Pho85, Pcl1, and Hms1 signaling governs Candida albicans morphogenesis induced by high temperature or Hsp90 compromise.
Temperature exerts powerful control over development and virulence of diverse pathogens. In the leading human fungal pathogen, Candida albicans, temperature governs morphogenesis, a key virulence trait. Many cues that induce the yeast to filament transition are contingent on a minimum of 37°C, whereas further elevation to 39°C serves as an independent inducer. The molecular chaperone Hsp90 is a key regulator of C. albicans temperature-dependent morphogenesis. Compromise of Hsp90 function genetically, pharmacologically, or by elevated temperature induces filamentation in a manner that depends on protein kinase A signaling but is independent of the terminal transcription factor, Efg1. Here, we establish that despite morphological and regulatory differences, inhibition of Hsp90 induces a transcriptional profile similar to that induced by other filamentation cues and does so independently of Efg1. Further, we identify Hms1 as a transcriptional regulator required for morphogenesis induced by elevated temperature or Hsp90 compromise. Hms1 functions downstream of the cyclin Pcl1 and the cyclin-dependent kinase Pho85, both of which are required for temperature-dependent filamentation. Upon Hsp90 inhibition, Hms1 binds to DNA elements involved in filamentous growth, including UME6 and RBT5, and regulates their expression, providing a mechanism through which Pho85, Pcl1, and Hms1 govern morphogenesis. Consistent with the importance of morphogenetic flexibility for virulence, deletion of C. albicans HMS1 attenuates virulence in a metazoan model of infection. Thus, we establish a new mechanism through which Hsp90 orchestrates C. albicans morphogenesis, and define novel regulatory circuitry governing a temperature-dependent developmental program, with broad implications for temperature sensing and virulence of microbial pathogens.


NBS1 Glu185Gln polymorphism and cancer risk: update on current evidence.
A number of studies have investigated the association between NBS1 Glu185Gln (rs1805794, E185Q) polymorphism and cancer risk, but the results remained controversial. Previous meta-analysis found a borderline significant impact of this polymorphism on cancer risk; however, the result might be relatively unreliable due to absence of numerous newly published studies. Thus, we conducted an updated meta-analysis. A systematic search was performed in PubMed and Embase databases until April 9, 2013. The odds ratios were pooled by the fixed-effects/random-effects model in STATA 12.0 software. As a result, a total of 48 case-control studies with 17,159 cases and 22,002 controls were included. No significant association was detected between the Glu185Gln polymorphism and overall cancer risk. As to subgroup analysis by cancer site, the results showed that this polymorphism could increase the risk for leukemia and nasopharyngeal cancer. Notably, the Glu185Gln polymorphism was found to be related to increased risk for urinary system cancer, but decreased risk for digestive system cancer. No significant associations were obtained for other subgroup analyses such as ethnicity, sample size and smoking status. In conclusion, current evidence did not suggest that the NBS1 Glu185Gln polymorphism was associated with overall cancer risk, but this polymorphism might contribute to the risk for some specific cancer sites due to potential different mechanisms. More well-designed studies are imperative to identify the exact function of this polymorphism in carcinogenesis.


Comparative evaluation of the electrophysiological, functional and ultrastructural effects of alpha lipoic acid and cyanocobalamin administration in a rat model of sciatic nerve injury.
Vitamin B12 and alpha lipoic acid (ALA) are known to promote functional and morphological recovery after peripheral nerve injury. To compare the regenerative and neuroprotective effects of vitamin B12 and ALA treatment after sciatic nerve injury. A total of 40 rats were randomly assigned to control (sciatic nerve exposure without injury or anastomosis), sham (sciatic nerve injury and epineural anastomosis were performed but no treatment was administered), PS (isotonic saline was administered for 12 weeks after surgery), ALA (2 mg/kg ALA was administered for 12 weeks after surgery), and vitamin B12 groups (2 mg/kg cyanocobalamin was administered for 12 weeks after surgery). Functional recovery was determined by footprint analysis, in vivo neurophysiology, and ex vivo histopathological examination. ALA treatment produced significant improvements in sciatic functional index values and non-significant improvements on electroneuromyography compared to vitamin B12 treatment. Upon histopathological examination, the regenerative effects of ALA were relevant to axonal structural recovery whereas vitamin B12 produced greater improvements in edema and myelination. While both vitamin B12 and ALA produced improvements after sciatic nerve injury, ALA was more functionally effective. The unique ultrastructural effects of vitamin B12 and ALA treatment should be considered in future studies.


Acoustic localization in an ostariophysian fish.
Under approximate free field conditions acoustic localization could be demonstrated in an ostariophysian fish, the ide (Leuciscus idus). The efficient vibration links of both succuli with the unpaired swimbladder (via the Weberian ossicles) do apparently not prclude directional hearing in this important group of freshwater fish.


Glycogen dynamics of crucian carp (Carassius carassius) in prolonged anoxia.
Mobilization of glycogen stores was examined in the anoxic crucian carp (Carassius carassius Linnaeus). Winter-acclimatized fish were exposed to anoxia for 1, 3, or 6 weeks at 2 °C, and changes in the size of glycogen deposits were followed. After 1 week of anoxia, a major part of the glycogen stores was mobilized in liver (79.5 %) and heart (75.6 %), and large decreases occurred in gill (46.7 %) and muscle (45.1 %). Brain was an exception in that its glycogen content remained unchanged. The amount of glycogen degraded during the first anoxic week was sufficient for the anaerobic ethanol production for more than 6 weeks of anoxia. After 3 and 6 weeks of anoxia, there was little further degradation of glycogen in other tissues except the brain where the stores were reduced by 30.1 and 49.9 % after 3 and 6 weeks of anoxia, respectively. One week of normoxic recovery following the 6-week anoxia was associated with a complete replenishment of the brain glycogen and partial recovery of liver, heart, and gill glycogen stores. Notably, the resynthesis of glycogen occurred at the expense of the existing energy reserves of the body in fasting fish. These findings indicate that in crucian carp, glycogen stores are quickly mobilized after the onset of anoxia, with the exception of the brain whose glycogen stores may be saved for putative emergency situations.


Long non-coding RNA LINC00628 functions as a gastric cancer suppressor via long-range modulating the expression of cell cycle related genes.
To discover new biomarkers for gastric cancer (GC) diagnose and treatment, we screened the lncRNAs in GC tissues from 5 patients. We found 6 lncRNAs had altered expression, and in the same time, the levels of their neighboring genes (located near 300 kb upstream or downstream of lncRNA locus) were significantly changed. After confirming the results of microarray by qRT-PCR in 82 GC patients, the biological function of LINC00628 was examined through cell proliferation and apoptosis, cell migration and invasion, colony formation assay and cell cycle detection. We confirmed that LINC00628 functions as a GC suppressor through suppressing proliferation, migration and colony formation of cancer cells. Furthermore, LINC00628 can also suppress the tumor size in mouse xenograft models. Although LINC00628 can modulate LRRN2 expression, the GC suppressor function of LINC00628 is not LRRN2 dependent. The result of mRNA microarray indicated that LINC00628 perform GC inhibitor function through long-range modulating cell cycle related genes. Importantly, we confirmed that LINC00628 mainly located in the nucleus and interacted with EZH2, and modulated genes expression by regulating H3K27me3 level. This research shed light on the role of dysregulated LINC00628 during GC process and may serve as a potential target for therapeutic intervention.


A case report of delayed lower intestinal bleeding after organophosphate poisoning.
Organophosphate poisoning is a serious issue and it results in significant casualties in developing countries. Since agriculture remains an important and necessary sector of human society and organophosphate are commonly used in agriculture, it is difficult to prevent organophosphate poisoning. Gastrointestinal bleeding is not a common but life threatening symptom of organophosphate poisoning. We report a rare case of gastrointestine bleeding due to organophosphate poisoning. A 78-year-old woman presented to our hospital approximately 12 h after ingesting a mouthful of organophosphate and benzodiazepines in a suicide attempt. Six weeks after successful medical treatment for respiratory failure, she developed recurring melena. Colonoscopy and esophagogastroduodenoscopy findings were negative for ulcers or bleeding. Enteroscopy revealed severe circumferential ulcers with luminal narrowing 10 cm proximal to the ileocecal valve. The patient underwent a 100-cm ileum resection after failed medical treatment and recovered uneventfully. The resected terminal ileum demonstrated severe inflammation and a sharp transitional zone between the healthy and injured mucosa approximately 50 cm proximal to the ileocecal valve. Pathological examination revealed an injured mucosa with inflammatory cell infiltration and structural damage. This case highlights a rare event of OP poisoning with late-onset lower gastrointestinal bleeding, which prolonged the patient's recovery course and parenteral alimentation period. We report a rare case of a patient with organophosphate poisoning, with late-onset lower GI tract bleeding, which raised clinical awareness regarding the organophosphate poisoning that induce intestinal symptoms.


Central and peripheral normal contrast sensitivity for static and dynamic sinusoidal gratings.
Contrast sensitivity for moving and stationary sine grating patterns was determined in central and peripheral parts of the visual field. The method was primarily developed as a possible screening procedure for visual defects in glaucoma. Contrast sensitivity to moving patterns seemed maximal both in central and in 10 degrees of eccentric viewing for square wave reversals of temporal frequencies 0.5-5 Hz. We selected 2Hz for the clinical procedure. Further, we have determined normal central and peripheral contrast sensitivity in 10 subjects 61-71 years-old, to serve as a basis for the glaucoma studies. We used this age group since glaucoma mainly affects elderly people. We confirmed that contrast sensitivity was higher for dynamic than for static presentation of gratings of low spatial frequencies (below 1 c/d) both centrally and peripherally. For patterns of medium or high spatial frequencies, dynamic and static stimuli were equally detectable. The absolute level of contrast sensitivity was higher centrally than peripherally in the interval 0.3-4 c/d. The lower visual hemifield exhibited greater sensitivity, for both static and dynamic gratings, than the upper one.


GABA release modified by adenosine receptors in mouse hippocampal slices under normal and ischemic conditions.
The excitatory glutamatergic neurons in the hippocampus are modulated by inhibitory GABA-releasing interneurons. The neuromodulator adenosine is known to inhibit the presynaptic release of neurotransmitters and to hyperpolarize postsynaptic neurons in the hippocampus, which would imply that it is an endogenous protective agent against cerebral ischemia and excitotoxic neuronal damage. Interactions of the GABAergic and adenosinergic systems in regulating neuronal excitability in the hippocampus is of crucial importance, particularly under cell-damaging conditions. We now characterized the effects of adenosine receptor agonists and antagonists on the release of preloaded [3H]GABA from hippocampal slices prepared from adult (3-month-old) mice, using a superfusion system. The effects were tested both under normal conditions and in ischemia induced by omitting glucose and oxygen from the superfusion medium. Basal and K+ -evoked GABA release in the hippocampus were depressed by adenosinergic compounds. Under normal conditions activation of both adenosine A1 and A2A receptors by the agonists R(-)N6-(2-phenylisopropyl)adenosine and CGS 21680 inhibited the K+ -evoked release, which effects were blocked by their specific antagonists, 8-cyclopentyl-1,3-dipropyl-xanthine and 3,7-dimethyl-1-propargylxanthine, respectively. Under ischemic conditions the release of both GABA and adenosine is markedly enhanced. The above receptor agonists then depressed both the basal and K+ -evoked GABA release, only the action of A2A receptors being however receptor-mediated. The demonstrated depression of GABA release by adenosine in the hippocampus could be deleterious to neurons and contribute to excitotoxicity.


