Nitrate, nitrate reduction and organic nitrogen in plants from different ecological and taxonomic groups of Central Europe.
48 plant species of the families Asteraceae, Chenopodiaceae, Ericaceae, Fabaceae, Lamiaceae, Polygonaceae and Urticaceae were investigated in 14 natural habitats of Central Europe having different nitrate supplies, with respect to their nitrate content, nitrate reductase activity (NRA) and organic nitrogen content. Plants that were flowering were selected where possible for analysis. The plants were subdivided into flowers, laminae, petioles+shoot axes and below-ground organs. Each organ was analyzed separately. Differences among species were found for the three variables investigated. Apart from the Fabaceae, which had particularly high concentrations of organic N, these differences reflect mainly the ecological behaviour, i.e. high nitrate and organic N contents and NRA values per g dry weight were found in species on sites rich in nitrate, and vice versa. Nitrate content, NRA and organic N content were correlated with "nitrogen figures" of Central European vascular plants defined by Ellenberg (1979). By use of regression equations this correlation was tested with species from other systematic groups. Some species were attributed with calculated "N figures" for the first time.


In situ quantification of mitochondrial respiration in permeabilized fibers of a marine invertebrate with low aerobic capacity.
The aim of this study was to design a protocol to allow the assessment of normal and alternative pathways for electron transport in mitochondria using an in situ approach (on permeabilized fibers) in high-resolution respirometry. We measured the oxygen consumption of permeabilized fibers from Nereis (Neanthes) virens with different substrates and the presence of ADP. To estimate the alternative oxidase (AOX) activity, antimycin A was introduced in order to inhibit complex III. Moreover, the apparent complex IV (COX) excess capacity was evaluated using different substrates to assess the implication of this complex in the partitioning of electrons during its progressive inhibition. Our in situ method enabled to quantify the activity of the normal COX pathway as well as the AOX pathway when different substrates were oxidized by either complex I, complex II or both. Using this approach, we confirmed that according to the substrates used, each pathway has a different role and consequently is otherwise involved in the partitioning of electrons through the electron transport system, and suggested that the AOX activity is triggered not only by the redox state of the cell but also by the type of substrates provided to mitochondria.


Evidence for a gamma-hydroxybutyrate (GHB) uptake by rat brain synaptic vesicles.
gamma-Hydroxybutyrate (GHB) is an endogenous metabolite of mammalian brain which is derived from GABA. Much evidence favours its role as an endogenous neuromodulator, synthesized, stored and released at particular synapses expressing specific receptors. One key step for GHB involvement in neurotransmission is its uptake by a specific population of synaptic vesicles. We demonstrate that this specific uptake exists in a crude synaptic vesicle pool obtained from rat brain. The kinetic parameters and the pharmacology of this transport are in favour of an active vesicular uptake system for GHB via the vesicular inhibitory amino acid transporter. This result supports the idea that GABA and GHB accumulate together and are coliberated in some GABAergic synapses of the rat brain, where GHB acts as a modulatory factor for the activity of these synapses following stimulation of specific receptors.


Bayesian networks elucidate complex genomic landscapes in cancer.
Bayesian networks (BNs) are disciplined, explainable Artificial Intelligence models that can describe structured joint probability spaces. In the context of understanding complex relations between a number of variables in biological settings, they can be constructed from observed data and can provide a guiding, graphical tool in exploring such relations. Here we propose BNs for elucidating the relations between driver events in large cancer genomic datasets. We present a methodology that is specifically tailored to biologists and clinicians as they are the main producers of such datasets. We achieve this by using an optimal BN learning algorithm based on well established likelihood functions and by utilising just two tuning parameters, both of which are easy to set and have intuitive readings. To enhance value to clinicians, we introduce (a) the use of heatmaps for families in each network, and (b) visualising pairwise co-occurrence statistics on the network. For binary data, an optional step of fitting logic gates can be employed. We show how our methodology enhances pairwise testing and how biologists and clinicians can use BNs for discussing the main relations among driver events in large genomic cohorts. We demonstrate the utility of our methodology by applying it to 5 cancer datasets revealing complex genomic landscapes. Our networks identify central patterns in all datasets including a central 4-way mutual exclusivity between HDR, t(4,14), t(11,14) and t(14,16) in myeloma, and a 3-way mutual exclusivity of three major players: CALR, JAK2 and MPL, in myeloproliferative neoplasms. These analyses demonstrate that our methodology can play a central role in the study of large genomic cancer datasets.


The syndrome of congenital absence of the pulmonary valve: pathological, clinical and surgical considerations.
Four cases of congenital absence of the pulmonary valve are described. Three of them underwent successful operation. The fourth case, operated on in the first days of life, died because of severe respiratory distress. After examining the embryological aspects of this malformation, its treatment is discussed in relation to particular respiratory problems in infants and to the possibility of inserting prosthetic valves in children undergoing elective surgical treatment.


Serine/Threonine-Protein Kinase 3 Facilitates Myocardial Repair After Cardiac Injury Possibly Through the Glycogen Synthase Kinase-3β/β-Catenin Pathway.
Background The neonatal heart maintains its entire regeneration capacity within days after birth. Using quantitative phosphoproteomics technology, we identified that SGK3 (serine/threonine-protein kinase 3) in the neonatal heart is highly expressed and activated after myocardial infarction. This study aimed to uncover the function and related mechanisms of SGK3 on cardiomyocyte proliferation and cardiac repair after apical resection or ischemia/reperfusion injury. Methods and Results The effect of SGK3 on proliferation and oxygen glucose deprivation/reoxygenation- induced apoptosis in isolated cardiomyocytes was evaluated using cardiomyocyte-specific SGK3 overexpression or knockdown adenovirus5 vector. In vivo, gain- and loss-of-function experiments using cardiomyocyte-specific adeno-associated virus 9 were performed to determine the effect of SGK3 in cardiomyocyte proliferation and cardiac repair after apical resection or ischemia/reperfusion injury. In vitro, overexpression of SGK3 enhanced, whereas knockdown of SGK3 decreased, the cardiomyocyte proliferation ratio. In vivo, inhibiting the expression of SGK3 shortened the time window of cardiac regeneration after apical resection in neonatal mice, and overexpression of SGK3 significantly promoted myocardial repair and cardiac function recovery after ischemia/reperfusion injury in adult mice. Mechanistically, SGK3 promoted cardiomyocyte regeneration and myocardial repair after cardiac injury by inhibiting GSK-3β (glycogen synthase kinase-3β) activity and upregulating β-catenin expression. SGK3 also upregulated the expression of cell cycle promoting genes G1/S-specific cyclin-D1, c-myc (cellular-myelocytomatosis viral oncogene), and cdc20 (cell division cycle 20), but downregulated the expression of cell cycle negative regulators cyclin kinase inhibitor P 21 and cyclin kinase inhibitor P 27. Conclusions Our study reveals a key role of SGK3 on cardiac repair after apical resection or ischemia/reperfusion injury, which may reopen a novel therapeutic option for myocardial infarction.


Quality of life 6 and 18 months after mild traumatic brain injury in early childhood: An exploratory study of the role of genetic, environmental, injury, and child factors.
Mild traumatic brain injury (mTBI) in early childhood is prevalent, and some children may be at risk for short- and long-term difficulties that could affect quality of life (QoL). Despite growing efforts to understand associations between potential risk factors and outcomes after injury, prognosis is elusive and lacks the inclusion of genetic variables which may convey additional predictive power. This study assessed which factors contribute to pediatric QoL 6 and 18 months post-recruitment in 159 participants (mTBI = 52; orthopedic injury [OI] = 43; typically developing controls [TDC] = 64) aged 18 to 60 months at the time of injury (M = 37.50, SD = 11.69). Family environment, injury characteristics, and child cognitive-behavioral functioning were assessed at 6 months via parent questionnaires and socio-cognitive assessment. QoL was determined using the Pediatric Quality of Life Inventory at both time points. Genetic information (Brain-derived neurotrophic factor [BDNF] genotype) was collected using saliva samples. Hierarchical regression analyses testing biological, family-environmental, injury and cognitive-behavioral factors revealed that the BDNF Val66Met polymorphism was a significant independent predictor of better QoL 6 months post-injury in the mTBI group. Lower parental distress significantly and independently predicted higher QoL 18 months after mTBI, and 6 months post-recruitment in the TDC group. At 18 months, models were non-significant for both control groups. Genetic factors involved in neuroplasticity may play an important role in recovery 6 months after mTBI and contribute to outcome via their interplay with environmental factors. Over time, family factors appear to become the primary determinants of post-mTBI outcome.


Maternal-fetal DNA admixture is associated with intrapartum mother-to-child transmission of HIV-1 in Blantyre, Malawi.
The mechanism of mother-to-child transmission (MTCT) of HIV-1 is not well described. Of 328 HIV-infected mother-infant pairs, we identified 91 that had discordant angiotensin I-converting enzyme and glutathione S-transferase M1 alleles. Maternal alleles in cord blood were quantified with real-time polymerase chain reaction, as indicators of microtransfusions. HIV-1 infected infants had more maternal DNA in cord blood than their uninfected counterparts. Increased maternal DNA in cord blood was associated with preterm delivery, low birth weight, and maternal immunosuppression. Intrapartum MTCT was associated with placental microtransfusions. The associations among placental microtransfusion, in-utero MTCT, maternal immunosuppression, and poor birth outcome should be further investigated.


Infants' localization of sounds in the median vertical plane: estimates of minimum audible angle.
Infants 6, 9, 12, 15, and 18 months of age were seated in a dark room directly facing an array of nine loudspeakers positioned along the median vertical plane. One loudspeaker was positioned at ear level, 0 degree, and four others each were positioned above and below 0 degree. To examine infants' resolution of auditory space in the median vertical plane we sought to determine the smallest angular shift in the vertical location of a sound that infants could reliably detect (i.e., minimum audible angle). A two-alternative forced-choice procedure was used in which a sequence of white noise bursts was presented initially at 0 degree, and then shifted vertically (i.e., above or below 0 degree) and continued to be presented until the infant made a directional response; correct responses were visually reinforced. The smallest angular shift in vertical location that was reliably detected systematically decreased with increasing age between 6 months (15 degrees) and 18 months (4 degrees), suggesting a finer partitioning of auditory space along the vertical axis over this age range. By 18 months infants' performance matched that of a group of adults tested under the same circumstances.


