[Effects of single ethanol administration on liver regeneration in rats].
The effects of a single ethanol administration on liver weight gain, RNA synthesis, DNA synthesis, and polyamine metabolism as parameters of liver regeneration in rat liver after partial hepatectomy were studied. Ethanol, given 1 hr before partial hepatectomy at the dose of 3 g/kg, inhibited RNA synthesis 4 hr after partial hepatectomy and DNA synthesis 24 hr after partial hepatectomy in the liver, but did not affect liver weight gain. Further, we studied the effects of a single ethanol administration on polyamine metabolism in order to elucidate the mechanism of the inhibition of liver regeneration by ethanol. Ethanol inhibited the increase in the putrescine level in the liver 4 and 8 hr after surgery, which was a metabolic product of ornithine decarboxylase. But spermidine and spermidine levels in the liver were not affected by ethanol administration. Hepatic spermidine N1-acetyl transferase activity increased by ethanol administration 6 hr after partial hepatectomy in compensation for the suppression of putrescine. Judging from these results, a single dose of ethanol inhibited liver regeneration polyamine metabolism after partial hepatectomy in rats.


Statistical thermodynamic analysis of peptide and protein insertion into lipid membranes.
A statistical thermodynamic approach is used to analyze the various contributions to the free energy change associated with the insertion of proteins and protein fragments into lipid bilayers. The partition coefficient that determines the equilibrium distribution of proteins between the membrane and the solution is expressed as the ratio between the partition functions of the protein in the two phases. It is shown that when all of the relevant degrees of freedom (i.e., those that change their character upon insertion into the membrane) can be treated classically, the partition coefficient is fully determined by the ratio of the configurational integrals and thus does not involve any mass-dependent factors, a conclusion that is also valid for related processes such as protein adsorption on a membrane surface or substrate binding to proteins. The partition coefficient, and hence the transfer free energy, depend only on the potential energy of the protein in the membrane. Expressing this potential as a sum of a "static" term, corresponding to the equilibrium (minimal free energy) configuration of the protein in the membrane, and a "dynamical" term representing fluctuations around the equilibrium configuration, we show that the static term contains the "solvation" and "lipid perturbation" contributions to the transfer free energy. The dynamical term is responsible for the "immobilization" free energy, reflecting the loss of translational and rotational entropy of the protein upon incorporation into the membrane. Based on a recent molecular theory of lipid-protein interactions, the lipid perturbation and immobilization contributions are then expressed in terms of the elastic deformation free energy resulting from the perturbation of the lipid environment by the foreign (protein) inclusion. The model is formulated for cylindrically shaped proteins, and numerical estimates are given for the insertion of an alpha-helical peptide into a lipid bilayer. The immobilization free energy is shown to be considerably smaller than in previous estimates of this quantity, and the origin of the difference is discussed in detail.


Measurement of the residual wedge angle of a nontransparent parallel plate with a modified cyclic path optical configuration.
A new technique for the measurement of the residual wedge angle (RWA) of a nontransparent nearly parallel plate (NPP), using a polarized He-Ne laser source, is proposed. A modified cyclic path optical configuration is used to produce counterpropagating collimated beams, which get reflected from the end surfaces of the NPP and are combined to produce two-beam Fizeau fringes, whose spacing is inversely proportional to the wedge angle of the NPP. The states of polarization of the beams reflected from the end surfaces of the NPP are transformed to opposite circular polarizations, and polarization phase shifts are applied between them. Phase shifting interferometry (PSI) has been used to determine the angular tilt between the interfering beams and, hence, the RWA of the NPP. Results obtained from a validation experiment are presented. The PSI-based technique does not suffer from any measurement ambiguities due to limitations in effective beam aperture.


New therapeutic options in patients prone to hypertension: a focus on direct Renin inhibition and aldosterone blockade.
Certain patient populations have a high prevalence of hypertension, including black, elderly, or obese patients; patients with metabolic syndrome, or frank diabetes; and patients with chronic kidney disease. Many of these patients experience renin-angiotensin-aldosterone system (RAAS) dysregulation, which is important because the RAAS plays a pivotal role in the pathogenesis of hypertension, cardiovascular disease, and renal dysfunction. Data available regarding newer approaches that target the RAAS, including direct renin inhibition and aldosterone receptor antagonism, in patients who often have hypertension are reviewed. Aliskiren, the first direct renin inhibitor, is effective in a number of these patient groups, including those who are black or obese or who have metabolic syndrome, renal impairment, or diabetes. In addition, in the setting of long-term angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, aldosterone receptor antagonists (spironolactone and eplerenone) provide another rational therapeutic approach for patients whose blood pressure is not controlled by standard therapies.


DNA aberrations of bladder mucosa in patients with transitional cell carcinomas.
DNA aberrations in bladder mucosa have been investigated in altogether 26 patients with aneuploid WHO grade 2 and 3 tumours (transitional cell carcinomas; TCC). In about 1/4 of the patients aneuploid cells were found only in the tumour. Hypotetraploid tumours showed the lowest frequency of involvement of the normal appearing mucosa of the trigone (43%). In hypertriploid tumours the corresponding value was 71%. In altogether 14 of the patients, the same type of aneuploid cells was found in the normal appearing mucosa as in the tumour. This indicates frequent involvement of the whole bladder mucosa in the tumour disease. In about 1/4 of the cases other types of ploidy aberrations were found in the normal appearing mucosa than in the tumour. This is indicative of preneoplastic changes in the mucosa, of which only one type of aberrations is associated with tumour growth. In some cases with multiple tumours of the bladder, all the tumours had the same aneuploid stemline, while in other cases the tumours were of different aneuploid stemlines. This is conformal with other reports of atypia in the surrounding mucosa in TCC and with the concept that recurrence of high grade tumours is the consequence of neoplastic involvement of the whole bladder.


Carboxylate binding in copper histidine complexes in solution and in zeolite Y: X- and W-band pulsed EPR/ENDOR combined with DFT calculations.
The complexes of copper with histidine exhibit a wide variety of coordination modes in aqueous solution. This stems from the three potential coordination sites of the histidine molecule and the existence of mono- and bis-complexes. The present work concentrates on the determination of the carboxylate binding mode, via the (13)C hyperfine coupling of the carboxyl, in a number of copper complexes in frozen solutions. These are then used as references for the determination of the coordination mode of two zeolite encapsulated complexes. The (13)C hyperfine coupling (sign and magnitude) was determined by a variety of advanced pulsed EPR and electron-nuclear double resonance (ENDOR) techniques carried out at conventional and high magnetic fields. These showed that while the carboxyl (13)C isotropic hyperfine coupling of an equatorially coordinated carboxylate is negative with a magnitude of 3-4 MHz, that of a free carboxylate is small ( approximately 1 MHz) and positive. To rationalize the experimentally determined ligand hyperfine couplings ((1)H and (13)C) and further understand their dependence on the coordination mode and degree of protonation, density functional theory (DFT) calculations were carried out on a number of model complexes, representing the different Cu-histidine complexes studied experimentally. The exchange-correlation functional used for the calculation of the EPR parameters was B3LYP with triple-zeta plus polarization (TZP) quality basis sets. While the polarization agreement between the magnitudes of the calculated and experimental values varied among the various nuclei, sometimes exhibiting deviations of up to 40%, an excellent agreement was found for the sign prediction. This shows the unique advantage of combining high field ENDOR, by which the sign of the hyperfine can often be determined, with DFT predictions for structure determination.


Light-Activated Antimicrobial Surfaces Using Industrial Varnish Formulations to Mitigate the Incidence of Nosocomial Infections.
Evidence has shown that hospital surfaces are one of the major vehicles of nosocomial infections caused by drug-resistant pathogens. Smart surface coatings presenting multiple antimicrobial activity mechanisms have emerged as an advanced approach to safely prevent this type of infection. In this work, industrial waterborne polyurethane varnish formulations containing for the first time cationic polymeric biocides (SPBs) combined with photosensitizer curcumin were developed to afford contact-active and light-responsive antimicrobial surfaces. SPBs were prepared by atom transfer radical polymerization, which allows control over the polymer features that influence antimicrobial efficiency (e.g., molecular weight), while natural curcumin was employed to impart photodynamic activity to the surface. Antibacterial testing against Gram-negative Escherichia coli revealed that glass surfaces coated with the new formulations displayed photokilling effect under white-light (42 mW/cm2) irradiation within only 15 min of exposure. In addition, it was observed a combined antimicrobial effect between the two biocides (cationic SPB and curcumin), with a higher reduction in the number of viable bacteria observed for the surfaces containing cationic SPB/curcumin mixtures in comparison with the one obtained for surfaces only with polymer or without biocides. The waterborne industrial varnish formulations allowed the formation of homogeneous films without the need for addition of a coalescing agent, which can be potentially applied in diverse surface substrates to reduce bacterial transmission infections in healthcare environments.


[A case of idiopathic hypoparathyroidism with slurred speech and mild dementia].
A case of idiopathic hypoparathyroidism (IHP) is discussed with reference to a study of rats maintained on various low-calcium diets. A 45-year-old man complained of difficulty speaking, especially an inability to speak loudly and of fine finger tremors over the past 2 or 3 years. His brain MRI showed marked calcification in the bilateral basal ganglia and cerebellum and his in sera findings showed low calcium, extremely low levels in all kinds of examined parathyroid hormones and 1,25 (OH)2D, thus we diagnosed idiopathic hypoparathyroidism. His finger tremors stopped soon after administration of 1 alpha D3 2 microgram/day as verified by calcium, phosphorus and creatinine levels in sera, however, a brain CT one year later showed no changes in calcification. As reported earlier in studies of deposition in the soft tissues, especially central nervous system tissues of rats maintained on low-calcium diets, it is difficult to reduce calcium deposition if symptoms appear in adults. Therefore, it is necessary to start therapy as soon as possible in order to prevent additional calcium deposition in the early stage of IHP.