Evidence for persistent and shared bacterial strains against a background of largely unique gut colonization in hospitalized premature infants.
The potentially critical stage of initial gut colonization in premature infants occurs in the hospital environment, where infants are exposed to a variety of hospital-associated bacteria. Because few studies of microbial communities are strain-resolved, we know little about the extent to which specific strains persist in the hospital environment and disperse among infants. To study this, we compared 304 near-complete genomes reconstructed from fecal samples of 21 infants hospitalized in the same intensive care unit in two cohorts, over 3 years apart. The genomes represent 159 distinct bacterial strains, only 14 of which occurred in multiple infants. Enterococcus faecalis and Staphylococcus epidermidis, common infant gut colonists, exhibit diversity comparable to that of reference strains, inline with introduction of strains from infant-specific sources rather than a hospital strain pool. Unlike other infants, a pair of sibling infants shared multiple strains, even after extensive antibiotic administration, suggesting overlapping strain-sources and/or genetic selection drive microbiota similarities. Interestingly, however, five strains were detected in infants hospitalized three years apart. Three of these were also detected in multiple infants in the same year. This finding of a few widely dispersed and persistent bacterial colonizers despite overall low potential for strain dispersal among infants has implications for understanding and directing healthy colonization.


Principle component analysis for nonlinear optical properties of thiophene-based metal complexes.
The simulation of molecular descriptors of thiophene-based metal complexes has been performed using Gaussian 03 and Atomistic toolkit Virtual Nanolab (ATK-VNL) software. It is found that with respect to the obtained molecular descriptors, the molecules show distinct properties. The dimensions of the data set being large, the principal components (PC1 and PC2) have been obtained using principal component analysis (PCA). Analysis has been done for the Linear regression of principal components with first hyperpolarizability and second hyperpolarizability of the molecules. The results indicate that, of all the calculated molecular descriptors of thiophene-based metal complexes, the molecular energy (E), ionization energy (EI), and molecular dipole moment (D) plays a dominant role in determining their nonlinear optical properties i.e., the hyperpolarizability value, of the studied molecules. Also, the molecular descriptors, polarizability (P) and molar refractivity (MR), show considerable impact on the nonlinear optical properties of the studied molecules.


Effects of adenosine analog PIA (n-phenylisopropyladenosine) on FSH-stimulated cyclic AMP (cAMP) production in the rat seminiferous epithelium.
In rat seminiferous epithelium, FSH-stimulated cAMP production is cyclically modulated by spermatogenic cells and is highest in stages XIV-V and lowest in stages VII-VIII of the epithelial cycle. Adenosine has been proposed to be an inhibitory paracrine molecule in Sertoli cells. In this paper the effect of adenosine analog n-phenylisopropyladenosine (PIA) on FSH-stimulated cAMP production was studied in staged rat seminiferous tubules. In low responsive stages VII-VIII of the cycle, 100 nM and 10 microM PIA inhibited FSH-stimulated cAMP production by 24% and 28%, respectively. To study whether PIA effect is mediated through Gi-protein, pertussis toxin (PT) pretreatment was used to block the Gi-protein. PT pretreatments of 3 or 18 h caused 42% or 16% elevation in FSH-stimulated cAMP production, respectively. PIA blocked the stimulation caused by PT pretreatment. At 38 days post irradiation, when spermatocytes and round spermatids were decreased in number, in stages VII-VIII of the cycle the inhibitory effect of PIA was abolished. In high responsive stages XIV-V of the cycle, 100 nM PIA stimulated cAMP production by 27%, while 10 microM PIA had no effect. At 38 days post irradiation FSH response was decreased by 19% when compared to non-irradiated level, and PIA stimulated FSH-stimulated cAMP production by 22%. The results suggest that there are stage-specific mechanisms for adenosine-dependent regulation of FSH-stimulated cAMP production in the rat seminiferous epithelium. Advanced spermatogenic cells seem to maintain the mechanisms that include PIA-mediated inhibition of FSH response. Other mechanisms than PT-sensitive Gi-protein seem to be involved in the inhibition.


Complications of water-soluble contrast lumbar myelography. Review of the literature and case report.
A historic review of the development of water-soluble contrast materials for lumbar myelography is presented. This is followed by a discussion of their advantages and complications, as well as a case report of convulsive segmental myoclonus, hypotension, and death after myelography associated with the use of dimeglumine locarmate (Dimer-X). A new nonionic material, metrizamide (Amipaque), is discussed, and its current clinical status is summarized.


Pharmacotherapy of insomnia.
Sleep disturbance is often the result of specific pathophysiologies of sleep or of psychiatric illness. When this is the case, specific treatment of these conditions is indicated. When such disorders are not found, hypnotics often play a useful role, particularly as adjunctive treatment while the patient receives behaviorally-oriented therapy. Considerations in choosing a hypnotic should include issues of residual daytime effects, special problems of the elderly, interaction with alcohol, dependence, and effects on respiration.


The use of microcomputers for the quantitation of light intensity patterns using digitized video signals.
We have developed an inexpensive yet versatile microcomputer-based system for quantitating light intensity levels in autoradiographs. This system employs a standard video camera interfaced to an analog-to-digital convertor. A program has been written for this system which can measure intensities within a defined region of an autoradiograph, permitting an easy and accurate quantitation of spots or bands of irregular shape.


Implementation of HIV non-occupational post-exposure prophylaxis for men who have sex with men in 2 cities of Southwestern China.
Non-occupational post-exposure prophylaxis (nPEP) has often relied on the joint work of emergency physicians and infectious disease specialists in busy emergency departments and human immunodeficiency virus (HIV)/sexually transmitted infections clinics abroad, where adherence education and follow-up are invariably reactive. In our pilot study, community-based organizations (CBOs) were invited to together implement the nPEP tailored to men who have sex with men (MSM) in 2 cities of Guangxi in Southwestern China, of which experiences and lessons drawn from would be provided to the promotion of nPEP in China.The study population enrolled MSM individuals prescribed nPEP from September 2017 to December 2019. One-to-one follow-ups by CBOs were applied through the treatment. Predictors of treatment completion were assessed by logistic regression.Of 271 individuals presented for nPEP, 266 MSM with documented treatment completion or non-completion, 93.6% completed the 28-day course of medication. Completion was associated with reporting side effects (aOR = .10; 95% CI: 0.02-0.38; P = .001). The follow-up rate of 91.9% was achieved based on the definition of loss to follow-up. No documented nPEP failures were found, although 1 MSM subsequently seroconverted to HIV due to ongoing high-risk behavior.CBOs' engagement in HIV nPEP, especially the "one-to-one" follow-up supports by peer educators partly ensure adherence and retention to nPEP. Tailored interventions are needed to address the subsequent high-risk behaviors among the MSM population.


A β-Catenin-TCF-Sensitive Locus Control Region Mediates GUCY2C Ligand Loss in Colorectal Cancer.
Sporadic colorectal cancers arise from initiating mutations in APC, producing oncogenic β-catenin/TCF-dependent transcriptional reprogramming. Similarly, the tumor suppressor axis regulated by the intestinal epithelial receptor GUCY2C is among the earliest pathways silenced in tumorigenesis. Retention of the receptor, but loss of its paracrine ligands, guanylin and uroguanylin, is an evolutionarily conserved feature of colorectal tumors, arising in the earliest dysplastic lesions. Here, we examined a mechanism of GUCY2C ligand transcriptional silencing by β-catenin/TCF signaling. We performed RNA sequencing analysis of 4 unique conditional human colon cancer cell models of β-catenin/TCF signaling to map the core Wnt-transcriptional program. We then performed a comparative analysis of orthogonal approaches, including luciferase reporters, chromatin immunoprecipitation sequencing, CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats) knockout, and CRISPR epigenome editing, which were cross-validated with human tissue chromatin immunoprecipitation sequencing datasets, to identify functional gene enhancers mediating GUCY2C ligand loss. RNA sequencing analyses reveal the GUCY2C hormones as 2 of the most sensitive targets of β-catenin/TCF signaling, reflecting transcriptional repression. The GUCY2C hormones share an insulated genomic locus containing a novel locus control region upstream of the guanylin promoter that mediates the coordinated silencing of both genes. Targeting this region with CRISPR epigenome editing reconstituted GUCY2C ligand expression, overcoming gene inactivation by mutant β-catenin/TCF signaling. These studies reveal DNA elements regulating corepression of GUCY2C ligand transcription by β-catenin/TCF signaling, reflecting a novel pathophysiological step in tumorigenesis. They offer unique genomic strategies that could reestablish hormone expression in the context of canonical oncogenic mutations to reconstitute the GUCY2C axis and oppose transformation.


Salubrinal, an endoplasmic reticulum stress blocker, modulates sleep homeostasis and activation of sleep- and wake-regulatory neurons.
Endoplasmic reticulum (ER) stress has been associated with the regulation of sleep and wake. We have previously shown that i.c.v. administration of a specific ER stress modulator, Salubrinal (SALUB), which inhibits global protein translation by blocking the dephosphorylation of eukaryotic initiation factor 2α (p-eIF2α), increased non-rapid eye movement (NREM) sleep. Here we report on the relationship between ER stress response and sleep homeostasis by measuring the amount and intensity of homeostatic recovery sleep in response to the i.c.v. administration of SALUB in adult freely behaving rats. We have also tested the hypothesis that SALUB induces sleep by activating sleep-promoting neurons and inhibiting wake-promoting neurons in the basal forebrain (BF) and hypothalamus by quantifying the effects of SALUB treatment on c-Fos expression in those neuronal groups. The present study found that i.c.v. administration of SALUB significantly modified the homeostatic sleep response. SALUB administered during sleep deprivation increased sleep intensity, indicated by slow-wave activity (SWA), during recovery sleep, whereas its administration during recovery sleep increased the amount of recovery sleep. We also found that SALUB induced c-Fos activation of GABAergic neurons in the sleep-promoting rostral median preoptic nucleus while simultaneously reducing c-Fos activation of wake-promoting lateral hypothalamic orexin-expressing neurons and magnocellular BF cholinergic neurons. The current findings suggest that ER stress pathway plays a role in the homeostatic control of NREM sleep in response to sleep deprivation and provides a mechanistic explanation for the sleep modulation by molecules signaling the need for brain protein synthesis.