Primary sclerosing cholangitis.
Primary sclerosing cholangitis was seen in only 7 of 6,494 biliary operations performed between 1948 and 1979. Fifteen more cases were seen in 1,467 biliary operations performed over a recent 5 year period. Surgery was directed primarily towards the differential diagnosis between cholangiocarcinoma and primary sclerosing cholangitis of the upper bile duct and the need for decompression (nine patients), accompanying gallstones (4 patients), and focal distal bile duct stricture with a question of cholangiocarcinoma (two patients). Invasive radiologic dilatation of the bile ducts was not possible in most instances. Two patients have had successful liver transplants and two more were pending at last follow-up.


Gender, risk perceptions, and smoking behavior.
The underlying reasons for gender differences in smoking behavior, and thus for the recent trends, are not well understood. Using a sample of 8592 Swedish adolescents aged 15-18, this paper contributes to the literature by exploring gender differences in smoking risk perceptions and in the responses to the latter. The results show significant gender differences in the perception of smoking mortality risk and in the perception of the addictiveness of smoking. Girls perceive the mortality risk of smoking as significantly greater than boys do, but they also perceive the addictiveness of cigarettes as less. These results persist after controlling for a wide range of background characteristics, including smoking risk information sources. Moreover, the findings suggest that while smoking information from sources such as teachers, pals, and own search, affect smoking mortality perceptions in a significant and positive manner among boys, no such effects are obtained among girls. Finally, our results show that both boys and girls take both the addictiveness and mortality risk of smoking into account when making their smoking decision. Moreover, the magnitude of the response is similar among boys and girls. This is in contrast to the general belief that females dislike risks to a greater extent than males.


Alterations in spontaneous electrical brain activity after an extreme mountain ultramarathon.
This study aimed to investigate the impact of an extreme mountain ultramarathon (MUM) on spontaneous electrical brain activity in a group of 16 finishers. By using 4-minute high-density electroencephalographic (EEG) recordings with eyes closed before and after a 330-km race (mean duration: 125 ± 17 h; sleep duration: 7.7 ± 2.9 h), spectral power, source localization and microstate analyses were conducted. After the race, power analyses revealed a centrally localized increase in power in the delta (0.5-3.5 Hz) and theta (4.0-7.5 Hz) frequency bands and a decrease in alpha (8.0-12.0 Hz) power at the parieto-occipital sites. Higher brain activation in the alpha frequency band was observed within the left posterior cingulate cortex, left angular gyrus and visual association areas. Microstate analyses indicated a significant decrease in map C predominance and an increase in the global field power (GFP) for map D at the end of the race. These changes in power patterns and microstate parameters contrast with previously reported findings following short bouts of endurance exercises. We discuss the potential factors that explain lower alpha activity within the parieto-occipital regions and microstate changes after MUMs. In conclusion, high-density EEG resting-state analyses can be recommended to investigate brain adaptations in extreme sporting activities.


Association of angiographic perfusion score following percutaneous coronary intervention for ST-elevation myocardial infarction with left ventricular remodeling at 6 weeks in GRACIA-2.
Higher angiographic perfusion score (APS) following percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) has been shown to be associated with improved clinical outcomes. The association between APS after STEMI and left ventricular remodeling as assessed by volumetric parameters derived from left ventriculography has not been assessed. The APS (the arithmetic sum of the TIMI Flow Grade (TFG) and TIMI Myocardial Perfusion grade (TMPG) before and after percutaneous coronary intervention (PCI), range of 0-12) was assessed in 168 patients from the GRACIA-2 trial. Left ventriculograms performed in the 30 degrees right anterior oblique projection were obtained among 148 patients at initial angiography (prior to PCI) and at 6 weeks. The association of APS with markers of left ventricular remodeling at 6-weeks was examined using left ventricular ejection fraction, delta end systolic volume, delta stroke volume and wall motion index. Full perfusion (APS 10-12), as compared to partial perfusion (APS 4-9) or failed perfusion (APS 0-3), was associated with a greater left ventricular ejection fraction (61.6% +/- 10.0 vs. 56.9% +/- 12.5 vs. 49.8% +/- 16.9, P = 0.015), a decrease in left ventricular end systolic volume indicating favorable remodeling (mean -4.1 cc +/- 17.3 vs. +2.0 cc +/- 17.3 vs. +9.8 cc +/- 16.1, P = 0.015), a greater improvement in left ventricular stroke volume (mean +13.7 cc +/- 17.1 vs. +6.7 cc +/- 15.5 vs. +1.2 cc +/- 13.4, P = 0.009) and a decreased wall motion index (number of chords in the hypokinetic region) (mean 15.1 +/- 16.4 vs. 21.4 +/- 20.5 vs. 32.9 +/- 22.1, P = 0.026) at 6 weeks. In conclusion, among patients treated with combined reperfusion and revascularization strategies for STEMI, higher APS is associated with more favorable markers of left ventricular remodeling and improved 6-week left ventricular function.


Comparison of two soluble guanylyl cyclase inhibitors, methylene blue and ODQ, on sodium nitroprusside-induced relaxation in guinea-pig trachea.
To clarify further the role of cyclic GMP in mediating the relaxant response in guinea-pig trachea induced by sodium nitroprusside (SNP), the effects of soluble guanylyl cyclase inhibitors, methylene blue and 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ) on SNP-induced muscle relaxation and cyclic GMP accumulation were determined. SNP (0.3-100 microM) evoked a concentration-dependent relaxation of guinea-pig isolated tracheas precontracted with 0.3 microM carbachol. Preincubation of the preparations with methylene blue (10, 30 and 100 microM) resulted in a slight but concentration-dependent prevention of the relaxant response to SNP. In contrast, the relaxation to SNP was extensively prevented by 3 microM ODQ and almost abolished by 10 microM ODQ. SNP (30 microM) induced a significant elevation of cyclic GMP accumulation (from 1.34+/-0.14 to 5.39+/-0.28 pmol mg(-1) protein, n= 5; P<0.001), which was partially attenuated by 100 microM methylene blue (3.11+/-0.51 pmol mg(-1) protein, n=5; P<0.05), whereas completely abolished by 10 microM ODQ (1.31+/-0.28 pmol mg(-1) protein, n = 5; P<0.001). Methylene blue, but not ODQ and Nomega-nitro-L-arginine methyl ester (L-NAME), caused a concentration-dependent contraction in the tracheal preparation. The tension produced by 100 microM methylene blue was 41.8+/-4.3% (0.3 microM carbachol as 100%; n = 12). Moreover, the non-selective muscarinic receptor antagonist atropine and the M3-selective antagonist 4-diphenylacetoxy-N-methylpiperidine methiodine greatly inhibited the contractile effect evoked by methylene blue (100 microM). In conclusion, this study provides substantial evidence that SNP-induced muscle relaxation in guinea-pig trachea is completely via a cyclic GMP-dependent mechanism. Furthermore, ODQ, but not methylene blue, will likely become an important tool in differentiating between cyclic GMP-dependent and -independent effects of nitric oxide.


Structure and dynamics of ion transport through gramicidin A.
Molecular dynamics calculations in which all atoms were allowed to move were performed on a water-filled ion channel of the polypeptide dimer gramicidin A (approximately 600 atoms total) in the head-to-head Urry model conformation. Comparisons were made among nine simulations in which four different ions (lithium, sodium, potassium, and cesium) were each placed at two different locations in the channel as well as a reference simulation with only water present. Each simulation lasted for 5 ps and was carried out at approximately 300 K. The structure and dynamics of the peptide and interior waters were found to depend strongly on the ion tested and upon its location along the pore. Speculations on the solution and diffusion of ions in gramicidin are offered based on the observations in our model that smaller ions tended to lie off axis and to distort the positions of the carbonyl oxygens more to achieve proper solvation and that the monomer-monomer junction was more distortable than the center of the monomer. With the potential energy surface used, the unique properties of the linear chain of interior water molecules were found to be important for optimal solvation of the various ions. Strongly correlated motions persisting over 25 A among the waters in the interior single-file column were observed.


[Cholinesterase activity in the Pacinian corpuscles in denervation and the application of colchicine to the nerve].
In the Pacinian corpuscles, cholinesterase activity was predominantly revealed along the plasma membrane and in the cytoplasm of the inner core cells. A faint quantity of histochemical end product was detected in the axis cylinder. An increased cholinesterase activity was found after the nerve transection. This change coincides in time with phagocytosis of degenerated axis cylinder by the inner core cells. A decrease in cholinesterase activity was observed in the Pacinian corpuscles after colchicine application to the nerve. This effect may be due to either the blockade of axoplasmic transport of cholinesterase in afferent nerve or/and to the elimination of the trophic influence exerted by the nerve on the cholinesterase activity in the inner care cells.


Quantitative Easing and bank risk-taking behavior.
In this paper, we examine the effect of reserve creation due to the Federal Reserve's Large-scale Asset Purchase programs on bank lending and risk-taking behavior. In particular, we test the existence of a risk-taking channel that induces banks with higher reserve accumulation due to the Fed's policy to increase the share of riskier loans. Exploiting the heterogeneity in the exposure to such asset purchase programs, as measured by relative mortgage-backed securities holdings in the banks' portfolios, we use difference-in-differences analysis to study the effect of the Fed's policies on the supply of total loans and the share of riskier loans such as real estate, commercial and industrial, and consumer loans. We find that the first and third round of Quantitative Easing (QE) policies led to an increase in both the total loans and the share of riskier loans within the banks' portfolios, supporting the risk-raking channel. The second round of QE on the other hand, had no significant impact on banks' lending behavior.


Haloperidol catalepsy consolidation in the rat as a model of neuromodulatory integration.
Haloperidol, a non-selective D(2) dopamine antagonist, both in vitro (1 microM) and in vivo (2.5 mg/kg i.p.), induced a long-term potentiation of K(+)-induced Ca(2+)-dependent release of endogenous noradrenaline and dopamine in rat brain cortical slices, by increasing the content of noradrenaline and dopamine known to be controlled by dopamine auto- and heteroreceptors. Haloperidol administration (2.5 mg/kg i.p.) evoked catalepsy and increased the content of noradrenaline and dopamine in the same structures of the brain. Haloperidol catalepsy consolidated without any additional learning and could be retrieved up to two weeks later by placing the animals in the test box. The catalepsy is disordered and retrieved only in the test box. The catalepsy was more intense on day 14 than on day 7. Injection of haloperidol immediately after conditioning evened the reflex retrieval on the following days. Moreover, learning increased the intensity of catalepsy in animals tested on the day of injection. Repeated testing of the reflex on the following days led to specific modifications of catalepsy retrieval. Pre-conditioned rats exhibited maximal catalepsy when tested immediately after being placed in the test box. These results suggest that both the processes of long-term potentiation and catalepsy consolidation are mediated by the same type of receptors, long-term modulation-inducing receptors. Endogenous neuromodulators, acting non-specifically or diffusely via their respective long-term modulation-inducing receptors, can initiate and consolidate generalized states which form the basis for emotional and motivational states.


