of the infectious agents.


Comparison of calcium and magnesium absorption: in vivo and in vitro studies.
Transport characteristics of Ca and Mg were compared at three different levels of the absorptive process in male (120-170 g) Wistar rats. Balance studies in intact rats revealed that fractional Ca absorption decreased with increased Ca intake so that net Ca absorption remained constant. Fractional Mg absorption decreased modestly with increased Mg intake so that net Mg absorption increased proportionately with increased dietary Mg. Everted duodenal sacs demonstrated the presence of active Ca absorption with serosal-to-mucosal (S/M) ratio of 2.65 +/- 0.20 (n = 6), which was greater than unity (P less than 0.001). In contrast, the S/M for Mg did not exceed unity. Mucosal duodenal Ca uptake exhibited a large saturable (Michaelis constant of 4.80 +/- 0.34 mM, maximal velocity of 4.71 +/- 0.13 nmol.min-1.mg-1) and a small nonsaturable component (0.12 +/- 0.01 nmol.min-1.mg-1) in 5-wk-old rats (120 g). In 72-wk-old rats (600 g) the diffusional component of Ca uptake became predominant, and the slope increased significantly to 0.32 +/- 0.01 (P less than 0.05). Duodenal Mg uptake was completely concentration dependent and exhibited no age-related changes.


Trace and major elements in food supplements of different origin: Implications for daily intake levels and health risks.
As the use of food supplements increases, voices are being raised questioning the safety of these products. As a contribution to understanding the trace and major elemental composition of food supplements and their potential health risks, this study presents concentrations of 71 elements in 138 supplements, categorised into synthetic products and three groups of products with natural ingredients. Concentrations were converted into average daily doses (ADDs) and compared to tolerable daily intakes (TDIs). For elements where we found significant ADDs relative to the TDI a comparison was also made to the normal dietary intake. Our main findings are that: 1) Most elements display highly variable concentrations in food supplements; more so than in normal foodstuff; 2) For ten of the analysed elements some products rendered ADDs > 50 % of the TDI. Half of the elements were essential (Fe, Mn, Se, Mo, Zn), and as such motivated in food supplements. The other half (As, Pb, Cd, Al, Ni) represent non-essential and highly toxic elements, where the occurrence in food supplements ought to be viewed as contamination. Although none of these toxic metals were declared on any product's table of content, several products gave high ADDs - in several cases even exceeding the TDIs; 3) The risk of reaching high ADDs for the toxic elements is strongly associated with products that contain marine ingredients (e.g. algae, mussels etc), and to some degree products of terrestrial plant-based origin. The health of consumers would benefit if food regulatory frameworks were updated to better address the risks of food supplements occasionally being contaminated with different toxic metals, for example by setting maximum permissible concentrations for a longer list of elements.


Ovarian steroid cell tumors: an immunohistochemical study including a comparison of calretinin with inhibin.
Ovarian steroid cell tumors, not otherwise specified (SCTs, NOS) are uncommon sex cord-stromal tumors that may be difficult to distinguish from other oxyphilic or clear-cell neoplasms. Immunohistochemical staining for inhibin, although generally useful in the diagnosis of SCTs, NOS, is not positive in every case and not all laboratories have this marker available. Recently, it has been reported that calretinin is expressed by sex cord-stromal tumors. We studied six SCTs, NOS for both calretinin and inhibin expression to evaluate the sensitivity of calretinin in comparison to inhibin. We also tested for CD99, Melan-A (A103), and S-100, other markers reported to be positive in these tumors. HMB-45 and MART-1 (Ab3) completed our panel of markers. All six tumors were positive for both calretinin and inhibin. Calretinin positivity was present in 60% to >90% of tumor cells, whereas inhibin reactivity ranged from <5% to >90% of tumor cells. Membranous staining for CD99 was present in one tumor. S-100-positive cells were seen in two tumors, whereas four tumors were immunoreactive for HMB-45. All six tumors were positive for Melan-A (A103), but in general the staining was less diffuse than with calretinin. All of the tumors were essentially negative for MART-1 (Ab3). The consistent diffuse staining of the tumors in this study for calretinin, in comparison to inhibin and Melan-A (A103), suggests that it is a sensitive marker for SCTs, NOS. MART-1 (Ab3) immunostaining may be useful for cases in which melanoma is considered in the differential diagnosis.


Effect of Low-Sodium versus Conventional Sodium Dialysate on Left Ventricular Mass in Home and Self-Care Satellite Facility Hemodialysis Patients: A Randomized Clinical Trial.
Fluid overload in patients undergoing hemodialysis contributes to cardiovascular morbidity and mortality. There is a global trend to lower dialysate sodium with the goal of reducing fluid overload. To investigate whether lower dialysate sodium during hemodialysis reduces left ventricular mass, we conducted a randomized trial in which patients received either low-sodium dialysate (135 mM) or conventional dialysate (140 mM) for 12 months. We included participants who were aged >18 years old, had a predialysis serum sodium ≥135 mM, and were receiving hemodialysis at home or a self-care satellite facility. Exclusion criteria included hemodialysis frequency >3.5 times per week and use of sodium profiling or hemodiafiltration. The main outcome was left ventricular mass index by cardiac magnetic resonance imaging. The 99 participants had a median age of 51 years old; 67 were men, 31 had diabetes mellitus, and 59 had left ventricular hypertrophy. Over 12 months of follow-up, relative to control, a dialysate sodium concentration of 135 mmol/L did not change the left ventricular mass index, despite significant reductions at 6 and 12 months in interdialytic weight gain, in extracellular fluid volume, and in plasma B-type natriuretic peptide concentration (ratio of intervention to control). The intervention increased intradialytic hypotension (odds ratio [OR], 7.5; 95% confidence interval [95% CI], 1.1 to 49.8 at 6 months and OR, 3.6; 95% CI, 0.5 to 28.8 at 12 months). Five participants in the intervention arm could not complete the trial because of hypotension. We found no effect on health-related quality of life measures, perceived thirst or xerostomia, or dietary sodium intake. Dialysate sodium of 135 mmol/L did not reduce left ventricular mass relative to control, despite improving fluid status. The Australian New Zealand Clinical Trials Registry, ACTRN12611000975998.


