Mitochondrial involvement in amyotrophic lateral sclerosis.
The causes of motor neuron death in amyotrophic lateral sclerosis (ALS) are so far unknown. The involvement of mitochondria in the disease was initially suggested by ultrastructural studies. More recently these observations have been supported by studies of mitochondrial function in ALS. Alterations in the activity of complexes which make up the mitochondrial electron transport chain have been recorded as well as mutations in the mitochondrial genome. The calcium buffering function of the mitochondria may also be affected in the disease. This review will discuss how mitochondrial dysfunction could be of relevance in ALS and the evidence that an alteration of mitochondrial function is a feature of the disease. The way in which the involvement of mitochondria fits with other aetiological hypotheses for ALS will also be discussed.


Rapid typing of apolipoprotein B DNA polymorphisms by DNA amplification. Association between Ag epitopes of human apolipoprotein B-100, a signal peptide insertion/deletion polymorphism, and a 3'flanking DNA variable number of tandem repeats polymorphism of the apolipoprotein B gene.
We present here rapid and efficient methods for the analysis of multiple variable apolipoprotein (apo) B loci using polymerase chain reaction based techniques. For illustrative purposes, we have applied these methods to establish an association between these polymorphisms and the apo B Ag immunological epitopes. The 5 DNA polymorphisms include 3 restriction endonuclease sites (for XbaI, EcoRI and MspI), a variable number of tandem repeat (VNTR) locus at the 3' end of the apo B gene, and an insertion/deletion polymorphism involving the signal peptide region of apo B. The latter two newly described polymorphisms are directly detectable following amplification and may have physiological effects on apo B expression because of their critical locations. All of these sites were typed using flanking oligonucleotides and the newly developed polymerase chain reaction. Amplification products were typed either directly (3' VNTR and signal peptide insertion/deletion alleles), or following specific enzyme digestion (for the restriction sites), or by allele specific oligonucleotides. The detailed methods presented will prove generally useful for rapidly typing DNA variation in the apo B gene. Using these techniques, we found a significant linkage disequilibrium between the Ag(t/z) locus and the 3' VNTR, and the Ag(c/g) locus and the signal peptide length polymorphism. Future association studies using these DNA polymorphisms should take into consideration that observed effects may be related to its linkage disequilibrium with the Ag loci and vice versa.


Targeting Tumor Glycans for Cancer Therapy: Successes, Limitations, and Perspectives.
Aberrant glycosylation is a hallmark of cancer and can lead to changes that influence tumor behavior. Glycans can serve as a source of novel clinical biomarker developments, providing a set of specific targets for therapeutic intervention. Different mechanisms of aberrant glycosylation lead to the formation of tumor-associated carbohydrate antigens (TACAs) suitable for selective cancer-targeting therapy. The best characterized TACAs are truncated O-glycans (Tn, TF, and sialyl-Tn antigens), gangliosides (GD2, GD3, GM2, GM3, fucosyl-GM1), globo-serie glycans (Globo-H, SSEA-3, SSEA-4), Lewis antigens, and polysialic acid. In this review, we analyze strategies for cancer immunotherapy targeting TACAs, including different antibody developments, the production of vaccines, and the generation of CAR-T cells. Some approaches have been approved for clinical use, such as anti-GD2 antibodies. Moreover, in terms of the antitumor mechanisms against different TACAs, we show results of selected clinical trials, considering the horizons that have opened up as a result of recent developments in technologies used for cancer control.


Three-dimensional carbon network-supported black phosphorus-cobalt heterojunctions: An efficient electrocatalyst for high-rate oxygen evolution.
Black phosphorus (BP), as a burgeoning two-dimensional material, has shown good electrocatalytic activity due to its unique electronic structure and abundant active sites.However, the presence of lone pair electrons in black phosphorus leads to its poor stability and rapid degradation in an oxygen/water environment, which greatly limits its practical application. Herein, BP-Co heterojunctions were synthesized on carbon nanotube@nitrogen-doped carbon (BP-Co/CNT@NC) by the pyrolysis of ZnCo-zeolitic imidazolate frameworks and subsequent solvothermal treatment. The BP-Co Schottky junction improved the electrocatalytic stability of BP, modulated its electronic structure, improved its conductivity and electron transfer during the electrocatalytic reaction. Density functional theory calculation was used to confirm the electron transfer and redistribution at the interface between BP and Co, which constructed an oppositely charged region and formed a strong built-in field. Energy band configuration analysis revealed a narrowed band gap because of the formation of BP-Co Schottky junction. Consequently, the optimized BP-Co/CNT@NC exhibited a superior oxygen evolution reaction (OER) performance, a low overpotential of 370 mV@100 mA/cm2, with a small Tafel slope of 40 mV/dec and good long-term stability. Particularly, the catalyst has an excellent OER performance at the high current density of 100-400 mA/cm2. This strategy improves the stability of BP electrocatalysts and strengthens their utilization in electrocatalytic applications.


Electronic patient records: domain message information model perinatology.
The Netherlands is developing a set of national domain information models to support electronic information exchange and electronic patient records (EPR). These domain information models aim to support the development, adoption, implementation and maintenance of the EPR in Dutch healthcare practice. This article describes the modelling for a pilot for mother- and childcare (perinatology). Cases' from perinatology are modelled using the Health Level 7 version 3 Reference Information Model (HL7 RIM) as the methodology and tools. Results include descriptions of care processes, communication and information that are broken down into interaction tables and tables with information. Next several domain information models for perinatology are drawn up. These models allow healthcare professionals to recognise their communication, content and work. Currently, the models facilitate discussion and critique by clinician and informaticians. The perinatology domain information models facilitate in building implementations because they contain sufficient details for EPR developers and for developers of messages for information exchange. The first results of the project are useful, despite the fact that HL7 RIM modelling methodology is still not finalized. The approach bridges professional content, technical implementation of messages, and future EPR development.


Is persistent bacterial infection good for your health?
Certain bacterial pathogens have evolved to survive in their human hosts for long periods without causing harm. Is it possible that these persistent bacterial infections provide a protective benefit to the host?


Diastolic suction in the human ventricle: observation during balloon mitral valvuloplasty with a single balloon.
Diastolic suction has been demonstrated experimentally as a ventricular negative pressure when the ventricle is allowed to relax completely in the absence of filling, but it has not been extensively studied in the in vivo human heart. In balloon mitral valvuloplasty with a single balloon, the mitral orifice is occluded and inflow is considered to be completely obstructed during a balloon inflation. To demonstrate diastolic suction in the human ventricle, we measured left ventricular pressure during valvuloplasty with a high-fidelity catheter tip manometer in 17 patients. Left ventricular pressure fell below zero during a balloon inflation in all patients (-2 to -12 mm Hg). The peak negative diastolic pressure showed significant correlations with end-systolic volume index (r = 0.53, p = 0.03) and with the ejection fraction (r = 0.80, p = 0.0001). Thus diastolic suction was demonstrated in the human beating heart, and the sucking effect was potent in the heart with small end-systolic volume and high-ejection fraction.


The talonavicular and subtalar joints: the "calcaneopedal unit" concept.
The talonavicular (TN) joint and the three subtalar (ST) joints are linked anatomically and functionally. Together they form the subtalar joint complex, where movement occurs between the calcaneopedal unit (CPU) (entire foot except the talus) and the talotibiofibular unit (talus held tightly by the ankle mortise). Many are unaware of the TN joint's dual membership: it is a component of the subtalar joint complex (talocalcaneonavicular joint) and also the transverse tarsal joint (with the calcaneal-cuboid joint). The anatomy of the articulating surfaces, movement of the CPU when unloaded, shifts and changes in CPU shape with weight bearing, application to clinical tests and X-ray interpretation, and the pathophysiology applications to pes cavovarus, pes planovalgus and congenital talipes equinovarus (club foot) will be reviewed here. The CPU concept corresponds to a horizontal segmentation of the foot. This is a useful supplement to the two other segmentation methods: frontal (hindfoot, midfoot and forefoot) and sagittal (medial and lateral columns). This horizontal segmentation solves the issues with the ST joint complex, which straddles the hindfoot and midfoot, and also the issues with the dual membership of the TN joint. This concept makes it easier to understand foot deformities, better interpret the clinical and radiological signs and deduce logical treatments.


Double-network hydrogel enhanced by SS31-loaded mesoporous polydopamine nanoparticles: Symphonic collaboration of near-infrared photothermal antibacterial effect and mitochondrial maintenance for full-thickness wound healing in diabetes mellitus.
Diabetic wound healing has become a serious healthcare challenge. The high-glucose environment leads to persistent bacterial infection and mitochondrial dysfunction, resulting in chronic inflammation, abnormal vascular function, and tissue necrosis. To solve these issues, we developed a double-network hydrogel, constructed with pluronic F127 diacrylate (F127DA) and hyaluronic acid methacrylate (HAMA), and enhanced by SS31-loaded mesoporous polydopamine nanoparticles (MPDA NPs). As components, SS31, a mitochondria-targeted peptide, maintains mitochondrial function, reduces mitochondrial reactive oxygen species (ROS) and thus regulates macrophage polarization, as well as promoting cell proliferation and migration, while MPDA NPs not only scavenge ROS and exert an anti-bacterial effect by photothermal treatment under near-infrared light irradiation, but also control release of SS31 in response to ROS. This F127DA/HAMA-MPDA@SS31 (FH-M@S) hydrogel has characteristics of adhesion, superior biocompatibility and mechanical properties which can adapt to irregular wounds at different body sites and provide sustained release of MPDA@SS31 (M@S) NPs. In addition, in a diabetic rat full thickness skin defect model, the FH-M@S hydrogel promoted macrophage M2 polarization, collagen deposition, neovascularization and wound healing. Therefore, the FH-M@S hydrogel exhibits promising therapeutic potential for skin regeneration.