Evolutionary history and variation in host range of three Stagonosporopsis species causing gummy stem blight of cucurbits.
Recently diverged species may form complexes of morphologically similar, yet genetically distinct lineages that occur in overlapping geographic ranges and niches. Using a multilocus sequencing approach we discovered that gummy stem blight of cucurbits is caused by three genetically distinct species: Stagonosporopsis cucurbitacearum (syn. Didymella bryoniae), Stagonosporopsis citrulli, and Stagonosporopsis caricae, which had previously been considered only a pathogen of papaya. Experiments showed that all three species are pathogenic to cucurbits in the genera Cucurbita, Cucumis, and Citrullus, but only S. caricae is aggressive to papaya. Species tree estimates show that S. citrulli and S. cucurbitacearum are phylogenetically distinct sister species, and that S. caricae is the ancestral lineage. The time estimate for divergence of S. caricae from the ancestor of S. cucurbitacearum and S. citrulli at 72 900 YBP pre-dates domestication of papaya and Cucurbita species in the American tropics. The divergence estimate observed for S. cucurbitacearum and S. citrulli at 10 900 YBP suggests that diversification of Cucurbita species and domestication of gourds and squashes could have driven their divergence. This work highlights the use of molecular systematics and population genetics to elucidate genetic identity among previously unassociated fungi and to understand the patterns of pathogen diversification.


Laparoscopic total gastrectomy with distal pancreatosplenectomy and D2 lymphadenectomy for advanced gastric cancer.
The standard lymph node dissection for advanced gastric cancer is a D2 dissection. Although D2 laparoscopy-assisted total gastrectomy with distal pancreatosplenectomy has been reported, no studies have reported a completely intra-abdominal laparoscopic approach, because of the technical difficulty of the procedure. We successfully performed this novel procedure in two patients with advanced gastric cancer located in the upper portion of the stomach. In fact, this surgery is technically feasible, and has a potential curability comparable with that of open surgery.


Synovial chondromatosis of the temporomandibular joint with extension into the middle cranial fossa and internal carotid canal.
This report presents the case of an extensive synovial chondromatosis of the temporomandibular joint (TMJ), with extension into the middle cranial fossa, middle ear, and carotid canal. Synovial chondromatosis of the TMJ is rare, particularly when associated with intracranial involvement. This case is unique owing to its size and the involvement with the internal carotid artery. The importance of a multidisciplinary approach in the surgical management of such a rare and complex form of this condition is highlighted.


The effects of heat exposure on tropical farm workers in Malaysia: six-month physiological health monitoring.
Farmers in tropical countries have been impacted by slow-onset heat stress. By comparing the nature of farming activities performed by conventional farmworkers and agroecological farmers, this study examined the changes in physiological health in responses to heat exposure through a six-month longitudinal study. Throughout the six-month follow-up period, the heat stress index (HSI), physiological strain indices (PSI), and physiological health parameters (BMI, blood glucose level, blood cholesterol level, uric acid level) were measured and repeated every two-month. Physiological parameters were recorded twice daily, before and during their first lunch break. This study found that slow-onset heat stress affects farmers differently. The health of agroecological farmers is more resistant to slow-onset extreme temperatures. Pre-existing metabolic health effects from pesticide exposure make conventional farmers more susceptible to extreme temperatures, delaying their bodies' adaptation to rising temperatures.


AtMSI4 and RbAp48 WD-40 repeat proteins bind metal ions.
The mammalian RbAp48 protein is the most extensively studied member of the conserved family of Msi1-like WD-40 repeat proteins, which are components of complexes involved in the assembly and modification of chromatin. We have isolated a plant homolog of RbAp48, AtMSI4. By metal affinity chromatography, zinc blotting and atomic absorption analysis, we demonstrate that purified recombinant RbAp48 and AtMSI4 proteins bind 3-4 metal ions per molecule of protein. Metal competition assays indicate a preference for zinc. Both N- and C-terminal halves of RbAp48 and AtMSI4 display zinc binding activity, suggesting it is an intrinsic property of the propeller structures likely to be formed by these proteins. Metal binding might mediate and/or regulate protein-protein interactions which are functionally important in chromatin metabolism.


Human papillomavirus type 16 E6 and E7 genotypes in head-and-neck carcinomas.
Human papillomavirus type 16 (HPV16) is associated with squamous cell carcinomas of the head and neck (HNSCC) particularly from the Waldeyer's tonsillar ring. A causal role of HPV16 in carcinogenesis is linked to the activity of the viral oncoproteins E6 and E7 which inactivate the cellular tumor suppressors p53 and pRB, respectively. Lack of E6 expression in HPV16-positive HNSCC has been reported, in some cases caused by disruption of the E6 gene. We have examined the status of the HPV16 E6-E7 gene region in tumor and metastasis samples of 24 HNSCC patients employing genomic PCR. No cases with a disrupted E6-E7 region could be identified. Sequence analysis of the E6-E7 segments revealed three different HPV16 E6-E7 genotypes: the HPV16 prototype (6 of 21 cases), the E6 variant T350G (8 of 21 cases), and the E6-E7 variant A131G/C712A (7 of 21 cases). The E6 variants T350G and A131G have been associated with increased oncogenic potential in cervical cancer patients depending on host genetic factors. Their high prevalence in the HNSCC samples studied indicates that they may be important also in HNSCC development.


Differential effect of tumor necrosis factor on proliferation of primary human keratinocytes and cell lines containing human papillomavirus types 16 and 18.
Keratinocytes immortalized by human papillomaviruses (HPV) 16 and 18 are partially resistant to the inhibition of proliferation exerted by transforming growth factor-beta (TGF-beta). To determine if this finding reflects a generalized resistance to inhibitory cytokines, we studied the effect of tumor necrosis factor-alpha (TNF-alpha) on subconfluent cultures of both normal and HPV-immortalized human foreskin keratinocytes. Whereas primary and HPV-16-immortalized keratinocytes were sensitive to TNF-alpha, HPV-18-immortalized keratinocytes (and those immortalized by simian virus 40) were resistant to the inhibitory effects of this cytokine. The ability of HPV-18 to induce a more resistant phenotype correlated with its more potent in vitro transforming activity and its apparent association with more aggressive tumors. Interestingly, the state of TNF-induced growth inhibition in normal or HPV-16-immortalized keratinocytes was not accompanied by a reduction in the expression of c-myc RNA or protein. This contrasts sharply with the ability of TGF-beta to inhibit c-myc RNA expression in normal cells. Evidently, the resistance of HPV-immortalized keratinocytes to TNF-alpha and TGF-beta proceeds along different regulatory pathways.


Application of kinesiology taping to equine abdominal musculature in a tension frame for muscle facilitation increases longitudinal activity at the trot.
Kinesiology taping (KT) has been used on human subjects for many years. More recently, KT has been used in sport horses. The physiological mechanisms involved remain unclear and its benefits are controversial. To investigate the effects of application of kinesiology taping to abdominal muscles on locomotor parameters before and after lungeing exercise in horses. Cross-over study. Eleven horses were tested twice, once with an application of KT without tension on abdominal muscles (condition 1) and once with a facilitation application of KT on abdominal muscles (condition 2). A triaxial accelerometric device, located in the trunk (Equimetrix system® ), was used at walk and trot in hand on a straight line before (30 min after the KT application) and after a lungeing session. Locomotor parameters were calculated, including stride frequency, regularity and symmetry, dorsoventral displacement and dorsoventral, mediolateral and longitudinal activities. At trot, the longitudinal activity was significantly higher for condition 2 than for condition 1, before (7.6 ± 1.8 W/kg vs. 5.4 ± 2.2 W/kg, P = .02) and after (7.3 ± 1.3 W/kg vs. 6.1 ± 1.7 W/kg, P = .005) the lungeing session. The speed was not measured. The recording conditions and the experimenter, unaware of conditions, were the same for all horses to limit variations. Kinesiology taping on abdominal muscles immediately increased longitudinal activity at trot in hand and this benefit was still present after a lungeing session. Longitudinal activity is a sought-after quality; thus, this method could be used as a way to enhance a training program. Future investigations are needed to confirm this result in horses being ridden.


A case of mu heavy-chain disease associated with hyperglobulinemia, anemia, and a positive Coombs test.
We report here for the first time a patient with mu heavy-chain disease (HCD), hyperimmunoglobulinemia, and a positive direct antiglobulin test (DAT, Coombs test). The heavy-chain diseases involve the proliferation of lymphoplasma cells of B cell origin and are characterized by the production of incomplete heavy chains devoid of light chains. The association of mu heavy-chain disease with either hyperglobulinemia or a positive DAT has not been reported in the literature to date. In this patient, immunofixation of serum proteins with monospecific antisera to alpha-, gamma-, mu,- or delta-chains and to kappa- and lambda-chains revealed a precipitation band with antibody to IgM, but not with kappa and lambda light-chain antibodies, indicating mu heavy-chain disease. Hyperglobulinemia was present, which is very uncommon for HCD. A DAT of the patient's red blood cells (RBC) was found to be strongly positive for anti-IgG but negative for anti-IgM, -IgA, -C3c, and -C3d. However, when the eluate from the patient's red blood cells was investigated with nephelometry, it was found to contain antigens reactive with anti-y as well with anti-mu-antiserum. When a DAT was performed with a randomly chosen test cell incubated with the eluate, the antibody-containing eluate was shown to react with anti-IgG as well as with anti-IgM-antiserum. In summary, the eluate from the patient's RBCs contained IgG and an immunoglobulin structure reactive with anti-IgM in an RBC agglutination assay as well as with anti-mu antiserum in a nephelometric investigation. Whether this IgM on the patient's erythrocytes is penta- or oligomeric, complete IgM, or the heavy chain cannot be concluded from these observations.