New and Recurrent Ulcerations after Free Tissue Transfer with Partial Bony Resection in Chronic Foot Wounds within a Comorbid Population.
Chronic foot wounds often require bony resection; however, altering the tripod of the foot carries a risk of new ulcer development nearing 70%. Resulting defects often require free tissue transfer (FTT) reconstruction; outcomes data for various bony resection and FTT options may guide clinical decision-making regarding bone and soft-tissue management. The authors hypothesized that alteration of the bony tripod will increase risk of new lesion development after FTT reconstruction. A single-center retrospective cohort analysis of patients undergoing FTT from 2011 through 2019 with bony resection and soft-tissue defects of the foot was performed. Data collected included demographics, comorbidities, wound locations, and FTT characteristics. Primary outcomes were recurrent lesion (RL) and new lesion (NL) development. Multivariate logistic regression and Cox hazards regression were used to produce adjusted odds ratios and hazard ratios. Sixty-four patients (mean age, 55.9 years) who underwent bony resection and FTT were included. Mean Charlson Comorbidity Index was 4.1 (SD 2.0), and median follow-up was 14.6 months (range, 7.5 to 34.6 months). Wounds developed after FTT in 42 (67.1%) (RL, 39.1%; NL, 40.6%). Median time to NL development was 3.7 months (range, 0.47 to 9.1 months). First-metatarsal defect (OR, 4.8; 95% CI, 1.5 to 15.7) and flap with cutaneous component (OR, 0.24; 95% CI, 0.07 to 0.8) increased and decreased odds of NL development, respectively. First-metatarsal defects significantly increase NL risk after FTT. The majority of ulcerations heal with minor procedures but require long-term follow-up. Soft-tissue reconstruction with FTT achieves success in the short term, but NL and RL occur at high rates in the months to years after initial healing. Risk, III.


A population-based sex-stratified study to understand how health status preceding traumatic brain injury affects direct medical cost.
To understand how pre-injury health status present five-years preceding traumatic brain injury (TBI) affects direct medical cost two years post-injury. Patients age ≥19 years in the emergency department (ED) or acute care for a TBI between April 1, 2007 and March 31, 2014 in Ontario, Canada (N = 55,669) were identified from population-based health administrative data. Forty-three factors of pre-injury health status (i.e., comorbidities and personal, social, and environmental factors) that were internally validated for the TBI population were assessed in this study. The outcome of interest was direct medical cost within two years of discharge. Sex-specific multivariable linear regressions were conducted to understand the associations between direct medical cost within two years of discharge and pre-injury health status. Patients who received care in the ED (81.9% of total sample) incurred a median cost of $2,492/male patient (average $12,342/patient) and $3,508/female patient (average $65,285/patient) within two years of injury; 37 pre-injury factors were significantly associated with increased direct medical costs. Patients who first received care for their TBI in acute care (18.1%) incurred a median cost of $25,081/male patient (average $63,060/patient) and $30,277/female patient (average $65,285/patient) within two years of injury; 21 factors were significantly associated with increased direct medical costs. Among more prevalent factors, those associated with increased medical cost by at least 50% included mental health disorders, substance abuse, disorders or medical conditions frequently observed among the elderly, cardiovascular disorders, stroke and emergencies involving the brain, metabolic disorders and abdominal symptoms, conditions and symptoms of abdomen and pelvis, genitourinary disorders and disorders of prostate, and pulmonary abdominal and other emergencies. Direct medical costs two years post-TBI differed significantly between patients with and without adverse pre-existing health status. Interdisciplinary teams to promote early identification of pre-existing health conditions and appropriate management and integration of these conditions in TBI care across the continuum of healthcare may be opportunities to reduce direct medical costs post-injury.