Ligand-induced internalization of TNF receptor 2 mediated by a di-leucin motif is dispensable for activation of the NFκB pathway.
Endocytosis is an important mechanism to regulate tumor necrosis factor (TNF) signaling. In contrast to TNF receptor 1 (TNFR1; CD120a), the relevance of receptor internalization for signaling as well as the fate and route of internalized TNF receptor 2 (TNFR2; CD120b) is poorly understood. To analyze the dynamics of TNFR2 signaling and turnover at the plasma membrane we established a human TNFR2 expressing mouse embryonic fibroblast cell line in a TNFR1(-/-)/TNFR2(-/-) background. TNF stimulation resulted in a decrease of constitutive TNFR2 ectodomain shedding. We hypothesized that reduced ectodomain release is a result of TNF/TNFR2 complex internalization. Indeed, we could demonstrate that TNFR2 was internalized together with its ligand and cytoplasmic binding partners. Upon endocytosis the TNFR2 signaling complex colocalized with late endosome/lysosome marker Rab7 and entered the lysosomal degradation pathway. Furthermore, we identified a di-leucin motif in the cytoplasmic part of TNFR2 suggesting clathrin-dependent internalization of TNFR2. Internalization defective TNFR2 mutants are capable to signal, i.e. activate NFκB, demonstrating that the di-leucin motif dependent internalization is dispensable for this response. We therefore propose that receptor internalization primarily serves as a negative feed-back to limit TNF responses via TNFR2.


Typhoid and dengue coinfection: case reports.
Both dengue and typhoid fever have emerged as major public health problems in India. Coinfection with both these diseases is rarely reported. Here we report two confirmed cases of concurrent illness of dengue with typhoid fever; both patients were managed as outpatients and recovered completely.


[Cyclic sciatica and extrauterine endometriosis].
Cyclic sciatica caused by ectopic endometriosis is an unusual cause of compression of a lumbar root, of the sciatic nerve or its plexus. A 38-year-old patient is presented with a history of menstruation associated with right-sided sciatica, which gradually developed over a 2 1/2-year period into disabling constant pain and a lumboradicular syndrome with signs of S1-root involvement. Suggested compression of the sciatic nerve by ectopic endometriosis in the sciatic notch region could be confirmed by CT and MR, by prompt response to hormonal suppression of ovarian function and by regression of the radiological findings. If the history of cyclic pain, local tenderness on deep palpation and the onset of referred pain in the buttock had been observed at the beginning, unnecessary and costly medico-technical procedures delaying diagnosis and treatment (including unnecessary physiotherapy) could have been avoided. Cyclic sciatica is discussed in a review of literature, and possibilities of treatment are discussed.


Functional benefits and cost/benefit analysis of continuous intrathecal baclofen infusion for the management of severe spasticity.
Intrathecally delivered baclofen has been used as a treatment for severe spasticity since 1984. Despite this, there are uncertainties surrounding the benefits of treatment and the costs involved. The authors assessed the evidence of benefits and identified costs and the cost/benefit ratio for continuous intrathecal baclofen infusion in the treatment of severe spasticity. A systematic literature review was conducted to estimate the effect of continuous intrathecal baclofen infusion on function and quality-of-life (QOL) measures in patients with severe spasticity. Outcomes were related to standard QOL scores to estimate potential gains in quality-adjusted life years (QALYs). Information on the costs of continuous intrathecal baclofen infusion was obtained from hospitals in the United Kingdom. This information was combined to estimate the cost/benefit ratio for the use of continuous intrathecal baclofen infusion in patients with different levels of disability from severe spasticity. Studies indicate that bedbound patients are likely to improve their mobility and become able to sit out of bed. Patients with severe spasm-related pain are likely to have major improvement or complete resolution of this pain. Many other benefits are also reported. Such benefits are related to costs per QALY in the range of 6,900 pounds to 12,800 pounds ($10,550-$19,570 US). In carefully selected patients who have not responded to less invasive treatments, continuous intrathecal baclofen infusion is likely to lead to worthwhile functional benefits. Continuous intrathecal baclofen infusion has an acceptable cost/benefit ratio compared with other interventions that are funded by the health service.


Hypopituitarism in the elderly: multifaceted clinical and biochemical presentation.
Hypopituitarism (HYPO) is a rare and under-investigated pathology in the elderly. to review our case records of patients > or =65 yrs with first diagnosis of anterior global hypopituitarism, in order to evaluate presentation symptoms, etiology, biochemical and hormonal pictures, pituitary morphology, and efficacy of therapy. 15 patients (65-82 yrs) were studied: in 11 (73%) HYPO was secondary to pituitary macroadenoma (non-secreting in 10 and GH-secreting in 1); in 3 it was associated to empty sella, and in 1 to pituitary hypoplasia. major presenting symptoms were visual-field defects and asthenia (40%) but also memory and/or gait impairment and nausea (30%) and depression (20%) were significantly observed. Dyslipidemia (73%), anemia (20%) and severe hyponatremia (13%) were found. After starting substitutive therapy and clinical improvement, 10 patients with macroadenoma underwent uneventful neurosurgery, which improved visual alterations but not pituitary function. Immunohistochemistry showed positivity for FSH in one patient and for GH in one patient. Six out of the eight patients with a post-surgical tumor remnant required treatment (surgery/radiotherapy/somatostatin analogue treatment in the acromegalic patient). The diagnosis of HYPO is often delayed in the elderly, since symptoms may be ascribed to aging and associated comorbidities. In our series, most of the aspecific symptoms were retrospectively addressed to HYPO since their resolution/improvement with replacement therapy. The prevalent cause of HYPO remains non-functioning pituitary macroadenomas. Hyponatremia can be a life-threatening presenting symptom. Symptoms considered apparently aspecific in the elderly should be investigated in order to possibly diagnose an important treatable disorder as HYPO.


Show Me the Invisible: Visualizing Hidden Content.
Content on computer screens is often inaccessible to users because it is hidden, e.g., occluded by other windows, outside the viewport, or overlooked. In search tasks, the efficient retrieval of sought content is important. Current software, however, only provides limited support to visualize hidden occurrences and rarely supports search synchronization crossing application boundaries. To remedy this situation, we introduce two novel visualization methods to guide users to hidden content. Our first method generates awareness for occluded or out-of-viewport content using see-through visualization. For content that is either outside the screen's viewport or for data sources not opened at all, our second method shows off-screen indicators and an on-demand smart preview. To reduce the chances of overlooking content, we use visual links, i.e., visible edges, to connect the visible content or the visible representations of the hidden content. We show the validity of our methods in a user study, which demonstrates that our technique enables a faster localization of hidden content compared to traditional search functionality and thereby assists users in information retrieval tasks.


Monomethylated cap structures facilitate RNA export from the nucleus.
RNA export from the nucleus has been analyzed in Xenopus oocytes. U1 snRNAs made by RNA polymerase II were exported into the cytoplasm, while U1 snRNAs synthesized by RNA polymerase III, and therefore with a different cap structure, remained in the nucleus. Export of the polymerase II-transcribed RNAs was inhibited by the cap analog m7GpppG. Spliced mRNAs carrying monomethylguanosine cap structures were rapidly exported, while hypermethylated cap structures delayed mRNA export. The export of a mutant precursor mRNA unable to form detectable splicing complexes was also significantly delayed by incorporation of a hypermethylated cap structure. The results suggest that the m7GpppN cap structure is likely to be a signal for RNA export from the nucleus.


Get in Touch With Dendritic Epithelial T Cells!
Innate and adaptive immune systems continuously interchange information and orchestrate their immune responses to protect the host. γδT cells play crucial roles, as they incorporate both innate and adaptive immune characteristics. Dendritic epidermal T cells (DETC) are specialized γδT cells, which are uniquely positioned to rapidly respond to skin wounds and infections. Their elongated dendrite morphology allows them to be in continuous contact with multiple neighboring keratinocytes and Langerhans cells. Cellular interactions are fundamental to the formation, activation and maintenance of immune cell functions during steady state and pathology. Recent technological advances, especially in the field of cellular imaging, have contributed greatly to the characterization of complex cellular interactions in a spatiotemporally resolved manner. In this review, we will highlight the often-underappreciated function of DETC and other γδT cells during steady state and an ongoing immune response. More specifically, we discuss how DETC-precursors are shaped in the fetal thymus during embryogenesis as well as how direct cell-cell interactions of DETC with neighboring epidermal cells shape skin homeostasis and effector functions. Furthermore, we will discuss seminal work and recent discoveries made in the γδT cell field, which have highlighted the importance of γδT cells in the skin, both in humans and mice.


Oxidative stress response in iron-induced acute nephrotoxicity: enhanced expression of heat shock protein 90.
Iron overload with ferric nitrilotriacetate (Fe-NTA) induces acute renal proximal tubular necrosis, a consequence of oxidative tissue damage, that leads to a high incidence of renal adenocarcinoma in rodents. In the present study, we determined the proteins preferentially produced in response to the Fe-NTA-induced oxidative injury. A single intraperitoneal Fe-NTA treatment led to the enhanced production of a number of proteins with molecular masses of 85-95 kDa. These included heat shock protein 90 (HSP90) as determined by immunoprecipitation. The enhanced production of HSP90 was prominent in the renal tubular cells. Steady accumulation of HSP90 was observed in the subacute toxicity experiments with multiple injections of Fe-NTA, suggesting that the enhanced production of HSP90 is important in increasing resistance to subsequent injury caused by the Fe-NTA-induced oxidative stress.


[The mother-child bond in transcultural situations].
Mothering techniques vary significantly from one culture to another. These techniques are transformed as women migrate and come into contact with other ways of forging the mother-child bond. Being aware of and respecting mothers' cultural customs is a challenge for modern day child care workers.


Tools for monitoring system suitability in LC MS/MS centric proteomic experiments.
With advances in liquid chromatography coupled to tandem mass spectrometry technologies combined with the continued goals of biomarker discovery, clinical applications of established biomarkers, and integrating large multiomic datasets (i.e. "big data"), there remains an urgent need for robust tools to assess instrument performance (i.e. system suitability) in proteomic workflows. To this end, several freely available tools have been introduced that monitor a number of peptide identification (ID) and/or peptide ID free metrics. Peptide ID metrics include numbers of proteins, peptides, or peptide spectral matches identified from a complex mixture. Peptide ID free metrics include retention time reproducibility, full width half maximum, ion injection times, and integrated peptide intensities. The main driving force in the development of these tools is to monitor both intra- and interexperiment performance variability and to identify sources of variation. The purpose of this review is to summarize and evaluate these tools based on versatility, automation, vendor neutrality, metrics monitored, and visualization capabilities. In addition, the implementation of a robust system suitability workflow is discussed in terms of metrics, type of standard, and frequency of evaluation along with the obstacles to overcome prior to incorporating a more proactive approach to overall quality control in liquid chromatography coupled to tandem mass spectrometry based proteomic workflows.