Lung endothelial ADAM17 regulates the acute inflammatory response to lipopolysaccharide.
Acute lung injury (ALI) is associated with increased vascular permeability, leukocyte recruitment, and pro-inflammatory mediator release. We investigated the role of the metalloproteinase ADAM17 in endotoxin-induced ALI with focus on endothelial ADAM17. In vitro, endotoxin-mediated induction of endothelial permeability and IL-8-induced transmigration of neutrophils through human microvascular endothelial cells required ADAM17 as shown by inhibition with GW280264X or shRNA-mediated knockdown. In vivo, ALI was induced by intranasal endotoxin-challenge combined with GW280264X treatment or endothelial adam17-knockout. Endotoxin-triggered upregulation of ADAM17 mRNA in the lung was abrogated in knockout mice and associated with reduced ectodomain shedding of the junctional adhesion molecule JAM-A and the transmembrane chemokine CX3CL1. Induced vascular permeability, oedema formation, release of TNF-α and IL-6 and pulmonary leukocyte recruitment were all markedly reduced by GW280264X or endothelial adam17-knockout. Intranasal application of TNF-α could not restore leukocyte recruitment and oedema formation in endothelial adam17-knockout animals. Thus, activation of endothelial ADAM17 promotes acute pulmonary inflammation in response to endotoxin by multiple endothelial shedding events most likely independently of endothelial TNF-α release leading to enhanced vascular permeability and leukocyte recruitment.


Diagnostic value of MPO plasma levels in patients admitted for suspected myocardial infarction.
Besides its well-established role in atherosclerosis, myeloperoxidase (MPO) has gained attention as a prognostic indicator in cardiovascular disease. Previous studies assessed MPO retrospectively and at a single time point. The current study aimed to evaluate the prognostic information of MPO prospectively and in consecutive measurements in patients presenting with chest pain. MPO plasma levels were determined in 274 consecutive chest pain patients admitted to the emergency room. A total of 100 patients (36.5%) were finally diagnosed for acute myocardial infarction (AMI). Patients with AMI had significantly higher MPO levels than patients without AMI. Importantly, MPO levels were elevated in patients finally diagnosed for AMI even when troponin I (TNI) was negative (cutoff: 0.032 ng/ml). Overall, MPO yielded a negative predictive value (NPV) of 85.5% (95% confidence interval (CI): 82.6-88.4) and a sensitivity for diagnosing AMI of 80.0% (95% CI: 75.8-84.2) compared to a NPV of 91.7% (95% CI: 89.5-94.0) and a sensitivity of 85.9% (95% CI: 82.3-89.5) for TNI. For patients with a symptom onset of ≤ 2 h the sensitivity of MPO increased to 95.8% (95% CI: 93.7-97.9) whereas the sensitivity of TNI dropped to 50.0% (95% CI: 44.8-55.2). The negative predictive value of MPO for this group of patients was 95.6% (95% CI: 94.0-97.3) compared to 73.3% (95% CI: 69.8-76.9) for TNI. The current data underscore the role of MPO as diagnostic marker in acute coronary disease; however the additive information derived from MPO is restricted to patients presenting in the early phase of symptom onset.


The risk of altering soil and sediment samples upon extract preparation for analytical and bio-analytical investigations--a review.
Organic total extracts play an important role in soil and sediment risk assessment. Beside a routine application in analytical chemistry, they are used in bio-analytical investigations as a "worst-case scenario" or, e.g., in order to simulate chronic intoxication, and as samples for effect-directed analysis. While theoretically providing highly reliable data and good reproducibility, the whole process of sample handling and extract preparation can lead to extracts that might fail to accurately represent a toxic potential of their corresponding sampling site. This review identifies and discusses the most important possible alterations that have the potential to lead to over and, more often, underestimation of the effectiveness of extracts. Since incorrect data will compromise soil and sediment risk assessment as a whole, results from analytical and bio-analytical investigations of extracts demand cautious interpretation. Reliability of extract testing grows with reproducibility; experiments should therefore be repeated with independent extraction replicates. New or optimized extraction procedures should circumvent the issues mentioned here while being suitable for routine application.


Isolation of the lymphocytosis promoting factor-haemagglutinin of Bordetella pertussis by affinity chromatography.
The lymphocytosis promoting factor-haemagglutinin of Bordetella pertussis was isolated from solutions obtained after cell disintegration by a novel affinity chromatographic method using an adsorbent composed of human haptoglobin covalently attached to a Sepharose 4B matrix. The haemagglutinin was bound to the adsorbent at pH 6.5 and eluted by a stepwise change to a pH 10 buffer. A 300--600-fold purification of the haemagglutinin was achieved by this one-step process. The chemical and biological properties of the haemagglutinin isolated by affinity chromatography were found to be similar to those of the protein isolated by other workers from culture supernatants. The affinity chromatographic method was found to be specific for the purification of the lymphocytosis promoting factor-haemagglutinin and no purification of the fimbrial-haemagglutinin of Bordetella pertussis was achieved by the method.


Occult Lymph Node Metastasis in Early-Stage Glottic Cancer in the National Cancer Database.
Early-stage glottic cancer (cT1-T2 cN0) may be treated by primary surgery or radiation. Elective treatment of the neck in clinically N0 disease is usually not performed due to low rates of regional lymph node metastasis. This study examines the role of elective neck dissection (END) and rate of occult nodal metastasis in cT1-T2 cN0 glottic cancer treated with primary surgery. Retrospective cohort study. The National Cancer Database was used to identify patients treated for early-stage glottic cancer. Demographic variables, disease characteristics, and overall survival were compared between the subgroups of patients who did and did not receive END. Factors predictive of occult lymph node metastasis were also identified using a multivariate logistic regression model. Thirty-eight percent of the 991 patients in this cohort underwent END. Younger age, treatment at an academic facility, advanced T-stage, and higher tumor grade were associated with receiving END. Sixteen percent of the 372 patients undergoing END had occult nodal metastasis. Higher tumor histopathologic grade was associated with occult metastasis (P = .004). While undergoing END did not affect significantly survival, those with occult metastasis had poorer survival (P < .001). END should be considered in cT1-T2 N0 glottic cancers with poorly differentiated or undifferentiated tumor histopathology. While END itself may not improve overall survival, identification of occult nodal metastasis is an important finding for prognostication. Level 3 Laryngoscope, 131:E1139-E1146, 2021.


In silico and in vitro evaluation of silibinin: a promising anti-Chikungunya agent.
Chikungunya virus (CHIKV) infection and subsequent high patient morbidity is a global threat. The present study aimed to identify the potent antiviral agent against Chikungunya virus, with minimum in vitro cytotoxicity. CHIKV nsP4 3D structure was determined using the I-TASSER server followed by its refinement and pocket determination. Furthermore, high-throughput molecular docking was employed to identify candidate CHIKV nsP4 inhibitors in a library containing 214 compounds. The top ranked compound was evaluated further with various assays, including cytotoxicity, antiviral activity, time of drug addition, viral entry attachment, and microneutralization assays. High-throughput computational screening indicated silibinin to have the best interaction with CHIKV nsP4 protein, immature and mature glycoproteins with highest negative free binding energy, - 5.24 to - 5.86 kcal/mol, and the lowest inhibitory constant, 50.47 to 143.2 µM. Further in vitro analysis demonstrated silibinin could exhibit statistically significant (p < 0.05) dose-dependent anti-CHIKV activity within 12.5-100-µM concentrations with CC50 as 50.90 µM. In total, 50 µM silibinin interfered with both CHIKV attachment (75%) and entry (82%) to Vero cells. Time of addition assay revealed silibinin interfered with late phase of the CHIKV replication cycle. Microneutralization assay revealed that silibinin could inhibit clearing of 50% Vero cell monolayer caused by CHIKV-induced CPE at a minimum dose of 25 µM. These data indicated silibinin to be a promising candidate drug against CHIKV infection.


Genetic control of HgCl2-induced IgE and autoimmunity by a 117-kb interval on rat chromosome 9 through CD4 CD45RChigh T cells.
Gold or mercury salts trigger a dramatic IgE response and a CD4 T-cell-dependent nephropathy in Brown-Norway (BN), but not in Lewis (LEW) rats. We previously identified the 1.1-Mb Iresp3 (immunoglobin response QTL3) locus on chromosome 9 that controls these gold salt-triggered immune disorders. In the present work, we investigated the genetic control of HgCl(2)-induced immunological disorders and assessed the relative contribution of the CD45RC(high) and CD45RC(low) CD4 T-cell subpopulations in this control. By using interval-specific congenic lines, we narrowed down Iresp3 locus to 117-kb and showed that BN rats congenic for the LEW 117-kb were protected from HgCl(2)-triggered IgE response and nephropathy. This 117-kb interval also controls CD45RC expression by CD4 T cells and the ability of CD45RC(high) CD4 T cells to trigger the autoimmune disorders resulting from HgCl(2) administration. This 117-kb region contains four genes, including Vav1, a strong candidate gene according to its cellular function and exclusive expression in hematopoietic cells. Thus, this study highlights the role of the CD45RC(high) CD4 T-cell subpopulation in the opposite susceptibility of BN and LEW rats to HgCl(2)-triggered immune disorders and identifies a 117-kb interval on chromosome 9 that has a key role in their functions.


Partial purification and characterization of the enzyme which converts precursor liver protein to factor X.
A rat liver post-microsomal supernatant enzyme, which carries out an epigenetic conversion of a protein contained in liver microsomes to Factor X, has been partially purified 250-fold in 50% yield by a combination of salt fractionation and gel filtration. The crude enzyme is stable to freezing and thawing but unstable at 4 degrees C. However, the partially purified enzyme is more stable at 4 degrees C. It requires Ca2+ and HCO3 minus for optimum formation of Factor X activity. The supernatant enzyme is vitamin K dependent and exhibits its maximum rate of formation of Factor X between pH 8 and 8.5.


Preoperative Management of Perihilar Cholangiocarcinoma.
Perihilar cholangiocarcinoma is a rare hepatobiliary malignancy that requires thoughtful, multidisciplinary evaluation in the preoperative setting to ensure optimal patient outcomes. Comprehensive preoperative imaging, including multiphase CT angiography and some form of cholangiographic assessment, is key to assessing resectability. While many staging systems exist, the Blumgart staging system provides the most useful combination of resectability assessment and prognostic information for use in the preoperative setting. Once resectability is confirmed, volumetric analysis should be performed. Upfront resection without biliary drainage or portal venous embolization may be considered in patients without cholangitis and an estimated functional liver remnant (FLR) > 40%. In patients with FLR < 40%, judicious use of biliary drainage is advised, with the goal of selective biliary drainage of the functional liver remnant. Percutaneous biliary drainage may avoid inadvertent contamination of the contralateral biliary tree and associated infectious complications, though the relative effectiveness of percutaneous and endoscopic techniques is an ongoing area of study and debate. Patients with low FLR also require intervention to induce hypertrophy, most commonly portal venous embolization, in an effort to reduce the rate of postoperative liver failure. Even with extensive preoperative workup, many patients will be found to have metastatic disease at exploration and diagnostic laparoscopy may reduce the rate of non-therapeutic laparotomy. Management of perihilar cholangiocarcinoma continues to evolve, with ongoing efforts to improve preoperative liver hypertrophy and to further define the role of transplantation in disease management.