Effect of the Pleiotropic Drug CNB-001 on Tissue Plasminogen Activator (tPA) Protease Activity in vitro: Support for Combination Therapy to Treat Acute Ischemic Stroke.
Current state-of-the-art acute ischemic stroke clinical trials are designed to study neuroprotectants when administered following thrombolysis; tissue plasminogen activator (tPA) is administered to patients within 3-4.5 hours of an ischemic event. Thus, in order to develop a novel neuroprotectant and move it forward to a clinical trial, it is important to assess the effects of the drug on tPA's proteolytic activity in vitro, prior to extensive in vivo analysis. In this study, we determined if CNB-001 [4-((1E)-2-(5-(4-hydroxy-3-methoxystyryl-)-1-phenyl-1H-pyrazoyl-3-yl)vinyl)-2-methoxy-phenol)], would affect, either enhance or inhibit tPA activity in vitro. In this tPA-inhibitor (plasminogen activator inhibitor-1; PAI-1 and 2,7-Bis-(4-Amidinobenzylidene)-Cycloheptan-1-One Dihydrochloride; tPA stop) controlled study, we used a chromogenic substrate (CH3SO2-D-hexahydrotyrosine-Gly-Arg-p-nitroanilide•AcOH) to study drug interactions in vitro, spectrophotometrically measuring protease released p-Nitroaniline from the substrate. We found that PAI-1 (0.25 μM) and tPA stop (5 μM) significantly (p<0.0001) inhibited substrate release, by 98.6% and 83.4%, respectively, thus inhibiting tPA activity in vitro. In comparison, CNB-001 (0.7-7 μM) reduced tPA activity by 28-32%, with an extrapolated IC50 value of 65.2-704 μM. Thus, although high concentrations of CNB-001 does affects tPA activity in vitro, the study supports the use of CNB-001 in combination with tPA to treat stroke, However, CNB-001 should be administered following thrombolysis to promote neuroprotection and repair.


Income-Related Inequality In Affordability And Access To Primary Care In Eleven High-Income Countries.
A high-performing health care system strives to achieve universal access, affordability, high-quality care, and equity, aiming to reduce inequality in outcomes and access. Using data from the 2020 Commonwealth Fund International Health Policy Survey, we report on health status, socioeconomic risk factors, affordability, and access to primary care among US adults compared with ten other high-income countries. We highlight health experiences among lower-income adults and compare income-related disparities between lower- and higher-income adults across countries. Results indicate that among adults with lower incomes, those in the US fare relatively worse on affordability and access to primary care than those in other countries, and income-related disparities across domains are relatively greater throughout. The presence of these disparities should strengthen the resolve to find solutions to eliminate income-related inequality in affordability and primary care access.


[Inicial care in severe pediatric trauma]
OBJECTIVES: To present objectively the therapeutic aspects for the management of child victim of trauma.METHODS: The most relevant articles about the management of acute trauma were selected.RESULTS: Children possess great potential for recovery after a trauma, however, inappropriate resuscitation is the major cause of death preventable.Care in the opening and maintenance of the airways, adequate input of fluid to the child victim of politrauma or burns as well as prompt diagnosis and effective management to internal bleeding has improved prognosis and can reduce mortality considerably. Initial assessment and management of the injured child requires immediate procedures towards respiratory failure, shock and life-threatening thoracic injuries in order to provide efficient ventilation, oxyge-nation and perfusion until definitive treatment is performed. Concomitantly, the cervical spine should be protected against new injuries or progression of established injury.CONCLUSIONS: Effective actions in order to prevent accidents and rigorous laws to protect children and adolescents, associated to training and practice of specific procedures to the politraumatized child could surely reduce the unacceptable morbi-mortality in our country.


Structural properties and cellular expression of AfrLEA6, a group 6 late embryogenesis abundant protein from embryos of Artemia franciscana.
Late embryogenesis abundant (LEA) proteins are intrinsically disordered proteins (IDPs) commonly found in anhydrobiotic organisms and are frequently correlated with desiccation tolerance. Herein we report new findings on AfrLEA6, a novel group 6 LEA protein from embryos of Artemia franciscana. Assessment of secondary structure in aqueous and dried states with circular dichroism (CD) reveals 89% random coil in the aqueous state, thus supporting classification of AfrLEA6 as an IDP. Removal of water from the protein by drying or exposure to trifluoroethanol (a chemical de-solvating agent) promotes a large gain in secondary structure of AfrLEA6, predominated by α-helix and exhibiting minimal β-sheet structure. We evaluated the impact of physiological concentrations (up to 400 mM) of the disaccharide trehalose on the folding of LEA proteins in solution. CD spectra for AfrLEA2, AfrLEA3m, and AfrLEA6 are unaffected by this organic solute noted for its ability to drive protein folding. AfrLEA6 exhibits its highest concentration in vivo during embryonic diapause, drops acutely at diapause termination, and then declines during development to undetectable values at the larval stage. Maximum cellular titer of AfrLEA6 was 10-fold lower than for AfrLEA2 or AfrLEA3, both group 3 LEA proteins. Acute termination of diapause with H2O2 (a far more effective terminator than desiccation in this Great Salt Lake, UT, population) fostered a rapid 38% decrease in AfrLEA6 content of embryos. While the ultimate mechanism of diapause termination is unknown, disruption of key macromolecules could initiate physiological signaling events necessary for resumption of development and metabolism.


Vertebral artery dissection presenting with isolated neck pain.
Unilateral pain in the cervical region and limitation of neck movements are nonspecific symptoms frequently encountered in daily medical practice. Vertebral artery dissection is rarely considered as a diagnostic possibility unless brainstem or cerebellar ischemia follows the acute pain. Three cases of vertebral artery dissection (VAD) having the sole complaint of pain of acute onset in the posterior neck region are presented. None of the patients had ever reported a similar pain, and the neurological examination was unremarkable in all of them. Doppler ultrasonography suggested VAD in 2 cases, and the diagnosis was confirmed with T1 fat-suppressed magnetic resonance imaging technique in all patients. Severe neck pain and/or occipital headache frequently accompanies ischemic symptoms in cases with VAD. The cases in this report emphasize that spontaneous and often unilateral posterior cervical pain of acute onset can be the only manifestation of a VAD. A high degree of suspicion especially in young patients with no past history of a similar pain can help to establish the diagnosis, thereby preventing erroneous and potentially hazardous therapeutic interventions such as physiotherapy or neck manipulation.