Functional and cytoarchitectural spinal cord protection by ATL-146e after ischemia/reperfusion is mediated by adenosine receptor agonism.
ATL-146e protects the spinal cord from ischemia/reperfusion injury, presumably via adenosine A(2A) receptor activation, but this relationship remains unproven. We hypothesized that spinal cord functional and cytoarchitectural preservation from ATL-146e would be lost with simultaneous administration of the specific adenosine A(2A) antagonist ZM241385 (ZM), thus proving that adenosine A(2A) receptor activation is responsible for the protective effects of this compound. New Zealand White rabbits underwent 45 minutes of infrarenal aortic cross-clamping. Groups (n = 10) included sham, ischemia, ischemia plus ATL-146e (ATL-146E), ischemia plus ZM, or ischemia with both compounds (agonist-antagonist). Tarlov scores were recorded every 12 hours. After 48 hours, the spinal cord was fixed for histology and microtubule-associated protein 2 immunohistochemistry. Tarlov scores at 48 hours were significantly better in the sham and ATL-146E groups (5.0 and 3.9, respectively) compared with the other three groups (all < or =1.3; P < .001). On hematoxylin and eosin, neuronal viability was higher in the sham, ATL-146E, and agonist-antagonist groups compared with the control and ZM groups (P < .05). Microtubule-associated protein 2 expression was preserved in the sham and ATL-146E groups but was lost in the ATL + ZM, ZM241385, and control groups. ATL-146e preserves the spinal cord in terms of both cytoarchitecture and function after reperfusion of the ischemic spinal cord, but this preservation is not completely blocked by competitive adenosine A(2A) receptor antagonism. Although ATL-146e does seem to partially function through activation of the adenosine A(2A) receptor, the neuroprotective mechanism may not be limited to this particular receptor.


A comprehensive profiling of innate immune responses in Eptesicus bat cells.
Bats (Order: Chiroptera), including those of the genus Eptesicus, have been reported to serve as reservoirs of several zoonotic viruses. Notably, bats have been reported to lack obvious symptoms of infection with such viruses and are thought to have unique immune system responses. However, the responses of their innate immune system, the first line of immunity, remain largely unclear. Here, we comprehensively analyzed the expression profiles in two Eptesicus bat cell lines to investigate their innate immune responses. The gene expression profiles after polyinosinic:polycytidylic acid [poly (I:C)] induction were similar between the two bat cell lines, but uniquely upregulated differentially expressed genes were also identified. We also revealed that the upregulated genes of Eptesicus bat cells were distinct from those of human epithelial cells in response to induction. Moreover, the basal expression levels of several immune-related genes were higher in bat cells than in human cells. We also identified unannotated novel transcripts that were upregulated after induction and novel microRNAs expressed in bat cells, some of which were upregulated by poly (I:C) treatment. This is the first report to illustrate the innate immune response in Eptesicus bat cells; therefore, this study provides basic and novel insights into bat innate immunity. Our data represent a valuable resource for future studies into bat immunity and the biology of Eptesicus bats.


Comparison of Py*+/dU*- charge transfer state dynamics in 5-(1-pyrenyl)-2'-deoxyuridine nucleoside conjugates with amido-, ethylenyl-, and ethynyl linkers.
Femtosecond, picosecond, and nanosecond transient absorbance (TA) and picosecond emission kinetics results are presented for three 5-(1-pyrenyl)-2'-deoxyuridine nucleosides each with a different two-atom linker joining pyrenyl C-1 to uracil C-5. The linkers are respectively -NHCO-, -(CH(2))(2)-, and -C[triple bond]C- for PAdU, PEdU, and PYdU. For all three nucleoside conjugates, most conformers undergo intramolecular charge transfer (CT) from their pyrenyl (1)(pi,pi) excited states to form Py(*+)/dU(*-) CT products in ultrashort times: <or=0.6 ps for PAdU, <or=30 ps for PEdU, and <or=100 ps for PYdU (instrumentally limited times). Additionally for all three nucleosides, a small fraction of conformers also undergoes slower intramolecular CT from their pyrenyl (1)(pi,pi) states in times as long as tens of nanoseconds. Importantly, for use of these nucleosides in studies of excess electron transport in DNA, the lifetimes the CT products in MeOH lengthen significantly in the above series: 6.0 ps for PAdU, 560 ps for PEdU (the shortest of three TA lifetime components), and 1.06 ns for PYdU. The effects on pyrenyl-dU nucleoside CT state dynamics due to adding oxygen via both aeration and oxygen saturation are also examined for the PEdU nucleoside in MeOH.


Root Canal Morphology of Mandibular Canine in an Iranian Population: A CBCT Assessment.
The present study was conducted to assess the morphology of mandibular canines using cone-beam computed tomography (CBCT) in a north Iranian population. For the morphological assessment of mandibular canines, 150 CBCT images taken from patients for different reasons were used. The mandibular canines were examined in sagittal, coronal and axial dimensions. The canal pattern, number of roots/canals, the tooth length, the orientation of the roots and the position of the apical foramina were evaluated and the effect of gender on each variable was assessed. The obtained data were analyzed using the Chi-square and student's t-tests. According to the Vertucci's criteria, the most common pattern was type I morphology (89.7%), followed by types III (5.7%), II (3.7%) and V (1%). No significant differences were observed between the male and female patients in terms of canal type (P>0.05). Gender difference is a factor which affected the root length and the number of mandibular canine root and root canal. There were 296 single-root and four double-root canines. The double-root canines and mandibular canine with two canals were significantly more common among men than women (P=0.00). The apical foramen was laterally positioned in 68.3% and centrally in 31.7% of the cases, and the root curvatures were mostly oriented toward the buccal region. No significant statistical difference was observed for mentioned parameters in right and left half of the jaw. Due the diverse morphology and the potential presence of a second mandibular canine among Iranians, dentists should perform endodontic treatments with greater care. CBCT is an accurate tool for the morphological assessment of root canals.


Two applications of time reversal mirrors: seismic radio and seismic radar.
Two seismic applications of time reversal mirrors (TRMs) are introduced and tested with field experiments. The first one is sending, receiving, and decoding coded messages similar to a radio except seismic waves are used. The second one is, similar to radar surveillance, detecting and tracking a moving object(s) in a remote area, including the determination of the objects speed of movement. Both applications require the prior recording of calibration Green's functions in the area of interest. This reference Green's function will be used as a codebook to decrypt the coded message in the first application and as a moving sensor for the second application. Field tests show that seismic radar can detect the moving coordinates (x(t), y(t), z(t)) of a person running through a calibration site. This information also allows for a calculation of his velocity as a function of location. Results with the seismic radio are successful in seismically detecting and decoding coded pulses produced by a hammer. Both seismic radio and radar are highly robust to signals in high noise environments due to the super-stacking property of TRMs.


Female urethra: MR imaging.
The potential of magnetic resonance (MR) imaging in the evaluation of the female urethra was studied in 64 patients. Spin-echo T1- and T2-weighted images were obtained in all 64 patients, and contrast-enhanced T1-weighted images were also obtained in 27 patients. Urethral pathologic conditions, established with urethroscopy or histologic examination, or both, included urethral diverticula, inflammatory granuloma, and primary and metastatic neoplasms. On T2-weighted images, all normal urethras demonstrated a characteristic targetlike appearance with differentiation among the outer ring of low signal intensity, the middle zone of higher signal intensity, and the center of low signal intensity. After injection of gadopentetate dimeglumine, the targetlike appearance of the normal urethra was seen on the T1-weighted images. Urethral diverticula were detected with MR imaging in all nine patients with that diagnosis, and in each, MR imaging demonstrated urethral expansion, distortion of the zonal anatomy, and presence of fluid in the middle zone. Primary or metastatic urethral neoplasms were also detected with MR imaging in every patient with the diagnosis, but differentiation between benign and malignant disease was not possible. Local staging of primary or metastatic malignant disease was correct in eight of the 11 patients. In three patients, the inflammatory changes could not be differentiated from tumor invasion, resulting in overestimation of tumor extent.


Depression management - from neurobiology to a shared care approach.
The management of depression has recently been the focus of several articles, in particular regarding the efficacy of pharmacological and other treatments. In order for these to be effective as possible, correct diagnosis, consideration of the underlying neurobiology and an appropriate provision of healthcare services must be ensured.


Cutting edge: recombinase-activating gene expression and V(D)J recombination in CD4+CD3low mature T lymphocytes.
The recombinase-activating genes, RAG-1 and RAG-2, can be expressed by a subset of B cells within germinal centers, where they mediate secondary V(D)J rearrangements. This receptor revision mechanism could serve either receptor diversification or tolerance-induced functions. Alternatively, it might rescue those cells the receptors of which have been damaged by somatic mutation. Less is known about the occurrence of similar mechanisms in T cells. Here we show that mature T cells with defective TCR surface expression can express RAG genes and are capable of initiating secondary V(D)J rearrangements. The possibility that a cell rescue mechanism based on the generation of a novel Ag receptor might be active in peripheral T cells is envisaged.


Targeted Rejection Triggers Differential Pro- and Anti-Inflammatory Gene Expression in Adolescents as a Function of Social Status.
Social difficulties during adolescence influence life-span health. To elucidate underlying mechanisms, we examined whether a noxious social event, targeted rejection (TR), influences the signaling pathways that regulate inflammation, which is implicated in a number of health problems. For this study, 147 adolescent women at risk for developing a first episode of major depression were interviewed every 6 months for 2.5 years to assess recent TR exposure, and blood was drawn to quantify leukocyte messenger RNA (mRNA) for nuclear factor-κB (NF-κB) and inhibitor of κB (I-κB) and the inflammatory biomarkers C-reactive protein and interleukin-6. Participants had more NF-κB and I-κB mRNA at visits when TR had occurred. These shifts in inflammatory signaling were most pronounced for adolescents high in perceived social status. These findings demonstrate that social rejection upregulates inflammatory gene expression in youth at risk for depression, particularly for those high in status. If sustained, this heightened inflammatory signaling could have implications for life-span health.


Supercritical fluid extraction as an on-line clean-up technique for rapid amperometric screening and alternative liquid chromatography for confirmation of paraquat and diquat in olive oil samples.
A rapid and simple method for the direct screening of paraquat (PQ) and diquat (DQ) in olive oil samples is proposed. The sample screening method involves supercritical fluid extraction (SFE) (clean-up followed by the extraction of the analytes) followed by continuous flow electrochemical detection. Those samples for which the total concentration is close to or above the threshold limit established by the Columbian Society for Social Protection (0.05 microg g(-1)) are subsequently analyzed by liquid chromatography (LC) with diode array detection (DAD). This confirmation method allows the determination of PQ and DQ in the range between 0.04 and 1.0 microg g(-1), with average relative standard deviations lower than 3.5%, and 0.003 and 0.002 microg g(-1) detection limits for PQ and DQ, respectively. The proposed arrangement opens up interesting prospects for the direct determination of polar pesticides in complex samples with a good throughput and a high level of automation.


