Four Functionally Distinct Regions in the Left Supramarginal Gyrus Support Word Processing.

We used fMRI in 85 healthy participants to investigate whether different parts of the left supramarginal gyrus (SMG) are involved in processing phonological inputs and outputs. The experiment involved 2 tasks (speech production (SP) and one-back (OB) matching) on 8 different types of stimuli that systematically varied the demands on sensory processing (visual vs. auditory), sublexical phonological input (words and pseudowords vs. nonverbal stimuli), and semantic content (words and objects vs. pseudowords and meaningless baseline stimuli). In ventral SMG, we found an anterior subregion associated with articulatory sequencing (for SP > OB matching) and a posterior subregion associated with auditory short-term memory (for all auditory > visual stimuli and written words and pseudowords > objects). In dorsal SMG, a posterior subregion was most highly activated by words, indicating a role in the integration of sublexical and lexical cues. In anterior dorsal SMG, activation was higher for both pseudoword reading and object naming compared with word reading, which is more consistent with executive demands than phonological processing. The dissociation of these four "functionally-distinct" regions, all within left SMG, has implications for differentiating between different types of phonological processing, understanding the functional anatomy of language and predicting the effect of brain damage.

Cerebral oximetry and its role in adult cardiac, non-cardiac surgery and resuscitation from cardiac arrest.

Monitors using near-infra red spectroscopy to assess cerebral oxygenation levels non-invasively in discrete areas of the brain have been used clinically for over 20 years. Interest has intensified recently, especially during cardiac surgery, and there are now five commercially available devices. Despite the attraction of being able to measure oxygen supply/demand in such a critical area, there has been only limited uptake of this technology in overall clinical anaesthetic practice. This narrative review aims to explore not only the rationale for using this technology but also the factors which have restricted its more widespread use.

The strange periodic comet machholz.

The recently discovered periodic comet Machholz 1986 VIII (1986e) travels closer to the sun than any known planet and any known comet with an orbital period of less than 150 years, thus providing astronomers with a unique object for studying cometary evolution. The comet is spiraling steadily closer to the sun, from perihelion distance q [unknown] 0.9 astronomical unit at about A.D. 700 to q [unknown] 0.13 at present (orbital period, 5.25 years), to an expected q [unknown] 0.03 by about 2450; should the comet survive such increasingly close perihelion passages, q will begin steadily to increase shortly thereafter. A review of observations made since discovery is presented, together with a discussion of numerical investigations of the comet's orbit over 4000 years and prospects for observing the upcoming return to perihelion in 1991.

Protective action of luminal bile salts in necrotizing acute pancreatitis in mice.

Bile salts in the intestinal lumen act to inhibit the release of cholecystokinin (CCK). Recent studies have shown that CCK may play a permissive role in the development of acute pancreatitis. In this study, the amount of luminal bile salts in female Swiss Webster mice was either decreased by feeding 4% (wt/wt) cholestyramine or increased by feeding 0.5% sodium taurocholate for 1 wk. Plasma levels of CCK were stimulated by cholestyramine and inhibited by taurocholate. Then, acute pancreatitis was induced either by caerulein injections, or by feeding a choline-deficient, ethionine-supplemented (CDE) diet. Feeding of cholestyramine significantly decreased survival from 25% to 0% in the CDE pancreatitis, and increased the magnitude of elevation of serum amylase levels and the extent of pancreatic necrosis in both models of pancreatitis; CCK-receptor blockade with CR-1409 completely abolished the adverse effects of cholestyramine. In contrast, feeding of taurocholate significantly increased survival to 100% and decreased the elevation of serum amylase and pancreatic necrosis; CCK-8 antagonized these actions of taurocholate. Luminal bile salts appear to provide a physiologic protection against necrotizing pancreatitis, at least in part, both by inhibiting the release of CCK and by promoting resistance of the pancreas to CCK excessive stimulation in vivo.