Effect of glutamine supplementation on protein metabolism and glutathione in tumor-bearing rats.
The effect of glutamine (GLN)-supplemented total parenteral nutrition (TPN) on tumor growth and protein metabolism was investigated in tumor-bearing rats. Six days after implantation of AH109A hepatoma, rats received isonitrogenous TPN without or with alanyl-glutamine (25% of total N) for a period of 6 days. Protein turnover was assessed by continuous infusion of l4C-leucine and levels of GLN and glutathione were determined in muscle, jejunum and liver. Diet had no effect on tumor parameters: weight (mean = 4.4 g), GLN and glutathione concentrations, protein synthesis rate and bromodeoxyuridine-labeling index. Body weight loss was less pronounced in the GLN group (-5.5 +/- 1.2 vs. -9.4 +/- 1.4 g/5d). Decrease in plasma and muscle GLN concentrations (-30% and -17% vs. healthy controls, respectively) was limited in tumor-bearing rats receiving GLN-enriched TPN (-15% and +3%). GLN-supplemented TPN increased muscle and jejunum fractional synthesis rates (36% and 25% vs. standard TPN, respectively) and reduced body protein breakdown in tumor-bearing animals (303 +/- 33 vs. 421 +/- 66 mumol Leu/Kg/h). Decrease in jejunum glutathione levels was partially abolished in the GLN group: -50% vs. -64% in the standard TPN group; no effect was noticed in other tissues. The authors conclude that GLN-supplemented TPN improves protein metabolism at both the whole body and the tissue level, and prevents GLN and glutathione deficiencies associated with tumor implantation.


Cerebral autofluorescence and thiamine deficiency in cerebrocortical necrosis.
A discrete pattern of autofluorescence of the cerebral cortex of ruminants suffering from cerebrocortical necrosis is seen under ultraviolet light. This offers a rapid and relatively simple aid to diagnosis of the disease. There is a clear correlation of the characteristic fluorescence with biochemical evidence of cerebrocortical necrosis in field material.


Unexpected kinetically controlled organoselenium-based isomaleimide: X-ray structure, hirshfeld surface analysis, 3D energy framework approach, and density functional theory calculation.
Reduction of 4,4'-diselanediyldianiline (1) followed by the reaction with bromo-4-(bromomethyl)benzene afforded the corresponding 4-((4-bromobenzyl)selanyl)aniline (2) in 85% yield. N-Maleanilic acid 3 was obtained in 94% yield via the reaction of selenoamine 2 with toxilic anhydride. Subsequent dehydration of N-maleanilic acid 3 using acetic anhydride furnished the unexpected isomaleimide 5-((4-((4-bromophenyl)selanyl)phenyl)imino)furan-2(5H)-one (4) instead of the maleimide 5. The molecular structure of compound 4 was confirmed by mass spectrometry, 1H- and 13C-NMR spectroscopy, and X-ray diffraction analysis. Their cytotoxicity was assessed against two oligodendrocytes, and their respective redox properties were evaluated using 2',7'-dichlorodihydrofluorescein diacetate (H2-DCFDA) assay. Furthermore, their antiapoptotic potential was also evaluated by flow cytometry. The compound crystallizes in triclinic P-1 space group with unit cell parameters a = 5.7880 (4) Å, b = 9.8913 (6) Å, c = 14.5951 (9) Å, V = 1731.0 (3) Å3 and Z = 2. The crystal packing is stabilized by intermolecular hydrogen bonding, π···π, C-Br···π stacking interactions, and other non-covalent interactions. The mapping of different Hirshfeld surfaces and 2D-fingerprint were used to investigate intermolecular interactions. The interaction energies that stabilize the crystal packing were calculated and graphically represented as framework energy diagrams. We present a computational investigation of compound 4's molecular structure at the Density Functional Theory level using the B3LYP method and the 6-31G ++ basis set in this paper. The optimized structure matches the experimental outcome. The global reactivity descriptors and molecular electrostatic potential (M.E.P.) map emphasize the molecule's reactive locations, allowing reactivity prediction. The charge transfer properties of molecules can be estimated by examining Frontier molecular orbitals.


Determination of a serum total calcium concentration threshold for accurate prediction of ionized hypercalcemia in dogs with and without hyperphosphatemia.
Total serum calcium (tCa) concentrations are poorly predictive of ionized calcium (iCa) status in dogs. There is an optimal threshold of tCa concentration that is highly predictive of ionized hypercalcemia and this threshold is higher in hyperphosphatemic dogs as compared to nonhyperphosphatemic dogs. Nonhyperphosphatemic (n = 1593) and hyperphosphatemic (n = 250) adult dogs. Retrospective medical record review of paired tCa and iCa concentration measurements in dogs presented to a university teaching hospital over a 5-year period. Positive and negative predictive values, sensitivity, and specificity were calculated for tCa concentration thresholds of 11.0-15.0 mg/dL (upper limit of laboratory reference interval = 11.5 mg/dL) in nonhyperphosphatemic and hyperphosphatemic groups. In nonhyperphosphatemic dogs, an optimal tCa concentration threshold of 12.0 mg/dL resulted in a positive predictive value of 93% (95% confidence interval [CI], 84%-98%) and sensitivity of 52% (95% CI, 43%-61%) for ionized hypercalcemia. An optimal tCa concentration threshold was not identified for hyperphosphatemic dogs. The nonhyperphosphatemic dogs had a higher prevalence of ionized hypercalcemia than the hyperphosphatemic dogs (7 versus 3%, P = .04) and a lower prevalence of ionized hypocalcemia (23 versus 62%, respectively; P < .001). High tCa concentrations are strongly predictive of ionized hypercalcemia in nonhyperphosphatemic adult dogs and should prompt further diagnostic testing to determine the underlying cause of hypercalcemia. In this population, dogs without increased tCa concentrations rarely had ionized hypercalcemia, but iCa concentrations still should be evaluated in patients with tCa concentrations within the reference interval if there is clinical suspicion for calcium abnormalities.


Smoking Behavior Changes during COVID-19 among Korean Adults.
In this study, we investigated the changes in smoking behavior during the COVID-19 outbreak in Korea in 2020. We also examined the influence of general characteristics and mental health problems due to COVID-19 on changes in smoking behavior. We collected data from August to October 2020 from adults aged 19 years and older from the Korea Community Health Survey (N=229,269). Among current smokers (N=39,534), 11.0% reported an increase in smoking, and 12.8% reported a decrease in smoking. Overall, 33.3% reported perceived stress and 3.7% reported depression. Participants reported COVID-related anxiety about infecting family (83.0%), economic damage (76.3%), blame or harm from others (66.5%), infection (60.6%), and death (31.3%). Lower education level, living alone, and poor subjective health status were associated with increased smoking. Being a woman and being of older age were associated with decreased smoking. Stress, depression, and anxiety about economic damage due to COVID-19 were more likely to result in increased smoking. Anxiety related to death due to COVID-19 was more likely to result in decreased smoking. These findings provide insight into the changes in smoking behavior caused by COVID-19.


A child with Epstein-Barr Virus-associated hemophagocytic lymphohistiocytosis complicated by coronary artery lesion mimicking Kawasaki disease.
There is considerable overlap between hemophagocytic lymphohistiocytosis (HLH) and Kawasaki disease (KD) in terms of aberrant immune response though the etiology of KD remains unknown. We present a case fulfilling the criteria of both HLH and KD complicated by coronary artery dilatation: HLH was confirmed to be triggered by Epstein-Barr virus. This case alarms us the possibility that even patients with HLH may be complicated by coronary artery lesion, which is one of the hallmarks of KD. We would like to draw attention that if features of KD become apparent in patients with HLH, echocardiographic examinations should be performed not to miss coronary artery lesion.


Immobilization of β-galactosidase from Lactobacillus plantarum HF571129 on ZnO nanoparticles: characterization and lactose hydrolysis.
β-Galactosidase from Lactobacillus plantarum HF571129 was immobilized on zinc oxide nanoparticles (ZnO NPs) using adsorption and cross-linking technique. Immobilized β-galactosidase showed broad-spectrum pH optima at pH 5-7.5 and temperature 50-60 °C. Fourier transform infrared spectroscopy (FTIR) and field emission scanning electron microscopy (FESEM) showed that β-galactosidase successfully immobilized onto supports. Due to the limited diffusion of high molecular weight substrate, K m of immobilized enzyme slightly increased from 6.64 to 10.22 mM, while V max increased from 147.5 to 192.4 µmol min(-1) mg(-1) as compared to the soluble enzyme. The cross-linked adsorbed enzyme retained 90 % activity after 1-month storage, while the native enzyme showed only 74 % activity under similar incubation conditions. The cross-linked β-galactosidase showed activity until the seventh cycle and maintained 88.02 % activity even after the third cycle. The activation energy of thermal deactivation from immobilized biocatalyst was 24.33 kcal/mol with a half-life of 130.78 min at 35 °C. The rate of lactose hydrolysis for batch and packed bed was found to be 0.023 and 0.04 min(-1).


Chronic amphetamine: effects on defensive flight in the rat.
Hooded rats were injected with physiological saline or d-amphetamine sulfate for 13 days on a schedule designed to mimic patterns of abuse: one injection on days 1-11, two injections on day 12, and three injections on day 13; amphetamine dosage for the first three injections was 3.5 mg/kg and for all subsequent injections was 5.0 mg/kg. Amphetamine-treated rats (Amphet) showed a dramatic flight reaction in response to a novel stimulus (mechanical robot) that did not elicit flight from saline control animals. Tested on a slow-moving treadmill that carried them toward the stimulus, Amphet rats accumulated only 15% of the trial time at the front of the apparatus nearest the stimulus and accumulated approximately 75% of the trial time at the extreme rear of the apparatus, farthest from the stimulus. Control tests of Amphet rats in the absence of the stimulus ruled out interpretations in terms of motor behavior. In fact, a major advantage of the present procedure is that animals are able to execute the relatively simple defense response despite the occurrence of motor stereotypy. These results suggest that the defense-response paradigm is suitable for the study of chronic amphetamine and may provide a useful adjunctive to existing models of amphetamine psychosis.