SMARCA4 mutations in KRAS-mutant lung adenocarcinoma: a multi-cohort analysis.
KRAS is a key oncogenic driver in lung adenocarcinoma (LUAD). Chromatin-remodeling gene SMARCA4 is comutated with KRAS in LUAD; however, the impact of SMARCA4 mutations on clinical outcome has not been adequately established. This study sought to shed light on the clinical significance of SMARCA4 mutations in LUAD. The association of SMARCA4 mutations with survival outcomes was interrogated in four independent cohorts totaling 564 patients: KRAS-mutant patients with LUAD who received nonimmunotherapy treatment from (a) The Cancer Genome Atlas (TCGA) and (b) the MSK-IMPACT Clinical Sequencing (MSK-CT) cohorts; and KRAS-mutant patients with LUAD who received immune checkpoint inhibitor-based immunotherapy treatment from (c) the MSK-IMPACT (MSK-IO) and (d) the Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) immunotherapy cohorts. Of the patients receiving nonimmunotherapy treatment, in the TCGA cohort (n = 155), KRAS-mutant patients harboring SMARCA4 mutations (KS) showed poorer clinical outcome [P = 6e-04 for disease-free survival (DFS) and 0.031 for overall survival (OS), respectively], compared to KRAS-TP53 comutant (KP) and KRAS-only mutant (K) patients; in the MSK-CT cohort (n = 314), KS patients also exhibited shorter OS than KP (P = 0.03) or K (P = 0.022) patients. Of patients receiving immunotherapy, KS patients consistently exhibited the shortest progression-free survival (PFS; P = 0.0091) in the MSK-IO (n = 77), and the shortest PFS (P = 0.0026) and OS (P = 0.0014) in the WFBCCC (n = 18) cohorts, respectively. Therefore, mutations of SMARCA4 represent a genetic factor leading to adverse clinical outcome in lung adenocarcinoma treated by either nonimmunotherapy or immunotherapy.


Structural explanation for the tunable substrate specificity of an E. coli nucleoside hydrolase: insights from molecular dynamics simulations.
Parasitic protozoa rely on nucleoside hydrolases that play key roles in the purine salvage pathway by catalyzing the hydrolytic cleavage of the N-glycosidic bond that connects nucleobases to ribose sugars. Cytidine-uridine nucleoside hydrolase (CU-NH) is generally specific toward pyrimidine nucleosides; however, previous work has shown that replacing two active site residues with Tyr, specifically the Thr223Tyr and Gln227Tyr mutations, allows CU-NH to process inosine. The current study uses molecular dynamics (MD) simulations to gain atomic-level insight into the activity of wild-type and mutant E. coli CU-NH toward inosine. By examining systems that differ in the identity and protonation states of active site catalytic residues, key enzyme-substrate interactions that dictate the substrate specificity of CU-NH are identified. Regardless of the wild-type or mutant CU-NH considered, our calculations suggest that inosine binding is facilitated by interactions of the ribose moiety with active site residues and Ca2+, and π-interactions between two His residues (His82 and His239) and the nucleobase. However, the lack of observed activity toward inosine for wild-type CU-NH is explained by no residue being correctly aligned to stabilize the departing nucleobase. In contrast, a hydrogen-bonding network between hypoxanthine and a newly identified general acid (Asp15) is present when the two Tyr mutations are engineered into the active site. Investigation of the single CU-NH mutants reveals that this hydrogen-bonding network is only maintained when both Tyr mutations are present due to a π-interaction between the residues. These results rationalize previous experiments that show the single Tyr mutants are unable to efficiently hydrolyze inosine and explain how the Tyr residues work synergistically in the double mutant to stabilize the nucleobase leaving group during hydrolysis. Overall, our simulations provide a structural explanation for the substrate specificity of nucleoside hydrolases, which may be used to rationally develop new treatments for kinetoplastid diseases.


Coping, social support, and depressive symptoms in Parkinson's disease.
Social support, depressive symptoms, and three methods of coping were assessed in 45 patients with Parkinson's disease (PD) and 24 comparably disabled controls. The PD subjects employed significantly fewer cognitive and behavioral coping strategies compared with the controls. Fewer depressive symptoms were related to increased cognitive coping in PD subjects. Behavioral coping strategies were associated with lesser depression among controls. Avoidance coping methods showed a marginally significant positive association with depressive symptoms in PD subjects. Social support was related to the significant coping predictors in each group, but was not related to depressive symptoms. Although correlational, these results might suggest that active (cognitive and behavioral) coping strategies are superior to avoidance strategies in attenuating the affective distress expected from chronic deteriorative illnesses.


Auditory attention in autism spectrum disorder: An exploration of volumetric magnetic resonance imaging findings.
Studies have shown that individuals with autism spectrum disorder (ASD) tend to perform significantly below typically developing individuals on standardized measures of attention, even when controlling for IQ. The current study sought to examine within ASD whether anatomical correlates of attention performance differed between those with average to above-average IQ (AIQ group) and those with low-average to borderline ability (LIQ group) as well as in comparison to typically developing controls (TDC). Using automated volumetric analyses, we examined regional volume of classic attention areas including the superior frontal gyrus, anterior cingulate cortex, and precuneus in ASD AIQ (n = 38) and LIQ (n = 18) individuals along with 30 TDC. Auditory attention performance was assessed using subtests of the Test of Memory and Learning (TOMAL) compared among the groups and then correlated with regional brain volumes. Analyses revealed group differences in attention. The three groups did not differ significantly on any auditory attention-related brain volumes; however, trends toward significant size-attention function interactions were observed. Negative correlations were found between the volume of the precuneus and auditory attention performance for the AIQ ASD group, indicating larger volume related to poorer performance. Implications for general attention functioning and dysfunctional neural connectivity in ASD are discussed.


Do SSRIs differ in their antidepressant efficacy.
Selective serotonin reuptake inhibitors (SSRIs) have been extensively studied worldwide and show at least equivalent efficacy to the tricyclic antidepressants (TCAs). Some of the SSRIs have demonstrated superior efficacy to TCAs in a number of subgroups including patients with severe depression, suicidal thoughts or depression associated with anxiety. There is currently a lack of direct comparative data between the different SSRIs, although the few studies which are available indicate overall equal efficacy. However, the pharmacodynamic and pharmacokinetic characteristics may result in different side-effects which might, in turn, lead to a characteristic pattern of use.


Soil biota reduce allelopathic effects of the invasive Eupatorium adenophorum.
Allelopathy has been hypothesized to play a role in exotic plant invasions, and study of this process can improve our understanding of how direct and indirect plant interactions influence plant community organization and ecosystem functioning. However, allelopathic effects can be highly conditional. For example allelopathic effects demonstrated in vivo can be difficult to demonstrate in field soils. Here we tested phytotoxicity of Eupatorium adenophorum (croftonweed), one of the most destructive exotic species in China, to a native plant species Brassica rapa both in sand and in native soil. Our results suggested that natural soils from different invaded habitats alleviated or eliminated the efficacy of potential allelochemicals relative to sand cultures. When that soil is sterilized, the allelopathic effects returned; suggesting that soil biota were responsible for the reduced phytotoxicity in natural soils. Neither of the two allelopathic compounds (9-Oxo-10,11-dehydroageraphorone and 9b-Hydroxyageraphorone) of E. adenophorum could be found in natural soils infested by the invader, and when those compounds were added to the soils as leachates, they showed substantial degradation after 24 hours in natural soils but not in sand. Our findings emphasize that soil biota can reduce the allelopathic effects of invaders on other plants, and therefore can reduce community invasibility. These results also suggest that soil biota may have stronger or weaker effects on allelopathic interactions depending on how allelochemicals are delivered.


Clinical presentation and management of acromegaly in elderly patients.
Acromegaly is a rare disease with a peak of incidence in early adulthood. However, enhanced awareness of this disease, combined with wide availability of magnetic resonance imaging (MRI), has increased the diagnosis of forms with mild presentation, especially in elderly patients. Moreover, due to increased life expectancy and proactive individualized treatment, patients with early-onset acromegaly are today aging. The aim of our study was to describe our cohort of elderly patients with acromegaly. This is a cross-sectional retrospective study of 96 outpatients. Clinical, endocrine, treatment, and follow-up data were collected using the electronic database of the University Hospital of Padova, Italy. We diagnosed acromegaly in 13 patients, aged ≥65 years, presenting with relatively small adenomas and low IGF-1 secretion. Among them, 11 patients were initially treated with medical therapy and half normalized hormonal levels after 6 months without undergoing neurosurgery (TNS). Remission was achieved after TNS in three out of four patients (primary TNS in two); ten patients presented controlled acromegaly at the last visit. Acromegaly-related comorbidities (colon polyps, thyroid cancer, adrenal incidentaloma, hypertension, and bone disease) were more prevalent in patients who had an early diagnosis (31 patients, characterized by a longer follow-up of 24 years) than in those diagnosed aged ≥65 years (5 years of follow-up). Elderly acromegalic patients are not uncommon. Primary medical therapy is a reasonable option and is effectively used, while the rate of surgical success is not reduced. A careful cost-benefit balance is suggested. Disease-specific comorbidities are more prevalent in acromegalic patients with a longer follow-up rather than in those diagnosed aged ≥65 years.


An Emotion Care Model using Multimodal Textual Analysis on COVID-19.
At the dawn of the year 2020, the world was hit by a significant pandemic COVID-19, that traumatized the entire planet. The infectious spread grew in leaps and bounds and forced the policymakers and governments to move towards lockdown. The lockdown further compelled people to stay under house arrest, which further resulted in an outbreak of emotions on social media platforms. Perceiving people's emotional state during these times becomes critically and strategically important for the government and the policymakers. In this regard, a novel emotion care scheme has been proposed in this paper to analyze multimodal textual data contained in real-time tweets related to COVID-19. Moreover, this paper studies 8-scale emotions (Anger, Anticipation, Disgust, Fear, Joy, Sadness, Surprise, and Trust) over multiple categories such as nature, lockdown, health, education, market, and politics. This is the first of its kind linguistic analysis on multiple modes pertaining to the pandemic to the best of our understanding. Taking India as a case study, we inferred from this textual analysis that 'joy' has been lesser towards everything (~9-15%) but nature (~17%) due to the apparent fact of lessened pollution. The education system entailed more trust (~29%) due to teachers' fraternity's consistent efforts. The health sector witnessed sadness (~16%) and fear (~18%) as the dominant emotions among the masses as human lives were at stake. Additionally, the state-wise and emotion-wise depiction is also provided. An interactive internet application has also been developed for the same.