New-onset atrial fibrillation in severe sepsis and risk of stroke and death: a critically appraised topic.
Severe sepsis has been associated with an increased risk of new-onset arrhythmias, namely atrial fibrillation (AF). Single-center and small-center studies suggest that new-onset AF is associated with higher mortality and prolonged hospitalization during severe sepsis. However, the relationship between new-onset AF in severe sepsis to prognosis is unknown. To determine whether new-onset AF increases the risk of stroke and death in severe sepsis. The objective was addressed through the development of a structured, critically appraised topic. This incorporated a clinical scenario, background information, a structured question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and fellow-level neurologists, a medical librarian, clinical epidemiologists, and context experts in the fields of vascular neurology, hospital neurology, critical care medicine, and cardiovascular medicine. A recent retrospective, population-based cohort study was selected and appraised to address this prognostic question. Patients were obtained from the California State Inpatient Database administrative claims data from nonfederal acute care hospitals from January 1 through December 31, 2007. Of the 3,144,787 patients, 49,082 (1.56%) had severe sepsis, defined by the validated International Classification of Disease, 9th Revision, Clinical Modification code 995.92. The a priori outcome measures included in-hospital ischemic stroke and mortality. New-onset AF occurred in 5.9% of patients with severe sepsis versus 0.65% of patients without severe sepsis [odds ratio, 6.82; 95% confidence interval (CI), 6.52-7.11; P<0.001]. Compared with severe sepsis patients without new-onset AF, patients with new-onset AF during severe sepsis had greater risks of in-hospital ischemic stroke (2.6% vs. 0.6% strokes; adjusted odds ratio, 2.70; 95% CI, 2.05-3.57; P<0.001) and in-hospital mortality (56% vs. 39% deaths; adjusted relative risk, 1.07; 95% CI, 1.04-1.11; P<0.001). Findings were robust across 2 separate definitions of severe sepsis and multiple sensitivity analyses. In patients with severe sepsis, new-onset AF seems to increase the risk of in-hospital stroke and mortality compared with patients with no or preexisting AF.


Sequential dependencies in recall of sequences: filling in the blanks.
Sequential dependencies can provide valuable information about the processes supporting memory, particularly memory for serial order. Earlier analyses have suggested that anticipation errors-reporting items ahead of their correct position in the sequence-tend to be followed by recall of the displaced item, consistent with primacy gradient models of serial recall. However, a more recent analysis instead suggests that anticipation errors are followed by further anticipation errors, consistent with chaining models. We report analyses of 21 conditions from published serial recall data sets, in which we observed a systematic pattern whereby anticipations tended to be followed by the "filling in" of displaced items. We note that cases where a different pattern held tended to apply to recall of longer lists under serial learning conditions or to conditions where participants were free to skip over items. Although the different patterns that can be observed might imply a dissociation (e.g., between short- and long-term memory), we show that these different patterns are naturally predicted by Farrell's (Psychological Review 119:223-271, 2012) model of short-term and episodic memory and relate to whether or not spontaneously formed groups of items can be skipped over during recall.


Human papillomavirus genome detection by in situ hybridization in fine-needle aspirates of metastatic lesions from head and neck squamous cell carcinomas.
Patients with head and neck squamous cell carcinoma (HNSCC) often present with metastatic disease. The diagnosis of metastatic lesions usually is determined by fine-needle aspiration. Human papillomavirus (HPV) is now being considered as a causative agent in a subset of HNSCC. The objectives of this study were, first; to search for the presence of HPV DNA by in situ hybridization (ISH) in metastatic lesions from HNSCC using alcohol-fixed, archival, cytopathologic material; second, to characterize the cytologic features of HPV-positive metastatic lesions of HNSCC; and, third, to determine whether there is a correlation between the presence of HPV DNA and the origin of metastatic lesions. The authors performed chromogenic ISH analysis for HPV DNA on fine-needle aspiration materials from metastatic lesions from 26 patients with HNSCC. Along with the ISH analysis, a detailed cytologic review was performed, and cytopathologic features were recorded. The HPV DNA status in metastatic lesion was correlated with cytopathologic features and primary tumor location. The integration of HPV DNA was visualized microscopically on tumor cell nuclei in 15% of aspirates. The anatomic locations of the study samples were as follows: 16 lymph node aspirates (11 cervical lymph nodes and 5 lymph nodes at other sites other), 5 tracheostomy sites, and 5 miscellaneous sites located on the head and neck area. Cytologic review revealed 13 keratinized and 13 nonkeratinized metastatic tumors. HPV DNA was detected in four metastatic sites (three lymph nodes and one tracheostomy site). All HPV DNA-positive tumors were of the nonkeratinizing type (P < 0.05; Fisher exact test). The origins of HPV-positive tumors included two laryngeal sites, one nasopharyngeal site, and one oral cavity site. The current findings showed that archival cytology slides can be used for HPV DNA detection with ISH. The results also showed that HPV DNA-containing HNSCC has distinctively nonkeratinizing cytologic features. The authors concluded that HPV DNA not only is involved in the initiation of tumoral processes but also plays an important role in the development of metastatic disease.