Correction: The nanotipped hairs of gecko skin and biotemplated replicas impair and/or kill pathogenic bacteria with high efficiency.

Correction for 'The nanotipped hairs of gecko skin and biotemplated replicas impair and/or kill pathogenic bacteria with high efficiency' by X. Li, et al., Nanoscale, 2016, 8, 18860-18869.

Invos Cerebral Oximeter compared with the transcranial Doppler for monitoring adequacy of cerebral perfusion in patients undergoing carotid endarterectomy.

AIM: The aim of this prospective study was to assess the correlation between signals obtained during carotid endarterectomy (CEA) under local (LA) or general anesthesia from the Somanetics Invos cerebral oximeter (CO) and transcranial Doppler (TCD). METHODS: Forty patients were enrolled in the study. The percentages fall in TCD mean flow velocity (FVm) and CO regional oxygen saturation (rSO2) on the ipsilateral side following clamping were recorded and the correlation coefficient and Spearman's coefficient of rank correlation were calculated. RESULTS: Fourteen patients were not included in the statistical analysis because either no TCD window or reliable TCD signal was obtained. The remaining 26 patients had a fall in either FVm, rSO2 or both during carotid clamping. There was a highly statistically significant correlation between the percentage fall in FVm and rSO2 with a correlation coefficient of 0.73, P<0.0001, with a 95% confidence interval (CI) for r=0.48 to 0.87; Spearman's coefficient of rank correlation (rho) =0.67, P=0.0008, with a 95% CI for rho=0.384 to 0.84. A significant decline in both TCD and rSO2 was noted in 3 patients under LA out of which 2 required shunts for alteration in conscious level. In 2 LA patients there was a significant decline in TCD but not in rSO2 and the endarterectomy was completed without a shunt. CONCLUSIONS: Regional oxygen saturation correlates well with FVm during carotid clamping. However, the inability to obtain reliable TCD FVm readings in 35% of patients is a serious disadvantage for this monitor. It appears that CO is a satisfactory and possibly superior device for monitoring adequacy of cerebral perfusion and oxygenation during CEA in comparison with the TCD.

Suppression of beta-catenin inhibits the neoplastic growth of APC-mutant colon cancer cells.

Mutations involving the adenomatous polyposis coli (APC) tumor suppressorgene/beta-catenin signaling pathway have been identified in the majority of colon carcinomas. However, the role of aberrant beta-catenin signaling in the neoplastic growth of APC-mutant colon cancer cells has not been directly studied. To address this question, antisense oligonucleotides have been used to specifically down-regulate beta-catenin expression in APC-mutant human colon carcinoma cells. Antisense-mediated suppression of beta-catenin inhibits the in vitro proliferation, anchorage-independent growth, and cellular invasiveness of APC-mutant human colon carcinoma cells. The systemic administration of beta-catenin antisense oligonucleotides down-regulates beta-catenin expression in vivo in human colon cancer xenografts in nude mice. Such treatment inhibits the tumorigenic growth of colon cancer xenografts and can completely eradicate tumors in some treated animals. These studies formally demonstrate the critical role of beta-catenin signaling in the neoplastic growth of APC-mutant colon cancer cells and suggest that strategies targeting beta-catenin may be of use in the therapy of colon cancer.

Bioinspired materials for regenerative medicine: going beyond the human archetypes.

The evolution of life has given rise to innumerable biomaterials with high levels of functional sophistication and performance among many thousands of different environments. The inexhaustible range of strategies and the intrinsic good design they possess can be readily included in the design of biomedical devices and materials, such as wound healing bandages and antibacterial surface coating implants. We highlight topical examples where various ingenious design strategies from biological models, originating more broadly from zoology and botany, have been appropriated into novel synthetic materials and structures for regenerative and material-based tissue engineering. Bioinspired materials engineering informed and enriched by the vast array of adaptations and strategies in nature, beyond human biology, will be instrumental in the future evolution of new more clinically acceptable pan-functional materials and structures with a broad range of uses in the regenerative sciences.