CPP-Based Bioactive Drug Delivery to Penetrate the Blood-Brain Barrier: A Potential Therapy for Glioblastoma Multiforme.
A large number of studies have been conducted on the treatment of glioblastoma multiforme (GBM). Chemotherapeutic drugs cannot penetrate deeply into the brain parenchyma due to the presence of the blood-brain barrier (BBB). Hence, crossing BBB is a significant obstacle in developing new therapeutic methods for GBM. Cell-penetrating peptides (CPPs) have emerged as new tools that can efficiently deliver various substances across BBB. CPPs beneficial properties, such as BBB penetration capacity, low toxicity, and the ability to achieve active targeting and controllable drug release, have made them worthy candidates for GBM treatment. However, their application is limited by several drawbacks, including lack of selectivity, insufficient transport efficacy, and low stability. In order to overcome the selectivity issue, tumor targeting peptides and sequences that can be activated at the target site have been embedded into the structure of CPPs. To overcome their insufficient transport efficacy into the cells, which is mostly due to endosomal entrapment, various endosomolytic moieties have been incorporated into CPPs. Finally, their instability in blood circulation can be solved through different modifications to their structures. As this field is moving beyond preclinical studies, the discovery of new and more efficient CPPs for GBM treatment has become crucial. Thus, by using display techniques, such as phage display, this encouraging treatment strategy can be developed further. Consequently, despite several challenges in CPPs application, recent progress in studies has shown their potential for the development of the next generation GBM therapeutics.


Integrated Analysis Reveals the Characteristics and Effects of SARS-CoV-2 Maternal-Fetal Transmission.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has caused a pandemic of coronavirus disease 2019 (COVID-19) and is threatening global health. SARS-CoV-2 spreads by air with a transmission rate of up to 15%, but the probability of its maternal-fetal transmission through the placenta is reported to be low at around 3.28%. However, it is still unclear that which tissues and developmental periods hold higher risks and what the underlying molecular mechanisms are. We conducted an integrated analysis of large-scale transcriptome and single-cell sequencing data to investigate the key factors that affect SARS-CoV-2 maternal-fetal transmission as well as the characteristics and effects of them. Our results showed that the abundance of cytomegalovirus (CMV) and Zika virus (ZIKV) infection-associated factors in the placenta were higher than their primarily infected tissues, while the expression levels of SARS-CoV-2 binding receptor angiotensin-converting enzyme II (ACE2) were similar between lung and placenta. By contrast, an important SARS-CoV-2 infection-associated factor, type II transmembrane serine protease (TMPRSS2), was poorly expressed in placenta. Further scRNA-Seq analysis revealed that ACE2 and TMPRSS2 were co-expressed in very few trophoblastic cells. Interestingly, during the embryonic development stages, the abundance of ACE2 and TMPRSS2 was much higher in multiple embryonic tissues than in the placenta. Based on our present analysis, the intestine in 20th week of embryonic development was at a high risk of SARS-CoV-2 infection. Additionally, we found that during the fetal development, ACE2 and TMPRSS2 were enriched in pathogen infection-associated pathways and may involve in the biological processes related to T-cell activation. In conclusion, our present study suggests that though the placenta provides a good physical barrier against SARS-CoV-2 infection for healthy fetal development, multiple embryonic tissues are under risks of the virus infection, which may be adversely affected once infected prenatally. Therefore, it is necessary to enhance maternal care to prevent the potential impact and harm of SARS-CoV-2 maternal-fetal transmission.


[Treatment of adrenocortical carcinomas is challenging].
Adrenocortical carcinomas (ACC) are rare tumours responsible for only 0.02% of the total number of malignant diseases. However the ACC are aggressive with a mean fiveyears survival of 20-50% and are often associated with increased production of adrenocortical hormones. The effect of the treatment is controversial and often based on small retrospective series or expert opinions. Centralization, international attention and collaboration in the treatment of ACC are mandatory. Randomized clinical trials are needed to determine the best treatment strategy in order to increase survival in patients with ACC.


Effects of the Mediterranean Diet on Morbidity from Inflammatory and Recurrent Diseases with Special Reference to Childhood Asthma.
Objective: For 15 years, we have been working with a nutritional programme based on the traditional Mediterranean diet (TMD) to complete the treatment of inflammatory and recurrent diseases (IRD), such as childhood asthma. The objective of this study is to verify the effects of TMD in the prevention and treatment of IRD by measuring the incidence of infant morbidity over 8 years. Material and Methods: The number of patients who suffered from IRD each year (just before the pandemic) was determined, as well as the frequentation and the percentage of scheduled and on-demand consultations. Results: The incidence of infant morbidity decreased as they were incorporated into a TMD, and we observed a progressive disappearance of IRD. At the beginning of the study, 20% of the patients had been diagnosed with some type of IRD. At the study's end, the prevalence of IRD decreased to less than 2%, and the use of drugs and surgical interventions decreased markedly. Conclusions: A diet based on the TMD reduces the incidence of infant morbidity and contributes to the disappearance of IRD, whereas some non-traditional foods with high antigenic power could be involved in the appearance of IRD.


[Cytometric analysis of neoplastic processes in the large intestine].
Examinations of macroscopically intact mucosa, of adenomas with various dysplasia degrees, and of adenocarcinoma have helped single out cytometric parameters and a number of morphologic characteristics describing the proliferation processes in the large intestine. Variability of the nuclear shape and size, the mitotic activity of the glandular epithelium, and the volumic fraction of proliferating DNA-synthesizing cells are characteristic of malignant processes.


Molecular cloning, characterization and localization of PfPK4, an eIF-2alpha kinase-related enzyme from the malarial parasite Plasmodium falciparum.
PfPK4, a protein kinase gene from the human malarial parasite Plasmodium falciparum, has been cloned utilizing oligonucleotide probing. The gene encodes a protein of a predicted length of 1123 amino acids, and within this amino acid sequence all the conserved regions characteristic of protein kinases can be identified. The catalytic kinase domain possesses highest identities (34-37%) with eukaryotic initiation factor-2alpha (eIF-2alpha) kinases, especially haem-regulated inhibitory (HRI) protein kinases. There are two kinase inserts in PfPK4, located at positions common to eIF-2alpha kinases. The first insert separates kinase subdomains IV and VI by 559 amino acids, and the second subdomains VII and VIII by 41 amino acids. Both inserts are larger than their homologues in eIF-2alpha kinases. The sequence of PfPK4 has one putative haemin-binding site. The recombinant protein, expressed in Escherichia coli, phosphorylates a synthetic peptide representing a substrate of eIF-2alpha kinases. Autophosphorylation and substrate phosphorylation are inhibited by haemin. Thus PfPK4 appears to be the first protozoan protein kinase related to eIF-2alpha kinases and might be the first non-mammalian HRI kinase. Western blots indicated that the protein is expressed as major forms of 80 and 90 kDa. Whereas the 80 kDa form is present throughout the intraerythrocytic development and in merozoites, the two 90 kDa forms are only found in mature parasites. One of the latter is also present in the membrane fraction of erythrocytes harbouring segmenters. Confocal microscopy detected the protein distributed throughout the trophozoite, whereas it was found in discrete foci (punctate distribution) in segmenters. PfPK4 co-localizes with P. falciparum 83 kDa antigen/apical membrane antigen-1 at the apical complex in segmenters and merozoites, but does not co-localize with rhoptry-associated protein-1.


An Archaeosome-Adjuvanted Vaccine and Checkpoint Inhibitor Therapy Combination Significantly Enhances Protection from Murine Melanoma.
Archaeosomes constitute archaeal lipid vesicle vaccine adjuvants that evoke a strong CD8⁺ T cell response to antigenic cargo. Therapeutic treatment of murine B16-ovalbumin (B16-OVA) melanoma with archaeosome-OVA eliminates small subcutaneous solid tumors; however, they eventually resurge despite an increased frequency of circulating and tumor infiltrating OVA-CD8⁺ T cells. Herein, a number of different approaches were evaluated to improve responses, including dose number, interval, and the combination of vaccine with checkpoint inhibitors. Firstly, we found that tumor protection could not be enhanced by repetitive and/or delayed boosting to maximize the CD8⁺ T cell number and/or phenotype. The in vivo cytotoxicity of vaccine-induced OVA-CD8⁺ T cells was impaired in tumor-bearing mice. Additionally, tumor-infiltrating OVA-CD8⁺ T cells had an increased expression of programmed cell death protein-1 (PD-1) compared to other organ compartments, suggesting impaired function. Combination therapy of tumor-bearing mice with the vaccine archaeosome-OVA, and α-CTLA-4 administered concurrently as well as α-PD-1 and an α-PD-L1 antibody administered starting 9 days after tumor challenge given on a Q3Dx4 schedule (days 9, 12, 15 and 18), significantly enhanced survival. Following multi-combination therapy ~70% of mice had rapid tumor recession, with no detectable tumor mass after >80 days in comparison to a median survival of 17-22 days for untreated or experimental groups receiving single therapies. Overall, archaeosomes offer a powerful platform for delivering cancer antigens when used in combination with checkpoint inhibitor immunotherapies.


One plus one makes more than two.
Pleasant memories rejuvenate and this letter is written to that purpose. Although dedicated to Barry Ganetzky, I hope it will please also those that shared their times with us in the lab of Seymour Benzer. For those too young to have so distant memories, I hope this text will teach them the same lessons we learnt then.


N-acylated alpha-amino acids as novel oral delivery agents for proteins.
A series of N-acylated alpha-amino acids were synthesized and shown to improve the oral delivery of two protein drugs, salmon calcitonin (sCT) and interferon-alpha. Forty-five compounds in this series were tested in vivo in rats and primates. A significant positive correlation was found between the log P of the acylated amino acids and the decrease in serum calcium following oral dosage of sCT in rats. Such a correlation was not found for interferon-alpha. These derivatized amino acids only weakly inhibited the activity of trypsin or leucine aminopeptidase. Histological examinations of rat intestinal tissue after oral dosing of acylated amino acid/protein combinations revealed no detectable pathology.