Deprescribing practices, habits and attitudes of geriatricians and geriatricians-in-training across Europe: a large web-based survey.
To provide an overview of the current deprescribing attitudes, practices, and approaches of geriatricians and geriatricians-in-training across Europe. An online survey was disseminated among European geriatricians and geriatricians-in-training. The survey comprised Likert scale and multiple-choice questions on deprescribing approaches and practices, deprescribing education and knowledge, and facilitators/barriers of deprescribing. Responses to the survey questions and participant characteristics were quantified and differences evaluated between geriatricians and geriatricians-in-training and between European regions. The 964 respondents (median age 42 years old; 64% female; 21% geriatricians-in-training) were generally willing to deprescribe (98%) and felt confident about deprescribing (85%). Despite differences across European regions, the most commonly reported reasons for deprescribing were functional impairment and occurrence of adverse drug reactions. The most important barriers for deprescribing were patients' unwillingness, fear of negative consequences, lack of time, and poor communication between multiple prescribers. Perceived risk of adverse drug reactions was highest for psychotropic drugs, nonsteroidal anti-inflammatory drugs, cardiovascular drugs, and opioid analgesics. Only one in four respondents (23% of geriatricians and 37% of geriatricians-in-training) think education in medical school had sufficiently prepared them for deprescribing in clinical practice. They reported that their future deprescribing activities would probably increase with improved information sharing between various prescribers, deprescribing recommendations in guidelines, and increased education and training. Approximately 90% think that a paradigm shift is required for prescribers and patients, increasing focus on the possible benefits of deprescribing (potentially) inappropriate medications. Based on the outcomes of this survey, we recommend investing in improved inter-professional communication, better education and evidence-based recommendations to improve future patient-centered deprescribing practices.


Technology for Diagnosis, Treatment, and Prevention of Cardiometabolic Disease in India.
Cardiometabolic diseases (CMD) are a major cause of mortality, morbidity and disability worldwide. Among Indians, CMD onset is at a much younger age and is prevalent in all sections of the society. Prevention, control and management of CMD and its risk factors is a major public health challenge, and alternative approaches need to be explored and integrated into public health programs. Advancements in the fields of computers, electronics, telecommunication and medicine have resulted in the rapid development of health-related technology. In this paper we provide an overview of the major technological advances in diagnosis, treatment and prevention within the field of CMD in the last few decades. This non-exhaustive review focuses on the most promising technologies that the authors feel might be of relevance in the Indian context. Some of the techniques detailed include advances in imaging and mobile phone technology, surgical techniques, electronic health records, Nano medicine, telemedicine and decision support systems.


Characterisation of anterior open bite in primary school-aged children: A preliminary study with artificial neural network analysis.
Non-nutritive sucking habits, bottle feeding, and facial hyperdivergency have been suggested as the influencing factors of anterior open bite (AOB). There was inconsistent reporting of prevalence and a gap of knowledge in the literature. The aim of this study was to investigate the prevalence of AOB in 7- to 12-year-olds, with a special interest to characterise the determinants of this malocclusion. A sample of 203 children aged 7 to 12 years were selected from a primary school in regional Australia. The legal guardian of each child completed a self-administered questionnaire. Data were assessed using methods of univariate statistics and neural analysis. The prevalence of AOB and thumb sucking was 24.1% and 23.2%, respectively. AOB was associated with the habit (correlation = 0.754) and duration (correlation = 0.574) of thumb sucking. Age, gender, birth order, feeding modality, sleep patterns, history of orthodontic treatment and tonsil, adenoid or grommet surgery, and parents' level of education were not related to AOB (correlation absolute value ≤ 0.474). Thumb sucking, specifically for prolonged duration, increases the risk of development of AOB. Cessation of thumb sucking habits should be encouraged at an early age to avoid the development of AOB.


The ecological risk of heavy metals in sediment from the Danube Delta.
The objectives of this study were to assess the sediment contamination with heavy metals and to investigate accordingly the ecological risk posed in the SE of the Danube Delta. Sediments are important in assessing the contamination as they act as reservoirs, transporters and contamination sources. Sediment samples were collected and analysed for lead, cadmium, arsenic and mercury, revealing levels higher than the background, especially for cadmium and mercury (Pb > As > Cd > Hg). Concentrations exceeding the probable effect limit were noticed for arsenic and mercury. The contamination indexes describe the study area as having almost half of the samples as contaminated (pollution load index-PLI 1.04), however the contamination is mostly low-to moderate (modified contamination degree-mCd 1.36). The sediment contamination poses mostly a low ecological risk (RI 94.8). The sediment quality guideline quotient (SQG-Q 0.29) describes a moderate impact, while the probable effect concentration quotient (PEC-Q 0.16) confirms that there are no levels likely to affect the aquatic biota. In our study area, the main Branch of the Danube River and the Secondary Delta are the most affected by contamination, while the narrow, reed abundant channels as the preferred habitat of most aquatic organisms, have a low contamination level.


Animal models of excessive alcohol consumption in rodents.
Numerous animal models have been developed to study excessive alcohol consumption in rodents. Use of such models has played a valuable role in elucidating biological underpinnings and environmental factors that mediate/promote excessive levels of alcohol drinking. A major obstacle in this work has been the need to overcome the natural tendency of rodents to either avoid alcohol or consume it in limited amounts that typically do not produce overt signs of intoxication. A variety of experimental approaches that entail modifying genetic and/or environmental factors have been employed to address this general problem and demonstrate excessive levels of alcohol consumption. Five different approaches that characterize animal models of excessive alcohol consumption are described: models that involve (a) scheduled access to alcohol; (b) scheduled periods of alcohol deprivation; (c) scheduled intermittent access to alcohol; (d) scheduled-induced polydipsia; and (e) dependence and withdrawal experience. Each of the models possesses unique experimental features that engender excessive levels of alcohol consumption. Both advantages and disadvantages for each model are described along with discussion of future challenges to be considered in developing more optimal models. Ultimately, the validity and usefulness of these models will lie in their ability to serve as a platform for studying biological underpinnings and environmental influences that drive increased motivation for alcohol seeking and consumption, as well as evaluation of treatment strategies that effectively reduce excessive levels of alcohol consumption.


Patients' substance abuse and the primary care physician: patterns of practice.
The Social Learning Theory concepts of self-efficacy and outcome expectations were used to study physician practice regarding patients' smoking, alcohol problems, OTC drug problems, and illicit drug use in a random sample of Texas primary care physicians. The highest proportion of physicians took histories and counseled patients regarding the abuse of cigarettes, followed by alcohol, OTC drugs, and illicit drugs. Outside referral was most likely for illicit drugs, followed by alcohol, OTC drugs, and smoking. Multivariate discriminant analysis showed year of graduation, specialty, self-efficacy, and outcome expectation for patient compliance to be predictive of many of the behavior/practice level combinations. More recently trained physicians, internists, and family practice specialists were more likely to practice in the substance abuse areas. Self-efficacy and outcome expectation were positively related to history-taking and counseling and negatively related to outside referral. Interventions to increase physicians' self-efficacy and expectations for patient compliance and to provide more realistic expectations for treatment "success" are needed, especially for physicians who are not recently trained. Further research to clarify the process by which physicians' cognitions of self-efficacy and outcome expectations influence their practice behavior is also recommended.


Activation of BCL1 cells by polyclonal activators and inhibition of growth and IgM secretion by anti-IgM.
Bacterial lipoprotein (LP) and lipopolysaccharide (LPS) both activated an in vitro line of the B-cell tumour BCL1 to IgM secretion, as determined by the protein A plaque assay. LPS but not LP activation was inhibited by polymyxin B. Activation with both LPS and LP resulted in a less than additive response. Several clones of BCL1 were tested, and all responded to both LPS and LP. Both LPS and LP induced broad dose-response curves in normal lymphocytes, recently cloned BCL1 cells, and cloned and synchronized (G1 phase) BCL1 cells. This suggests that the dose-response curve cannot be due to accumulation of responding cells with different threshold sensitivities for activation. We cannot exclude the possibility that the broad dose-response curve is due to a heterogeneity of the LPS or LP preparation. The results indicate that LPS and LP induce similar signals in BCL1 cells. Furthermore, binding to the cell membrane and activation of BCL1 cells by LPS or LP seem to be separate events. An anti-IgM antiserum inhibited spontaneous DNA synthesis and spontaneous and LP-induced IgM secretion of BCL1 cells. Equal inhibition was observed with F(ab')2 fragments but not with Fab fragments of the antiserum, suggesting that cross-linking of IgM bound to the cell surface membrane-induced inhibition. Supernatants from concanavalin A (Con A)-activated spleen cells induced BCL1 cells to secrete IgM. Fab anti-IgM added alone to BCL1 cells did not induce IgM secretion. Furthermore, Fab anti-IgM plus Con A supernatant did not induce a higher response than the supernatant alone. This suggests that inductive signals via the IgM receptor do not occur in BCL1 cells.


An update on glucose-6-phosphate dehydrogenase deficiency in children from Brazzaville, Republic of Congo.
Malaria transmission-blocking anti-malarial drugs, such as primaquine, offers an effective strategy for reducing the incidence of falciparum malaria. However, this drug induces haemolytic anaemia among glucose-6-phosphate dehydrogenase (G6PD) deficient individuals. The distribution of G6PD deficiency in Brazzaville, Republic of Congo and the association of G6PD deficiency with haemoglobin levels and blood cell counts were investigated. A total of 212 febrile children were recruited for this study. Plasmodium falciparum diagnosis was conducted by microscopy and nested PCR. Sanger sequencing was used to assess G6PD deficiency by detecting 202G>A (rs1050828) and 376A>G (rs1050829) single nucleotide polymorphisms. Two hundred and twelve children were successfully genotyped for G6PD variants. Overall, 13% (27/212) of the children were G6PD deficient and 25% (25/100) females were heterozygous (11 BA- and 14 A+A-). The remaining 160 children had a normal G6PD genotype. The mean red blood and mean platelet counts were significantly lower in hemizygous male (G6PD A-) participants than in normal male (G6PD A+ or B) participants (p < 0.05). This study gives an update on G6PD deficiency among Congolese children. Understanding the distribution of G6PD deficiency in other geographical regions is recommended before primaquine is adopted in the malaria control programme.


Development of a scanning microscopy by total internal reflection coupled with thermal lens spectroscopy.
Non-destructive measurement of a small region on a solid/liquid interface is of great importance in physical chemistry and biochemistry, especially in the research of thin films and cell membranes. Optical methods for surface analysis with high lateral resolution are suitable methods for monitoring them. We now report a new scanning optical microscopic method to which total internal reflection coupled with a thermal lens technique was introduced. Its lateral resolution was estimated both experimentally and theoretically. To experimentally estimate the resolution, the grid patterns of thin photoresist films with well-defined lateral structures were measured. The experimental resolution was about 45 microm, which was almost same as the diameter of the excitation beam at a glass/sample interface. From this result, it was verified that this new scanning microscopy ideally worked.