The CounterACT Research Network: basic mechanisms and practical applications.
The National Institutes of Health has developed a comprehensive research program that includes research centers of excellence, individual research projects, small business projects, contracts, and interagency agreements to conduct basic, translational, and clinical research aimed at the discovery and/or identification of better medical countermeasures against chemical threat agents. Chemical threats include chemical warfare agents, toxic industrial and agricultural chemicals, and toxins and other chemicals that could be used intentionally as an act of terror or by large-scale accidents or natural disasters. The overarching goal of this research program is to enhance our medical response capabilities during an emergency. The program is named Countermeasures Against Chemical Threats (CounterACT). It supports translational research, applying ideas, insights, and discoveries generated through basic scientific inquiry to the treatment or prevention of mortality and morbidity caused by chemical threat agents. The categories of research supported under this program include creation and development of screening assays and animal models for therapy development, identification of candidate therapeutics, obtaining preliminary proof-of-principle data on the efficacy of candidate therapeutics, advanced efficacy and preclinical safety studies with appropriate animal models using Good Laboratory Practices (GLP), and clinical studies, including clinical trials with new drugs. Special consideration is given to research relevant to people who are particularly vulnerable, including the young, the elderly, and individuals with pre-existing medical conditions.


Modelling of the feed-to-fillet transfer of ethoxyquin and one of its main metabolites, ethoxyquin dimer, to the fillet of farmed Atlantic salmon (Salmon salar L.).
Ethoxyquin (EQ) is an antioxidant supplemented to feed ingredients, mainly fish meal, which is currently under re-evaluation for use in the food production chain. EQ is partly metabolized into several metabolites of which the ethoxyquin dimer (EQDM) accumulates most in the farmed fish fillet. In this study, the feed-to-fillet transfer of dietary EQ and EQDM in Atlantic salmon fillet was investigated, and a physiologically based pharmacokinetic (PBPK-) two-compartmental model was developed, based on experimental determined EQ and EQDM uptake, metabolism, and elimination kinetics. The model was verified with an external data-set and used to simulate the long term (>1.5 years) EQ and EQDM feed-to fillet transfer in Atlantic salmon under realistic farming conditions such as the seasonal fluctuations in feed intake, growth, and fillet fat deposition. The model predictions showed that initial EQDM levels in juvenile fish are the driving factor in final levels found in food-producing animals, while for EQ the levels in feed, and seasonal variations were the driving factor for food EQ levels.


Comprehensive genomic transcriptomic tumor-normal gene panel analysis for enhanced precision in patients with lung cancer.
A CMS approved test for lung cancer is based on tumor-only analysis of a targeted 35 gene panel, specifically excluding the use of the patient's normal germline tissue. However, this tumor-only approach increases the risk of mistakenly identifying germline single nucleotide polymorphisms (SNPs) as somatically-derived cancer driver mutations (false positives). 621 patients with 30 different cancer types, including lung cancer, were studied to compare the precision of tumor somatic variant calling in 35 genes using tumor-only DNA sequencing versus tumor-normal DNA plus RNA sequencing. When sequencing of lung cancer was performed using tumor genomes alone without normal germline controls, 94% of variants identified were SNPs and thus false positives. Filtering for common SNPs still resulted in as high as 48% false positive variant calling. With tumor-only sequencing, 29% of lung cancer patients had a false positive variant call in at least one of twelve genes with directly targetable drugs. RNA analysis showed 18% of true somatic variants were not expressed. Thus, sequencing and analysis of both normal germline and tumor genomes is necessary for accurate identification of molecular targets. Treatment decisions based on tumor-only analysis may result in the administration of ineffective therapies while also increasing the risk of negative drug-related side effects.


Extending palliative care is there a role for preventive medicine?
Historically, the concept of palliative care has been limited to hospice and end-of-life services. Recently, palliative care has been expanded to emphasize its integration throughout an illness. We suggest that palliative care provides an opportunity to prevent illness. Palliative care providers can effectively reduce the risk of illness in families by employing methods and strategies of preventive medicine. We illustrate three such cases. Patients and survivors may benefit from appropriate recognition and referral to prevent potential medical, social, and psychological problems. For preventive medicine to become fully exploited by palliative care providers, curricula will need to be developed. Risk assessment indicators of heritable and acquired conditions will define core functions of this educational process. Relevant topics should encompass basic preventive medicine methods, methods to disseminate assigned risk to the palliative care team, and referral mechanisms to specialists with expertise in the identified area(s) of concern. Opportunities to integrate preventive care into end-of-life services will create a new dimension for comprehensive palliative care.


Physical map of the origin of defective DNA in herpes simplex virus type 1 DNA.
The origin of defective DNA (dDNA) of the Patton strain of herpes simplex virus type 1 (HSV-1) was physically mapped with BamHI in the parental DNA. The dDNA obtained from virus passaged at high multiplicities of infection was resistant to cleavage with HindIII, whereas digestion with EcoRI yielded a cluster of fragments 5.4 to 5.7 megadaltons (Mdal) in size. Cleavage with BamHI gave a cluster of fragments 2.6 to 3.2 Mdal in size, plus two homogeneous, comigrating 1-Mdal fragments. One of the latter fragments contained the single EcoRI site approximately 65 base pairs from one end. Hybridization of in vitro labeled dDNA probe to EcoRI, HindIII, BamHI, and Hpa I digests of nondefective HSV-1 DNA demonstrated that, in addition to the S-region terminal repeat, only one end of the S region was involved in the generation of this class of dDNA. Thus, the dDNA probe did not hybridize to either the S region 3.0-Mdal HindIIIN fragment or a 3.0-Mdal BamHI fragment of the adjacent 8.7-Mdal HindIIIG fragment, but did hybridize to four BamHI fragments of HindIII G (approximately 5.7 Mdal). The cluster of 2.6- to 3.2-Mdal fragments obtained with BamHI digestion of dDNA appears to represent a novel junction between the termination of dDNA adjacent to the 3.0-Mdal BamHI fragment in HindIII G and the 2.0- to 2.3-Mdal BamHI fragment terminal in HSV-1 DNA.