Feasibility of measuring radiation-induced DNA double strand breaks and their repair by pulsed field gel electrophoresis in freshly isolated cells from the mouse RIF-1 tumor.
To examine the technical feasibility of pulsed field gel electrophoresis (PFGE) as a predictive assay for the radioresponsiveness of tumors. Induction and repair of DNA double strand breaks (DSBs) in a freshly prepared cell suspension from a RIF-1 tumor (irradiated ex vivo) was compared with DSB induction and repair in exponentially growing RIF-1 cells in culture (irradiated in vitro). A murine RIF-1 tumor grown in vivo was digested, and cells were exposed to x-rays (ex vivo) at doses of 1 to 75 Gy. DNA damage was measured using CHEF (clamped homogeneous electric fields) electrophoresis. Repair kinetics were studied at 37 degrees C for 4 h after irradiation. Radiosensitivity was determined by clonogenic assay, and cell cycle distributions by flow cytometry. For comparison, a trypsinized suspension of exponentially growing RIF-1 cells in vitro was run parallel with each ex vivo experiment. Induction of DSBs, expressed as % DNA extracted from the plug, was similar in the in vitro and ex vivo irradiated cells. Compared to repair rates in vitro cultured RIF-1 cells, repair kinetics in a freshly prepared cell suspension from the tumor were decreased, unrelated to differences in radiosensitivity. Differences in repair could not be explained by endogenous DNA degradation, nor by influences of enzymes used for digestion of the tumor. A lower plating efficiency and differences in ploidy (as revealed by flow cytometry) were the only reproducible differences between in vivo and in vitro grown cells that may explain the differences in repair kinetics. The current results do not support the idea that PFGE is a technique robust enough to be a predictive assay for the radiosensitivity of tumor cells.


Nobiletin protects against diabetes-induced testicular injury via hypophysis-gonadal axis upregulation and amelioration of oxidative stress.
Testicular injury is one of the most serious problems associated with diabetes mellitus. The present study aimed to compare the effects of two different doses of nobiletin and analyze its mechanisms of action against diabetes-induced testicular impairment in rats. Streptozotocin injection was used to induce diabetes. Diabetic rats received nobiletin orally at 10 or 25 mg/kg daily for 30 days. Diabetic rats displayed significant elevations in glucose, glycosylated hemoglobin (HbA1c), Homeostatic Model of Insulin Resistance (HOMA-IR), and pro-inflammatory cytokines, while the serum levels of insulin, testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were significantly reduced. Histological changes to positivity for caspase-3 and decreased androgen receptors (AR) immunoexpression were observed in diabetic rats. Both doses of nobiletin improved hyperglycemia, reduced pro-inflammatory cytokines, and augmented insulin, testosterone, LH, and FSH levels. LH and FSH receptors and cytochrome P450 17 α-hydroxylase (CYP17A1) were markedly downregulated in terms of both gene and protein expression in testicular tissues of the diabetic group, effects that were markedly ameliorated with both doses of nobiletin. In addition, both doses significantly reduced lipid peroxidation and caspase-3 immunoexpression and improved the activity of the antioxidant enzymes and AR in testicular tissues of the diabetic group. Both nobiletin doses showed protective effects against diabetes-induced testicular injury by reducing oxidative stress, hyperglycemia, inflammation, and caspase-3 and upregulating the hypophysis-gonadal axis and AR. The high dose of nobiletin was more effective than the lower one.


Heart rate dynamics and behavioral responses during acute emotional challenge in corticotropin-releasing factor receptor 1-deficient and corticotropin-releasing factor-overexpressing mice.
The role of corticotropin-releasing factor in autonomic regulation of heart rate, heart rate variability and behavior responses was investigated in two genetic mouse models: corticotropin-releasing factor receptor 1-deficient mice, and corticotropin-releasing factor-transgenic mice overexpressing corticotropin-releasing factor. Heart rate was recorded by radio-telemetry during novelty exposure and auditory fear conditioning. Locomotor activity and freezing served as behavioral indices. Locomotor activity and heart rate were invariably increased in response to novelty exposure in both corticotropin-releasing factor receptor 1-deficient mice and littermate wild-type controls. The heart rate responses during retention of conditioned auditory fear and the exponential relationship between heart rate and heart rate variability were unaffected by genotype. Moreover, conditioned fear responses inferred from multiple behavioral measures including freezing did not differ between corticotropin-releasing factor receptor 1-deficient and corticotropin-releasing factor receptor 1 wild-type control mice. Corticotropin-releasing factor-transgenic mice exhibited markedly reduced locomotor activity during novelty exposure when compared with littermate wild-type controls. Baseline and novelty-driven heart rate was slightly elevated in corticotropin-releasing factor-transgenic mice, whereas the novelty-induced increase of heart rate was not different between genotypes. In contrast, corticotropin-releasing factor-transgenic mice did not display a heart rate response indicative of conditioned auditory fear. It is concluded that corticotropin-releasing factor receptor 1-deficiency does not affect heart rate adjustment and behavioral responses to acute fearful stimuli. The resiliency of behavioral and cardiovascular patterns elevation argues against the involvement of corticotropin-releasing factor receptor 1 in acute emotional regulation on these two functional levels despite an absent corticosterone elevation in corticotropin-releasing factor receptor 1-deficient mice. It is hypothesized that the lack of a conditioned heart rate response in corticotropin-releasing factor-transgenic mice is attributable to an impairment of cognitive function. The results are compared with those of corticotropin-releasing factor receptor 2-deficient mice, and the role of the corticotropin-releasing factor system in cardiovascular regulation is discussed.


Dynamic changes of α-hexachlorocyclohexane and its enantiomers in various tissues of Japanese Rabbits (Oyctolagus cuniculus) after oral or dermal exposure.
Japanese Rabbits (Oyctolagus cuniculus) were exposed to α-hexachlorocyclohexane (α-HCH) either orally or dermally and concentrations of α-HCH and its two enantiomers were measured at different time intervals in the blood, intestine, liver, kidney, fat, brain, and muscle. The time trends were quantified using toxicokinetic models. It was found that absorption and elimination of α-HCH in blood were first-order processes which can be characterized by a single compartmental kinetic model. The absorption of dermally exposed α-HCH in blood was more than one order of magnitude faster than that of orally exposed α-HCH. The transport of α-HCH from the blood to other tissues was characterized using a two-compartment model. The accumulation rates were different among tissues depending on blood flow rate and fat content. Significant correlation was revealed between α-HCH concentration and fat content for various tissues either before or 1 d after the exposure. However, there was no such correlation at 10 min immediately after the exposure. The enantiomeric fraction (EF) of α-HCH in rabbit blood was nearly racemic before the exposure and increased to 0.73 and 0.82 after oral or dermal exposure, respectively. The result of a toxicokinetic modeling suggested that the strong enantioenrichment of (+)-α-HCH was primarily because the elimination rate of (-)-α-HCH was more than two times higher than that of (+)-α-HCH. The EFs for other tissues also increased dramatically after the exposure and the EFs in brain reached as high as 0.99 due to enantioselective transport across the blood brain barrier.


Predicting facial characteristics from complex polygenic variations.
Research into the importance of the human genome in the context of facial appearance is receiving increasing attention and has led to the detection of several Single Nucleotide Polymorphisms (SNPs) of importance. In this work we attempt a holistic approach predicting facial characteristics from genetic principal components across a population of 1266 individuals. For this we perform a genome-wide association analysis to select a large number of SNPs linked to specific facial traits, recode these to genetic principal components and then use these principal components as predictors for facial traits in a linear regression. We show in this proof-of-concept study for facial trait prediction from genome-wide SNP data that some facial characteristics can be modeled by genetic information: facial width, eyebrow width, distance between eyes, and features involving mouth shape are predicted with statistical significance (p<0.03).


The distribution and lipid composition of ultracentrifugally separated lipoproteins of young and old rat plasma.
The lipoproteins of young and old Wistar rats differ markedly in distribution and chemical composition. The major differences are: (1) the presence of high levels of free and esterified cholesterol, triglycerides and free fatty acids in the lipoproteins of old rat plasma when lipids are analyzed/100 ml of plasma. However, the ratio of total cholesterol to protein mass indicates the presence of comparable cholesterol pools in all lipoprotein fractions of young and old rats excepting the d 1.063--1.21 fraction where a higher cholesterol pool in old rats is indicated. (2) The amount of sphingomyelin increases in lipoprotein fractions of old rat plasma thereby actually decreasing the lecithin/sphingomyelin ratio in these plasma fractions. (2) Unsaturated fatty acids predominate in young rat plasma lipoproteins, and saturated fatty acids predominate in old rat lipoprotein fractions. The ratio of polyunsaturated (linoleic, linolenic, arachidonic) to saturated (palmitic, stearic) fatty acids in young rat sera was 0.89 and in old rat sera, 0.55.


Structural investigation of the capsular polysaccharide from a clinical isolate of Fusobacterium necrophorum subspecies necrophorum biotype a strain LA 81-617.
A capsular polysaccharide (CPS) from Fusobacterium necrophorum subspecies necrophorum biotype A strain LA 81-617 was isolated from a saline cell wash and purified by gel and anion-exchange chromatography. The structure of the CPS was studied by one- and two-dimensional 1H and 13C NMR spectroscopy techniques in combination with electrospray ionization mass spectrometry (ESI-MS). The CPS was found to resemble the bacterial cell-wall murein polysaccharide backbone, consisting of N-acetylglucosamine and N-acetylmuramic acid (MurNAc) components, with the following structure:-[-4-β-MurNAc-4-β-GlcNAc-]n-with N-acetyl-1,6-anhydro-β-muramic acid at the reducing end. This is the first report on the structure of F. necrophorum capsular polysaccharide.


Pitfalls in the use of high energy X rays to treat tumors in the lung.
The problem of central axis dose reduction for high energy photon beams of small cross-sectional area traversing normal lung tissue is well known. An additional problem, which may be not as well appreciated, is the loss of electronic equilibrium on the periphery of high energy photon beams, resulting in an increase in the penumbra occurring in lung. We have compared profiles of x-ray beams ranging in energy from 4 MV to 18 MV. The profiles were measured at 10-cm depth in unit-density and lung-density (0.26) phantoms. At the highest energy the 20% to 80% physical penumbra width was measured to be 7.5 mm in the unit-density material, whereas in the lung phantom the width was 18 mm. At 4 MV the situation was reversed; that is, the penumbra was slightly smaller in the lung phantom. Most computer programs for radiation therapy treatment planning do not take into account this change in beam profile when calculating dose in the lung. As a result, unanticipated underdosing inside the field and greater dose outside the field can occur when high-energy X rays are used.