The nanotipped hairs of gecko skin and biotemplated replicas impair and/or kill pathogenic bacteria with high efficiency.

We show that gecko microspinules (hairs) and their equivalent replicas, bearing nanoscale tips, can kill or impair surface associating oral pathogenic bacteria with high efficiency even after 7 days of repeated attacks. Scanning Electron Microscopy suggests that there is more than one mechanism contributing to cell death which appears to be related to the scaling of the bacteria type with the hair arrays and accessibility to the underlying nano-topography of the hierarchical surfaces.

Diversification and enrichment of clinical biomaterials inspired by Darwinian evolution.

UNLABELLED: Regenerative medicine and biomaterials design are driven by biomimicry. There is the essential requirement to emulate human cell, tissue, organ and physiological complexity to ensure long-lasting clinical success. Biomimicry projects for biomaterials innovation can be re-invigorated with evolutionary insights and perspectives, since Darwinian evolution is the original dynamic process for biological organisation and complexity. Many existing human inspired regenerative biomaterials (defined as a nature generated, nature derived and nature mimicking structure, produced within a biological system, which can deputise for, or replace human tissues for which it closely matches) are without important elements of biological complexity such as, hierarchy and autonomous actions. It is possible to engineer these essential elements into clinical biomaterials via bioinspired implementation of concepts, processes and mechanisms played out during Darwinian evolution; mechanisms such as, directed, computational, accelerated evolutions and artificial selection contrived in the laboratory. These dynamos for innovation can be used during biomaterials fabrication, but also to choose optimal designs in the regeneration process. Further evolutionary information can help at the design stage; gleaned from the historical evolution of material adaptations compared across phylogenies to changes in their environment and habitats. Taken together, harnessing evolutionary mechanisms and evolutionary pathways, leading to ideal adaptations, will eventually provide a new class of Darwinian and evolutionary biomaterials. This will provide bioengineers with a more diversified and more efficient innovation tool for biomaterial design, synthesis and function than currently achieved with synthetic materials chemistry programmes and rational based materials design approach, which require reasoned logic. It will also inject further creativity, diversity and richness into the biomedical technologies that we make. All of which are based on biological principles. Such evolution-inspired biomaterials have the potential to generate innovative solutions, which match with existing bioengineering problems, in vital areas of clinical materials translation that include tissue engineering, gene delivery, drug delivery, immunity modulation, and scar-less wound healing. STATEMENT OF SIGNIFICANCE: Evolution by natural selection is a powerful generator of innovations in molecular, materials and structures. Man has influenced evolution for thousands of years, to create new breeds of farm animals and crop plants, but now molecular and materials can be molded in the same way. Biological molecules and simple structures can be evolved, literally in the laboratory. Furthermore, they are re-designed via lessons learnt from evolutionary history. Through a 3-step process to (1) create variants in material building blocks, (2) screen the variants with beneficial traits/properties and (3) select and support their self-assembly into usable materials, improvements in design and performance can emerge. By introducing biological molecules and small organisms into this process, it is possible to make increasingly diversified, sophisticated and clinically relevant materials for multiple roles in biomedicine.

HER2/neu antisense targeting of human breast carcinoma.

Overexpression of the HER2/neu oncogene is observed in approximately 30% of human breast carcinoma specimens. HER2/neu overexpression is a negative prognostic factor in breast cancer patients. Cancer cells that overexpress HER2/neu may also be less sensitive to chemotherapy. In order to further define mechanisms by which HER2/neu overexpression drives neoplastic cell growth and chemoresistance, antisense oligonucleotides (ODNs) have been utilized to selectively down-regulate HER2/neu expression in human breast cancer cells. Such antisense ODNs suppress HER2/neu mRNA and protein levels in a dose-dependent, sequence-specific manner. Down-regulation of HER2/neu expression in HER2/neu overexpressing breast cancer cells inhibits cell cycle progression in G0/G1 and results in apoptotic cell death. In tissue culture studies, combined treatment of HER2/ neu overexpressing breast cancer cells with HER2/neu antisense ODNs and conventional chemotherapeutic agents results in synergistic inhibition of cancer cell growth and activation of apoptotic cell death mechanisms. These studies have been extended to demonstrate synergistic antitumor effects following systemic treatment with antisense ODNs plus doxorubicin in nude mice bearing human breast carcinoma xenografts. Collectively these findings demonstrate that HER2/neu overexpression stimulates anti-apoptotic cell survival mechanisms and suggest that HER2/neu antisense ODNs may be of use in cancer therapeutics.