Static and dynamic functional connectivity variability of the anterior-posterior hippocampus with subjective cognitive decline.
Subjective cognitive decline (SCD) is a putative Alzheimer's disease (AD) precursor without objective neuropsychological deficits. The hippocampus plays an important role in cognitive function and emotional responses and is generally aberrant in SCD. However, previous studies have mainly focused on static functional connectivity (sFC) by resting-state functional magnetic resonance imaging (fMRI) in SCD individuals, and it remains unclear whether hippocampal dynamic functional connectivity (dFC) changes exist in SCD and whether those changes are associated with subtle changes in cognitive function or affect. Seventy SCD patients and 65 healthy controls were recruited. Demographic data, comprehensive neuropsychology assessments, and resting-state fMRI data were collected. The bilateral anterior and posterior hippocampi were selected as seeds to investigate the static and dynamic functional connectivity alterations in SCD. Compared to healthy controls, subjects with SCD exhibited: (1) decreased sFC between the left caudal hippocampus and left precuneus; (2) decreased dFC variability between the bilateral caudal hippocampus and precuneus; (3) increased dFC variability between the bilateral rostral hippocampus and caudate nucleus; and (4) increased dFC variability between the left rostral hippocampus and left olfactory cortex. Additionally, the attention scores were positively correlated with dFC variability between the left posterior hippocampus and left precuneus, and the dFC variability between the bilateral anterior hippocampus and caudate nucleus was positively correlated with depression scores and negatively correlated with global cognition scores. SCD individuals exhibited abnormal sFC and dFC in the anterior-posterior hippocampus, and abnormal dFC was more widespread than abnormal sFC. A combination of sFC and dFC provides a new perspective for exploring the brain pathophysiological mechanisms in SCD and offers potential neuroimaging biomarkers for the early diagnosis and intervention of AD.


Reduction in recurrent cardiovascular events with prasugrel compared with clopidogrel in patients with acute coronary syndromes from the TRITON-TIMI 38 trial.
In the TRITON-TIMI 38 trial, greater platelet inhibition with prasugrel reduced the first occurrence of the primary endpoint (cardiovascular death, MI, or stroke) compared with clopidogrel in patients with an acute coronary syndrome (ACS) undergoing planned percutaneous coronary intervention. We hypothesized that prasugrel would reduce not only first events but also recurrent primary endpoint events and therefore total events compared with clopidogrel. Poisson regression analysis was performed to compare the number of occurrences of the primary endpoint between prasugrel and clopidogrel in TRITON-TIMI 38. Landmark analytic methods were used to evaluate the risk of a recurrent primary endpoint event following an initial non-fatal endpoint event. Among patients with an initial non-fatal event, second events were significantly reduced with prasugrel compared to clopidogrel (10.8 vs. 15.4%, HR 0.65, 95% CI 0.46-0.92; P = 0.016), as was CV death following the non-fatal event (3.7 vs. 7.1%, HR 0.46, 95% CI 0.25-0.82; P = 0.008). Overall there was a reduction of 195 total primary efficacy events with prasugrel vs. clopidogrel (rate ratio 0.79, 95% CI 0.71-0.87; P < 0.001). Recurrent bleeding events occurred infrequently (TIMI major non-CABG bleeds: four with prasugrel and two with clopidogrel). Study drug discontinuation was frequent following the initial major bleeding event (42% of patients discontinued study drug). While standard statistical analytic techniques for clinical trials censor patients who experience a component of the primary composite endpoint, total cardiovascular events remain important to both patients and clinicians. Prasugrel, a more potent anti-platelet agent, reduced both first and subsequent cardiovascular events compared with clopidogrel in patients with ACS.


Non-interpenetrating honeycomb-like 2D [6,3] network built by a novel trigonal metalloligand.
The combination of a novel trigonal metalloligand and linear linker affords the large non-interpenetrating honeycomb-like 2D [6,3] network in spite of the large hexagon lattice dimension.


Identification of oligosaccharides formed during stachyose hydrolysis by Pectinex Ultra SP-L.
The commercial enzyme preparation Pectinex Ultra SP-L containing fructosyltransferase activity was used to hydrolyze stachyose. During this reaction, besides the formation of mono-, di-, and trisaccharides (DP(3)), the presence of one pentasaccharide (DP(5)) and a new oligosaccharide (DP(6)) has been detected by gas chromatography. DP(5) and DP(6) oligosaccharides were isolated and fully characterized for the first time by an extensive nuclear magnetic resonance (NMR) study. Complete structure elucidation and full proton and carbon assignments were carried out using 1D ((1)H, (13)C) and 2D (gCOSY, multiplicity-edited gHSQC, gHSQC-TOCSY, and gHMBC) NMR experiments. The two oligosaccharides were shown to be stachyose-based structures; the pentasaccharide has a fructose unit linked to the C-1 of the fructose end of stachyose, and the hexasaccharide has a fructose unit linked to the C-1 of the fructose end of the pentasaccharide. The fructosyltransferase activity present in Pectinex Ultra SP-L allows new uses of this commercial enzyme preparation in the synthesis of oligosaccharides derived from alpha-galactosides.


Identifying quality outliers in a large, multiple-institution database by using customized versions of the Simplified Acute Physiology Score II and the Mortality Probability Model II0.
To assess whether customized versions of the Simplified Acute Physiology Score (SAPS) II and the Mortality Probability Model (MPM) II0 agree on the identity of intensive care unit quality outliers within a multiple-center database. Retrospective database analysis. Patient subset of the Project IMPACT database consisting of 39,617 adult patients admitted to surgical, medical, and mixed surgical-medical intensive care units at 54 hospitals between 1995 and 1999 who met inclusion criteria for SAPS II and MPM II0. Customized versions of SAPS II and MPM II0 were obtained by fitting new logistic regressions to the data by using the risk score as the independent variable and outcome at hospital discharge as the dependent variable. The data set was divided randomly into a training set and a validation set. Each model was customized by using the training set; model performance was then assessed in the validation set by using the area under the receiver operating characteristic curve and the Hosmer-Lemeshow statistic. The final models were based on the entire data set. The level of agreement between the customized models on the identity of quality outliers was evaluated by using kappa analysis. Both customized models exhibited good discrimination and good calibration in this database. The area under the receiver operating characteristic curve was 0.83 for MPM II0 and 0.872 for SAPS II following model customization. The Hosmer-Lemeshow statistic was 12.3 ( >.14) for MPM II0, and 8.17 (p >.42) for SAPS II, after customization. Kappa analysis showed only fair agreement between the two customized models with regard to the identity of the quality outliers: kappa = 0.44 (95% confidence interval, 0.24, 0.65). Customization of SAPS II and MPM II0 to the Project IMPACT database resulted in well-calibrated models. Despite this, the models exhibited only a moderate level of agreement in which hospitals were designated as quality outliers. Seventeen of the 54 hospitals were categorized differently depending on which of the two scoring systems was used. Therefore, the rating of quality of care appears, in part, to be a function of the prediction model used.


SM-20302, a nonpeptide GPIIb/IIIa receptor antagonist, exhibits a wide therapeutic window in a newly developed hemorrhage model in mice.
We have developed a gastrointestinal hemorrhage model in mice and thereby assessed the potential risk of bleeding following administration of SM-20302, a nonpeptide GPIIb/IIIa receptor antagonist. First, SM-20302 selectively inhibited the interaction between human platelets and fibrinogen in vitro. Second, SM-20302 dose-dependently inhibited ADP-induced ex vivo platelet aggregation in mice and produced an ED50 value of 0.02 mg/kg. ED50 values of cyclo(RGDT)2, aspirin and ticlopidine were 0.48, 0.74 and 13.3 mg/kg, respectively. Finally, the bleeding risk of SM-20302 was examined in our newly developed hemorrhage model. Gastrointestinal hemorrhage was assessed 24 h later when the antiplatelet agents tested were administered to mice prior to the oral dosing of 0.1 N hydrochloric acid in 90% ethanol. The resulting hemorrhage was classified into three grades, major, minor or no bleeding, primarily based on the criteria used in the TIMI trial. All compounds tested induced gastrointestinal hemorrhage in a dose-dependent manner. Minimum hemorrhagic doses, MHDs, of SM-20302, cyclo (RGDT)2, aspirin and ticlopidine were 3, 3, 1 and 100 mg/kg, respectively. The potential risk of bleeding was assessed by the ratio of MHD to ED50 value. MHD/ED50 values of SM-20302, cyclo(RGDT)2, aspirin and ticlopidine were calculated to be 150, 6.3, 1.4 and 7.5, respectively. These results suggest that this experimental hemorrhage model may be useful for the evaluation of the bleeding complications of antiplatelet agents and that SM-20302 may have a wider therapeutic window than nonspecific integrin inhibitor and conventional antiplatelet agents.


Polarity protein Par3 sensitizes breast cancer to paclitaxel by promoting cell cycle arrest.
Paclitaxel, belongs to tubulin-binding agents (TBAs), shows a great efficacy against breast cancer via stabilizing microtubules. Drug resistance limits its clinical application. Here we aimed to explore a role of Polarity protein Par3 in improving paclitaxel effectiveness. Breast cancer specimens from 45 patients were collected to study the relationship between Par3 expression and paclitaxel efficacy. The Kaplan-Meier method was used for survival analysis. Cell viability was measured in breast cancer cells (SK-BR-3 and T-47D) with Par3 over-expression or knockdown. The flow cytometry assays were performed to measure cell apoptosis and cell cycle. BrdU incorporation assay and Hoechst 33,258 staining were performed to measure cell proliferation and cell apoptosis, respectively. Immunofluorescence was used to detect microtubule structures. Par3 expression was associated with good response of paclitaxel in breast cancer patients. Consistently, Par3 over-expression significantly sensitized breast cancer cells to paclitaxel by promoting cell apoptosis and reducing cell proliferation. In Par3 overexpressing cells upon paclitaxel treatment, we observed intensified cell cycle arrests at metaphase. Further exploration showed that Par3 over-expression stabilized microtubules of breast cancer cells in response to paclitaxel and resists to microtubules instability induced by nocodazole, a microtubule-depolymerizing agent. Par3 facilitates polymeric forms of tubulin and stabilizes microtubule structure, which aggravates paclitaxel-induced delay at the metaphase-anaphase transition, leading to proliferation inhibition and apoptosis of breast cancer cells. Par3 has a potential role in sensitizing breast cancer cells to paclitaxel, which may provide a more precise assessment of individual treatment and novel therapeutic targets.


Floquet Engineering a Bosonic Josephson Junction.
We study Floquet engineering of the tunnel coupling between a pair of one-dimensional bosonic quasicondensates in a tilted double-well potential. By modulating the energy difference between the two wells, we reestablish tunnel coupling and precisely control its amplitude and phase. This allows us to initiate coherence between two initially uncorrelated Bose gases and prepare different initial states in the emerging sine-Gordon Hamiltonian. We fully characterize the Floquet system and study the dependence of both equilibrium properties and relaxation on the modulation.