Sequences of the A-MuLV protein needed for fibroblast and lymphoid cell transformation.
The role of various segments (gag or v-abl) of the Abelson murine leukemia virus (A-MuLV) genome in both lymphoid cell and fibroblast transformation was examined by deletion of areas from cloned, plasmid DNA representations of the genome. The deleted plasmids were tested by transfection into fibroblasts and by infection of bone marrow cells using virus stocks derived from the fibroblast transfectants. Deletion of gag coding sequence from the A-MuLV protein did not affect fibroblast transforming activity but abolished lymphoid transforming activity. The gag- A-MuLV genomes were very unstable in transformed fibroblasts leading to large secondary deletions in v-abl sequences. The gag- A-MuLV proteins also had lower autophosphorylation than their gag+ counterparts although cells transformed by gag- virus had a normal elevation of protein-linked phosphotyrosine. Systematic deletion of v-abl sequences showed that only 45,000 to the 130,000 molecular weight of v-abl sequence in the A-MuLV protein is needed for fibroblast transformation and, at most, slightly more is needed for lymphoid cell transformation.


Genetic control of muscle development: learning from Drosophila.
Muscle development involves a complex sequence of time and spatially regulated cellular events leading to the formation of highly specialised syncytial muscle cells displaying a common feature, the capacity of contraction. Analyses of mechanisms controlling muscle development reveals that the main steps of muscle formation including myogenic determination, diversification of muscle precursors, myoblast fusion and terminal differentiation involve the actions of evolutionarily conserved genes. Thus dissecting the genetic control of muscle development in simple model organisms appears to be an attractive way to get insights into core genetic cascade that orchestrate myogenesis. In this respect, particularly insightful have been data generated using Drosophila as a model system. Notably, the interplay between intrinsic and extrinsic cues that determine the early myogenic decisions leading to the specification of muscle progenitors and those controlling myoblasts fusion are much better characterised in Drosophila than in vertebrate species. Also, adult Drosophila myogenesis, which leads to the formation of vertebrate-like multi-fibre muscles, emerges as a particularly well-adapted system to study normal and aberrant muscle development.


Plasma metabolic signatures for intracranial aneurysm and its rupture identified by pseudotargeted metabolomics.
The vital metabolic signatures for IA risk stratification and its potential biological underpinnings remain elusive. Our study aimed to develop an early diagnosis model and rupture classification model by analyzing plasma metabolic profiles of IA patients. Plasma samples from a cohort of 105 participants, including 75 IA patients in unruptured and ruptured status (UIA, RIA) and 30 control participants were collected for comprehensive metabolic evaluation using ultra-high-performance liquid chromatography-mass spectrometry-based pseudotargeted metabolomics method. Furthermore, an integrated machine learning strategy based on LASSO, random forest and logistic regression were used for feature selection and model construction. The metabolic profiling disturbed significantly in UIA and RIA patients. Notably, adenosine content was significantly downregulated in UIA, and various glycine-conjugated secondary bile acids were decreased in RIA patients. Enriched KEGG pathways included glutathione metabolism and bile acid metabolism. Two sets of biomarker panels were defined to discriminate IA and its rupture with the area under receiver operating characteristic curve of 0.843 and 0.929 on the validation sets, respectively. The present study could contribute to a better understanding of IA etiopathogenesis and facilitate discovery of new therapeutic targets. The metabolite panels may serve as potential non-invasive diagnostic and risk stratification tool for IA.


Associations between neutrophil-lymphocyte ratio and monocyte to high-density lipoprotein ratio with left atrial spontaneous echo contrast or thrombus in patients with non-valvular atrial fibrillation.
The importance of inflammation in thrombosis is increasingly appreciated. Neutrophil-lymphocyte ratio (NLR) and monocyte to high-density lipoprotein ratio (MHR) are important indicators of systemic inflammation. This study aimed to investigate the associations between NLR and MHR with left atrial appendage thrombus (LAAT) and spontaneous echo contrast (SEC) in patients with non-valvular atrial fibrillation. This retrospective, cross-sectional study enrolled 569 consecutive patients with non-valvular atrial fibrillation. Multivariable logistic regression analysis was used to investigate independent risk factors of LAAT/SEC. Receiver operating characteristic (ROC) curves were used to evaluate the specificity and sensitivity of NLR and MHR in predicting LAAT/SEC. Subgroup and Pearson correlation analyses were used to assess the correlations between NLR and MHR with the CHA2DS2-VASc score. Multivariate logistic regression analysis showed that NLR (OR: 1.49; 95%CI: 1.173-1.892) and MHR (OR: 2.951; 95%CI: 1.045-8.336) were independent risk factors for LAAT/SEC. The area under the ROC curve of NLR (0.639) and MHR (0.626) was similar to that of the CHADS2 score (0.660) and CHA2DS2-VASc score (0.637). Subgroup and Pearson correlation analyses showed significant but very weak associations between NLR (r = 0.139, P < 0.05) and MHR (r = 0.095, P < 0.05) with the CHA2DS2-VASc score. Generally, NLR and MHR are independent risk factors for predicting LAAT/SEC in patients with non-valvular atrial fibrillation.


Toxigenic fungi isolated from dried vine fruits in Argentina.
To evaluate the potential for mycotoxin production by fungi in dried vine fruits, the mycobiota was determined both before and after surface disinfection. Predominant genera were Aspergillus (50.2%), Eurotium (21.4%) and Penicillium (13.5%). Aspergillus section Nigri ("black aspergilli") were isolated with relatively high frequency. Aspergillus niger was the most common species but only 3 of 293 isolates screened were ochratoxin A (OTA) producers. Aspergillus carbonarius was less common but 96% of 48 strains screened were ochratoxigenic. OTA was not produced by A. japonicus. Other toxigenic fungi detected were A. ochraceus (3 strains produced OTA), Aspergillus flavus (5 strains produced cyclopiazonic acid but not aflatoxins), P. citrinum (19 strains were strong citrinin producers) and Alternaria alternata (15 strains were producers of tenuazonic acid, alternariol and alternariol methyl ether). In spite of the high incidence of A. carbonarius capable of producing OTA, low levels of this toxin were detected in the samples analysed.


Myocyte diameter and fractional area of collagen are not associated with survival time of outpatients with idiopathic dilated cardiomyopathy: a study based on right ventricular endomyocardial biopsies.
Morphometric data obtained from the analysis of endomyocardial biopsy might be useful to evaluate prognosis of patients with dilated cardiomyopathy. We measured the myocyte diameter, its coefficient of variation and the fractional area of collagen in right ventricular endomyocardial biopsies of 35 outpatients with idiopathic dilated cardiomyopathy. None of the evaluated histological parameter was associated with the survival time of the patients (range: 2 to 5588; median: 706 days). Right ventricular endomyocardial biopsy should not be indicated to predict evolution or fatal outcome in patients with idiopathic dilated cardiomyopathy.


Nonword reading by adults who stutter in a transparent orthography.
Using word- and nonword-reading passages in Kannada, which has a transparent orthography, we attempted to determine (a) whether orthographic differences between English and Kannada may explain the observed differences in stutter rates on nonwords, and (b) whether longer nonwords, like words, incur higher rates of stutters. Stutters are defined as sound or syllable repetitions, sound prolongations, broken words or nonwords (a pause within a word or nonword), abnormal pauses, and intrusive vowel-like sounds. Twenty-six persons, who stutter, read the word and nonword passages. The nonwords were created by changing the first syllable of each word; otherwise words and nonwords were equivalent in length and syllable structure. Stutters were counted from audio-recordings and statistically analyzed. PWS stuttered on words in varying amounts and in significantly larger amounts on nonwords. Stutter frequency increased roughly in proportion to the increase in the length of phonological words (previously known) and nonwords (reported for the first time here). The results cannot be attributed to the difficulty of pronouncing nonwords because Kannada orthography has a one-to-one relationship between the written and spoken forms of words. Speech production is a multi-stage process consisting of ideation, lemma selection, phonological word creation, and the articulatory planning and execution. Because nonwords lack meaning and clearly identifiable part of speech, it appears that stutters arise late in the speech production process at the phonological word formation and articulatory planning stages. Meaning, lexicality, and morphosyntax may not contribute significantly to the occurrence of stutters.


Laparoscopic antireflux surgery in neurologically impaired children.
From May 1996 to April 2002, 48 laparoscopic fundoplications were performed after failure of medical treatment in 47 neurologically impaired infants and children affected by gastroesophageal reflux. Indications for surgery included vomiting, recurrent upper airway infections, failure of medical therapy, feeding difficulties with failure to gain weight, and instrumental (barium swallow and pHmetry) diagnosis of gastroesophageal reflux. A standard approach was adopted, with minimal access modifications according to the patients' characteristics. In two patients, laparoscopic surgery had to be converted to open surgery because of severe kyphoscoliosis and accidental left emidiaphragm perforation. In another patient undergoing a laparoscopic Nissen fundoplication, a re-do laparoscopic operation was performed. Postoperative analgesia was administered during the first 12 h, and fluid intake and feeding were begun on days 1 and 2, respectively. All patients clinically improved except two; a paraesophageal hernia developed in one, and a stenosis developed in the other. We strongly believe that laparoscopic fundoplication can be successfully adopted in neurologically impaired children as well as in pediatric patients as a whole, with the same advantages and far fewer drawbacks than are expected in adults.


Histologic Features Associated with Deep Invasion in Dermatofibrosarcoma Protuberans.
Dermatofibrosarcoma protuberans (DFSP) is a rare, slow-growing cutaneous tumor that can invade the subcutaneous tissue, muscle tissue, and even bone. To identify histologic features associated with greater depth of invasion, i.e., local aggressiveness, in DFSP. We analyzed associations between histologic features of DFSP (e.g., type of subcutaneous invasion, histologic pattern, cell type, areas of fibrosarcoma) and the presence and absence of muscle fascia involvement. We studied 155 cases of DFSP. The following histologic characteristics were significantly associated with involvement of the muscle fascia: the presence of a sheetlike pattern, a high degree of cellular pleomorphism, and more than 1 mitotic figure. The tumor did not extend beyond the subcutaneous tissue in the majority of cases (62.6%), but there was involvement of the fascia or galea aponeurotica in 17 cases (11%) and of the muscle tissue in 36 cases (23.2%). Histologic patterns, degree of pleomorphism, and number of mitotic figures are important predictors of deep invasion (fascia or muscle) in DFSP; these layers can be involved in up to 30% of cases.


Effect of peroral administration of xylitol on the oxidoreductase activity of human blood cells and certain chemical properties of saliva and serum.
The effect of xylitol on the activity of certain oxidoreductases of human granulocytes, lymphocytes, and erythrocytes was studied both in vivo and in vitro. The effect of xylitol consumption on certain chemical properties of serum and whole saliva was also investigated. Short-term peroral administration of 0.6 g xylitol or glucose per kg body weight and day had a similar effect on leucocyte peroxidase levels. 0.07-0.2 M xylitol and glucose did not differ in their effects on leucocyte peroxidase levels in vitro either. Peroral administration of xylitol increased the whole saliva lactoperoxidase levels compared to glucose administration, but the differences were not significant. The results suggested that although the consumption of xylitol may under certain circumstances increase the peroxidatic capacity of saliva, that of leucocytes is not significantly affected.