The IF(1) inhibitor protein of the mitochondrial F(1)F(0)-ATPase.

Recent studies on the IF(1) inhibitor protein of the mitochondrial F(1)F(0)-ATPase from molecular biochemistry to possible pathophysiological roles are reviewed. The apparent mechanism of IF(1) inhibition of F(1)F(0)-ATPase activity and the biophysical conditions that influence IF(1) activity are summarized. The amino acid sequences of human, bovine, rat and murine IF(1) are compared and domains and residues implicated in IF(1) function examined. Defining the minimal inhibitory sequence of IF(1) and the role of conserved histidines and conformational changes using peptides or recombinant IF(1) is reviewed. Luft's disease, a mitochondrial myopathy where IF(1) is absent, is described with respect to IF(1) relevance to mitochondrial bioenergetics and clinical observations. The possible pathophysiological role of IF(1) in conserving ATP under conditions where cells experience oxygen deprivation (tumor growth, myocardial ischemia) is evaluated. Finally, studies attempting to correlate IF(1) activity to ATP conservation in myocardial ischemic preconditioning are compared.

The reaction of cow beta-lactoglobulin with tetracyanoaurate(III).

The reaction of cow beta-lactoglobulin with Au(CN)-4 is shown to label the free sulphydryl group on the protein by a reductive mechanism yielding a stable complex. High salt concentrations are shown to affect the pH-dependent conformational transition (N in equilibrium R yields S). It is hoped that Au(CN)-4 may be of more widespread use as a specific heavy-atom label for the isomorphous replacement method.

Contingency, causation, and adaptive inference.

In contingency judgment tasks involving 2 event types, individuals weight the a and b cells of a 2 x 2 contingency table more than the c and d cells. Some theorists have argued that they can provide normative justifications for this weighting and that the weighting reflects simple heuristics that are adaptive in the real world. The authors show that, to avoid error, individual judgments about real contingencies should be more subtle than these supposedly adaptive heuristics allow.

Rational design, synthesis, and crystallographic analysis of a hydroxyethylene-based HIV-1 protease inhibitor containing a heterocyclic P1'--P2' amide bond isostere.

The rational design and synthesis of a highly potent inhibitor of HIV-1 protease have been accomplished. The inhibitor, SB 206343, is based on a model derived from the structure of the MVT-101/HIV-1 protease complex and contains a 4(5)-acylimidazole ring as an isosteric replacement for the P1'--P2' amide bond. It is a competitive inhibitor with an apparent inhibition constant of 0.6 nM at pH 6.0. The three-dimensional structure of SB 206343 bound in the active site of HIV-1 protease has been determined at 2.3 A resolution by X-ray diffraction techniques and refined to a crystallographic discrepancy factor, R (= sigma parallel Fo magnitude of/Fc parallel/sigma magnitude of), of 0.194. The inhibitor is held in the enzyme by a set of hydrophobic and polar interactions. N-3 of the imidazole ring participates in a novel hydrogen-bonding interaction with the bound water molecule, demonstrating the effectiveness of the imidazole ring as an isosteric replacement for the P1'--P2' amide bond in hydroxyethylene-based HIV-1 protease inhibitors. Also present are hydrogen-bonding interactions between N-1 of the imidazole ring and the carbonyl of Gly-127 as well as between the imidazole acyl carbonyl oxygen and the amide nitrogen of Asp-129, exemplifying the peptidomimetic nature of the 4(5)-acylimidazole isostere. All of these interactions are in qualitative agreement with those predicted by the model.