Dynamic Structural Brain Changes in Anorexia Nervosa: A Replication Study, Mega-analysis, and Virtual Histology Approach.
Several, but not all, previous studies of brain structure in anorexia nervosa (AN) have reported reductions in gray matter volume and cortical thickness (CT) in acutely underweight patients, which seem to reverse upon weight gain. The biological mechanisms underlying these dynamic alterations remain unclear. In this structural magnetic resonance imaging study, we first replicated and extended previous results in (1) a larger independent sample of 75 acutely underweight adolescent and young adult female patients with AN (acAN; n = 54 rescanned longitudinally after partial weight restoration), 34 weight-recovered individuals with a history of AN (recAN), and 139 healthy controls (HC); and 2) a greater combined sample compiled of both our previous samples and the present replication sample (120 acAN [90 rescanned longitudinally], 68 recAN, and 207 HC). Next, we applied a "virtual histology" approach to the combined data, investigating relations between interregional profiles of differences in CT and profiles of cell-specific gene expression. Finally, we used the ENIGMA toolbox to relate aforementioned CT profiles to normative structural and functional connectomics. We confirmed sizeable and widespread reductions of CT as well as volumes (and, to a lesser extent, surface area) in acAN and rapid increases related to partial weight restoration. No differences were detected between either short- or long-term weight-recovered patients and HC. The virtual histology analysis identified associations between gene expression profiles of S1 pyramidal cells and oligodendrocytes and brain regions with more marked differences in CT, whereas the remaining regions were those with a greater expression of genes specific to CA1 pyramidal, astrocytes, microglia, and ependymal cells. Furthermore, the most affected regions were also more functionally and structurally connected. The overall data pattern deviates from findings in other psychiatric disorders. Both virtual histology and connectomics analyses indicated that brain regions most affected in AN are also the most energetically demanding.


Kinetics and modeling of Pb (II) adsorption in pellet biochar based on micro-computed tomography characterization.
Biochar, a cost-effective adsorbent for the removal of heavy metals from aqueous solutions, has gained increasing attention. In this study, an advanced micro-computed tomography (micro-CT) system was used to investigate the adsorption kinetics by direct localization and visualization of Pb (II) on wheat straw pellet biochar. The normalized digital images indicating the dynamic changes of Pb (II) adsorption on biochar samples at different initial Pb (II) concentrations of 100, 200, 300, and 400 mg/L and adsorption times were obtained. It was found that image grayscale (GS) changes over adsorption time (t) followed the power function, GSe/GSt=2.45∗t-0.27. Based on this finding, modified pseudo-first-order (PFO) and pseudo-second-order (PSO) models incorporated with time-dependent kinetic constants kPFOt=KPFO∗GSe/GSt and kPSOt=KPSO∗GSe/GSt were proposed, resulting in a better interpretation of the adsorption mechanism. The micro-CT-guided novel approach demonstrated visual evidence-based superiority and should prove valuable to the existing body of research in related fields.


[CD44v and nm23-H1 gene product expression and its clinical significance in human recurrent bladder cancer].
To investigate the expression of the CD44v and nm23-H1 gene products and its clinical significance in human recurrent bladder cancer. The CD44v and nm23-H1 gene products in 45 cases of bladder cancer were analysed quantitatively by flow cytometry and cytoimmunofluorescence staining. The CD44v gene product overexpression and nm23-H1 gene product low expression were correlated with invasive extent and recurrence of bladder cancer (P < 0.05). The correlation coefficients between CD44v gene product and nm23-H1 gene product were gamma = -0.2876 in bladder cancer. The correlation coefficients between CD44v gene product and nm23-H1 gene product were gamma = -0.4238 in recurrent bladder cancer. The expression of CD44v and nm23-H1 gene product cooperated in growth and progress of bladder cancer. Both CD44v and nm23-H1 gene products were an objective indication of invasive extent and recurrence of bladder cancer.


Comparative Analysis of Pharmacokinetics and Metabolites of Three Main Terpenoids before and after Compatibility of Frankincense and Myrrh in Rats by UHPLC-MS.
3-acetyl-11-keto-beta-boswellic acid (AKBA) and 11-keto-boswellic acid (KBA) are the main active components of frankincense as pentacyclic triterpenoids, which are designated by the European Pharmacopoeia 8.0 as the quality standard for the evaluation of Indian frankincense, 2-methoxy-8,12-epoxygermacra- 1(10),7,11-trien-6-one (MCS134) is a non-volatile sesquiterpene compound in myrrh. In this paper, the absorption pharmacokinetics and metabolites of AKBA, KBA and MCS134 after frankincense, myrrh and their compatibility were analyzed, elaborated their absorption and metabolism mechanism and provided the ideas for the research on the bioactive components of frankincense and myrrh compatibility in vivo. The area under the blood concentration time curve (AUC), half-life (t1/2) and drug clearance (CL) of AKBA, KBA and MCS134 in rats were analyzed by LC-TQ / MS. The metabolites of AKBA, KBA and MCS134 in rats were analyzed by ultra-high pressure liquid chromatography with a linear ion trap-high resolution Orbitrap mass spectrometry system (UHPLC-LTQ-Orbitrap-MS). The results showed that AKBA, KBA and MCS134 reached the maximum plasma concentration at about 2 h, 2 h and 15 min, respectively. AUC0-t and t1/2 of the three components increased in varying degrees after compatibility, and the clearance/ bioavailability (CL/F) decreased. AKBA, KBA and MCS134 were metabolized in phase I and phase II in rats, and there represented differences before and after compatibility. After the compatibility of frankincense and myrrh, the absorption of effective components was improved to some extent, and there were some differences in the metabolites in rats. The results provide ideas for elucidating the in vivo effect mechanism of frankincense and myrrh.


The role of brain-derived neurotrophic factor in the regulation of cell growth and gene expression in melanotrope cells of Xenopus laevis.
Brain-derived neurotrophic factor (BDNF) is, despite its name, also found outside the central nervous system (CNS), but the functional significance of this observation is largely unknown. This review concerns the expression of BDNF in the pituitary gland. While the presence of the neurotrophin in the mammalian pituitary gland is well documented its functional significance remains obscure. Studies on the pars intermedia of the pituitary of the amphibian Xenopus laevis have shown that BDNF is produced by the neuroendocrine melanotrope cells, its expression is physiologically regulated, and the melanotrope cells themselves express receptors for the neurotrophin. The neurotrophin has been shown to act as an autocrine factor on the melanotrope to promote cell growth and regulate gene expression. In doing so BDNF supports the physiological function of the cell to produce and release α-melanophore-stimulating hormone for the purpose of adjusting the animal's skin color to that of its background.


A quantitative analysis of human astrocytosis.
The number of astrocytes in an atrophic human brain was counted with the aid of immunohistochemistry for glial fibrillary acidic protein. Microscopically, astrocytosis was remarkable in the cerebral neocortex and white matter. Taking the cortical atrophy into consideration, however, the total number of astrocytes in the cortical layers II-VI was not increased. The number of astrocytes in the white matter was not increased either. It is indicated that astrocytosis does not always mean hyperplasia (net increase of total number) of astrocytes.


Computer-aided prostate cancer detection using texture features and clinical features in ultrasound image.
In this paper, we propose a new prostate detection method using multiresolution autocorrelation texture features and clinical features such as location and shape of tumor. With the proposed method, we can detect cancerous tissues efficiently with high specificity (about 90-95%)and high sensitivity (about 92-96%) by the measurement of the number of correctly classified pixels. Multiresolution autocorrelation can detect cancerous tissues efficiently, and clinical knowledge helps to discriminate the cancer region by location and shape of the region and increases specificity. The support vector machine is used to classify tissues based on those features. The proposed method will be helpful in formulating a more reliable diagnosis, increasing diagnosis efficiency.


A facile approach to the scalable preparation of thermoplastic/carbon nanotube composites.
Disentangling and dispersing multiwalled carbon nanotubes (MWCNTs) in thermoplastics by the existing melt compounding facilities where neither solvent nor liquid chemicals are allowed remains a great challenge. This challenge is addressed herein by combining ball milling with melt compounding. Specifically, ball milling is applied to disentangle MWCNTs and to eventually liberate each tube from agglomeration, and then the tubes are melt compounded with SSFs (PA6). A uniformly distributed MWCNT network is observed; obvious load transfer from the matrix to the tubes is evidenced by the presence of many firmly embedded tubes on the fracture surface. The electrical conductivity percolation threshold of PA6/MWCNT composites is found to be 2.5-3.0 wt%, in comparison with 5.0-8.0 wt% for PA6/stainless steel fiber composites. The PA6/MWCNT composite at 10.0 wt% shows a 76% increase in flexural modulus and 58% in flexural strength.


Some synaptic inputs and ascending projections of lateralis posterior thalamic neurons.
(1) Some synaptic inputs and telencephalic targets of lateralis intermedius-lateralis posterior (LI-LP) thalamic neurons have been investigated in the encéphale isolé cat by recording extracellular unit discharges and focal slow waves following stimulation of cortical areas 5 and 7, center median (CM) thalamic nucleus and mesencephalic reticular formation (RF). (2) Orthodromic and/or antidromic discharges in LI-LP neurons following anterior suprasylvian stimulation are electrophysiological evidence of thalamocortical reciprocal pathway in this "association" system. A few neurons were backfired from several cortical stimulated foci at different latencies, thus suggesting the existence of LI-LP output cells with branching axons. The numerous cases of cortically elicited synaptic excitation in LI-LP cells, taken together with evidence of an unexpectedly high proportion of corticothalamic neurons found in parallel experiments of this laboratory on areas 5 and 7, support the suggestion that complex functions of the "association" cortex partially depend on its downstrem connections with thalamic integrative structures. (3) Monosynaptic and oligosynaptic excitatory projections link the brain stem reticular core with LI-LP nuclear group. For some neurons, this is a high-security pathway as shown by the ability of thalamic cells to follow at short latencies fast repetitive reticular shocks. The RF-elicited phasic excitation is followed by a period of suppressed spontaneous and evoked discharge. The excitatory projections from the upper brain stem RF to the LI-LP nuclei are discussed in relation to disfacilitatory phenomena in thalamocortical systems due to withdrawal of reticulofugal ascending activation at sleep onset.


Generalizability assessment of COVID-19 3D CT data for deep learning-based disease detection.
Artificial intelligence technologies in classification/detection of COVID-19 positive cases suffer from generalizability. Moreover, accessing and preparing another large dataset is not always feasible and time-consuming. Several studies have combined smaller COVID-19 CT datasets into "supersets" to maximize the number of training samples. This study aims to assess generalizability by splitting datasets into different portions based on 3D CT images using deep learning. Two large datasets, including 1110 3D CT images, were split into five segments of 20% each. Each dataset's first 20% segment was separated as a holdout test set. 3D-CNN training was performed with the remaining 80% from each dataset. Two small external datasets were also used to independently evaluate the trained models. The total combination of 80% of each dataset has an accuracy of 91% on Iranmehr and 83% on Moscow holdout test datasets. Results indicated that 80% of the primary datasets are adequate for fully training a model. The additional fine-tuning using 40% of a secondary dataset helps the model generalize to a third, unseen dataset. The highest accuracy achieved through transfer learning was 85% on LDCT dataset and 83% on Iranmehr holdout test sets when retrained on 80% of Iranmehr dataset. While the total combination of both datasets produced the best results, different combinations and transfer learning still produced generalizable results. Adopting the proposed methodology may help to obtain satisfactory results in the case of limited external datasets.