The intrinsically disordered N-terminus of the voltage-dependent anion channel.
The voltage-dependent anion channel (VDAC) is a critical β-barrel membrane protein of the mitochondrial outer membrane, which regulates the transport of ions and ATP between mitochondria and the cytoplasm. In addition, VDAC plays a central role in the control of apoptosis and is therefore of great interest in both cancer and neurodegenerative diseases. Although not fully understood, it is presumed that the gating mechanism of VDAC is governed by its N-terminal region which, in the open state of the channel, exhibits an α-helical structure positioned midway inside the pore and strongly interacting with the β-barrel wall. In the present work, we performed molecular simulations with a recently developed force field for disordered systems to shed new light on known experimental results, showing that the N-terminus of VDAC is an intrinsically disordered region (IDR). First, simulation of the N-terminal segment as a free peptide highlighted its disordered nature and the importance of using an IDR-specific force field to properly sample its conformational landscape. Secondly, accelerated dynamics simulation of a double cysteine VDAC mutant under applied voltage revealed metastable low conducting states of the channel representative of closed states observed experimentally. Related structures were characterized by partial unfolding and rearrangement of the N-terminal tail, that led to steric hindrance of the pore. Our results indicate that the disordered properties of the N-terminus are crucial to properly account for the gating mechanism of VDAC.


Mycorrhizal Infection Can Ameliorate Abiotic Factors in Urban Soils.
Once abandoned, urban and post-industrial lands can undergo a re-greening, the natural regeneration and succession that leads to surprisingly healthy plant communities, but this process is dependent upon microbial activity and the health of the parent soil. This study aimed to evaluate the effects of arbuscular mycorrhizal fungi (AMF) in facilitating plant production in post-industrial soils. In so doing, we helped to resolve the mechanism through which AMF ameliorate environmental stress in terrestrial plants. An experiment was established in which rye grass (Lolium perenne) was grown in two heavy metal-contaminated soils from an urban brownfield in New Jersey, USA, and one non-contaminated control soil. One set of the treatments received an AMF inoculum (four species in a commercial mix: Glomus intraradices, G. mosseae, G. etunicatum and G. aggregatum) and the other did not. Upon harvest, dried plant biomass, root/shoot ratio, AMF colonization, and extracellular soil phosphatase activity, a proxy for soil microbial functioning, were all measured. Plant biomass increased across all treatments inoculated with AMF, with a significantly higher average shoot and root mass compared to non-inoculated treatments. AMF colonization of the roots in contaminated soil was significantly higher than colonization in control soil, and the root/shoot ratio of plants in contaminated soils was also higher when colonized by AMF. Mycorrhizal infection may help plants to overcome the production limits of post-industrial soils as is seen here with increased infection and growth. The application of this mechanistic understanding to remediation and restoration strategies will improve soil health and plant production in urban environments.


Intraoperative Ischemic Stroke in Elective Spine Surgery: A Retrospective Study of Incidence and Risk.
. Retrospective study. . To determine incidence, risk factors, complications, and early postoperative outcome in patients with intraoperative ischemic stroke during elective spine surgery. . Overall, stroke is the fifth leading cause of death in the United States and the second leading cause of death worldwide. It can be a catastrophic event and the main cause of neurological disability in adults. . A retrospective review of the electronic medical records of patients who underwent elective spine surgery between January 2016 and November 2018 at a larger tertiary referral center was conducted. Patients with infection and neoplastic disease were excluded. Patient demographics, pre- and postoperative neurological status, surgical treatment, surgical time, blood loss, intraoperative abnormalities, risk factors, history of stroke, medical treatment, diagnostics, hospital stay, complications, and mortality were collected. . Out of 5029 surgically treated patients receiving elective spine surgery, a total of seven patients (0.15%) were identified who developed an ischemic stroke during the surgical procedure. Patients were predominantly females (n = 6). Ischemic pontine stroke occurred in two patients. Further distributions of ischemic stroke were: left caudate nucleus, left posterior inferior cerebellar artery, left external capsule, left middle cerebral artery, and acute ischemic supratentorial spots. The main risk factors identified for intraoperative ischemic stroke include hypertension, diabetes, smoking, dyslipidemia, and possibly major intraoperative CSF leak. Three patients (43%) had neurological deficits which did not improve during hospital stay. Two patients recovered fully and two patients died. Therefore, in-hospital mortality rate of this subset of patients was 29%. . With the increase of spinal procedures, it is important to identify patients at risk for having an ischemic stroke and to optimize their comorbidities preoperatively. Patients with intraoperative ischemic stroke carry a higher risk for morbidity and mortality during the index hospitalization. 4.