A check on rational drug design: crystal structure of a complex of human immunodeficiency virus type 1 protease with a novel gamma-turn mimetic inhibitor.

We have previously reported (Newlander et al., J. Med. Chem. 1993, 36, 2321-2331) the design of human immunodeficiency virus type 1 (HIV-1) protease inhibitors incorporating C7 mimetics that lock three amino acid residues of a peptide sequence into a gamma-turn. The design of one such compound, SB203238, was based on X-ray structures of reduced amide aspartyl protease inhibitors. It incorporates a gamma-turn mimetic in the P2-P1' position, where the carbonyl of the C7 ring is replaced with an sp3 methylene group yielding a constrained reduced amide. It shows competitive inhibition with Ki = 430 nM at pH 6.0. The three-dimensional structure of SB203238 bound to the active site of HIV-1 protease has been determined at 2.3 A resolution by X-ray diffraction and refined to a crystallographic R-factor (R = sigma magnitude of Fo magnitude of - magnitude of Fc magnitude of /sigma magnitude of Fo magnitude of, where Fo and Fc are the observed and calculated structure factor amplitudes, respectively) of 0.177. The inhibitor lies in an extended conformation in the active site; however, because of the constrained geometry of the C7 ring, it maintains fewer hydrogen bonds with the protein than in most other HIV-1 protease-inhibitor complexes. More importantly, the inhibitor binds to the enzyme differently than predicted in its design, by binding with the P2-P1' alpha-carbon atoms shifted by approximately one-half a residue toward the N-terminus from their presumed positions. This study illustrates the importance of structural information in an approach to rational drug design.

Nucleated erythrocytes and intraventricular hemorrhage in preterm neonates.

OBJECTIVES: Increased circulating nucleated erythrocytes (NRBCs) in the newborn period can be markers of chronic fetal hypoxia, which in turn may be a risk factor for intracranial hemorrhage (IVH). To evaluate the relation between chronic intrauterine hypoxia and IVH, we compared the courses of the absolute NRBC (ANRBC) count in preterm newborns with and without intracranial hemorrhage. METHODS: We measured ANRBC counts in the first 6 days of life in appropriate for gestational age newborns at 32 weeks' gestation or earlier with (n = 46) and without (n = 103) IVH, who were not at risk for altered erythropoiesis. RESULTS: The ANRBC counts at birth were higher in infants who developed severe IVH than in control infants without IVH (P < .03). The ANRBC counts peaked on day 2 or 3 in newborns with IVH, but declined continuously from a peak on day 1 in the control group. Stepwise regression analysis of multiple variables revealed that the grade of IVH had the greatest impact on ANRBC counts. An ANRBC count of at least 2.0 x 10(9)/L on day 1 of life had a sensitivity of 63% and a specificity of 79% in predicting grade III or IV IVH: CONCLUSION: An elevated or increasing ANRBC count in a preterm newborn is a potential marker for an impending or present severe IVH, respectively, and may reflect a state of altered prenatal or postnatal erythropoiesis.

Nucleated red blood cells in healthy infants of women with gestational diabetes.