Can a brief peer-led group training intervention improve health literacy in persons living with HIV? Results from a randomized controlled trial.
The goal of this study was to determine if a 6-week, peer-led intervention improves health literacy and numeracy among people living with HIV (PLWH). We used a randomized controlled trial with repeated measurements, which included six, 90-minute, group-based training sessions. We recruited PLWH participants (n = 359) from safety-net practices in the New York City Metropolitan area and Rochester, NY. Participants were randomly assigned (1:1) to an intervention group (n = 180) or a control group (n = 179). Outcome measures were collected at baseline, eight weeks post-baseline, and at six months using the Brief Estimate of Health Knowledge and Action-HIV (BEHKA-HIV), the Electronic Health Literacy Scale (eHEALS), the Rapid Estimate of Adult Literacy (REALM), and the Newest Vital Sign (NVS). The intervention group had statistically significant improvements in eHealth literacy and BEHKA-HIV compared to the control group. There were no statistically significant changes in general health literacy or numeracy in either group. The intervention had the greatest impact on participants with the lowest levels of eHealth literacy at baseline. The intervention had a positive impact on participants' HIV health literacy and eHealth literacy. Our findings have implications for broadening the function of peer-workers in the health care continuum.


Morphology of male and female reproductive systems in the ground beetle Apotomus and the peculiar sperm ultrastructure of A. rufus (P. Rossi, 1790) (Coleoptera, Carabidae).
Relatively few studies have focused on evolutionary losses of sexually selected male traits. We use light and electron microscopy to study the male and female reproductive anatomy of Apotomus ground beetles (Coleoptera, Carabidae), a lineage that we reconstruct as likely having lost sperm conjugation, a putative sexually selected trait. We pay particular attention to the structure of the testes and spermatheca. Both of these organs share a strikingly similar shape-consisting of long blind canals arranged into several concentric overlapping rings measuring approximately 18 mm and 19.5 mm in total length, respectively. The similarity of these structures suggests a positive evolutionary correlation between female and male genital organs. Males are characterized by unifollicular testes with numerous germ cysts, which contain 64 sperm cells each, and we record a novel occurrence of sperm cyst "looping", a spermatogenic innovation previously only known from some fruit fly and Tenebrionid beetle sperm. The sperm are very long (about 2.7 mm) and include an extraordinarily long helicoidal acrosome, a short nucleus, and a long flagellum. These findings confirm the structural peculiarity of sperm, testis, and female reproductive tract (FRT) of Apotomus species relative to other ground beetles, which could possibly be the result of shifts in sexual selection.


Butyrate inhibits mouse fibroblasts at a control point in the G1 phase.
Butyrate block 3T6 cells in the G1 phase of the cell cycle approximately 5--6 h prior to the start of the S phase. Serum factors are required before as well as after the butyrate-sensitive steps in G1 in order to allow cells to start DNA synthesis. 3T6 cells infected with SV40 or with polyoma virus are also blocked at the same stage in G1 in the presence of the fatty acid. However, events before as well as after the butyrate-sensitive step do not require serum in virus-infected cells. The sensitivity of the initiation of cellular DNA synthesis to increasing concentrations of butyrate is the same for serum-stimulated or for virus-infected cells. A similar and parallel effect on DNA synthesis is observed if cells are incubated in the presence of very small amounts of cycloheximide. After release of the cycloheximide-induced G1 arrest about 4--6 h have to pass before cells enter the S phase. Cells stably transformed by SV40 are considerably more resistant to low cycloheximide concentrations and to butyrate. These data are discussed in the light of the hypothesis that both low concentrations of cycloheximide and sodium butyrate block cells at a control point in G1 by interference with the synthesis of one or more rapidly turning over, cell cycle-specific proteins.


Prevention of everolimus-related stomatitis in women with hormone receptor-positive, HER2-negative metastatic breast cancer using dexamethasone mouthwash (SWISH): a single-arm, phase 2 trial.
Stomatitis is a class effect associated with the inhibition of mTOR and is associated with everolimus therapy for breast cancer. Topical steroids might reduce stomatitis incidence and severity, and the need for dose reductions and interruptions of everolimus. Anecdotal use of topical steroid oral prophylaxis has been reported in patients with breast cancer. We aimed to assess dexamethasone-based mouthwash for prevention of stomatitis in patients with breast cancer. This US-based, multicentre, single-arm, phase 2 prevention study enrolled women aged 18 years and older with postmenopausal status who had histologically or cytologically confirmed metastatic hormone receptor-positive, HER2-negative breast cancer. Beginning on day 1 of cycle 1, patients received everolimus 10 mg plus exemestane 25 mg daily, with 10 mL of alcohol-free dexamethasone 0·5 mg per 5 mL oral solution (swish for 2 min and spit, four times daily for 8 weeks). After 8 weeks, dexamethasone mouthwash could be continued for up to eight additional weeks at the discretion of the clinician and patient. The primary endpoint was incidence of grade 2 or worse stomatitis by 8 weeks assessed in the full analysis set (patients who received at least one dose of everolimus and exemestane and at least one confirmed dose of dexamethasone mouthwash) versus historical controls from the BOLERO-2 trial (everolimus and exemestane treatment in patients with hormone receptor-positive advanced breast cancer who were not given dexamethasone mouthwash for prevention of stomatitis). This trial is registered at ClinicalTrials.gov, number NCT02069093. Between May 28, 2014, and Oct 8, 2015, we enrolled 92 women; 85 were evaluable for efficacy. By 8 weeks, the incidence of grade 2 or worse stomatitis was two (2%) of 85 patients (95% CI 0·29-8·24), versus 159 (33%) of 482 patients (95% CI 28·8-37·4) for the duration of the BOLERO-2 study. Overall, 83 (90%) of 92 patients had at least one adverse event. The most frequently reported grade 3 and 4 adverse events in the safety set were hyperglycaemia (seven [8%] of 92 patients), rash (four [4%]), and dyspnoea (three [3%]). Serious adverse events were reported in 20 (22%) patients; six (7%) were deemed treatment related, with dyspnoea (three [3%]) and pneumonia (two [2%]) reported most frequently. 12 (13%) of 92 patients had adverse events suspected to be related to treatment that led to discontinuation of everolimus and exemestane (the most common were rash, hyperglycaemia, and stomatitis, which each affected two [2%] patients). Prophylactic use of dexamethasone oral solution substantially reduced the incidence and severity of stomatitis in patients receiving everolimus and exemestane and could be a new standard of oral care for patients receiving everolimus and exemestane therapy. Novartis Pharmaceuticals Corporation.


From menarche to menopause: coronary artery atherosclerosis and protection in cynomolgus monkeys.
The effects on atherogenesis of stress, pregnancy, and oral contraceptive therapy were studied in a nonhuman primate model. The stress of social subordination was associated with ovarian dysfunction, unfavorable lipoprotein changes, and increased coronary artery atherosclerosis compared with nonstressed (socially dominant) or normal monkeys. Although pregnant animals exhibited lower high-density lipoprotein cholesterol concentrations, they had only one half as much diet-induced coronary artery atherosclerosis as their nonpregnant counterparts. Monkeys treated with an Ovral-like regimen also exhibited adverse lipoprotein changes. Nevertheless, prevalence and extent of coronary artery plaques decreased. We conclude that estrogen is an important factor in the animals' "female protection" against diet-induced atherosclerosis. We also suggest that the lowering of high-density lipoproteins by the progestin component of higher-dose contraceptives is not necessarily atherogenic if a sufficiently potent exogenous estrogen is administered concomitantly.


DPPC:MPOx chimeric advanced Drug Delivery nano Systems (chi-aDDnSs): physicochemical and structural characterization, stability and drug release studies.
Chimeric advanced Drug Delivery nano Systems (chi-aDDnSs) could be defined as mixed nanosystems composed of different biomaterials that can be organized into new nanostructures that can offer advantages as drug carriers. In this work, we report on the self assembly behavior and on stability studies of chi-aDDnSs consisting of DPPC (dipalmitoylphosphatidylcholine) and poly(2-methyl-2-oxazoline)-grad-poly(2-phenyl-2-oxazoline) (MPOx) gradient copolymer in Phosphate Buffer Saline (PBS). Light scattering techniques were used in order to extract information on their physicochemical and structural characteristics (i.e. ζ-potential, Polydispersity Index (PD.I.), size/shape and morphology), while their stability was also studied as a function of gradient block copolymer content, as well as temperature. The colloidal stability of the chimeric nanovectors and their thermoresponsive behavior indicates that these nanosystems could be considered as sterically stabilized nanocontainers. DPPC:MPOx chimeric advanced Drug Delivery nano Systems were found to be effective nanocontainers for the incorporation of indomethacin (IND). The combination of gradient block copolymers with phospholipids for the development of novel chimeric nanovectors is reported for the first time and appears very promising, mostly due to the fact that the MPOx acts as a modulator for the release rate of the IND.


Thinking beyond 'outbreak': The contentious politics of the science of early warning and overdose epidemic.
This Commentary on the article, "Early warnings and slow deaths: A sociology of outbreak and overdose" by Tim Rhodes and Kari Lancaster, reflects upon rapid response reflexes invoked in societal responses to 'emergency,' 'epidemic,' 'crisis,' and disasters, all of which require immediate action with no time to think. Epidemiology has given us machines for producing 'fact' about the 'opioid overdose epidemic' that promote the forgetting of the ways in which apparatuses of social control enact the production of facticity. While facts are supposed to be epistemologically reliable and worthy, the work of Rhodes and Lancaster invites us to de-subscribe to these beliefs and re-member our way towards developing slower, more thorough, and more thoughtful ways of seeing a wider array of "indicators, signals, evidence, and narratives of an ecological kind" (Rhodes and Lancaster 2023; this issue). This Commentary focuses on the practices of 'early warning' in social, political, and economic context.


Inhibitory effects of epigallocatechin gallate on compound 48/80-induced mast cell activation and passive cutaneous anaphylaxis.
Epigallocatechin gallate (EGCG) is a principle phenolic antioxidant found in a variety of plants, including green and black tea. The anti-allergic effect of EGCG is unknown. The purpose of this study is to investigate the effects of EGCG on compound 48/80-induced mast cell activation and passive cutaneous anaphylaxis. For this, the influences of EGCG on the compound 48/80-induced cutaneous reaction were measured in vivo and the effects of EGCG on the compound 48/80-induced mast cell activations were examined in vitro. Results are below: as 1) EGCG significantly inhibited compound 48/80-induced passive cutaneous anaphylaxis, 2) the compound 48/80-induced degranulation, calcium influx and histamine release of rat peritoneal mast cells (RPMCs) were significantly inhibited by the pretreatment with EGCG, and 3) the compound 48/80-mediated inhibition of cAMP level in RPMCs was significantly increased by the pretreatment with EGCG. These results suggested that EGCG, the most abundant polyphenol in green tea, inhibits the compound 48/80-induced mast cell activation and the increase of vascular permeability, and potentially serve as effective therapeutic tools for allergic diseases.