Differential production of metalloproteinases after instilling various urban air particle samples to rat lung.
Lung injury and inflammation are associated with exposure to various types of particulate air pollutants. The present study was used to determine whether metalloproteinases (MMPs) are secreted after instilling dust samples into the lung, and to relate levels of specific MMPs to different fractions of the ambient air particle sample EHC-93. Rats received an intratracheal injection of 5 mg dust samples in 0.5 ml water and were killed at intervals from 4 hours to 28 days later particle samples were EHC-93 whole dust, and the insoluble, leached, and soluble fractions of the same dust. Samples prepared from EHC-2K dust were also used, as were solutions of zinc and copper chloride. All samples induced inflammation as measured by increased inflammatory cells in bronchoalveolar lavage (BAL) fluid; the highest levels were found 1 to 3 days after instilling the whole dust. This dust also induced production of MMP-2 and MMP-9 as shown in zymograms. The leached dust induced predominantly MMP-9, which was maximal at 4 hours and 1 day. In contrast, the soluble fraction induced almost exclusive 4 MMP-2, also maximal at 4 hours and 1 day; this enzyme was also produced in response to soluble zinc, the most prevalent soluble metal in the EHC samples. The results demonstrate the rapid production and secretion of MMPs in the lung after particle deposition. A differential pattern of MMP production is seen with MMP-9, likely from inflammatory cells, being produced in response to the insoluble particles, and MMP-2, likey from epithelial cells, being produced in response to the water-soluble fraction of the atmospheric dust.


Sinapic acid alleviates 5-fluorouracil-induced nephrotoxicity in rats via Nrf2/HO-1 signalling.
Fluoropyrimidine 5-fluorouracil (5-FU) is a DNA analogue broadly used in chemotherapy, though treatment-associated nephrotoxicity limits its widespread clinical use. Sinapic acid (SA) has potent antioxidant, anti-inflammatory, and anti-apoptotic effects, we investigated its protective effects against 5-FU-induced nephrotoxicity in a rat model. We designated four treatment groups each Group I (control) received five intraperitoneal saline injections (once daily) from days 17 to 21; Group II received five intraperitoneal injections of 5-FU (50 mg/kg/day) from days 17 to 21; Group III received an oral administration of SA (40 mg/kg) for 21 days and five intraperitoneal injections of 5-FU (50 mg/kg/day) from days 17 to 21; and Group IV received an oral administration of SA (40 mg/kg) for 21 days (n-six rats in each group). blood samples were collected on day 22 from each group. Animals were sacrificed and their kidneys removed, and instantly frozen. 5-FU caused oxidative stress, inflammation, and activation of the apoptotic pathway by upregulating Bax and Caspase-3 and downregulating Bcl-2. However, SA exposure reduced serum toxicity indicators, boosted antioxidant defences, and reduced kidney apoptosis, which was confirmed by histopathological analysis. Therefore, prophylactic administration of SA could inhibit 5-FU-induced renal injuries in rats via suppression of renal inflammation and oxidative stress, primarily through regulation of NF-κB and proinflammatory cytokines, inhibition of renal apoptosis, and restoration of tubular epithelial antioxidant activities and cytoprotective defences.


Apixaban: An Optimal Agent for the Treatment of Cancer-Associated Venous Thromboembolism?
Apixaban, a direct inhibitor of activated coagulation factor X (FXaI), is being frequently selected for treatment and prevention of venous thromboembolism (VTE). Several reports about possible use of oral FXaI in patients with cancer-associated VTE (CA-VTE) have been published recently. The efficacy/safety profile of oral FXaI anticoagulation in patients with CA-VTE seems promising; however, several problems remain unanswered. The pharmacologic profile of apixaban could prefer this agent for the treatment of CA-VTE. Currently available medical literature was searched and reviewed to summarize data regarding the use of apixaban for the prevention and treatment of cancer-associated VTE. Apixaban therapy in patients with cancer and VTE is expected to increase as clinicians gain more experience and reassurance with data from real-world studies that are generally promising. Several studies demonstrated that apixaban exhibits noninferiority to warfarin and low molecular weight heparin in preventing recurrent thrombosis in cancer-associated VTE. Nevertheless, there are still concerns regarding the bleeding associated with apixaban therapy, and regarding the optimal management of these bleeding emergencies. Although currently available evidence confirms the noninferiority of apixaban for reduction of the risk of recurrent VTE in patients with cancer; there are still concerns regarding the safety, especially in selected subpopulations of these patients.


Fluid Flow Induced Calcium Response in Bone Cell Network.
In our previous work, bone cell networks with controlled spacing and functional intercellular gap junctions had been successfully established by using microcontact printing and self assembled monolayers technologies [Guo, X. E., E. Takai, X. Jiang, Q. Xu, G. M. Whitesides, J. T. Yardley, C. T. Hung, E. M. Chow, T. Hantschel, and K. D. Costa. Mol. Cell. Biomech. 3:95-107, 2006]. The present study investigated the calcium response and the underlying signaling pathways in patterned bone cell networks exposed to a steady fluid flow. The glass slides with cell networks were separated into eight groups for treatment with specific pharmacological agents that inhibit pathways significant in bone cell calcium signaling. The calcium transients of the network were recorded and quantitatively evaluated with a set of network parameters. The results showed that 18α-GA (gap junction blocker), suramin (ATP inhibitor), and thapsigargin (depleting intracellular calcium stores) significantly reduced the occurrence of multiple calcium peaks, which were visually obvious in the untreated group. The number of responsive peaks also decreased slightly yet significantly when either the COX-2/PGE(2) or the NOS/nitric oxide pathway was disrupted. Different from all other groups, cells treated with 18α-GA maintained a high concentration of intracellular calcium following the first peak. In the absence of calcium in the culture medium, the intracellular calcium concentration decreased slowly with fluid flow without any calcium transients observed. These findings have identified important factors in the flow mediated calcium signaling of bone cells within a patterned network.


Leveraging Rules of Nonsense-Mediated mRNA Decay for Genome Engineering and Personalized Medicine.
Nonsense-mediated mRNA decay (NMD) is a eukaryotic mRNA quality control and regulatory process that plays direct roles in human health and disease. In this Minireview, we discuss how understanding the molecular events that trigger NMD can facilitate strategic targeting of genes via CRISPR/Cas9 technologies and also inform disease diagnostics and treatments.


Roles of bladder distension, urinary pH and urinary sodium ion concentration in cell proliferation of urinary bladder epithelium in rats ingesting sodium salts.
The relative importance of bladder distension, urinary pH and sodium ion concentration for cell proliferation in the bladder epithelium of rats fed various sodium salts was investigated. When a diet containing 5% NaHCO3 was fed to male rats, the bladder epithelium showed an increase in replicating cells, together with distension, increased urine pH and high urine sodium ion concentration. Cell proliferation also occurred when bladders were subjected to distension in vivo by mechanical (female) or physiological (male) means. Inclusion of CaCO3 in the diet produced high urinary pH without alteration in the other factors and did not induce cell proliferation. Increased proliferation occurred when CaCO3 was combined with these mechanical or physiological treatments. Thus, high urinary pH was of secondary importance to bladder distension as a causative factor, but acted to enhance cell proliferation when distension occurred. Similar findings were obtained with regard to sodium ion concentration. In conclusion, this study demonstrated that bladder distension is one of the prerequisites for promoter-induced cell proliferation in the bladder epithelium, with high urinary pH and sodium ion concentration.


Changes in corneal high order aberrations and anterior chamber parameters following scleral fixated intraocular lens implantation.
To evaluate the change in corneal high order aberrations (HOAs) and anterior chamber parameters following scleral fixation in aphakic patients using the Scheimpflug camera system. This retrospective study included patients who were aphakic after phacoemulsification surgery and underwent scleral-fixed intraocular lens (SF-IOL) implantation with Z suture technique between 2010 and 2022. Preoperative and postoperative best corrected visual acuity (BCVA), anterior segment parameters and corneal aberrations were evaluated with a combined Scheimpflug-Placido disk corneal topography device (Sirius Costruzione Strumenti Oftalmici, Florence, Italy). The following values were recorded: Simulated keratometry (SimK), flat meridian (K1), steep meridian (K2), iridocorneal angle (ICA), temporal anterior chamber angle (T-ACA), nasal anterior chamber angle (N-ACA), horizontal anterior chamber diameter (HACD), anterior chamber volume (ACV), corneal volume (CV), total Root Mean Square (RMS), high order aberrations (HOAs), spherical aberration, coma, trefoil, quadrifoil, and secondary astigmatism. The study included 31 eyes of 31 patients (mean age: 63.00 ± 19.41 years, 17 males/14 females). Postoperative BCVA was better than preoperative BCVA (p = 0.012). Postoperatively, there was a statistically significant increase in ACV and CV values and a statistically significant decrease in K2 (p = 0.009, p = 0.032, p = 0.015). Preoperative T-ACA and preoperative and postoperative ACV were negatively correlated with postoperative intraocular pressure (r=-0.427 p = 0.033, r=-0.406 p = 0.032 and r=-0.561 p = 0.001). There were statistically significant postoperative increases in corneal RMS, trefoil and HOAs for 3 mm pupil diameter (p = 0.0177, p = 0.001, p = 0.031) and in corneal RMS, trefoil and quadrifoil aberrations for 6 mm pupil diameter (p = 0.033, p = 0.001, p = 0.001). In conclusion, SF-IOL implantation with Z-suture technique used for visual rehabilitation of aphakic patients may affect visual quality by increasing corneal HOAs while improving visual acuity.


Peritoneal implantation of endodermal sinus tumor of the pineal region via a ventriculoperitoneal shunt. Cytodiagnosis with immunocytochemical demonstration of alpha-fetoprotein.
A 17-year-old male developed an endodermal sinus tumor in the pineal region that metastasized to the peritoneal cavity via a ventriculoperitoneal shunt and caused ascites. Neoplasm was diagnosed by cytologic examination of the peritoneal fluid, and the precise histologic nature of the neoplasm was confirmed by immunocytochemistry, which demonstrated alpha-fetoprotein in the neoplastic cells.