Changes of intracellular calcium regulation in Alzheimer's disease and vascular dementia.
Free intracellular calcium ([Ca2+]i) represents probably the most important intracellular messenger for many signal transduction pathways. Due to this crucial role of [Ca2+]i, it has been assumed that alterations of [Ca2+]i are critically involved in brain aging and in the pathophysiology of Alzheimer's disease (AD). This hypothesis is corroborated by several studies demonstrating changes of [Ca2+]i in peripheral cells from AD patients. However, the findings are still controversial. Using blood lymphocytes and neutrophils as two different peripheral model systems, we evaluated several parameters of intracellular Ca2+ regulation in a very large group of AD patients and non-demented controls. We found no major difference in Ca2+ homeostasis, since neither the basal [Ca2+]i, nor the activation-induced Ca2+ responses differed among neutrophils or lymphocytes from aged controls and AD patients. However, we observed a delayed Ca2+ response of AD lymphocytes after phytohemagglutinin (PHA) stimulation indicating an impaired function of Ca2+ influx-controlling mechanisms. Furthermore, we studied whether differences exist in Ca2+ regulation between lymphocytes from patients with vascular dementia and AD patients, to define AD-specific alterations and to distinguish between the two dementia groups and non-demented control subjects respectively. First evidences indicate that Ca2+ mobilization in lymphocytes is specifically impaired in lymphocytes from patients with vascular dementia.


Negative phototropism of the shoots helps temperate liana Hedera helix L. to locate host trees under habitat conditions.
Lianas employ a variety of searching mechanisms to find support; however, it is not clear to what extent environmental signals are used to help direct the search. Several adventitious root climbers have been shown to bend away from light and grow toward darker areas or objects, in one case including actual tree trunks. In the literature, this negative phototropism (NP) has also been informally and inconsistently reported from a temperate root climber Hedera helix L. (common ivy). In this study, rigorous laboratory tests have confirmed the occurrence of NP in both seedlings and prostrate shoots of H. helix. Furthermore, a field experiment with potted ivy seedlings placed around tree trunks demonstrated their ability to remotely locate trees. This finding was corroborated by a survey of growth directions in wild-growing prostrate ivy shoots in two woodland habitats. An additional outdoor experiment showed that the ability to locate support is expressed in shade but supressed by full sun conditions. These results show that H. helix uses NP to locate support and indicate that this ability is a component of the species' shade escape strategy.


Comparative genome analysis of three euplotid protists provides insights into the evolution of nanochromosomes in unicellular eukaryotic organisms.
One of the most diverse clades of ciliated protozoa, the class Spirotrichea, displays a series of unique characters in terms of eukaryotic macronuclear (MAC) genome, including high fragmentation that produces nanochromosomes. However, the genomic diversity and evolution of nanochromosomes and gene families for spirotrich MAC genomes are poorly understood. In this study, we assemble the MAC genome of a representative euplotid (a new model organism in Spirotrichea) species, Euplotes aediculatus. Our results indicate that: (a) the MAC genome includes 35,465 contigs with a total length of 97.3 Mb and a contig N50 of 3.4 kb, and contains 13,145 complete nanochromosomes and 43,194 predicted genes, with the majority of these nanochromosomes containing tiny introns and harboring only one gene; (b) genomic comparisons between E. aediculatus and other reported spirotrichs indicate that average GC content and genome fragmentation levels exhibit interspecific variation, and chromosome breaking sites (CBSs) might be lost during evolution, resulting in the increase of multi-gene nanochromosome; (c) gene families associated with chitin metabolism and FoxO signaling pathway are expanded in E. aediculatus, suggesting their potential roles in environment adaptation and survival strategies of E. aediculatus; and (d) a programmed ribosomal frameshift (PRF) with a conservative motif 5'-AAATAR-3' tends to occur in longer genes with more exons, and PRF genes play an important role in many cellular regulation processes. The online version contains supplementary material available at 10.1007/s42995-023-00175-0.


Psychometric evaluation of PHQ-9 and GAD-7 among community health volunteers and nurses/midwives in Kenya following a nation-wide telephonic survey.
Nurses/midwives and Community Health Volunteers (CHVs) are exposed to chronic stressors putting them at risk of developing mental health problems. This has been exacerbated by the COVID-19 pandemic. There is limited empirical evidence of the burden of mental health problems among health care workers partly due to the lack of adequately standardized and validated measures for use among health care workers in Sub-Saharan Africa. This study aimed to perform the psychometric evaluation of the PHQ-9 and GAD-7 administered to nurses/midwives and CHVs across 47 counties in Kenya. Between June and November 2021, a national survey on mental well-being and resilience among nurses/midwives and CHVs was conducted via telephone interviews. The survey had a total sample size of 1907 nurses/midwives and 2027 CHVs. Cronbach's alpha and MacDonalds' omega were used to evaluate the scale's internal consistency. Confirmatory Factor Analysis (CFA) was used to test the one-factor structure of the scales. Multi-group CFA was applied to evaluate the generalizability of the scales across the Swahili and English versions, and among male and female health workers. The Spearman correlation was used to assess the tools' divergent and convergent validity. The internal consistency of PHQ-9 and GAD-7 was good, with alpha and omega values above 0.7 across study samples. CFA results indicated a one-factor structure of the PHQ-9 and GAD-7 for both nurses/midwives and CHVs. Multi-group CFA showed that both scales were unidimensional across both language and sex. The PHQ-9 and GAD-7 were significantly negatively correlated with resilience and work engagement, supporting divergent validity. The PHQ-9 and GAD-7 were also significantly positively correlated with resilience and work engagement, supporting divergent validity. The PHQ-9 and GAD-7 are unidimensional, reliable, and valid tools for screening depression and anxiety among nurses/midwives and CHVs. The tools can be administered in a similar population or study setting using either Swahili or English.


Sung Wan Kim - Early events in blood/material interactions.
Sung Wan Kim's initial efforts as an independent investigator were focused on improving the understanding of the early events in blood/material interactions with the goal to develop blood compatible materials for application in medical devices and prostheses. These initial efforts were centered around blood protein adsorption on biomaterials and related mechanisms of thrombus formation (thrombosis). Ultimately, Sung Wan's efforts were expanded to studies of the non-thrombogenic nature of heparinized biomaterials, prostaglandin biomaterials, and block copolymer systems. These studies were supported by two NIH grants for 22 and 19 years, respectively, and a NIH Career Development Award. Moreover, these studies resulted in over 140 peer-reviewed publications and training of many students and postdoctoral scientists. The intent of this paper is to identify key concepts, papers, and contributions by Sung Wan and his colleagues that fall within the four aforementioned research categories. In this context, many of Sung Wan's early efforts contributed directly to Utah's biomaterials efforts and the Total Artificial Heart program at the time, while providing the foundation for the productive international Triangle Collaboration as well as his following work in polymer-controlled drug releasing systems.


Liposomal amphotericin B for prophylaxis of invasive fungal infections in high-risk paediatric patients with chemotherapy-related neutropenia: interim analysis of a prospective study.
Invasive fungal infections (IFI) are a major cause of morbidity and mortality in patients with cancer. A retrospective analysis of children with cancer at high risk for IFI treated at Münster University Hospital showed that the incidence (7.4% vs. 1.8%) and lethality (28.1% vs. 0) of documented IFI were lower in patients receiving systemic antifungal prophylaxis with liposomal amphotericin B (l-AmB) in comparison to a historical control group. To determine whether this decline in incidence and lethality was due to antifungal prophylaxis or was produced by advances in diagnostic procedures and early empirical antifungal therapy, a prospective study was initiated. Patients in the prophylaxis arm received thrice-weekly 1 mg kg(-1) body weight l-AmB, whilst patients in the early intervention arm received no prophylaxis. Diagnostic procedures and antifungal therapy for suspected or proven IFI were initiated as clinically indicated for all patients. The primary endpoint of the study was the incidence of IFI. Secondary endpoints were the use of therapeutic doses of l-AmB, the safety of prophylactic l-AmB, and the total consumption of l-AmB for antifungal therapy. The interim analysis after 1 year showed no differences between the two approaches with respect to the incidence of IFI and to safety issues.


Nanocurcumin: A novel strategy in treating ankylosing spondylitis by modulating Th17 cells frequency and function.
Ankylosing spondylitis (AS) is a chronic rheumatic disease which mainly affects the axial skeleton and sacroiliac joints. T-helper 17 (Th17) cells have been reportedly involved in AS pathogenesis. Nanocurcumin is considered to be beneficial, as an anti-inflammatory compound, in AS patients treatment. In this study, Th17-related immunological parameters were evaluated in AS patients. Transcription factors messenger RNA (mRNA) expression level, cytokines, and related microRNAs (miRNAs) were measured by real-time polymerase chain reaction. Additionally, Th17 frequency and cytokines secretion were evaluated by flow cytometry and enzyme-linked immunosorbent assay tests, respectively. The frequency of Th17 was higher in AS patients. Gained data from nanocurcumin group also demonstrated that retinoic acid-related orphan receptor γ (RORγt) and interleukin-17 (IL-17) mRNA expression levels were significantly decreased (P = 0.0001 and 0.0006, respectively), as the decrease also happened in Th17-associated miRNAs including miR-141, miR-155, and miR-200 ( P = 0.04, P = 0.02, and P < 0.0001, respectively). Posttreatment data of miR-155 and miR-200 in the nanocurcumin and placebo groups also showed a higher expression level in the placebo group compared with nanocurcumin-treated patients. Some clinical symptoms of AS patients were also improved at the end of the treatment process. The results of this study showed the potential ability of nanocurcumin to regulate Th17 cells activity in AS patients. This study provided further evidence on the function and underlying mechanism of nanocurcumin helping better treatment of AS.