Inhibition of platelet function: does it offer a chance of better cancer progression control?
Thrombocytosis is frequently (10 to 57%) observed in cancer patients. Although the mechanisms underlying thrombocytosis are not yet fully elucidated, tumor-derived factors with thrombopoietin-like activity, growth factors, platelet-derived microparticles, and factors released from bone marrow endothelial cells as well as growth factors secreted by megakaryocytes (acting via an autocrine loop) are claimed to influence this process. The course of cancer is strongly associated with hypercoagulable state, which results from direct influences of tumor cells themselves and various indirect mechanisms. Activated platelets provide procoagulant surface amplifying the coagulation process. It is well documented that proteins of the hemostatic system influence different steps of metastasis, angiogenesis, and proteolytic events. Much less is known about the role of platelets in tumor growth and their possible contribution to prevention of tumor cells from the host immune system. Multidirectional activities of platelets during tumor development and metastatic dissemination create a possibility of introducing antiplatelet agents in anticancer therapy. The spectrum of plausible therapies includes antibodies against glycoprotein IIb-IIIa, direct thrombin inhibitors, protease activated receptor-1 targeted therapy, as well as cyclooxygenase (COX) and lipoxygenase (LOX) inhibitors. However, there is no sufficient information on a specific type of cancer where progression does depend on platelet function. Despite numerous experimental studies conducted, to date none of the new specific antiplatelet agents were tested in clinical trials in a cancer patient population.


Improving signal prediction performance of neural networks through multiresolution learning approach.
In this paper, we extend the original work on multiresolution learning for neural networks, and present new developments on the multiresolution learning paradigm. The contributions of this paper include: (1) proposing a new concept and method of adjustable neural activation functions in multiresolution learning to improve neural network learning efficacy and generalization performance for signal predictions; (2) providing new insightful explanations for the multiresolution learning paradigm from a multiresolution optimization perspective; (3) exploring underlying ideas why the multiresolution learning scheme associated with adjustable activation functions would be more appropriate for the multiresolution learning paradigm; and (4) providing rigorous validations to evaluate the multiresolution learning paradigm with adjustable activation functions and comparing it with the schemes of multiresolution learning with fixed activation functions and traditional learning. This paper presents systematically new analytical and experimental results on the multiresolution learning approach for training an individual neural network model, demonstrates our integral solution on neural network learning efficacy, and illustrates the significant improvements on neural networks' generalization performance and robustness for nonlinear signal predictions.


Shifts Between and Among Populations of Wheat Rhizosphere Pseudomonas, Streptomyces and Phyllobacterium Suggest Consistent Phosphate Mobilization at Different Wheat Growth Stages Under Abiotic Stress.
Climate change models predict more frequent and prolonged drought events in Central Europe, which will exert extraordinary pressure on agroecosystems. One of the consequences is drought-related nutrient limitations for crops negatively affecting agricultural productivity. These effects can be mitigated by beneficial plant growth promoting rhizobacteria. In this study, we investigated the potential of cultivable bacterial species for phosphate solubilization in the rhizosphere of winter wheat at two relevant growth stages - stem elongation and grain filling stages. Rhizosphere samples were collected in the Global Change Experimental Facility in Central Germany, which comprises plots with conventional and organic farming systems under ambient and future climate. Phosphate-solubilizing bacteria were selectively isolated on Pikovskaya medium, phylogenetically classified by 16S rRNA sequencing, and tested for in vitro mineral phosphate solubilization and drought tolerance using plate assays. The culture isolates were dominated by members of the genera Phyllobacterium, Pseudomonas and Streptomyces. Cultivation-derived species richness and abundance of dominant taxa, especially within the genera Phyllobacterium and Pseudomonas, as well as composition of Pseudomonas species were affected by wheat growth stage. Pseudomonas was found to be more abundant at stem elongation than at grain filling, while for Phyllobacterium the opposite pattern was observed. The abundance of Streptomyces isolates remained stable throughout the studied growth stages. The temporal shifts in the cultivable fraction of the community along with considerable P solubilization potentials of Phyllobacterium and Pseudomonas species suggest functional redundancy between and among genera at different wheat growth stages. Phosphate-solubilizing Phyllobacterium species were assigned to Phyllobacterium ifriqiyense and Phyllobacterium sophorae. It is the first time that phosphate solubilization potential is described for these species. Since Phyllobacterium species showed the highest drought tolerance along all isolates, they may play an increasingly important role in phosphate solubilization in a future dryer climate.


Evolution of function of a fused metazoan tRNA synthetase.
The origin and evolution of multidomain proteins are driven by diverse processes including fusion/fission, domain shuffling, and alternative splicing. The 20 aminoacyl-tRNA synthetases (AARS) constitute an ancient conserved family of multidomain proteins. The glutamyl-prolyl tRNA synthetase (EPRS) of bilaterian animals is unique among AARSs, containing two functional enzymes catalyzing ligation of glutamate and proline to their cognate transfer RNAs (tRNAs). The ERS and PRS catalytic domains in multiple bilaterian taxa are linked by variable number of helix-turn-helix domains referred to as WHEP-TRS domains. In addition to its canonical aminoacylation activities, human EPRS exhibits a noncanonical function as an inflammation-responsive regulator of translation. Recently, we have shown that the WHEP domains direct this auxiliary function of human EPRS by interacting with an mRNA stem-loop element (interferon-gamma-activated inhibitor of translation [GAIT] element). Here, we show that EPRS is present in the cnidarian Nematostella vectensis, which pushes the origin of the fused protein back to the cnidarian-bilaterian ancestor, 50-75 My before the origin of the Bilateria. Remarkably, the Nematostella EPRS mRNA is alternatively spliced to yield three isoforms with variable number and sequence of WHEP domains and with distinct RNA-binding activities. Whereas one isoform containing a single WHEP domain binds tRNA, a second binds both tRNA and GAIT element RNA. However, the third isoform contains two WHEP domains and like the human ortholog binds specifically to GAIT element RNA. These results suggest that alternative splicing of WHEP domains in the EPRS gene of the cnidarian-bilaterian ancestor gave rise to a novel molecular function of EPRS conserved during metazoan evolution.