Phosphorylation of the Ca2+ pump intermediate in intact red cells, isolated membranes and inside-out vesicles.
Ca2+-entry into intact red cells containing [32P]-ATP increases the phosphorylation of the 150 000 dalton polypeptide of the membrane. This phosphorylation occurs even in Mg2+-depleted red cells. Extracellular lanthanum applied during ATP-depletion further increases the Ca2+-induced phosphorylation. In fragmented membranes or resealed insideout vesicles (IOVs) membrane bound Mg2+ is sufficient to catalyze the phosphorylation of spectrin 2 and Band 3 polypeptides with low concentrations (less than micron of [32P]-ATP. In Ca-EDTA buffers one single polypeptide is phosphorylated which is located in the 150 000 molecular weight region. KmCa for phosphorylation is much lower (0.2 micron) than for active Ca2+ transport (40 micron) in IOVs. Lanthanum induced phosphorylation (up to 250 micron Lafree) is significantly greater than Ca2+-induced phosphorylation. Hg2+ inhibits both Ca2+ and La3+ induced phosphorylation. Ca2+-induced labelling can be rapidly "chased" by unlabelled ATP+Mg2+, but not with EGTA+Mg2+. Dephosphorylation in Ca2+ phosphorylated membranes and IOVs is significantly inhibited by La3+. It can be concluded that the mechanism of La3+ and Hg2+ inhibition of the Ca2+ pump is different in intact cells and isolated membranes or Iovs.


Establish an allele-specific real-time PCR for Leishmania species identification.
Leishmaniasis is a serious neglected tropical disease that may lead to life-threatening outcome, which species are closely related to clinical diagnosis and patient management. The current Leishmania species determination method is not appropriate for clinical application. New Leishmania species identification tool is needed using clinical samples directly without isolation and cultivation of parasites. A probe-based allele-specific real-time PCR assay was established for Leishmania species identification between Leishmania donovani and L. infantum for visceral leishmaniasis (VL) and among L. major, L. tropica and L. donovani/L. infantum for cutaneous leishmaniasis (CL), targeting hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and spermidine synthase (SPDSYN) gene with their species-specific single nucleotide polymorphisms (SNPs). The limit of detection of this assay was evaluated based on 8 repeated tests with intra-assay standard deviation < 0.5 and inter-assay coefficients of variability < 5%. The specificity of this assay was tested with DNA samples obtained from Plasmodium falciparum, Toxoplasma gondii, Brucella melitensis and Orientia tsutsugamushi. Total 42 clinical specimens were used to evaluate the ability of this assay for Leishmania species identification. The phylogenetic tree was constructed using HGPRT and SPDSYN gene fragments to validate the performance of this assay. This new method was able to detect 3 and 12 parasites/reaction for VL and CL respectively, and exhibited no cross-reaction with P. falciparum, T. gondii, B. melitensis, O. tsutsugamushi and non-target species of Leishmania. Twenty-two samples from VL patients were identified as L. donovani (n = 3) and L. infantum (n = 19), and 20 specimens from CL patients were identified as L. major (n = 20), providing an agreement of 100% compared with sequencing results. For further validation, 29 sequences of HGPRT fragment from nine Leishmania species and 22 sequences from VL patients were used for phylogenetic analysis, which agreed with the results of this new method. Similar results were obtained with 43 sequences of SPDSYN fragment from 18 Leishmania species and 20 sequences from CL patients. Our assay provides a rapid and accurate tool for Leishmania species identification which is applicable for species-adapted therapeutic schedule and patient management.


Signals at the bacteriophage phi 29 DNA replication origins required for protein p6 binding and activity.
Protein p6 of Bacillus subtilis phage phi 29 binds specifically to the ends of the viral DNA that contain the replication origins, giving rise to a nucleoprotein structure. DNA regions recognized by protein p6 have been mapped by deletion analysis and DNase I footprinting. Main protein p6-recognition signals have been located between nucleotides 62 and 125 at the right phi 29 DNA end and between nucleotides 46 and 68 at the left end. In addition, recognition signals are also present at other sites within 200-300 bp at each phi 29 DNA end. Protein p6 does not seem to recognize a specific sequence in the DNA, but rather a structural feature, which could be bendability. The formation of the protein p6-DNA nucleoprotein complex is likely to be the structural basis for the protein p6 activity in the initiation of replication.


Development and validation of MRI-based radiomics signatures models for prediction of disease-free survival and overall survival in patients with esophageal squamous cell carcinoma.
To develop and validate an optimal model based on the 1-mm-isotropic-3D contrast-enhanced StarVIBE MRI sequence combined with clinical risk factors for predicting survival in patients with esophageal squamous cell carcinoma (ESCC). Patients with ESCC at our institution from 2015 to 2017 participated in this retrospective study based on prospectively acquired data, and were randomly assigned to training and validation groups at a ratio of 7:3. Random survival forest (RSF) and variable hunting methods were used to screen for radiomics features and LASSO-Cox regression analysis was used to build three models, including clinical only, radiomics only and combined clinical and radiomics models, which were evaluated by concordance index (CI) and calibration curve. Nomograms and decision curve analysis (DCA) were used to display intuitive prediction information. Seven radiomics features were selected from 434 patients, combined with clinical features that were statistically significant to construct the predictive models of disease-free survival (DFS) and overall survival (OS). The combined model showed the highest performance in both training and validation groups for predicting DFS ([CI], 0.714, 0.729) and OS ([CI], 0.730, 0.712). DCA showed that the net benefit of the combined model and of the clinical model is significantly greater than that of the radiomics model alone at different threshold probabilities. We demonstrated that a combined predictive model based on MR Rad-S and clinical risk factors had better predictive efficacy than the radiomics models alone for patients with ESCC. • Magnetic resonance-based radiomics features combined with clinical risk factors can predict survival in patients with ESCC. • The radiomics nomogram can be used clinically to predict patient recurrence, DFS, and OS. • Magnetic resonance imaging is highly reproducible in visualizing lesions and contouring the whole tumor.


Investigation of the Chemical Composition, Antimicrobial, and Antioxidant Activity of Endemic Onosma halophila Boiss. & Heldr.
The Onosma halophila Boiss. & Heldr. belongs to the Boraginaceae family and it is endemic species from Turkey that distributes in Salt Lake (Tuz Gölü) and the surrounding salty steppes. In this study, the chemical content, antimicrobial, and antioxidant activity of endemic O. halophila were determined for the first time. Thirty-one components were identified by GC-MS analysis in O. halophila. Antimicrobial activity was tested against a total of eight microorganisms, including three Gram-positive, three Gram-negative bacterial strains, and two fungal strains, using the Micro dilution technique. The obtained extracts showed strong antifungal and antibacterial activity. The MIC value of extracts samples against the tested strains ranged from 15.625 to 125 μg/mL. In addition, it was determined that the extracts had different levels of antioxidant activity. The IC50 values were determined 45.20-1760 µg/mL for DPPH radical scavenging assay, 3.125-1016 µg/mL for H2O2 radical scavenging assay, and 147.12-1837 µg/mL for superoxide radical scavenging assay, respectively. As a result, it has been determined that O. halophila has the potential to be used in complementary medicine and various ethnobotanical fields in future due to the important components it contains.


Undergraduate experience of surgical teaching and its influence and its influence on career choice.
The purpose of this survey was to determine the views of final year medical students in Melbourne regarding both undergraduate surgical teaching and the students' career aspirations. A structured questionnaire was given to all final year medical students at Monash and Melbourne Universities in 2003. The questions dealt with the factors influencing graduating medical students, including theatre experience, encouragement/support from surgeons, presence of mentors, lifestyle factors and gender issues. The response rate was 61.2% (251/410). Of these, 50.6% were male, 32.3% declared an interest in surgical training with the remainder either uncertain (24%) or uninterested (44%). Male students were more likely to be interested in surgery. General surgery was the most popular field (69%), followed by plastic surgery (37%) and orthopaedic surgery (35%). Of respondents, 78% reported positive influences towards pursuing a surgical career during their undergraduate years, while 63% reported a negative experience. A total of 67% believed that the current curriculum is adequate and 43% that there is enough support/encouragement towards a surgical career. Only 44% of respondents reported that surgeons are approachable. Lifestyle and family factors were the most important career influence. In particular, 57% of female respondents felt discouraged from pursuing a surgical career and 99% of these women reported lifestyle/family factors as the main source of discouragement, with a further 72% identifying a lack of female role models. This survey highlights important issues in current undergraduate perception of surgical teaching and higher training. Issues that may encourage or discourage a graduating student to pursue a surgical career are identified.


Clinical profile and risk factors of recurrent pneumonia in children at Qena governorate, Egypt.
There is a scarce research study on recurrent pneumonia in children, particularly in the developing world. This study aimed to analyse the clinical characteristics, risk factors and underlying causes of recurrent pneumonia in children. It was a case-control study involved 87 children with ≥2 episodes of radiographically confirmed pneumonia in a single year or ≥3 episodes at any time with a radiographic clearing of densities between attacks. Controls were 87 age and gender-matched children who had never suffered pneumonia. Demographic and clinical characteristics of patients and controls were compared and evaluated for the detection of possible underlying conditions that may be the incriminated risk factor of pneumonia recurrence. During one-year study, 763 patients were admitted with pneumonia and 87 (11.4%) of them met the definition of recurrent pneumonia. There were 48 (55.2%) males and 39 (44.8%) females. The mean age at diagnosis of recurrent pneumonia was 7.15 ± 1.72 years. Prematurity, small birth weight and presence of respiratory distress at birth were significantly different between patients and controls. Aspiration, congenital heart disease, gastroesophageal reflux, oro-motor incoordination, wheezing and asthma were significant risk factors for recurrent pneumonia. Our study showed that 11.40% of children with pneumonia had recurrent form and that most of them had an underlying illness. The most common detected risk factors for recurrent pneumonia were rural residence, low socioeconomic standard, over-crowding, prematurity and presence of respiratory distress at birth. Aspiration, congenital heart diseases, wheezing and asthma were found to be the main underlying illnesses associated with pneumonia recurrences.