Diagnosis and management of connective tissue disease-associated interstitial lung disease in Australia and New Zealand: A position statement from the Thoracic Society of Australia and New Zealand.
Pulmonary complications in CTD are common and can involve the interstitium, airways, pleura and pulmonary vasculature. ILD can occur in all CTD (CTD-ILD), and may vary from limited, non-progressive lung involvement, to fulminant, life-threatening disease. Given the potential for major adverse outcomes in CTD-ILD, accurate diagnosis, assessment and careful consideration of therapeutic intervention are a priority. Limited data are available to guide management decisions in CTD-ILD. Autoimmune-mediated pulmonary inflammation is considered a key pathobiological pathway in these disorders, and immunosuppressive therapy is generally regarded the cornerstone of treatment for severe and/or progressive CTD-ILD. However, the natural history of CTD-ILD in individual patients can be difficult to predict, and deciding who to treat, when and with what agent can be challenging. Establishing realistic therapeutic goals from both the patient and clinician perspective requires considerable expertise. The document aims to provide a framework for clinicians to aid in the assessment and management of ILD in the major CTD. A suggested approach to diagnosis and monitoring of CTD-ILD and, where available, evidence-based, disease-specific approaches to treatment have been provided.


Comparison between hydroxychloroquine and systemic corticosteroids in IgA nephropathy: a two-year follow-up study.
Hydroxychloroquine (HCQ) is recommended as a treatment for IgA nephropathy (IgAN) to control proteinuria. The long-term effects of HCQ compared to systemic corticosteroid therapy remain unclear. We conducted a retrospective case‒control study at Peking University First Hospital. Thirty-nine patients with IgAN who received HCQ for at least 24 months without corticosteroids (CSs) or other immunosuppressive agents were included. Thirty-nine matched patients who received systemic CS therapy were selected using propensity score matching. Clinical data over a 24-month period were compared. In the HCQ group, the level of proteinuria decreased from 1.72 [1.44, 2.35] to 0.97 [0.51, 1.37] g/d (-50.5 [-74.0, -3.4] %, P < 0.001) at 24 months. A significant decline in proteinuria was also found in the CS group, but no significant differences were found between the HCQ group and CS group in the levels of proteinuria (0.97 [0.51, 1.37] vs. 0.53 [0.25, 1.81] g/d, P = 0.707) and change rates (-50.5% [-74.0%, -3.4%] vs. -63.7% [-78.5%, -24.2%], P = 0.385) at 24 months. In addition, the decline rates of eGFR between the HCQ and CS groups were comparable (-7.9% [-16.1%, 5.8%] vs. -6.6% [-14.9%, 5.3%], P = 0.758). More adverse events were observed in the CS group. Long-term use of HCQ can maintain stable renal function with minimal side effects. In patients who cannot tolerate corticosteroids, HCQ might be an effective and safe supportive therapy for IgAN.


The risk of thrombo-embolic events is increased in patients with germ-cell tumours and can be predicted by serum lactate dehydrogenase and body surface area.
The aim of this study was to evaluate the risk of thrombo-embolic events (TEE) in patients with germ-cell tumours (GCT) who receive cisplatin-based chemotherapy, to compare this risk to that of a matched control group of non-GCT cancer patients, and to identify risk factors of TEE. The rate of TEE during the 6 months following the initiation of chemotherapy was assessed in 100 consecutive patients with GCT and in 100 controls with various neoplasms who were matched on sex and age, and who received first-line cisplatin-based chemotherapy during the same period of time at Institut Gustave Roussy, Villejuif, France. Data were subsequently tested on a validation group of 77 GCT patients treated in Lyon, France. A total of 19 patients (19%) (95% confidence interval (CI): 13-28) and six patients (6%) (95% CI: 3-13) had a TEE in the GCT group and the non-GCT control group, respectively (relative risk (RR): 3.4; P<0.01). Three patients from the GCT group died of pulmonary embolism. In multivariate analysis, two factors had independent predictive value for TEE: a high body surface area (>1.9 m2) (RR: 5 (1.8-13.9)) and an elevated serum lactate dehydrogenase (LDH) (RR: 6.4 (2.3-18.2)). Patients with no risk factor (n=26) and those with at least one risk factor (n=71) had a probability of having a TEE of 4% (95% CI: 1-19) and 26% (95% CI: 17-37), respectively. In the GCT validation set, 10 (13%) patients had a TEE; patients with no risk factor and those with at least one risk factor had a probability of having a TEE of 0 and 17% (95% CI: 10-29), respectively. Patients with GCT are at a higher risk for TEE than patients with non-GCT cancer while on cisplatin-based chemotherapy. This risk can be accurately predicted by serum LDH and body surface area. This predictive index may help to study prospectively the impact of thromboprophylaxis in GCT patients.


An alternative design for long-term stability testing of large molecules: a scientific discussion paper from an EBF Topic Team.
Long-term stability testing of drug candidates in biological matrix is a key parameter in bioanalytical method validation. The European Bioanalysis Forum formed a Topic Team to evaluate the use of isochronic design for long-term stability testing of large molecules. Isochronic design is based on storage of samples at a reference temperature (below -130°C) where the samples are considered stable. The stability samples are stored at the intended storage temperature and then transferred to the reference temperature, while a set of reference samples is stored the entire storage period at the reference temperature. Stability and reference samples will then be analyzed in one run at the end of the storage period. The mean concentrations of the stability samples are compared either to their nominal concentrations or to the mean concentrations of the reference samples. The design minimizes day-to-day variation, reduces workload and adds to the flexibility in the laboratory.


Neuron types in the central nucleus of the inferior colliculus that project to the medial geniculate body.
At least four neuron types, distinguished on the basis of dendritic and cell body morphology, were labeled in the central nucleus of the inferior colliculus after horseradish peroxidase injections into the medial geniculate body of the cat. Most labeled cells had disc-shaped dendritic fields whose orientation and arrangement into layers were important identifying features. Most labeled cells were small or medium-sized disc-shaped cells with dendritic fields and cell bodies of corresponding size. These cell types appeared to have dispersed Nissl substance and infrequent axosomatic endings. Large disc-shaped cells, identified by their large dendritic fields and somata, were also labeled. These may have had a different Nissl pattern, including both perinuclear cisterns and clumps of granular endoplasmic reticulum, and numerous axosomatic synaptic endings. Stellate cells, which constituted the fourth labeled cell type, were distinguished by their spherical dendritic fields composed of dendrites radiating in all directions, especially across the layers formed by the disc-shaped cells. Stellate cells probably corresponded to neurons with stacks or clumps of granular endoplasmic reticulum, an irregular nuclear envelope, and frequent axosomatic contacts. These results suggest that many of the cell types previously identified in studies using the Golgi method send their axons to the medical geniculate body. The results also raise the possibility that Nissl pattern and dendritic morphology of central nucleus cell types are related. The presence of several types of neurons in the central nucleus with axons ascending to the thalamus may provide a structural basis for some type of parallel information processing in this part of the central auditory system.


Leveraging the Electronic Medical Record to Increase Distribution of Low Literacy Asthma Education in the Emergency Department.
Though low literacy asthma education is effective at reducing emergency department (ED) use, few interventions are administered in the ED. The aim was to increase the number of parents of children with asthma receiving education in the ED to 50% receiving written and 30% receiving video education over 12 months. Using quality improvement methods, the team planned interventions including improvement of nursing workflow and availability of written and video education. Nurse champions performed peer-to-peer education regarding educational materials and health literacy-focused communication. An asthma education order opening the nursing flowsheet, which linked to written and video materials and documentation was created. The order was placed in highly used ED asthma order sets. The percent of parents receiving written or video education was followed on statistical process control charts. Balancing measures included: ED length of stay, discharge length, 30 day ED return visits, and 365 day return visits with hospitalization. The mean number of parents receiving written education at baseline was 28% and improved to 52%. Special cause variation was noted after order roll-out. Video education increased from a baseline of 0% of parents receiving to 32% with special cause variation after order roll-out. No special cause was noted in balancing measures. Revisits with hospitalization within 365 days showed a decreasing trend after order roll-out. Implementation of workflow improvement, education, and the addition of a functional education order in an existing order set led to a meaningful improvement in distribution of a low literacy asthma education intervention.


The correlation between dynamic functional architecture and response to electroconvulsive therapy combined with antipsychotics in schizophrenia.
Attempts to determine why some patients respond to electroconvulsive therapy (ECT) are valuable in schizophrenia. Schizophrenia is associated with aberrant dynamic functional architecture, which might impact the efficacy of ECT. We aimed to explore the relationship between pre-treatment temporal variability and ECT acute efficacy. Forty-eight patients with schizophrenia and 30 healthy controls underwent functional magnetic resonance imaging to examine whether patterns of temporary variability of functional architecture differ between high responders (HR) and low responders (LR) at baseline. Compared with LR, HR exhibited significantly abnormal temporal variability in right inferior front gyrus (IFGtriang.R), left temporal pole (TPOsup.L) and right middle temporal gyrus (MTG.R). In the pooled patient group, ∆PANSS was correlated with the temporal variability of these regions. Patients with schizophrenia with a distinct dynamic functional architecture appear to reveal differential response to ECT. Our findings provide not only an understanding of the neural functional architecture patterns that are found in schizophrenia but also the possibility of using these measures as moderators for ECT selection.


T-cell responses following Natural Influenza Infection or Vaccination in Solid Organ Transplant Recipients.
Little is known about cell-mediated immune responses to natural influenza infection in solid organ transplant (SOT) patients. The aim of our study was to evaluate the CD4+ and CD8+ responses to influenza A and B infection in a cohort of SOT patients. We collected peripheral blood mononuclear cells at influenza diagnosis and four weeks later from 31 SOT patients during the 2017-2018 influenza season. Infection-elicited influenza-specific CD4+ and CD8+ T-cell responses were measured using flow cytometry and intracellular cytokine staining and compared to responses following influenza vaccine in SOT patients. Natural infection was associated with a significant increase in CD4+ T-cell responses. For example, polyfunctional cells increased from 21 to 782 and from 193 to 1436 cells per 106 CD4+ T-cells among influenza A/H3N2 and B-infected patients (p = 0.006 and 0.004 respectively). Moreover, infection-elicited CD4+ responses were superior than vaccine-elicited responses for influenza A/H1N1 (931 vs 1; p = 0.026), A/H3N2 (647 vs 1; p = 0.041) and B (619 vs 1; p = 0.004). Natural influenza infection triggers a significant increase in CD4+ T-cell responses in SOT patients. Infection elicits significantly stronger CD4+ responses compared to the influenza vaccine and thereby likely elicits better protection against reinfection.