Involvement of the modifier gene of a human Mendelian disorder in a negative selection process.
Identification of modifier genes and characterization of their effects represent major challenges in human genetics. SAA1 is one of the few modifiers identified in humans: this gene influences the risk of renal amyloidosis (RA) in patients with familial Mediterranean fever (FMF), a Mendelian autoinflammatory disorder associated with mutations in MEFV. Indeed, the SAA1 alpha homozygous genotype and the p.Met694Val homozygous genotype at the MEFV locus are two main risk factors for RA. HERE, WE INVESTIGATED ARMENIAN FMF PATIENTS AND CONTROLS FROM TWO NEIGHBORING COUNTRIES: Armenia, where RA is frequent (24%), and Karabakh, where RA is rare (2.5%). Sequencing of MEFV revealed similar frequencies of p.Met694Val homozygotes in the two groups of patients. However, a major deficit of SAA1 alpha homozygotes was found among Karabakhian patients (4%) as compared to Armenian patients (24%) (p = 5.10(-5)). Most importantly, we observed deviations from Hardy-Weinberg equilibrium (HWE) in the two groups of patients, and unexpectedly, in opposite directions, whereas, in the two control populations, genotype distributions at this locus were similar and complied with (HWE). The excess of SAA1alpha homozygotes among Armenian patients could be explained by the recruitment of patients with severe phenotypes. In contrast, a population-based study revealed that the deficit of alpha/alpha among Karabakhian patients would result from a negative selection against carriers of this genotype. This study, which provides new insights into the role of SAA1 in the pathophysiology of FMF, represents the first example of deviations from HWE and selection involving the modifier gene of a Mendelian disorder.


The effect of an occlusion-induced delay on braking behavior in critical situations: A driving simulator study.
To share results of an experiment that used visual occlusion for a new purpose: inducing a waiting time. Senders was a leading figure in human factors. In his research on the visual demands of driving, he used occlusion techniques. In a simulator experiment, we examined how drivers brake for different levels of urgency and different visual conditions. In three blocks (1 = brake lights, 2 = no brake lights, 3 = occlusion), drivers followed a vehicle at 13.4 or 33.4 m distance. At certain moments, the lead vehicle decelerated moderately (1.7 m/s2) or strongly (6.5 m/s2). In the occlusion condition, the screens blanked for 0.4 s (if 6.5 m/s2) or 2.0 s (if 1.7 m/s2) when the lead vehicle started to decelerate. Participants were instructed to brake only after the occlusion ended. The lack of brake lights caused a delayed response. In the occlusion condition, drivers adapted to the instructed late braking by braking harder. However, adaptation was not always possible: In the most urgent condition, most participants collided with the lead vehicle because the ego-vehicle's deceleration limits were reached. In non-urgent conditions, some drivers braked unnecessarily hard. Furthermore, while waiting until the occlusion cleared, some drivers lightly touched the brake pedal. This experimental design demonstrates how drivers (sometimes fail to) adjust their braking behavior to the criticality of the situation. The phenomena of biomechanical readiness and (inappropriate) dosing of the brake pedal may be relevant to safety, traffic flow, and ADAS design.


A Novel Mechanism To Prevent H2S Toxicity in Caenorhabditis elegans.
Hydrogen sulfide (H2S) is an endogenously produced signaling molecule that can be cytoprotective, especially in conditions of ischemia/reperfusion injury. However, H2S is also toxic, and unregulated accumulation or exposure to environmental H2S can be lethal. In Caenorhabditis elegans, the hypoxia inducible factor (hif-1) coordinates the initial transcriptional response to H2S, and is essential to survive exposure to low concentrations of H2S. We performed a forward genetic screen to identify mutations that suppress the lethality of hif-1 mutant animals in H2S. The mutations we recovered are specific for H2S, as they do not suppress embryonic lethality or reproductive arrest of hif-1 mutant animals in hypoxia, nor can they prevent the death of hif-1 mutant animals exposed to hydrogen cyanide. The majority of hif-1 suppressor mutations we recovered activate the skn-1/Nrf2 transcription factor. Activation of SKN-1 by hif-1 suppressor mutations increased the expression of a subset of H2S-responsive genes, consistent with previous findings that skn-1 plays a role in the transcriptional response to H2S. Using transgenic rescue, we show that overexpression of a single gene, rhy-1, is sufficient to protect hif-1 mutant animals in H2S. The rhy-1 gene encodes a predicated O-acyltransferase enzyme that has previously been shown to negatively regulate HIF-1 activity. Our data indicate that RHY-1 has novel, hif-1 independent, function that promotes survival in H2S.