Transverse piezoelectric field-effect transistor based on single ZnO nanobelts.
A transverse piezoelectric field-effect transistor (TP-FET) based on single ZnO nanobelts has been fabricated on a metallic graphite substrate in an atomic force microscope (AFM). The source-to-drain current of the TP-FET was found to decrease with increasing loading force under a positive bias due to the carrier-trapping effect and the creation of a charge-depletion zone. This TP-FET can be applied as a force/pressure sensor for measuring nanoNewton forces ranged from 0 to 700 nN.


Familial hypomagnesemia--hypercalciuria and pseudotumor cerebri.
Approximately 30 patients with familial hypomagnesemia-hypercalciuria have been reported. We describe an 8-year-old girl with cardinal findings of familial hypomagnesemia-hypercalciuria (hypomagnesemia, hypermagnesiuria, hypercalciuria, renal insufficiency, hyperuricemia, elevated serum parathormone, hyposthenuria and nephrocalcinosis), who received combination therapy consisting of magnesium salts, thiazide diuretic and potassium supplementation. At the 4-year follow-up investigation under this treatment, the patient was found to have cerebral pseudotumor (increased intracranial pressure with normal or small ventricles on neuroimaging, no evidence of an intracranial mass and normal cerebrospinal fluid composition) with papilledema and visual field defects. Thiazide therapy was terminated and the cerebral pseudotumor disappeared. The authors hypothesize that cerebral pseudotumor in this patient was related to severe hypocalcemia, as a consequence of profound hypomagnesemia induced by protracted thiazide treatment. To our knowledge, this is the first report of a child with familial hypomagnesemia-hypercalciuria who developed pseudotumor cerebri after thiazide therapy.


Building blocks for a public health ethics framework for the geriatric community.
The elderly population is steadily growing in South Africa. However, there is limited strategic planning or policy initiatives to address this group's vulnerability resulting in several public health ethical issues that need to be considered and addressed. This article aims to develop a public health ethics framework for the geriatric community with the purpose to review ethical implications when working with the geriatric community. The Q-methodology was selected for data collection. Fifteen statements were ranked by means of a five-point Likert-scale questionnaire. Twenty-two participants from six geriatric institutions participated in the ranking of the statements. The ranking of the statements confirmed the need for a public health ethics framework to provide guidance when working with the geriatric community and to evaluate decisions about geriatric care. Such a framework should be application-based and practice-oriented which can assist in addressing unfamiliarity with public health ethics in general and can extend the capacity for decision-making. The ranking of these statements contributed to the scope of the planned framework, by considering the vulnerability of healthcare practitioners (as community of practitioners) and the geriatric community as a basis from which to promote justice in public health programmes. Based on the ranking of statements, eight building blocks for a public health ethics framework were identified. The building blocks are imbedded in professional ethics and care ethics. The proposed framework can give rise to social justice in public health and the ability to evaluate what the ethical implications are for public health policies, programmes and interventions aimed at the geriatric community.


Paleoceanography of the Late Cretaceous northwestern Tethys Ocean: Seasonal upwelling or steady thermocline?
In this study we attempted to assess whether seasonal upwelling or a steady thermocline persisted at the western margin of the Tethys Ocean during the late Turonian-early Coniacian interval. For this scope, we employed novel and published stable oxygen isotope (δ18O) data of various organisms (bivalves, bivalves, brachiopods, fish and belemnites). New seasonally resolved temperature estimates were based on the δ18O record of sequentially sampled inoceramid (Inoceramus sp.) and rudist (Hippurites resectus) shells from the Scaglia Rossa and Gosau deposits of northern Italy and western Austria, respectively. Diagenetic screening was performed using reflected light, cathodoluminescence (CL), scanning electron microscopy (SEM) and stable isotope analysis. Originally preserved δ13C and δ18O values were used to characterize the lifestyle of the bivalves and detect vital effects that could have biased oxygen isotope-based temperature reconstructions. Inoceramid δ18O values provide-for the first time-information on temperatures of Tethyan benthic waters, which were, on average, 14.4 ± 0.6 °C and fluctuated seasonally within a range of less than 2 °C. Such a thermal regime is in line with the temperatures postulated for late Turonian boreal water masses and support the existence of a cold water supply from the North Atlantic to the Tethyan bottom. Bottom cooling, however, did not affect the shallow water environment. In fact, the rudist-based temperature estimates for shallow water environment revealed a mean annual range of 11 °C, between 24 and 35 °C (assuming a seasonally constant δ18Ow = 1.0 ‰), which are among the warmest temperatures recorded over the entire Late Cretaceous. Our findings, thus, suggest a strong thermal and food web decoupling between the two environments. The absence of a seasonal vertical homogenization of different water bodies suggests the existence of a steady thermocline and, therefore, contrasts with the presence of an active coastal upwelling in the region as hypothesized by previous authors.


Circulating tumor DNA detection in head and neck cancer: evaluation of two different detection approaches.
The use of non-invasive biomarkers such as circulating tumor DNA (ctDNA) in head and neck tumors may be of relevance in early diagnosis and eventually improved outcome. We evaluated two different approaches from two case series in Europe and South America including (i) targeted screening of ctDNA mutations, and (ii) detection of TP53 mutations in plasma and oral rinses without previous knowledge of mutational status in tumor samples. Targeted sequencing in 5 genes identified ctDNA mutations in plasma among 42% of HNSCC cases, 67% of who were early stage cases. No association was found between ctDNA mutation detection and overall survival. Sequencing of the entire coding region of the TP53 gene resulted in identification of TP53 mutations in 76% of tumor cases. However, concordance of mutation detection was low between tumor, oral rinses (11%) and plasma (2,7%) samples. Identification of 5 pathogenic TP53 mutations in oral rinses from 3 non-cancer controls gives additional evidence of mutation occurrence in individuals without a diagnosed cancer and presents an additional challenge for the development of ctDNA diagnostic assays.


[Clinical effect of three dimensional human body scanning system BurnCalc in the evaluation of burn wound area].
Objective: To validate the clinical effect of three dimensional human body scanning system BurnCalc developed by our research team in the evaluation of burn wound area. Methods: A total of 48 burn patients treated in the outpatient department of our unit from January to June 2015, conforming to the study criteria, were enrolled in. For the first 12 patients, one wound on the limbs or torso was selected from each patient. The stability of the system was tested by 3 attending physicians using three dimensional human body scanning system BurnCalc to measure the area of wounds individually. For the following 36 patients, one wound was selected from each patient, including 12 wounds on limbs, front torso, and side torso, respectively. The area of wounds was measured by the same attending physician using transparency tracing method, National Institutes of Health (NIH) Image J method, and three dimensional human body scanning system BurnCalc, respectively. The time for getting information of 36 wounds by three methods was recorded by stopwatch. The stability among the testers was evaluated by the intra-class correlation coefficient (ICC). Data were processed with randomized blocks analysis of variance and Bonferroni test. Results: (1) Wound area of patients measured by three physicians using three dimensional human body scanning system BurnCalc was (122±95), (121±95), and (123±96) cm(2,) respectively, and there was no statistically significant difference among them ( F=1.55, P>0.05). The ICC among 3 physicians was 0.999. (2) The wound area of limbs of patients measured by transparency tracing method, NIH Image J method, and three dimensional human body scanning system BurnCalc was (84±50), (76±46), and (84±49) cm(2,) respectively. There was no statistically significant difference in the wound area of limbs of patients measured by transparency tracing method and three dimensional human body scanning system BurnCalc (P>0.05). The wound area of limbs of patients measured by NIH Image J method was smaller than that measured by transparency tracing method and three dimensional human body scanning system BurnCalc (with P values below 0.05). There was no statistically significant difference in the wound area of front torso of patients measured by transparency tracing method, NIH Image J method, and three dimensional human body scanning system BurnCalc (F=0.33, P>0.05). The wound area of side torso of patients measured by transparency tracing method, NIH Image J method, and three dimensional human body scanning system BurnCalc was (169±88), (150±80), and (169±86) cm(2,) respectively. There was no statistically significant difference in the wound area of side torso of patients measured by transparency tracing method and three dimensional human body scanning system BurnCalc (P>0.05). The wound area of side torso of patients measured by NIH Image J method was smaller than that measured by transparency tracing method and three dimensional human body scanning system BurnCalc (with P values below 0.05). (3) The time for getting information of wounds of patients by transparency tracing method, NIH Image J method, and three dimensional human body scanning system BurnCalc was (77±14), (10±3), and (9±3) s, respectively. The time for getting information of wounds of patients by transparency tracing method was longer than that by NIH Image J method and three dimensional human body scanning system BurnCalc (with P values below 0.05). The time for getting information of wounds of patients by three dimensional human body scanning system BurnCalc was close to that by NIH Image J method (P>0.05). Conclusions: The three dimensional human body scanning system BurnCalc is stable and can accurately evaluate the wound area on limbs and torso of burn patients.


Do aurophilic interactions compete against hydrogen bonds? Experimental evidence and rationalization based on ab initio calculations.
[M(C6F5)(N(H)=CPh2)] (M = Ag (1) and Au (2)) complexes have been synthesized and characterized by X-ray diffraction analysis. Complex 1 shows a ladder-type structure in which two [Ag(C6F5)(N(H)=CPh2)] units are linked by a Ag(I)-Ag(I) interaction in an antiparallel disposition. The dimeric units are associated through hydrogen bonds of the type N-H...F(ortho). On the other hand, gold(I) complex 2 displays discrete dimers also in an antiparallel conformation in which both Au(I)-Au(I) interactions and N-H.F(ortho) hydrogen bonds appear within the dimeric units. The features of these coexisting interactions have been theoretically studied by ab initio calculations based on four different model systems in order to analyze them separately. The interactions have been analyzed at HF and MP2 levels of theory showing that, in this case, even at larger distances. The Au(I)-Au(I) interaction is stronger than Ag(I)-Ag(I) and that N-H.F hydrogen bonding and Au(I)-Au(I) contacts have a similar strength in the same molecule, which permits a competition between these two structural motifs giving rise to different structural arrangements.