Blood lead and carboxyhemoglobin levels in chainsaw operators.
Fallers in the British Columbia west coast lumber industry often work in climatic and local conditions where little ventilation in their immediate environment is possible. Under these conditions carbon monoxide (CO) and lead fumes from exhaust gases could build up and become a serious occupational hazard. This study monitored the environmental exposure of six fallers to carbon monoxide, nitrogen oxides, and lead under conditions where buildup of these agents would be expected. At the same time blood samples were taken to correlate these environmental concentrations to carboxyhemoglobin (COHb) and blood lead levels. Although there was a highly significant difference between the fallers and the controls regarding the exposure to CO and lead as well as their corresponding COHb and blood lead levels, the environmental and blood concentration of the agents in question did not exceed the maximum allowable concentrations. Temporary short fluctuations in carboxyhemoglobin levels were not monitored in this study and cannot be ruled out as a potential occupational hazard.


Social engagement and depressive symptoms in late life: longitudinal findings.
The purpose is to investigate whether social engagement protects against depressive symptoms in older adults. Three waves of data from a representative cohort study of community-dwelling adults aged 65 years and above from the New Haven Established Populations for the Epidemiologic Study of the Elderly are examined using random effects models. Social engagement (an index combining social and productive activity) is associated with lower CES-D scores after adjustment for age, sex, time, education, marital status, health and functional status, and fitness activities. This association is generally constant with time, suggesting a cross-sectional association. In addition, social engagement is associated with change in depressive symptoms, but only among those with CES-D scores below 16 at baseline. Social engagement is independently associated with depressive symptoms cross-sectionally. A longitudinal association is seen only among those not depressed at baseline.


Structural properties of myosin from the particulate fraction of human blood platelets.
Fractionation of human blood platelets has revealed that myosin, a contractile and mechanochemical protein, is present in both the soluble and particulate fraction. The aim of this study was to elucidate whether platelets contain more than one myosin isoform, especially in view of the fact that in other cellular systems (cardiac muscle, amoeba) several myosin isoenzymes were found. The particulate fraction was solubilized by Triton X-100, and the myosin was purified by the same procedure used for the cytoplasmic myosin. The final preparation contained, in addition to myosin, a 130-kDa polypeptide, which was observed also in myosin preparations obtained from the soluble fraction. The electrophoretic mobilities of the two myosins were identical under both dissociating and nondissociating conditions. Comparison of the molecular structure of the heavy chain of the two myosins by limited proteolysis with Staphylococcus aureus V8 protease showed that the proteolytic fragments of the two myosins were rather similar, with only minor alterations in the quantitative distribution of the products. Two-dimensional peptide mapping of the iodinated tryptic peptides of the myosin heavy chains indicated that at least one peptide is missing in the map of the particulate myosin, as compared to its soluble counterpart. According to the two-dimensional peptide map, the 130-kDa polypeptide seems to be a proteolytic fragment of the myosin heavy chain and most probably the rod portion of the molecule. The observed minor variations in the structure of myosins isolated from the soluble and the fractions of human platelets may reflect differences in their respective physiological functions.


Skewed X inactivation in an X linked nystagmus family resulted from a novel, p.R229G, missense mutation in the FRMD7 gene.
This study aimed to identify the underlying genetic defect of a large Turkish X linked nystagmus (NYS) family. Both Xp11 and Xq26 loci were tested by linkage analysis. The 12 exons and intron-exon junctions of the FRMD7 gene were screened by direct sequencing. X chromosome inactivation analysis was performed by enzymatic predigestion of DNA with a methylation-sensitive enzyme, followed by PCR of the polymorphic CAG repeat of the androgen receptor gene. The family contained 162 individuals, among whom 28 had NYS. Linkage analysis confirmed the Xq26 locus. A novel missense c.686C>G mutation, which causes the substitution of a conserved arginine at amino acid position 229 by glycine (p.R229G) in exon 8 of the FRMD7 gene, was observed. This change was not documented in 120 control individuals. The clinical findings in a female who was homozygous for the mutation were not different from those of affected heterozygous females. Skewed X inactivation was remarkable in the affected females of the family. A novel p.R229G mutation in the FRMD7 gene causes the NYS phenotype, and skewed X inactivation influences the manifestation of the disease in X linked NYS females.


Impact of fasting and postprandial state on plasma carnitine concentrations during aerobic exercise in type 2 diabetes.
The effects of metabolic states of fasting and post-absorption on plasma concentrations of free carnitine (FC), acylcarnitine (AC) and total carnitine (TC) were compared during submaximal exercise in subjects with type 2 diabetes mellitus. Ten sedentary men (54+/-5 years) treated with oral hypoglycaemic agents were tested on two separate occasions: following an overnight fast and 2 h after a 395-kcal standardised breakfast. Exercise was performed at 60% of [Formula: see text]O(2peak) on a cycle ergometer for 60 min. Blood samples were drawn at rest for baseline values and following 60 min of exercise and 30 min of recovery. Our results show that: (1) baseline levels of TC, FC and AC were similar in fasted and postprandial groups, (2) TC and AC levels were increased during exercise in the fasted group only, (3) FC levels were decreased during exercise in both fasted and postprandial state and (4) the AC/FC ratio increased during exercise in the fasted group. Our results indicate that the metabolic state of the diabetic patient is associated with a different plasma carnitine status. These patterns may reflect differences in energy metabolism associated with fasting and postprandial hyperglycaemia.


Ultrasound elastography in the assessment of post-stroke muscle stiffness: a systematic review.
Post-stroke muscle stiffness is a major challenge in the rehabilitation of stroke survivors, with no gold standard in clinical assessment. Muscle stiffness is typically evaluated by the Modified Ashworth Scale or the Tardieu Scale; however, these can have low reliability and sensitivity. Ultrasound elastography is an advanced imaging technology that can quantitatively measure the stiffness of a tissue and has been shown to have good construct validity when compared to clinically assessed muscle stiffness and functional motor recovery. The purpose of this article is to systematically review the literature regarding the change in muscle stiffness as measured by ultrasound elastography in stroke survivors. Scopus, PubMed, Embase, CINAHL, MEDLINE and Cochrane Library were searched for relevant studies that assessed the change in stiffness of post-stroke muscle stiffness measured by ultrasound elastography following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. In total, 29 articles were identified, using either strain elastography and shear wave elastography to measure the stiffness of muscles in stroke survivors, most frequently in the biceps and medial gastrocnemius muscles. The stiffness was typically higher in the paretic compared to the non-paretic or healthy control. Other variations that increased the stiffness include increasing the joint angle and introducing a passive stretch or muscle activation. The paretic muscle has also been assessed pre- and post-treatment demonstrating a decrease in stiffness. Ultrasound elastography is a promising imaging technology for determining the muscle stiffness in stroke survivors with need for a standardized imaging protocol.


Effects of mobile phone application combined with or without self-monitoring of blood glucose on glycemic control in patients with diabetes: A randomized controlled trial.
There is potential for mobile applications to deliver new self-management interventions for chronic disease, especially in diabetes. The aim of the present study was to evaluate the effects of a mobile phone application (MPA) combined with or without self-monitoring of blood glucose (SMBG) on glycemic control in patients with diabetes. The study was a 24-week period, four-arm parallel group, non-blinded, randomized trial. A total of 185 patients with mean age of 52 years were randomized to group A (no MPA and no SMBG), group B (SMBG only), group C (MPA only) and group D (both MPA and SMBG were used). Changes in glycated hemoglobin (HbA1c), fasting plasma glucose and 1,5-anhydroglucitol from baseline to week 24 were analyzed. At 24 weeks, the HbA1c levels in patients of all groups decreased significantly from baseline. There were significant differences in the proportions of patients that achieved HbA1c <7% between groups, especially in group C and group D, compared with group A at week 24 (60.4%, 62.2% vs 25.5%, all P < 0.05). 1,5-Anhydroglucitol changes were obvious in group A and group C at week 24 from baseline (all P < 0.05 within groups). Factorial analysis of anova showed that MPA intervention was the main effective factor for HbA1c change (F = 4.59, P = 0.034), and there was no effect on HbA1c change for SMBG intervention (P = 0.975). Implementation of the MPA, Diabetes-Carer, is effective in improving the proportion of HbA1c <7% in patients with type 2 diabetes.


Lichen sclerosus and lichen planus: a spectrum of disease? Report of two cases and review of the literature.
There has long been controversy concerning the relationship between lichen planus and lichen sclerosus. Whilst these two conditions are now considered distinct, there are shared clinical and pathological features. We now describe two patients with the cutaneous involvement of both lichen planus and lichen sclerosus, presenting a review of similar reported cases and discussing the implications for pathogenesis of these two diseases. Neither lichen planus (LP) nor lichen sclerosus (LS) are uncommon yet they have only infrequently been reported as coexisting. In his original description of LS, however, Hallopeau considered it to be a variant of LP and Gougerot has also commented on a possible common pathogenesis for the two conditions. Features which tend to support such as association include the distribution of the cutaneous lesions, histopathological features such as hydropic basal cell degeneration and a band-like lymphohistiocytic infiltrate in the dermis, and the reported association with autoimmune disease. We now report two patients in whom coexistent cutaneous LS and LP was confirmed histologically.


Effects of polymorphisms in nucleotide-binding oligomerization domains 1 and 2 on biomarkers of the metabolic syndrome and type II diabetes.
The innate immune receptor toll-like receptor 4 (TLR4) has been implicated in mediating some of the effects of dietary lipids on inflammation and type 2 diabetes (T2D). Similar to TLR4, the nucleotide-binding oligomerization domains (Nods) 1 and 2 are also proteins of innate immunity, which can respond to lipids and initiate pro-inflammatory signalling that plays a role in the aetiology of T2D. The objective was to determine the effect of Nod1 (Glu266Lys) and Nod2 (Ser268Pro) genotypes on factors associated with the metabolic syndrome (MetS), and whether they modify the association between dietary lipids and biomarkers of the MetS. Men and women (n = 998) between the ages of 20-29 years were genotyped for both polymorphisms, completed a one-month, semiquantitative food frequency questionnaire and provided a fasting blood sample. The Glu266Lys polymorphism in Nod1 was not associated with any of the biomarkers of the MetS, but modified the association between dietary saturated fat (SFA) and insulin sensitivity, as measured by HOMA-IR (p for interaction = 0.04). Individuals with the Glu/Glu or Glu/Lys genotype showed no significant relationship between dietary SFA and HOMA-IR (β = -0.002 ± 0.006, p = 0.77; and β = -0.003 ± 0.006, p = 0.61), while those with the Lys/Lys genotype showed a positive association (β = 0.033 ± 0.02, p = 0.03). The Nod2 Ser268Pro polymorphism was not associated with components of the MetS and did not modify the relationship between dietary lipid intake and the biomarkers of MetS. In summary, the Nod1 Glu266Lys polymorphism modifies the relationship between dietary SFA intake and HOMA-IR, suggesting that Nod1 may act as an intracellular lipid sensor affecting insulin sensitivity.