The use of in vitro maturation in stimulated antagonist in vitro fertilization cycles of normo-hyperresponder women due to arrested follicular development: A rescue procedure.
To evaluate the impact of rescue in vitro maturation (IVM) on the clinical outcomes of women with arrested follicular development in stimulated in vitro fertilization (IVF) cycles. This is a retrospective review of 13 patients who were evaluated as normo-hyperresponders for ovarian stimulation. The main outcome measure was the clinical pregnancy and livebirth rates. The purpose of gonadotropin stimulation in patients undergoing IVF is to retrieve multiple oocytes by avoiding multifetal gestation and Ovarian Hyperstimulation syndrome (OHSS). The ovarian response to stimulation ranges from poor response to OHSS, which is related to the follicular number and the dose of the gonadotropins used. However, in some cycles of normo-hyperresponder women, follicular development decelerates or ceases. Close follow-up in a daily manner and increasing the dose of gonadotropins did not change the follicular arrest. This clinical situation has two edges; one is cycle cancellation, which has undesired psychological outcomes for women and the IVF team, and second one is the prolongation of the IVF cycle. For such circumstances, IVM may be a valuable option. Stimulated IVF cycles were converted to IVM as a rescue IVM procedure following detailed informed consent of the women who were close to cycle cancellation. Thirteen 13 IVM cycles and their clinical outcomes are presented. Six women achieved pregnancies, but only 4 delivered 5 healthy live born. The other two women had biochemical loss during follow-up. Based on the data obtained, it can be concluded that gonadotropin-stimulated cycles with follicular arrest at the edge of cancellation can be shifted to rescue IVM procedures with reasonable clinical outcomes.


Alteration of neonatal rat parotid gland acinar cell proliferation by guandethidine-induced sympathectomy.
Newborn rats were injected with guanethidine-sulfate (20 micrograms/g body weight) every 48 hr from 12 hr after birth until day 14 (eight injections per animal). The guanethidine treatment resulted in an 86% absolute reduction in cell number in the superior cervical ganglia of 15 day old rats. The cells which remained after guanethidine treatment showed destruction of mitochondria and an extensive decrease in endoplasmic reticulum. Chemical sympathectomy with guanethidine induced a 3.1 hr lengthening of the acinar cell generation cycle time (17.4 hr to 20.5 hr), resulting from a longer G1 period (6.9 hr in the control group as compared to 10.5 hr in the guanethidine-treated group), as well as a cecrease in the mean percentage of [3H]thymidine-labeled acinar cells (22.3 +/- 0.5% to 19.3 +/- 0.5%) and mean acinar cell mitotic index (2.6 +/- 0.2% to 2.1 +/- 0.1%). A circadian rhythm was found to exist in parotid gland acinar cell mitotic activity of 15 day old rats and the amplitude of the rhythm was reduced from 26.5% to 14.9% in guanethidine-treated rats. This study indicates that the diminution of sympathetic influence on the developing parotid gland results in a slight, but significant alteration in acnar cell proliferation.


Bmi1 counteracts hematopoietic stem cell aging by repressing target genes and enforcing the stem cell gene signature.
Polycomb-group proteins are critical regulators of stem cells. We previously demonstrated that Bmi1, a component of polycomb repressive complex 1, defines the regenerative capacity of hematopoietic stem cells (HSCs). Here, we attempted to ameliorate the age-related decline in HSC function by modulating Bmi1 expression. The forced expression of Bmi1 did not attenuate myeloid-biased differentiation of aged HSCs. However, single cell transplantation assays revealed that the sustained expression of Bmi1 augmented the multi-lineage repopulating capacity of aged HSCs. Chromatin immunoprecipitation-sequencing of Bmi1 combined with an RNA sequence analysis showed that the majority of Bmi1 direct target genes are developmental regulator genes marked with a bivalent histone domain. The sustained expression of Bmi1 strictly maintained the transcriptional repression of their target genes and enforced expression of HSC signature genes in aged HSCs. Therefore, the manipulation of Bmi1 expression is a potential approach against impairments in HSC function with aging.


The protective effects of β-cryptoxanthin on inflammatory bone resorption in a mouse experimental model of periodontitis.
We examined the effects of β-cryptoxanthin, a typical carotenoid, on inflammatory periodontitis. β-Cryptoxanthin suppressed lipopolysaccharide (LPS)-induced osteoclast formation in co-cultures of bone marrow cells and osteoblasts. In a mouse model of periodontitis, it suppressed bone resorption in the mandibular alveolar bone in vitro and restored alveolar bone loss induced by LPS in vivo. β-Cryptoxanthin might protect against periodontal disease.


Crystal structure of μ-oxalodi-hydroxamato-bis-[(2,2'-bipyrid-yl)(di-methyl sulfoxide-κO)copper(II)] bis-(perchlorate).
The centrosymmetric binuclear complex, [Cu2(C2H2N2O4)(C10H8N2)2(C2H6OS)2](ClO4)2, contains two copper(II) ions, connected through an N-deprotonated oxalodi-hydroxamic acid dianion, two terminal 2,2'-bi-pyridine ligands, and two apically coordinating dimethylsulfoxide mol-ecules. Two non-coordinating perchlorate anions assure electrical neutrality. The copper(II) ions in the complex dication [Cu2(C10H8N2)2(μ-C2H2N2O4)(C2H6SO)2](2+) are in an O2N3 square-pyramidal donor environment, the Cu-Cu separation being 5.2949 (4) Å. Two hydroxamate groups in the deprotonated oxalodi-hydroxamic acid are located trans to one each other. In the crystal, O-H⋯O and C-H⋯O hydrogen bonds link the complex cations to the perchlorate anions. Further C-H⋯O hydrogen bonds combine with π-π contacts with a centroid-to-centroid separation of 3.6371 (12) Å to stack the mol-ecules along the a-axis direction.


Eukaryotic DNA replication.
Recent discoveries suggest that the initiation of eukaryotic DNA replication involves at least two steps--one occurring near the completion of mitosis and the other at the onset of S phase--that bring about the ordered assembly of initiator proteins at the origin. The identification and characterization of components involved in promoting or antagonizing each of these steps has provided a preliminary understanding of how replication initiation is regulated so precisely during the cell cycle.


Marine debris ingestion in loggerhead sea turtles, Caretta caretta, from the Western Mediterranean.
Marine debris represents an important threat for sea turtles, but information on this topic is scarce in some areas, such as the Mediterranean sea. This paper quantifies marine debris ingestion in 54 juvenile loggerhead sea turtles (Caretta caretta) illegally captured by fishermen in Spanish Mediterranean waters. Curved carapace length was measured, necropsies were performed and debris abundance and type was recorded. Different types of debris appeared in the gastrointestinal tract of 43 turtles (79.6%), being plastics the most frequent (75.9%). Tar, paper, Styrofoam, wood, reed, feathers, hooks, lines, and net fragments were also present. A regression analysis showed that the volume of debris increased proportionally to the size of the turtles. The high variety of debris found and the large differences in ingestion among turtles indicated low feeding discrimination of this species that makes it specially prone to debris ingestion. Our data suggest that more severe control of litter spills and greater promotion of environmental educational programmes are needed in the Western Mediterranean.


Direct treatment of fetal supraventricular tachycardia after failed transplacental therapy.
Digitalization by direct intramuscular injection of the fetus successfully controlled supraventricular tachycardia at 24 weeks' gestation after more traditional intensive trials of transplacental therapy with digoxin, verapamil, and procainamide, either separately or in combination, had failed. The fetal pharmacokinetics were calculated from fetal blood samples obtained by cordocentesis. No clear evidence of placental transfer of digoxin administered to the mother could be found despite a digoxin concentration in the mother that ranged from 1.8 to 2.6 ng/ml for 4 days. After direct fetal digitalization we calculated that the coefficient of elimination for digoxin from the fetus was 0.0463 h-1, and digoxin elimination half-life was 15.9 hours. The latter time span is substantially less than the 50-hour half-life previously reported in newborn infants with low birth weight. The fetal/maternal concentration ratio of procainamide was 0.914. However, maternal clearance of procainamide (9.7 ml/kg-1/min-1) was twice as long as the clearance reported for nonpregnant patients undergoing fast acetylation. We conclude first, that at least in the dose of this ill fetus, little digoxin administered to the mother crossed the placentae; and second, that while direct fetal therapy with digoxin is effective, the necessary frequent number of injections render this therapy impractical. Direct fetal digitalization should probably be reserved for the preterm fetus who has evidence of heart failure and has not responded to maternally administered therapy other than digoxin.


Rolling and adhesion of apoptotic monocytes is impaired by loss of functional cell surface-expressed P-selectin glycoprotein ligand-1.
Apoptosis induces cellular membrane changes that are thought to be linked to thrombotic processes, for example, surface exposure of procoagulant phosphatidylserine (PtdSer), upregulation of tissue factor (TF), and microvesicle formation. The latter, though, could downregulate this cellular response by shedding prothrombotic membrane elements, for example, integrins and TF. To test this hypothesis, etoposide-treated, apoptotic, monocytic cells (human monocytic leukemia cell line [THP-1]) were examined for rolling and adhesion on adherent platelets and for TF expression. Etoposide treatment did not result in a significant change in TF antigen expression. However, TF activity, measured in a continuous factor Xa generation assay, was increased fivefold concomitantly with increased exposure of PtdSer. Laminar flow adhesion assays specific for interaction between P-selectin and P-selectin glycoprotein ligand-1 (PSGL-1) revealed that in contrast to non-treated cells, apoptotic cells did not roll or firmly attach on adherent platelets. Lack of apoptotic THP-1 platelet interaction could be attributed to both a loss of cell surface-expressed PSGL-1 and loss of functional PSGL-1 as a result of disruption of the binding of PSGL-1 with the cytoskeleton. Etoposide-induced apoptosis in THP-1 cells evokes a procoagulant response by increasing TF activity associated with an increased PtdSer exposure. However, in contrast to TF, PSGL-1 shedding and loss of function, makes that apoptotic monocytes are unlikely involved in a thrombotic action because of their inability to adhere to an injured vessel wall or developing thrombus.


Clinicopathological features and post-resection outcomes of biliary cystadenoma and cystadenocarcinoma of the liver.
Biliary cystadenoma (BCA) and biliary cystadenocarcinoma (BCAC) account for 5%-10% of liver cystic diseases. In this study, we analysed the clinical presentation and surgical management of patients with BCA and BCAC. We retrospectively analysed the medical records of 23 BCA and 7 BCAC cases diagnosed between January 2007 and December 2013. There was a statistically significant difference in age (p=0.044) and sex (p=0.048) between BCA and BCAC groups. In the BCA group, 17 patients showed no symptoms (74%), 5 had abdominal pain (22%) and 1 showed abdominal distension (4%). In the BCAC group, two patients were without any symptoms (29%), three had abdominal pain (43%), one showed abdominal distension (14%) and one had fever and chills (14%). The cystic lesion size was widely variable; thus, there was no statistical difference (p=0.84). Complete resection was performed in all patients with BCA and BCAC. No tumour recurrence developed in patients with BCA. In patients with BCAC, 1-, 3- and 5-year disease-free survival rates were 100%, 85.7% and 57.1%, respectively, and 1-, 3- and 5-year overall patient survival rates were 100%, 100% and 75.0%, respectively. It is difficult to distinguish between BCA and BCAC via clinical manifestations and diagnostic imaging findings. Surgical resection is the treatment of choice for BCA and BCAC, and patient prognosis after complete resection was very favourable.