Casual household transmission of human immunodeficiency virus.
The consistent conclusion of many studies and reviews is that there is no evidence for casual household transmission of human immunodeficiency virus (HIV). The objective of this study was to analyze the evidence for casual household transmission. Data were obtained from published studies identified by computer searching, bibliographies, and consultations with experts. The analysis indicated that casual household transmission is a route of HIV transmission.


Effects of reinforcer quality and step size on rats' performance under progressive ratio schedules.
The Mathematical Principles of Reinforcement (MPR) model accurately predicts performance in fixed ratio (FR) schedules of reinforcement. The aim of the present study was to assess the generality of MPR with rats responding under progressive ratio (PR) schedules of different step sizes (PR1 or PR3) that provided either food or saccharin pellets. The results showed that the rats responding for saccharin pellets produced higher breakpoints (i.e., completed higher ratios) than those responding for food pellets. In terms of theoretical parameters, one finding unanticipated on the basis of MPR was that the a parameter (specific activation) was higher for the PR3 schedules. This finding suggests that specific activation may be affected indirectly by motor parameters of the task.


Comparison of system identification techniques in the analysis of a phantom for studying shaken-baby syndrome.
This article compares two techniques for estimating the parameters describing the motion of a phantom designed to investigate shaking baby syndrome. Parameters of a simple computational model and an impulse response function for a linear second order system were both fitted using kinematic measurements of the motion of an inverted jointed pendulum. From the two methods respectively, the rotational stiffness of the joint was calculated to be 1.396 kgm(2) s(-2) and 1.355 kgm(2) s(-2) and the damping coefficient was calculated to be 0.0142 kgm(2) s(-1) and 0.0133 kgm(2) s(-1). The parameter estimates were similar demonstrating that the two techniques were comparable. Identifying accurate parameters will allow more complex phantoms to be modeled, and will provide insight into the relationship between the shaking of the torso and the resultant head motion during shaken baby syndrome.


Association between internal carotid artery morphometry and posterior communicating artery aneurysm.
The goal of this study was to directly measure the association between the internal carotid artery (ICA) morphometry and the presence of ICA-posterior communicating artery (PCOM) aneurysm. The authors intraoperatively measured the length of the supraclinoid ICA because it is impossible to radiologically determine the exact location of the anterior clinoid process. We used an image analyzer with a CT angiogram to measure the angle between the skull midline and the terminal segment of the ICA (ICA angle), as well as the diameter of the ICA. The lengths and diameters of the supraclinoid ICA and the ICA angle were compared among PCOM aneurysms, anterior communicating artery (ACOM) aneurysms, and middle cerebral artery (MCA) bifurcation aneurysms (n=27 each). Additionally, the lengths and the diameters of M1 and A1 were compared for each aneurysm. The lengths of the supraclinoid ICA were 11.9+/-2.3 mm. The lengths of the supraclinoid ICA in patients with ICA-PCOM aneurysms (9.7+/-2.8 mm) were shorter than those of patients with ACOM aneurysms (13.8+/-2.2 mm, Student's t-test, p<0.001) and with MCA bifurcation aneurysms (12.2+/-1.9 mm, Student's t-test, p<0.001). The diameters of the supraclinoid ICA and A1 in patients with ACOM aneurysms were larger than those in patients with MCA bifurcation aneurysms (Student's t-test, p<0.05). There were no significant differences in the lengths of M1 and A1, ICA angle, or diameter of M1 for each aneurysm. These results suggest that the relatively shorter length of the supraclinoid ICA may be a novel risk factor for the development of ICA-PCOM aneurysm with higher hemodynamic stress.


Loss of Flot2 expression in deep cerebellar nuclei neurons of mice with Niemann-Pick disease type C.
Niemann-Pick disease type C (NPC) is caused by a deficiency of the NPC1 or NPC2 gene, leading to storages of unesterified cholesterol and sphingolipids. Cerebellar ataxia is a main symptom of NPC and the deep cerebellar nuclei (DCN) is the sole signal output of the cerebellum. In this study, we explored the pathological changes in DCN neurons of Npc1 knockout mice (Npc1-). We first demonstrated that DCN neurons of Npc1- mice had prominent ganglioside GM2 accumulation in the late endosomes but not in the lysosomes. More importantly, Flot2 expression, a marker for the lipid rafts, was lost. Single-nucleus RNA sequencing analysis revealed a generalized reduction in gene expression in DCN neurons, though Camk1d, encoding one of the Ca2+/calmodulin-dependent protein kinases (CaMKs), increased in expression. We treated Npc1- mice with CaMK inhibitor KN-93, but CaMK1D expression increased further. We also fed Npc1- mice with two medications for NPC. We found that miglustat, a sphingolipid synthesis inhibitor, increased the expression of Flot2. Moreover, N-acetyl l-leucine (NALL), an experimental medicine for NPC, recovered Flot2 expression. Therefore, our data suggest that in Npc1- mice, GM2 sequestration and the loss of lipid rafts lead to cell dysfunction and symptoms of NPC.


IL-4 expressing cells are recruited to nerve after injury and promote regeneration.
Interleukin-4 (IL-4) has garnered interest as a cytokine that mediates regeneration across multiple tissues including peripheral nerve. Within nerve, we previously showed endogenous IL-4 was critical to regeneration across nerve gaps. Here, we determined a generalizable role of IL-4 in nerve injury and regeneration. In wild-type (WT) mice receiving a sciatic nerve crush, IL-4 expressing cells preferentially accumulated within the injured nerve compared to affected sites proximal, such as dorsal root ganglia (DRGs), or distal muscle. Immunohistochemistry and flow cytometry confirmed that eosinophils (CD45+, CD11b+, CD64-, Siglec-F+) were sources of IL-4 expression. Examination of targets for IL-4 within nerve revealed macrophages, as well as subsets of neurons expressed IL-4R, while Schwann cells expressed limited IL-4R. Dorsal root ganglia cultures were exposed to IL-4 and demonstrated an increased proportion of neurons that extended axons compared to cultures without IL-4 (control), as well as longer myelinated axons compared to cultures without IL-4. The role of endogenous IL-4 during nerve injury and regeneration in vivo was assessed following a sciatic nerve crush using IL-4 knockout (KO) mice. Loss of IL-4 affected macrophage accumulation within injured nerve compared to WT mice, as well as shifted macrophage phenotype towards a CD206- phenotype with altered gene expression. Furthermore, this loss of IL-4 delayed initial axon regeneration from the injury crush site and subsequently delayed functional recovery and re-innervation of neuromuscular junctions compared to wild-type mice. Given the role of endogenous IL-4 in nerve regeneration, exogenous IL-4 was administered daily to WT mice following a nerve crush to examine regeneration. Daily IL-4 administration increased early axonal extension and CD206+ macrophage accumulation but did not alter functional recovery compared to untreated mice. Our data demonstrate IL-4 promotes nerve regeneration and recovery after injury.


BMI-based radiation dose reduction in CT colonography.
There is potential for x-ray dose reduction in computed tomography colonography (CTC) relative to body mass index (BMI). We evaluated the association between BMI and three-dimensional (3D) CTC image quality to assess the potential utility of BMI as the basis for radiation dose reduction in CTC. Ninety-six consecutive patients underwent CTC and were randomized for scanning at 15 or 30 mAs. Extremely obese patients (BMI > 50) were excluded. Each patient was scanned supine and prone on a multidetector CT scanner. Postprocessing CTC visualization was performed on a dedicated workstation. Three independent observers assessed 3D image quality using a four-point scale. Image noise was measured in both the abdomen and pelvis. The association between BMI and image noise was examined using random-effects linear regression models. Logistic regression was used to examine the relationship between BMI, mAs, and conspicuity scores. Statistically significant differences in image noise were observed between 15 and 30 mAs in both the abdomen and pelvis, and the difference was greater with increasing BMI. A positive relationship was detected between BMI and noise in the abdomen (P < .001) and pelvis (P < .001). Inverse correlation was identified between BMI and conspicuity scores in the abdomen (P = .01) and pelvis (P < .001). Overall conspicuity scores were reduced for both 15 and 30 mAs groups as BMI increased. The radiation dose for CTC can be reduced by 40% and 70% below commonly employed doses for overweight and normal BMI patients, respectively, by using a BMI-adjusted dose reduction approach. Conspicuity scores dropped in obese patients with reduced dose suggesting that standard accepted doses should be utilized in that group.


Cardioprotective activity of chalcones in ischemia/reperfusion-induced myocardial infarction in albino rats.
There is a comprehensive body of experimental and clinical evidence suggesting that exogenous supplementation of natural antioxidants or augmentation of endogenous antioxidants attenuates the damage caused by myocardial infarction. To evaluate the cardioprotective effects of Cl-chalcone and F-chalcone against ischemia/reperfusion (I/R)-induced myocardial infarction in rats. Myocardial infarct size was measured using the staining agent 2,3,5-triphenyltetrazolium chloride. Malondialdehyde was measured in serum and heart tissue, and superoxide dismutase and catalase in heart tissue were measured spectrophotometrically. I/R resulted in significant cardiac necrosis, indicated by a rise in the end products of myocardial lipid peroxidation (malondialdehydes). A loss of antioxidative enzymes (superoxide dismutase and catalase) in heart tissue was also observed in animals subjected to in vivo myocardial I/R injury. The present study demonstrated that treatment with Cl-chalcone and F-chalcone significantly limited infarct size, partially but significantly attenuated the level of lipid peroxidation and moderated the loss of antioxidant reserves in rats subjected to 30 min coronary artery occlusion followed by a 4 h reperfusion in comparison with I/R groups. The results of the present study suggest that chalcones have cardioprotective activity against I/R-induced myocardial infarction in rats.