Evaluation of efficacy and safety of finasteride 1 mg in 3177 Japanese men with androgenetic alopecia.
Before now, there has been no study of finasteride use exceeding 1 year in Japanese men with androgenetic alopecia (AGA) except the study subsequently conducted from the development phase. Since the launch of finasteride, no study in a larger population had been reported. Ethnic variation of the onset age, progressive nature and degree of hair loss of androgenetic alopecia are known. The therapeutic effect of oral finasteride (Propecia) was examined on androgenetic alopecia of Japanese men. The efficacy and safety of finasteride (1 mg tablet) was evaluated in Japanese men with AGA in the long term. The study enrolled 3177 men given finasteride 1 mg/day from January 2006 to June 2009 at our clinic. Efficacy was evaluated in 2561 men by the modified global photographic assessment; the photographs were assessed using the standardized 7-point rating scale. Safety data were assessed by interviews and laboratory tests in all men enrolled in the study. The overall effect of hair growth was seen in 2230 of 2561 men (87.1%), in whom hair greatly (11.1%), moderately (36.5%) and slightly (39.5%) increased. The response rate improved with increasing duration of treatment. Adverse reactions occurred in 0.7% (23/3177) of men; seven men discontinued treatment based on risk-benefit considerations. No specific safety problems associated with long-term use were observed. This study represents data collected at a single institution. Many patients did not receive follow-up examination. In Japanese men with AGA, oral finasteride used in the long-term study maintained progressive hair regrowth without recognized side-effect.


Learning, life history, and productivity : Children's lives in the Okavango Delta, Botswana.
This article introduces a new model of the relationship between growth and learning and tests a set of hypotheses related to the development of adult competency using time allocation, anthropometric, and experimental task performance data collected between 1992 and 1997 in a multiethnic community in the Okavango Delta, Botswana. Building on seminal work in life history theory by Hawkes, Blurton Jones and associates, and Kaplan and associates, the punctuated development model presented here incorporates the effects of both growth and learning constraints on age-specific task performance. In addition, the payoff to investment in two forms of embodied capital, growth-based and learning-based, are examined in relation to features of the socioecology, including subsistence economy and family composition.The three main findings are:1.The development of adult competency in specific tasks entails a steplike relationship between growth- and experience-based forms of embodied capital in the ontogeny of ability acquisition.2.There is a trade-off between the acquisition of experience-based embodied capital in the form of skills and knowledge and immediate productivity among children. Time allocation to these alternatives is primarily determined by the short- and long-term costs and benefits to parents of investment in children's embodied capital.3.The availability of laborers and the overall labor requirements of the household are major determinants of investment in alternate forms of embodied capital and resulting variation in children's time allocation. The value of children's labor to their parents is dependent upon the opportunity costs to engaging in other activities not only for the child in question but also for potential substitute laborers. These results have important implications for our understanding of the role of growth and learning in the evolution of the human juvenile period, as well as for our understanding of cross-cultural variation in child growth and development and patterns of work and play.


Fast-diffusing p75NTR monomers support apoptosis and growth cone collapse by neurotrophin ligands.
The p75 neurotrophin (NT) receptor (p75NTR) plays a crucial role in balancing survival-versus-death decisions in the nervous system. Yet, despite 2 decades of structural and biochemical studies, a comprehensive, accepted model for p75NTR activation by NT ligands is still missing. Here, we present a single-molecule study of membrane p75NTR in living cells, demonstrating that the vast majority of receptors are monomers before and after NT activation. Interestingly, the stoichiometry and diffusion properties of the wild-type (wt) p75NTR are almost identical to those of a receptor mutant lacking residues previously believed to induce oligomerization. The wt p75NTR and mutated (mut) p75NTR differ in their partitioning in cholesterol-rich membrane regions upon nerve growth factor (NGF) stimulation: We argue that this is the origin of the ability of wt p75NTR , but not of mut p75NTR, to mediate immature NT (proNT)-induced apoptosis. Both p75NTR forms support proNT-induced growth cone retraction: We show that receptor surface accumulation is the driving force for cone collapse. Overall, our data unveil the multifaceted activity of the p75NTR monomer and let us provide a coherent interpretative frame of existing conflicting data in the literature.


Engraftment Effects after Intra-Bone Marrow versus Intravenous Allogeneic Stem Cell Transplantation in a Reduced-Intensity Conditioning Dog Leukocyte Antigen-Identical Canine Model.
Following conventional i.v. hematopoietic stem cell transplantation (IV-HSCT), most of the hematopoietic stem cells get trapped in peripheral organs and do not reach the bone marrow niche. A promising approach to overcome this cell loss during the homing process seems to be the infusion of hematopoietic stem cells directly into the bone marrow cavity (intra-bone marrow [IBM]-HSCT). This study aimed to investigate the engraftment efficiency of IBM-HSCT compared with IV-HSCT following reduced-intensity conditioning in a canine HSCT model. Furthermore, the impact of 2 different graft infusion rates during IBM-HSCT on the engraftment was evaluated. Dogs received 4.5 Gy total body irradiation for conditioning at day -1 and 15 mg/kg cyclosporin A twice daily at days -1 to +35 as immunosuppression. The IV-HSCT group (n = 7) received unmodified bone marrow. The IBM-HSCT cohorts received buffy coat-enriched bone marrow that was applied into the humerus and femur simultaneously with an infusion time of either 10 minutes (IBM10; n = 8) or 60 minutes (IBM60; n = 7). Statistical analyses were performed using the Kruskal-Wallis test followed by the Mann-Whitney U test with Bonferroni correction for multiple comparisons. Statistical significance was declared at Bonferroni-adjusted P < .017. All dogs initially engrafted. One dog of the IBM10 cohort died at day +15 from infection. All 21 evaluable dogs developed a durable mixed donor chimerism over the course of 112 days. Engraftment kinetics did not differ significantly across the 3 groups. Leukocyte and platelet nadirs, as well as the durations of leukopenia and thrombocytopenia, were comparable in the 3 groups. Signs of toxicity for ingestion, body temperature, activity, and defecation did not show statistically significant differences among the 3 groups; only weight loss was greater in the IBM60 group compared with the IV group. IBM-HSCT following reduced-intensity conditioning resulted in an engraftment efficiency and hematopoietic recovery comparable to that seen with conventional IV-HSCT. In addition, modification of the graft infusion rate had no impact on engraftment and hematopoietic recovery in the canine IBM-HSCT model.


Helical, nonracemic inorganic-organic hybrid polymers of cadmium halides with pentadentate bis(oxazoline) ligands.
A chiral, nonracemic pentadentate pyridine bis(oxazoline) ligand forms unprecedented P-helical inorganic-organic hybrid polymers with cadmium halides. The one-dimensional chains consist of Lambda2-configured pentagonal-bipyramidal cadmium complexes with metal-centered chirality bridged by [CdX4]2- tetrahedra via shared halide atoms. In the solid state, the overall helicity exhibits strongly directed orientation parallel to the crystallographic axis a.


Lymphotoxin-β receptor-NIK signaling induces alternative RELB/NF-κB2 activation to promote metastatic gene expression and cell migration in head and neck cancer.
Head and neck squamous cell carcinomas (HNSCC) preferentially spread to regional cervical tissues and lymph nodes. Here, we hypothesized that lymphotoxin-β (LTβ), receptor LTβR, and NF-κB-inducing kinase (NIK), promote the aberrant activation of alternative NF-κB2/RELB pathway and genes, that enhance migration and invasion of HNSCC. Genomic and expression alterations of the alternative NF-kB pathway were examined in 279 HNSCC tumors from The Cancer Genome Atlas (TCGA) and a panel of HNSCC lines. LTβR is amplified or overexpressed in HNSCC of the larynx or oral cavity, while LTβ, NIK, and RELB are overexpressed in cancers arising within lymphoid oropharyngeal and tonsillar sites. Similarly, subsets of HNSCC lines displayed overexpression of LTβR, NIK, and RELB proteins. Recombinant LTβ, and siRNA depletion of endogenous LTβR and NIK, modulated expression of LTβR, NIK, and nuclear translocation of NF-κB2(p52)/RELB as well as functional NF-κB promoter reporter activity. Treatment with a NIK inhibitor (1,3[2H,4H]-Iso-Quinoline Dione) reduced the protein expression of NIK and NF-κB2(p52)/RELB, and blocked LTβ induced nuclear translocation of RELB. NIK and RELB siRNA knockdown or NIK inhibitor slowed HNSCC migration or invation in vitro. LTβ-induces expression of migration and metastasis related genes, including hepatocyte growth/scatter factor receptor MET. Knockdown of NIK or MET similarly inhibited the migration of HNSCC cell lines. This may help explain why HNSCC preferentially migrate to local lymph nodes, where LTβ is expressed. Our findings show that LTβ/LTβR promotes activation of the alternative NIK-NF-κB2/RELB pathway to enhance MET-mediated cell migration in HNSCC, which could be potential therapeutic targets in HNSCC.


Infrared spectra of carbonyl hemoglobins: characterization of dynamic heme pocket conformers.
The infrared spectra for carbon monoxide complexed to hemoglobins were examined in the C-O stretch region. Deconvolution of the spectra requires four bands and supports the presence of four distinct conformers at the ligand binding site. Most typical hemoglobins exhibit only one predominant conformer for each subunit represented by a band at 1951 cm-1 in contrast to myoglobins, which typically exist in two major conformations. Several hemoglobins with an enlarged heme pocket are shown to shift the C-O frequency into the higher frequency conformer regions. Many factors, including pH, temperature, solvents, and divalent metals, are also shown to be capable of expanding the heme pocket. Only very specific structural changes that can reduce the size of the heme pocket will result in the lower frequency conformers. The weighted averages of the multiple CO vibrational frequencies are linearly related to the single 13CO NMR chemical shift values and to the exponential of fast CO on-rates. Conformer interconversion occurs at a rate greater than 10(4) s-1. The infrared C-O stretch spectra provide qualitative and quantitative information on the structural dynamics, stability, and ligand binding properties of hemoglobins.


Effects of potassium supply on limitations of photosynthesis by mesophyll diffusion conductance in Carya cathayensis.
Potassium (K) influences the photosynthesis process in a number of ways; however, the mechanisms underlying the photosynthetic response to differences in K supply are not well understood. Concurrent measurements of gas exchange and chlorophyll fluorescence were made to investigate the effect of K nutrition on photosynthetic efficiency and mesophyll conductance (g(m)) in hickory seedlings (Carya cathayensis Sarg.) in a greenhouse. The results show that leaf K concentrations < 0.7-0.8% appeared to limit the leaf net CO2 assimilation rate (A), and that the relative limitation of photosynthesis due to g(m) and stomatal conductance (g(s)) decreased with increasing supplies of K. However, a sensitivity analysis indicated that A was most sensitive to the maximum carboxylation rate of Rubisco (V(c,max)) and the maximum rate of electron transport (J(max)). These results indicate that the photosynthetic rate is primarily limited by the biochemical processes of photosynthesis (V(c,max) and J(max)), rather than by g(m) and g(s) in K-deficient plants. Additionally, g(m) was closely correlated with g(s) and the leaf dry mass per unit area (M(A)) in hickory seedlings, which indicates that decreased g(m) and g(s) may be a consequence of leaf anatomical adaptation.