Preparing for Facial Feminization Surgery.
Preparing for facial feminization surgery (FFS) or gender-affirming facial surgery is a daunting task. Patients do extensive research online to see what FFS means. Oftentimes it is the patients who are educating their physicians when discussing medical clearance or the esteemed "therapy letter." The therapy letter is a letter that details the support for surgery in a stable patient and reaffirms the need to have FFS in a person diagnosed with gender dysphoria. This typically follows the World Professional Association for Transgender Health standards-of-care guidelines. Besides having the therapy letter, patients must be counseled on concurrent mental health illnesses.


Investigating the role of Kinesin family in lung adenocarcinoma via integrated bioinformatics approach.
Lung cancer is the leading cause of mortality from cancer worldwide. Lung adenocarcinoma (LUAD) is a type of non-small cell lung cancer (NSCLC) with highest prevalence. Kinesins a class of motor proteins are shown to be involved in carcinogenesis. We conducted expression, stage plot and survival analyses on kinesin superfamily (KIF) and scrutinized the key prognostic kinesins. Genomic alterations of these kinesins were studied thereafter via cBioPortal. A protein-protein interaction network (PPIN) of selected kinesins and 50 closest altering genes was constructed followed by gene ontology (GO) term and pathway enrichment analyses. Multivariate survival analysis based on CpG methylation of selected kinesins was performed. Lastly, we conducted tumor immune infiltration analysis. Our results found KIF11/15/18B/20A/2C/4A/C1 to be significantly upregulated and correlated with poor survival in LUAD patients. These genes also showed to be highly associated with cell cycle. Out of our seven selected kinesins, KIFC1 showed the highest genomic alteration with highest number of CpG methylation. Also, CpG island (CGI) cg24827036 was discovered to be linked to LUAD prognosis. Therefore, we deduced that reducing the expression of KIFC1 could be a feasible treatment strategy and that it can be a wonderful individual prognostic biomarker. CGI cg24827036 can also be used as a therapy site in addition to being a great prognostic biomarker.


HIV-1 Tat protein enhances the intracellular growth of Leishmania amazonensis via the ds-RNA induced protein PKR.
HIV-1 co-infection with human parasitic diseases is a growing public health problem worldwide. Leishmania parasites infect and replicate inside macrophages, thereby subverting host signaling pathways, including the response mediated by PKR. The HIV-1 Tat protein interacts with PKR and plays a pivotal role in HIV-1 replication. This study shows that Tat increases both the expression and activation of PKR in Leishmania-infected macrophages. Importantly, the positive effect of Tat addition on parasite growth was dependent on PKR signaling, as demonstrated in PKR-deficient macrophages or macrophages treated with the PKR inhibitor. The effect of HIV-1 Tat on parasite growth was prevented when the supernatant of HIV-1-infected macrophages was treated with neutralizing anti-HIV-1 Tat prior to Leishmania infection. The addition of HIV-1 Tat to Leishmania-infected macrophages led to inhibition of iNOS expression, modulation of NF-kB activation and enhancement of IL-10 expression. Accordingly, the expression of a Tat construct containing mutations in the basic region (49-57aa), which is responsible for the interaction with PKR, favored neither parasite growth nor IL-10 expression in infected macrophages. In summary, we show that Tat enhances Leishmania growth through PKR signaling.


ALS-causing SOD1 mutants generate vascular changes prior to motor neuron degeneration.
We report here that amyotrophic lateral sclerosis-linked superoxide dismutase 1 (SOD1) mutants with different biochemical characteristics disrupted the blood-spinal cord barrier in mice by reducing the levels of the tight junction proteins ZO-1, occludin and claudin-5 between endothelial cells. This resulted in microhemorrhages with release of neurotoxic hemoglobin-derived products, reductions in microcirculation and hypoperfusion. SOD1 mutant-mediated endothelial damage accumulated before motor neuron degeneration and the neurovascular inflammatory response occurred, indicating that it was a central contributor to disease initiation.


The effect of digitalis on experimental myocardial infarct size and hemodynamics.
Early studies suggested that digitalis exacerbated ischemia (ST segment data); however, there are no studies assessing the effect of this agent on anatomic infarct size with the use of a risk zone technique. Therefore, the aim of this study was to assess quantitatively whether digitalis extends necrosis in a model of coronary artery occlusion. Anesthetized dogs were subjected to 6-hour occlusion and, 30 minutes after occlusion, were randomized to digoxin (250 micrograms bolus/5 min intravenously, n = 9) or saline (n = 9) groups. At 6 hours, in vivo area at risk was determined by monastral blue dye injection and area of necrosis was assessed by tetrazolium staining. Heart rate and blood pressure were not different between groups before treatment or at 6 hours after occlusion. Left ventricular dP/dt was similar in both groups before occlusion (2350 +/- 293 mm Hg/sec digoxin vs 1839 +/- 122 mm Hg/sec saline, p = NS), but after 6 hours of coronary occlusion, had increased in the digoxin group to 2583 +/- 340 mm Hg/sec while it decreased in the saline group to 1517 +/- 128 mm Hg/sec (p less than 0.05 between groups at 6 hours), suggesting that digoxin increased contractility. Area at risk was 17.7 +/- 1.3% of the left ventricle in the digoxin group and 20.9 +/- 2.0% of the left ventricle in the saline group (p = NS). Area of necrosis, expressed as a percentage of area at risk, was 90.0 +/- 3.5% in the digoxin group vs 88.6 +/- 2.1% in the saline group (p = NS). Therefore, during acute myocardial infarction, digitalis confers a moderate increase in contractility without extending necrotic damage.


[HBV infection downregulated Mre11 expression and induced genome instability].
Prolonged infection with Hepatitis B virus (HBV) has been recognized as a major factor for hepatocellular carcinoma (HCC). In this study, we studied the host protein Mrel11 fluctuations after HBV infection which might be eventually contributed to cell transformation. Western Blot was monitored to detect the expression of Mre11, and RNA interference was used to downregulate protein expression. Then, Ligation mediated PCR was used to detect the level of DNA double strand breaks. Mre11 protein was downregulated when HBV infection occured, and the downregulated expression was also seen in HCC tissue. By RNA interference, we found that Mre11 knockdown caused DNA instability. Mre11 expression downregulation contributed at least partially to cell transformation caused by HBV infection.


Balanitis.
Balanitis, inflammation of the glans penis, is a frequently presenting genital disorder. It may be infectious and sexually transmissible, or commonly represents a noninfectious dermatologic condition. Accurate diagnosis is essential for management.


Baseline characteristics and analysis of predictors of the Outcome of septic pulmonary embolism in children: a retrospective observational study.
Septic pulmonary embolism is a rare disease in children. We aimed to assess the clinical, microbiological, and radiological characteristics and outcomes of pediatric septic pulmonary embolism (SPE) and to identify any predictive factors for in-hospital mortality in patients with this unusual disease to enhance prognosis and treatment. A retrospective study to search the electronic medical records of children admitted to the pediatric pulmonology unit, Tanta University hospital with the diagnosis of SPE between January 2015 and June 2022. Seventeen pediatric patients were identified; ten males and seven females with a mean age of 9.4 ± 5.2 years. The most common presenting complaints were fever and shortness of breath (n = 17) followed by chest pain (n = 9), pallor (n = 5), limb swelling (n = 4), and back pain (n = 1). Methicillin-resistant Staphylococcus aureus (MRSA) was the most common causative pathogen in nine patients. The most common extra-pulmonary septic foci were septic arthritis in five patients (29.4%), septic thrombophlebitis in four patients (23.5%), and infective endocarditis in two patients (11.8%). All patients exhibited wedge-shaped peripheral lesions and feeding vessel sign in CT chest, whereas bilateral diffuse lesions, nodular lesions, and cavitation were present in 94.1% of patients, pleural effusion was identified in 58.8% of patients, and pneumothorax was detected in 41.2% of patients. Fifteen patients improved and survived (88.2%), while two patients died (11.8%). Early diagnosis of SPE with vigorous early therapy is critical for a better outcome, including appropriate antibiotics and timely surgical interference to eradicate extra-pulmonary septic foci.


Phylogeography and genomic epidemiology of SARS-CoV-2 in Italy and Europe with newly characterized Italian genomes between February-June 2020.
The aims of this study were to characterize new SARS-CoV-2 genomes sampled all over Italy and to reconstruct the origin and the evolutionary dynamics in Italy and Europe between February and June 2020. The cluster analysis showed only small clusters including < 80 Italian isolates, while most of the Italian strains were intermixed in the whole tree. Pure Italian clusters were observed mainly after the lockdown and distancing measures were adopted. Lineage B and B.1 spread between late January and early February 2020, from China to Veneto and Lombardy, respectively. Lineage B.1.1 (20B) most probably evolved within Italy and spread from central to south Italian regions, and to European countries. The lineage B.1.1.1 (20D) developed most probably in other European countries entering Italy only in the second half of March and remained localized in Piedmont until June 2020. In conclusion, within the limitations of phylogeographical reconstruction, the estimated ancestral scenario suggests an important role of China and Italy in the widespread diffusion of the D614G variant in Europe in the early phase of the pandemic and more dispersed exchanges involving several European countries from the second half of March 2020.


Adiposity rebound may be a predictive index of body size for adolescents-Based on retrospective cohort data in a Japanese rural area.
We aimed to examine whether the timing of adiposity rebound (AR) could be a predictive index of body size in Japanese adolescents. The longitudinal individual data of 1438 Japanese children, including 714 boys and 724 girls born between 2001 and 2007, were obtained from child health check-ups conducted at ages 1.5, 2, 3, and 5 years, and then yearly after the age of 6 years. We examined whether the timing of AR could be used to estimate the body size at 14 years of age. The AR had a normal distribution with a mean occurrence at age 6-7 years. The odds ratio of having obesity at age 14 were 8.32 for boys and 4.81 for girls, whereas boys and girls with later AR at the same age had a relative risk of thinness of 6.27 and 8.14, respectively. The probability that children with an early AR (i.e., <6 years old) would be obese was nearly 40%. Similar to obesity, the probability of thinness at 14 years remained approximately 8% for both sexes. The findings suggest that early AR could raise the risk of obesity, and AR could later raise the risk of thinness. However, both probabilities of AR timing as predictors of adolescent weight status may only be about 10%-20%. This study cannot clearly determine whether the results were influenced by other factors after controlling for the timing of AR. Future studies that also consider lifestyle and genetic factors are warranted.