OBJECTIVE: To evaluate whether absolute nucleated red blood cell (RBC) counts are elevated in large-for-gestational-age (LGA) infants of women with gestational diabetes compared with appropriate-for-gestational-age (AGA) infants of women with or without gestational diabetes. METHODS: We compared absolute nucleated RBC counts during the first 12 hours of life in three groups of term, vaginally delivered infants, LGA infants of women with gestational diabetes (n = 20), AGA infants of women with gestational diabetes (n = 20), and AGA infants of nondiabetic women (n = 30). We excluded infants of women with hypertension, smoking, alcohol or drug abuse, and those with fetal heart rate abnormalities in labor, low Apgar scores, hemolysis, blood loss, or chromosomal anomalies. RESULTS: There were no significant differences among groups in gestational age, gravidity, parity, maternal analgesia, 1- and 5-minute Apgar scores, and lymphocyte counts. Corrected white blood cell counts and hematocrit were significantly higher in LGA infants of women with gestational diabetes than in the other groups. The median nucleated RBC count was significantly higher in LGA infants of women with gestational diabetes (0.56 x 10(9)/L, range 0-1.8 x 10(9)/L) than AGA infants of women with gestational diabetes (0.13 x 10(9)/L, range 0-0.65 x 10(9)/L) and controls (0.0005 x 10(9)/L, range 0-0.6 x 10(9)/L) (P < .001). Multiple regression analysis showed that absolute nucleated RBC count was significantly correlated with birth weight (or macrosomia) and maternal diabetic status (r2 = .25, P < .001 for the multiple regression, contribution of birth weight r2 = .19, and diabetes r2 = .06). CONCLUSION: At birth, term LGA infants born to women with gestational diabetes had higher absolute nucleated RBC counts compared with AGA infants born to women with gestational diabetes and controls.

Nucleated red blood cells in infants of smoking mothers.

OBJECTIVE: To evaluate whether the absolute nucleated red blood cell (RBC) count is elevated in term, appropriate for gestational age (AGA) infants born to smoking women. METHODS: We compared absolute nucleated RBC counts taken during the first 12 hours of life in two groups of term, vaginally delivered, AGA infants, one group born to mothers who smoked during pregnancy (n = 30) and the other born to mothers who did not smoke (n = 30). We excluded infants of women with diabetes, hypertension, or alcohol or drug abuse, and infants with heart rate abnormalities, hemolysis, blood loss, or chromosomal anomalies. RESULTS: There were no differences between the groups in birth weight, gestational age, maternal age, gravidity, parity, maternal analgesia during labor, 1- and 5-minute Apgar scores, corrected white blood cell counts, lymphocyte counts, or hematocrits. The median absolute nucleated RBC count in infants of smoking mothers was 0.5 x 10(9)/L (range 0 to 5.0) versus 0.0005 x 10(9)/L (range 0 to 0.6) in nonsmoking controls (P < .002). Regression analysis that included Apgar scores, gestational age, and number of cigarettes smoked per day showed a significant correlation of absolute nucleated RBC count only with the number of cigarettes smoked per day (P < .001). CONCLUSION: At birth, term AGA infants born to smoking mothers have increased circulating absolute nucleated RBC counts compared with controls. The absolute nucleated RBC count in newborns correlates with the number of cigarettes smoked during pregnancy.

The significance of western equine encephalomyelitis viral infections in Aedes trivittatus (Diptera: Culicidae) in Iowa. I. Variation in susceptibility of Aedes trivittatus to experimental infection with three strains of western equine encephalomyelitis virus.

F1 pregnancy obtained from field-collected Aedes trivittatus were evaluated for susceptibility to infection with western equine encephalomyelitis (WEE) virus by intrathoracic inoculation and by oral imbibition of virus-blood suspensions through a membrane. Mosquitoes were uniformly susceptible to infection by intrathoracic inoculation of three strains of WEE virus, but minimum infective doses varied as much as 2,000 to 12,000-fold between strains by membrane feeding. Dose-response data obtained by membrane feeding also indicated that field strains of A. trivittatus were quite heterogeneous in their susceptibility to WEE virus since some individual mosquitoes could be infected by ingestion of low virus concentrations while others could not be infected by a 20,000-fold increase in virus concentration. Moreover, A. trivittatus showed a greater affinity for a WEE viral strain isolated from this species than for a WEE viral strain isolated from Culex tarsalis, even though the site, date of collection, and passage history of these isolates were identical. Field strains of A. trivittatus were relatively refractory to oral infection with WEE virus.