Aspect-based classification of vaccine misinformation: a spatiotemporal analysis using Twitter chatter.
The spread of misinformation of all types threatens people's safety and interrupts resolutions. COVID-19 vaccination has been a widely discussed topic on social media platforms with numerous misleading and fallacious information. This false information has a critical impact on the safety of society as it prevents many people from taking the vaccine, decelerating the world's ability to go back to normal. Therefore, it is vital to analyze the content shared on social media platforms, detect misinformation, identify aspects of misinformation, and efficiently represent related statistics to combat the spread of misleading information about the vaccine. This paper aims to support stakeholders in decision-making by providing solid and current insights into the spatiotemporal progression of the common misinformation aspects of the various available vaccines. Approximately 3800 tweets were annotated into four expert-verified aspects of vaccine misinformation obtained from reliable medical resources. Next, an Aspect-based Misinformation Analysis Framework was designed using the Light Gradient Boosting Machine (LightGBM) model, which is one of the most advanced, fast, and efficient machine learning models to date. Based on this dataset, spatiotemporal statistical analysis was performed to infer insights into the progression of aspects of vaccine misinformation among the public. Finally, the Pearson correlation coefficient and p-values are calculated for the global misinformation count against the vaccination counts of 43 countries from December 2020 until July 2021. The optimized classification per class (i.e., per an aspect of misinformation) accuracy was 87.4%, 92.7%, 80.1%, and 82.5% for the "Vaccine Constituent," "Adverse Effects," "Agenda," "Efficacy and Clinical Trials" aspects, respectively. The model achieved an Area Under the ROC Curve (AUC) of 90.3% and 89.6% for validation and testing, respectively, which indicates the reliability of the proposed framework in detecting aspects of vaccine misinformation on Twitter. The correlation analysis shows that 37% of the countries addressed in this study were negatively affected by the spread of misinformation on Twitter resulting in reduced number of administered vaccines during the same timeframe. Twitter is a rich source of insight on the progression of vaccine misinformation among the public. Machine Learning models, such as LightGBM, are efficient for multi-class classification and proved reliable in classifying vaccine misinformation aspects even with limited samples in social media datasets.


Rapid photooxidation and removal of As(III) from drinking water using Fe-Mn composite oxide.
Fe-Mn composite oxide (FMO) is widely applied to the oxidation and removal of As(III) from water. However, As(III) can directly reduce manganese oxides, decreasing the oxidation capacity or reusability and thereby greatly limiting the applicability of FMO. Here, the oxidation capacity and reusability of FMO for As(III) were efficiently improved by light radiation, and the effect of typical coexisting ions (SO42- and Ca2+) on the removal of As(III) was also studied. O2•- produced from excited manganese oxide and ligand-to-metal charge transfer in iron oxide-As(III) complex enhanced As(III) oxidation and removal under light radiation. At an initial As(III) concentration of 1000 μg L-1, the total As concentration was respectively decreased to 11.5, 1.5 and 4.4 μg L-1 under darkness, UV light and sunlight at 180 min, and could be reduced to below the guideline limitation of drinking water (10 μg L-1) within 40 and 60 min under UV light and sunlight, respectively. SO42- exhibited negligible effect on As removal efficiency because FMO had obviously lower adsorption capacity and selectivity for SO42- than for As(V). The adsorption of coexisting Ca2+ on manganese oxide decreased the negative charge on the FMO surface, thereby improving As(III) adsorption and oxidation. FMO exhibited excellent reusability, and a total As removal efficiency of 99.1% was still maintained after five cycles of an adsorption-desorption process under UV light. This work elucidates the photochemical oxidation and removal mechanism of FMO for As(III), and proposes a low-cost and efficient method for the detoxification of As(III)-contaminated drinking water.


Structure of histone mRNA stem-loop, human stem-loop binding protein, and 3'hExo ternary complex.
Metazoan replication-dependent histone messenger RNAs (mRNAs) have a conserved stem-loop (SL) at their 3'-end. The stem-loop binding protein (SLBP) specifically recognizes the SL to regulate histone mRNA metabolism, and the 3'-5' exonuclease 3'hExo trims its 3'-end after processing. We report the crystal structure of a ternary complex of human SLBP RNA binding domain, human 3'hExo, and a 26-nucleotide SL RNA. Only one base of the SL is recognized specifically by SLBP, and the two proteins primarily recognize the shape of the RNA. SLBP and 3'hExo have no direct contact with each other, and induced structural changes in the loop of the SL mediate their cooperative binding. The 3' flanking sequence is positioned in the 3'hExo active site, but the ternary complex limits the extent of trimming.


Long-acting β2-adrenoreceptor agonists suppress type 1 interferon expression in human plasmacytoid dendritic cells via epigenetic regulation.
The combination of inhaled long-acting β2-adrenoreceptor (LABA) and inhaled glucocorticoid (ICS) is a major therapy for asthma. However, the increased risk of infection is still a concern. Plasmacytoid dendritic cells (pDCs) are the predominant cells producing type 1 interferon (IFN) against infection. The effect of LABA/ICS on type 1 IFN expression in human pDCs is unknown. Circulating pDCs were isolated from healthy human subjects and were pretreated with glucocorticoid (GCS), LABA or a cAMP analog, and were stimulated with Toll-like receptor (TLR) agonist CpG (TLR9) or imiquimod (TLR7) in the presence of IL-3. The expression of type 1 IFN (IFN-α/β) were measured by ELISA. The mechanisms were investigated using receptor antagonists, pathway inhibitors, Western blotting and chromatin immunoprecipitation. GCS suppressed TLR-induced IFN-α expression, and LABA enhanced the suppressive effect. LABA alone also suppressed TLR-induced IFN-α/β expression, and the effect was reversed by the β2-adrenoreceptor antagonist ICI118551. Dibutyryl-cAMP, a cAMP analog, conferred a similar suppressive effect, and the effect was abrogated by the exchange protein directly activated by cAMP (Epac) inhibitor HJC0197 or intracellular free Ca2+ chelator BAPTA-AM. Formoterol suppressed TLR-induced phosphorylation of mitogen-activated protein kinase (MAPK)-p38/ERK. Formoterol suppressed interferon regulatory factor (IRF)-3/IRF-7 expression. Formoterol suppressed CpG-induced translocation of H3K4 specific methyltransferase WDR5 and suppressed H3K4 trimethylation in the IFNA and IFNB gene promoter region. LABA suppressed TLR7/9-induced type 1 IFNs production, at least partly, via the β2-adrenoreceptor-cAMP-Epac-Ca2+, IRF-3/IRF-7, the MAPK-p38/ERK pathway, and epigenetic regulation by suppressing histone H3K4 trimethylation through inhibiting the translocation of WDR5 from cytoplasm to nucleus. LABA may interfere with anti-viral immunity.


Path efficiency of ant foraging trails in an artificial network.
In this paper we present an individual-based model describing the foraging behavior of ants moving in an artificial network of tunnels in which several interconnected paths can be used to reach a single food source. Ants lay a trail pheromone while moving in the network and this pheromone acts as a system of mass recruitment that attracts other ants in the network. The rules implemented in the model are based on measures of the decisions taken by ants at tunnel bifurcations during real experiments. The collective choice of the ants is estimated by measuring their probability to take a given path in the network. Overall, we found a good agreement between the results of the simulations and those of the experiments, showing that simple behavioral rules can lead ants to find the shortest paths in the network. The match between the experiments and the model, however, was better for nestbound than for outbound ants. A sensitivity study of the model suggests that the bias observed in the choice of the ants at asymmetrical bifurcations is a key behavior to reproduce the collective choice observed in the experiments.


Psychological effects during reduced training in distance runners.
Reduced training is most frequently employed by swimmers prior to an important competition. To investigate what occurs during reduced training in runners, ten well-trained adult male distance runners trained for 4 weeks at their baseline training distance (BT), followed by a 3-week period of a 70% reduction in training volume (RT). At the same time each week the subjects completed the Profile of Moods States (POMS) and Physical Self-Efficacy Scale (PSES). Overall and leg ratings of perceived exertion (RPE) were given each week while running at two consistent speeds on a motor-driven treadmill. Responses to the POMS, PSES, and Sport Competition Anxiety Test were also obtained prior to 5-km races during BT and RT. Pre-race and weekly global mood state was improved (less negative) during RT. Pre-race vigor decreased significantly (P less than 0.01) at RT week 2 as compared with BT, and then increased significantly (P less than 0.01) at RT week 3 as compared with week 2. Pre-race tension decreased significantly (P less than 0.05) at RT week 3. A significant (P less than 0.01) drop in testing day fatigue occurred at RT week 1 as compared with BT. Reduced RPEs were also noted during RT weeks 2 and 3 at the slower running speed. No differences were found for competition anxiety or physical self-efficacy. Racing performance remained constant throughout the study. These results suggest that the subjects were unaccustomed to RT, but maintained a positive mood state particularly when it was realized that performance capability was unaltered.


Spontaneous regression of malignant lymphoma of the lumbar spine.
Spontaneous regression of diffuse B-cell type lymphoma of the lumbar vertebra is reported. A 61-year-old woman experienced spontaneous disappearance of a large psoas mass associated with an infiltrating process of the lumbar vertebrae. The biopsy of the residual change after spontaneous regression revealed reactive foamy histiocytes and small lymphocytes with no atypia. The lesion recurred 7 months later with no systemic treatment in the interim, when the diagnosis of lymphoma was finally made. Spontaneous regression may be related to potentiation of the host immune response, which affects tumor growth.


Thyroid function in normal subjects in Iceland and Northeast Scotland.
A comparative study was made of thyroid function in samples of 'well' subjects, from separate geographical areas with dissimilar dietary iodine levels. In the area with the higher iodine level, Iceland, the prevalence of positive thyroid antibody tests and serum thyrotrophin levels were lower, while the capacity of the thyroid to respond to exogenous thyrotrophin was higher than in NE Scotland, an area with lower iodine levels. In contrast the prevalence of positive tests for another organ-specific antibody, gastric parietal cell antibody, was higher in Iceland. These observations are consistent with the reported differences in the incidence rates for thyrotoxicosis and gastric carcinoma in the areas studied. The results are in agreement with our findings in two groups of post-thyroidectomy patients from the same populations. This study provides support for the view that differences in the prevalence of constitutional and environmental factors in different populations contribute to the variation in reported outcome of treatment for thyroid disease.


Exploration and characterization of chemical stimulators to maximize the wax ester production by Euglena gracilis.
Euglena gracilis, a phototrophic protist, is a valuable biomass producer that is often employed in sustainable development efforts. E. gracilis accumulates wax esters as byproducts during anaerobic ATP production via the reductive tricarboxylic acid cycle, utilizing the storage carbohydrate β-1,3-glucan paramylon as the carbon source. Here, we report a library screening for chemical stimulators that accelerate both wax ester production and paramylon consumption. Among the 115 compounds tested, we identified nine compounds that increased wax ester production by more than 2.0-fold relative to the solvent control. In the presence of these nine compounds, the paramylon content decreased compared with the control experiment, and the residual paramylon content varied between 7% and 26% of the initial level. The most active compound, 1,4-diaminoanthracene-9,10-dione (OATQ008), stimulated wax ester production up to 2.7-fold within 24 h, and 93% of the cellular paramylon was consumed. In terms of the structural features of the chemical stimulators, we discuss the potential target sites to stimulate wax ester production in mitochondria under anaerobic conditions.