Manganese levels in a jaundiced long-term total parenteral nutrition patient: potentiation of haloperidol toxicity? Case report and literature review.
Manganese is vital in human nutrition. When oral intake is precluded, the recommended parenteral supplementation is 0.15 to 0.8 mg/day. Manganese is excreted primarily in the bile; during cholestasis, serum manganese levels may rise, and manganese toxicity ensue. Neuropsychiatric symptoms are prominent. Phenothiazine-derivative drugs may potentiate manganese toxicity. Serum or whole blood manganese levels should guide manganese therapy in jaundiced patients.


Self-assembled liquid-crystalline gels designed from the bottom up.
Liquid crystals are often combined with polymers to influence the liquid crystals' orientation and mechanical properties, but at the expense of reorientation speed or uniformity of alignment. We introduce a new method to create self-assembled nematic liquid-crystal gels using an ABA triblock copolymer with a side-group liquid-crystalline midblock and liquid-crystal-phobic endblocks. In contrast to in situ polymerized networks, these physical gels are homogeneous systems with a solubilized polymer network giving them exceptional optical uniformity and well-defined crosslink density. Furthermore, the unusually high-molecular-weight polymers used allow gels to form at lower concentrations than previously accessible. This enables these gels to be aligned by surface anchoring, shear, or magnetic fields. The high content of small-molecule liquid crystal (>/=95%) allows access to a regime of fast reorientation dynamics.


Self-organisation of an oligodeoxynucleotide containing the G- and C-rich stretches of the direct repeats of the human mitochondrial DNA.
Stretches of cytosines and guanosines have been shown in vitro to adopt non-canonical structures known as i-motifs and G-quartets, respectively. When combined, such sequences are expected to either retain their structure or form duplexes or triple helices. All these structures may occur in vivo whenever the sequence criteria are met. Such stretches are present in the circular genome of human mitochondria, as two 10 nucleotide-long perfect tandem direct repeats (DR1 and DR2). The DR1 and DR2 repeats are G-rich on the heavy strand and C-rich on the light strand. Previous results suggested that during replication, transient formation of a parallel GGC triple helix between the neo-synthesised G-rich DR1 and the double-stranded homologous DR2 could be involved in a rearrangement process leading to genome instability. In order to get structural insights into the interaction between the two repeats, we have studied by nuclear magnetic resonance (NMR) the assembly properties of a 24-mer oligodeoxyribonucleotide in which the C- and G-rich segments of the DRs are covalently tethered by a TTTT linker. We show here that this 24-mer self-associates into a triplex-containing symmetrical tetramer. The core of the structure is composed of anti-parallel Watson-Crick (WC) base pairs. Two additional strands are hydrogen-bonded to the Hoogsteen side of the Gs, thus forming CGC(+) triple helices, with G-rich ends folding into G-quartets. These results suggest that such structures could occur when the two DRs are put to close proximity in a biological context.


Clinical features and treatment outcomes of pediatric Langerhans cell histiocytosis with macrophage activation syndrome-hemophagocytic lymphohistiocytosis.
Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm. A few LCH patients had Macrophage activation syndrome-hemophagocytic lymphohistiocytosis (MAS-HLH), a life-threatening, hyper-inflammatory syndrome. We retrospectively described the clinical-biological characteristics of a series of 28 pediatric LCH patients with MAS-HLH in a single center. We further analyzed the difference in treatment outcomes between second-line chemotherapy (cytarabine and cladribine) and targeted therapy (dabrafenib) for BRAF-V600E-positive patients. LCH patients with MAS-HLH were aged < 2 years, harbored high frequencies of risk organ, skin, or lymph nodes involvement, and most of them carried BRAF-V600E mutation in lesions (88.0%) or plasma (90.5%). Patients were firstly treated with the initial induction first-line therapy (vindesine-steroid combination), and most of them (26/28) failed to control the active MAS-HLH after one six-week course of induction treatment. Then they were shifted to second-line chemotherapy or targeted therapy dabrafenib. BRAF-V600E-mutant patients treated with dabrafenib had prompt resolution of MAS-HLH signs and symptoms with less toxicity than second-line chemotherapy. Moreover, the progression-free survival (PFS) rate for patients given dabrafenib was much higher than those treated with chemotherapy (4 year-PFS: 75% vs. 14.6%, P = 0.034). LCH patients with MAS-HLH harbored specific clinical-biology characteristics compared to the multisystem LCH without MAS-HLH. The BRAF inhibitor dabrafenib provides a promising treatment option for LCH with MAS-HLH.


Distinct methane-dependent biogeochemical states in Arctic seafloor gas hydrate mounds.
Archaea mediating anaerobic methane oxidation are key in preventing methane produced in marine sediments from reaching the hydrosphere; however, a complete understanding of how microbial communities in natural settings respond to changes in the flux of methane remains largely uncharacterized. We investigate microbial communities in gas hydrate-bearing seafloor mounds at Storfjordrenna, offshore Svalbard in the high Arctic, where we identify distinct methane concentration profiles that include steady-state, recently-increasing subsurface diffusive flux, and active gas seepage. Populations of anaerobic methanotrophs and sulfate-reducing bacteria were highest at the seep site, while decreased community diversity was associated with a recent increase in methane influx. Despite high methane fluxes and methanotroph doubling times estimated at 5-9 months, microbial community responses were largely synchronous with the advancement of methane into shallower sediment horizons. Together, these provide a framework for interpreting subseafloor microbial responses to methane escape in a warming Arctic Ocean.


Adolescent girls' Instagram and TikTok use: Examining relations with body image-related constructs over time using random intercept cross-lagged panel models.
The literature on body image ramifications of girls' uses of appearance-focused social media (ASM) is limited, and even non-existing in terms of TikTok uses. With this brief report, we aimed to fill this gap in the literature by analyzing three waves of data on girls' ASM use and body image-related constructs (i.e., internalization of beauty ideals and body image self-discrepancy) using random-intercept cross-lagged panel models (RI-CLPMs). The total sample consisted of 229 girls (Mage = 15.12, SD = 1.50). Controlling for age and body mass index (BMI), the RI-CLPMs revealed that neither TikTok nor Instagram were predictive of subsequent increases or decreases in internalization of beauty ideals and body image self-discrepancy. Lower scores on body image self-discrepancy at W2 (i.e., wanting to have a thinner body) did predict higher uses of Instagram at W3. No evidence for between-person effects was garnered. The results enrich our knowledge on long-term implications of girls' Instagram and TikTok use for their body image. They further underline the need for research that more specifically disentangles the role of different appearance-related activities on social media and their impact on girls' body image constructs.


"In vivo" effects of lithium sulphate on the turnover of rat tissue nucleotides.
The effects of lithium sulphate following acute administration to Wistar rats - in therapeutic and toxic doses - were investigated, using as markers the levels and turnover of brain, kidney and liver nucleotides. Adenine- and guanine-dependent nucleotides were assayed concomitantly, using a high- performance liquid chromatographic method. Following acute administration, lithium's effects on 3',5'- cAMP levels were more significant at hepatic and cerebral level, in a dose-dependant manner. The effect on 3',5'-cGMP had tissue specificity and was not dose-dependant. It might be possible that 3',5'-cGMP is a better indicator of lithium toxicity than 3',5'-cAMP.


The glutamatergic projection from the prefrontal cortex to the nucleus accumbens core is required for cocaine-induced decreases in ventral pallidal GABA.
Cocaine-primed reinstatement of drug seeking is associated with a decrease in extracellular GABA in the ventral pallidum (VP). The present study investigated the neural mechanism of this cocaine-induced decrease in VP GABA by determining if activity of the glutamatergic projection from the medial prefrontal cortex (PFC) to the nucleus accumbens is required for the effect. Microdialysis was performed to measure extracellular GABA in the VP while simultaneously, either a combination of the GABA agonists baclofen and muscimol was microinjected into the PFC, or the AMPA/kainate glutamate receptor antagonist CNQX was microinjected into the accumbens core. Inhibition of the PFC with GABA agonists and blockade of AMPA glutamate receptors in the accumbens core were both sufficient to prevent the cocaine-induced decrease in VP GABA, further implicating increased activity of the cortico-striato-pallidal circuit in relapse to drug seeking.


Blood concentrations and biological effects of androstanediols at the onset of puberty in the female rat.
Androstanediols are the major products of the immature rat ovary. About two-thirds are present in blood as sulfates. One of the sulfate conjugates was identified as 5 alpha-androstane-3 beta,17 beta-diol-3-monosulfate. This steroid effectively inhibits postcastrational LH elevation in a concentration in which it is present in blood. Other androstanediol sulfates examined were without this activity. In the immature rat, levels of 3 alpha- and 3 beta-diol decrease sharply before the first ovulation. In Wistar rats, PMSG-treatment induced a similar decline in these steroids. When ovulation in PMSG-treated rats was blocked by pentobarbitone, the LH-surge and the decline of the 3 alpha- and 3 beta-diols was delayed. Thus, it seems that the decline in the blood concentration of the diols depends on the first LH surge.


Sequential quantification of number and mass of microplastics in municipal wastewater using Fourier-transform infrared spectroscopy and pyrolysis gas chromatography-mass spectrometry.
Plastic pollution is a significant environmental concern because microplastics (MPs) accumulate in various ecosystems; therefore, the accurate identification and quantification of MPs in environmental samples is crucial. This study presents a new sequential analytical method that combines Fourier-transform infrared spectroscopy (FTIR) and pyrolysis-gas chromatography/mass spectrometry (Pyr-GC/MS) to characterize and quantify MPs. FTIR with a microscope allows the identification of the polymer type and physical dimensions of MPs, whereas Pyr-GC/MS enables determining the chemical composition of MPs with plastic additives. Pretreated wastewater influent samples spiked with reference MPs were filtered through an Al2O3 disk for FTIR analysis, and the surface contents were collected and subjected to Pyr-GC/MS analysis. The mass of the reference MPs estimated using FTIR were in good agreement but were slightly lower than those obtained using Pyr-GC/MS. This finding supports the notion that the proposed sequential method can be used to determine both the number and the mass of MPs in environmental samples.