Signaling of transcriptional chemistry in the on-line detection format.
A critical analysis of optical and acoustic wave instrumentation for examining the transcription apparatus and its regulation is given in the present review. The physico-chemical parameters derived from such in vitro experiments are important from a biophysical standpoint. The overall mechanism of transcription is composed of several mechanisms such as DNA-binding and promoter selection, closed and open polymerase complex formation, initiation of RNA synthesis, elongation and termination. Surface plasmon resonance (SPR) and fluorescence spectroscopy are widely employed techniques for investigating these mechanisms in real time. Although the binding of nucleotides, transcription factors (TFs) and inhibitors to RNA polymerase (RNAP) and the DNA template have been studied extensively, the synthesis of mRNA has not been investigated in detail except by methods based on electrophoresis. The use of acoustic wave physics for investigating transcriptional chemistry offers not only a time-course analysis but also the potential to gain insight into structural changes that occur during the process.


Evaluating maize phenotypic variance, heritability, and yield relationships at multiple biological scales across agronomically relevant environments.
A challenge to improve an integrative phenotype, like yield, is the interaction between the broad range of possible molecular and physiological traits that contribute to yield and the multitude of potential environmental conditions in which they are expressed. This study collected data on 31 phenotypic traits, 83 annotated metabolites, and nearly 22,000 transcripts from a set of 57 diverse, commercially relevant maize hybrids across three years in central U.S. Corn Belt environments. Although variability in characteristics created a complex picture of how traits interact produce yield, phenotypic traits and gene expression were more consistent across environments, while metabolite levels showed low repeatability. Phenology traits, such as green leaf number and grain moisture and whole plant nitrogen content showed the most consistent correlation with yield. A machine learning predictive analysis of phenotypic traits revealed that ear traits, phenology, and root traits were most important to predicting yield. Analysis suggested little correlation between biomass traits and yield, suggesting there is more of a sink limitation to yield under the conditions studied here. This work suggests that continued improvement of maize yields requires a strong understanding of baseline variation of plant characteristics across commercially-relevant germplasm to drive strategies for consistently improving yield.


Fabrication of a "progress bar" colorimetric strip sensor array by dye-mixing method as a potential food freshness indicator.
Colorimetric sensing is a low-cost, intuitive method for monitoring the freshness of food. We prepared a colorimetric strip sensor array by mixing different amounts of bromophenol blue (BPB) and bromocresol green (BCG). As results of NH3 simulation, the array strip turned from yellow to blue, and the number of blue spots increased with the increasing NH3, like a progress bar. Although the actual color is quite different, the color-changing trend was consistent with the simulated model calculated by a computer. The progress bar results remained stable under three lighting conditions. Furthermore, in the Cod preservation experiment, the color-changing progress of the strip sensor array is consistent with the simulation and can indicate Cod freshness while providing more distinguish levels. Therefore, a "progress bar" indicator built by this strategy possess the potential of realizing nondestructive, more accurate, and commercially available food quality monitoring through the naked eye and smart equipment recognition.


Renin-angiotensin system blockade and the risk of hyperkalemia in chronic hemodialysis patients.
Blockade of the renin-angiotensin system by angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers can cause hyperkalemia in patients with chronic renal insufficiency who are not on dialysis, but the risk of hyperkalemia in hemodialysis patients is unknown. We conducted a prospective study of 251 adult hemodialysis patients to determine if renin-angiotensin system blockade was associated with hyperkalemia, defined as a predialysis serum potassium concentration of 5.5 mmol/L or higher. Medication use was determined by chart review and patient interview. Predialysis serum potassium concentration was measured monthly. There were 367 episodes of hyperkalemia during 1877 person-months of follow-up. After adjustment for potential confounding variables and for clustering of episodes by patient, use of an ACE inhibitor or an angiotensin receptor blocker was associated with a significantly higher risk of hyperkalemia (odds ratio [OR] = 2.2; 95% confidence interval [CI]: 1.4 to 3.4). The increased risk of hyperkalemia with renin-angiotensin system blockade was seen in anuric dialysis patients (OR = 2.3; 95% CI: 1.3 to 4.2), as well as those with residual renal function (OR = 2.1; 95% CI: 1.0 to 4.1). The use of ACE inhibitors or angiotensin receptor blockers is independently associated with an increased risk of developing hyperkalemia in chronic hemodialysis patients. The serum potassium concentration should be closely monitored when these medications are prescribed for hemodialysis patients.


Metabolic Modifier Screen Reveals Secondary Targets of Protein Kinase Inhibitors within Nucleotide Metabolism.
Biosynthesis of the pyrimidine nucleotide uridine monophosphate (UMP) is essential for cell proliferation and is achieved by the activity of convergent de novo and salvage metabolic pathways. Here we report the development and application of a cell-based metabolic modifier screening platform that leverages the redundancy in pyrimidine metabolism for the discovery of selective UMP biosynthesis modulators. In evaluating a library of protein kinase inhibitors, we identified multiple compounds that possess nucleotide metabolism modifying activity. The JNK inhibitor JNK-IN-8 was found to potently inhibit nucleoside transport and engage ENT1. The PDK1 inhibitor OSU-03012 (also known as AR-12) and the RAF inhibitor TAK-632 were shown to inhibit the therapeutically relevant de novo pathway enzyme DHODH and their affinities were unambiguously confirmed through in vitro assays and co-crystallization with human DHODH.


Configurations of early risk and their association with academic, cognitive, emotional and behavioural outcomes in middle childhood.
Risk factors for children's development are multifarious and co-occur, having cumulative as well as individual impacts. Yet common configurations of early childhood risks remain little understood. The current study aimed to identify patterns of early risk exposure and to examine their relationship with diverse outcomes in middle childhood. Using latent class analysis in a large, community-based, UK sample (N = 13,699), we examined 13 putative risk factors to identify patterns of exposure. Four risk configurations were identified: low (65 %), socio-demographic (14 %), family dysfunction (12 %), and multiple (9 %) risk classes. As expected, children in the low risk group fared best on all outcome measures, and those with multiple risk, worst. Importantly, specificity in associations with outcomes emerged, such that cognitive outcomes were predominantly linked with socio-demographic adversities, emotional difficulties with family dysfunction, and conduct problems increased across risk classes. Better understanding of configurations of childhood risk exposures may help to target resources for children in need.


Mapping analytical hierarchy process research to sustainable development goals: Bibliometric and social network analysis.
The drive to achieve the Sustainable Development Goals (SDGs) becomes more urgent as the 2030 deadline draws near, increasing research in various sectors. Nevertheless, studies that systematically map Analytical Hierarchy Process (AHP) publications with the SDGs need to be more conspicuously lacking. Our study adds a new perspective to the field by creatively bridging this knowledge gap using the Elsevier SDG Mapping Initiative. To find research clusters, trends, and themes linked to SDGs and their connection to environmental sustainability, we thoroughly analyzed 29,897 publications from 2012 to 2022. The analysis showed that SDG 15, SDG 7, SDG 12, SDG 13, and SDG 11 were the top five SDGs, with an environmental focus among the 17 SDGs. These top SDGs had many clusters connected to them, illustrating various sustainability-related problems. The study also looked at connections between SDGs, the nations with the highest rates of productivity, the top contributors, and the journals with the highest citation counts. We discovered three separate SDG clusters using co-occurrence network analysis, each representing a different SDG. We discovered relevant SDGs using Matrice d'impacts croisés multiplication appliquée á un classment (MICMAC) analysis and centrality indicators like eigenvector and betweenness. This novel method for publishing analysis combines an AHP focus that aligns with the SDGs with social network analysis and centrality metrics. Our research advances knowledge of how the AHP technique can assess initiatives supporting the SDGs. We offer essential insights into prioritizing sustainable development measures by identifying research clusters, trends, and issues related to environmental sustainability. This study highlights the subject's most important SDGs, productive nations, helpful organizations, and significant journals.


Comparison of Medical and Mental Health Sequelae Following Hospitalization for COVID-19, Influenza, and Sepsis.
People who survive hospitalization for COVID-19 are at risk for developing new cardiovascular, neurological, mental health, and inflammatory autoimmune conditions. It is unclear how posthospitalization risks for COVID-19 compare with those for other serious infectious illnesses. To compare risks of incident cardiovascular, neurological, and mental health conditions and rheumatoid arthritis in 1 year following COVID-19 hospitalization against 3 comparator groups: prepandemic hospitalization for influenza and hospitalization for sepsis before and during the COVID-19 pandemic. This population-based cohort study included all adults hospitalized for COVID-19 between April 1, 2020, and October 31, 2021, historical comparator groups of people hospitalized for influenza or sepsis, and a contemporary comparator group of people hospitalized for sepsis in Ontario, Canada. Hospitalization for COVID-19, influenza, or sepsis. New occurrence of 13 prespecified conditions, including cardiovascular, neurological, and mental health conditions and rheumatoid arthritis, within 1 year of hospitalization. Of 379 366 included adults (median [IQR] age, 75 [63-85] years; 54% female), there were 26 499 people who survived hospitalization for COVID-19, 299 989 historical controls (17 516 for influenza and 282 473 for sepsis), and 52 878 contemporary controls hospitalized for sepsis. Hospitalization for COVID-19 was associated with an increased 1-year risk of venous thromboembolic disease compared with influenza (adjusted hazard ratio, 1.77; 95% CI, 1.36-2.31) but with no increased risks of developing selected ischemic and nonischemic cerebrovascular and cardiovascular disorders, neurological disorders, rheumatoid arthritis, or mental health conditions compared with influenza or sepsis cohorts. In this cohort study, apart from an elevated risk of venous thromboembolism within 1 year, the burden of postacute medical and mental health conditions among those who survived hospitalization for COVID-19 was comparable with other acute infectious illnesses. This suggests that many of the postacute consequences of COVID-19 may be related to the severity of infectious illness necessitating hospitalization rather than being direct consequences of infection with SARS-CoV-2.