Patterning and Separating Infected Bacteria Using Host–Parasite and Virus–Antibody Interactions

Bacteria were selectively deposited on substrates patterned with poly(ethylene glycol) (PEG) microstructures by using host-parasite and virus-antibody interactions. In this scheme viruses were used to attach onto a host bacterium, Escherichia coli (E. coli). The E. coli expressing the virus were selectively adhered to the regions pretreated with an antibody against the virus proteins while E. coli without the virus showed no selectivity. Single or aggregated cell arrays were fabricated depending on the initial pattern size with respect to the size of E. coli. The current approach could be a general route to spatially positioning or controlling adhesion of other biological species that are not accessible by conventional methods and as a tool for separating and isolating specific cell populations based on host-parasite interactions.     

Infant–mother and infant–sibling attachment in Zambia

This study, the first in Zambia using the Strange Situation Procedure (SSP) to observe attachment relationships and the “very first” observational study of infant–sibling attachment, examined patterns of infant–mother and infant–sibling attachment, and tested their association. We included siblings who were substantially involved in caregiving activities with their younger siblings. We hypothesized that infants would develop attachment relationships to both mothers and siblings; the majority of infants would be classified as securely attached to both caregivers, and infant–mother and infant–sibling attachment would be unrelated. The sample included 88 low-income families in Lusaka, Zambia (average of 3.5 children; SD = 1.5). The SSP distributions (infant–mother) were 59% secure, 24% avoidant and 17% resistant, and 46% secure, 20% avoidant, 5% resistant and 29% disorganized for three- and four-way classifications, respectively. The infant–sibling classifications were 42% secure, 23% avoidant and 35% resistant, and 35% secure, 23% avoidant, 9% resistant and 33% disorganized for three- and four-way classifications, respectively. Infant–mother and infant–sibling attachment relationships were not associated.     

The blood–brain and the blood–cerebrospinal fluid barriers: function and dysfunction

The central nervous system (CNS) is tightly sealed from the changeable milieu of blood by the blood–brain barrier (BBB) and the blood–cerebrospinal fluid (CSF) barrier (BCSFB). While the BBB is considered to be localized at the level of the endothelial cells within CNS microvessels, the BCSFB is established by choroid plexus epithelial cells. The BBB inhibits the free paracellular diffusion of water-soluble molecules by an elaborate network of complex tight junctions (TJs) that interconnects the endothelial cells. Combined with the absence of fenestrae and an extremely low pinocytotic activity, which inhibit transcellular passage of molecules across the barrier, these morphological peculiarities establish the physical permeability barrier of the BBB. In addition, a functional BBB is manifested by a number of permanently active transport mechanisms, specifically expressed by brain capillary endothelial cells that ensure the transport of nutrients into the CNS and exclusion of blood-borne molecules that could be detrimental to the milieu required for neural transmission. Finally, while the endothelial cells constitute the physical and metabolic barrier per se, interactions with adjacent cellular and acellular layers are prerequisites for barrier function. The fully differentiated BBB consists of a complex system comprising the highly specialized endothelial cells and their underlying basement membrane in which a large number of pericytes are embedded, perivascular antigen-presenting cells, and an ensheathment of astrocytic endfeet and associated parenchymal basement membrane. Endothelial cell morphology, biochemistry, and function thus make these brain microvascular endothelial cells unique and distinguishable from all other endothelial cells in the body. Similar to the endothelial barrier, the morphological correlate of the BCSFB is found at the level of unique apical tight junctions between the choroid plexus epithelial cells inhibiting paracellular diffusion of water-soluble molecules across this barrier. Besides its barrier function, choroid plexus epithelial cells have a secretory function and produce the CSF. The barrier and secretory function of the choroid plexus epithelial cells are maintained by the expression of numerous transport systems allowing the directed transport of ions and nutrients into the CSF and the removal of toxic agents out of the CSF. In the event of CNS pathology, barrier characteristics of the blood–CNS barriers are altered, leading to edema formation and recruitment of inflammatory cells into the CNS. In this review we will describe current knowledge on the cellular and molecular basis of the functional and dysfunctional blood–CNS barriers with focus on CNS autoimmune inflammation.     

Emergence and evolution of the renin–angiotensin–aldosterone system

The renin-angiotensin-aldosterone system (RAAS) is not the sole, but perhaps the most important volume regulator in vertebrates. To gain insights into the function and evolution of its components, we conducted a phylogenetic analysis of its main related genes. We found that important parts of the system began to appear with primitive chordates and tunicates and that all major components were present at the divergence of bony fish, with the exception of the Mas receptor. The Mas receptor first appears after the bony-fish/tetrapod divergence. This phase of evolutionary innovation happened about 400 million years ago. We found solid evidence that angiotensinogen made its appearance in cartilage fish. The presence of several RAAS genes in organisms that lack all the components shows that these genes have had other ancestral functions outside of their current role. Our analysis underscores the utility of sequence comparisons in the study of evolution. Such analyses may provide new hypotheses as to how and why in today's population an increased activity of the RAAS frequently leads to faulty salt and volume regulation, hypertension, and cardiovascular diseases, opening up new and clinically important research areas for evolutionary medicine.     

Saccade–vergence dynamics and interaction in children and in adults

Peak velocity, duration and accuracy of eye movements (saccade, vergence and combined saccade–vergence eye movements) were investigated in fourteen normal children (4.5 to 12 years of age) and ten normal adults (22 to 44 years of age). Horizontal movements from both eyes were recorded simultaneously by the oculometer, a photoelectric device. Peak velocity of all eye movements, saccades, and vergence (convergence and divergence), attains adult levels by the age of 4.5 years and there is no significant change over the age range studied (4.5 to 44 years). Vergence duration is longer only in young children (below 8 years of age). The reciprocal interaction between saccade and vergence during combined movements known in adults, i.e. acceleration of the vergence by the saccade (increase of velocity and decrease of duration) and deceleration of the saccade by the vergence (decrease of velocity and increase of duration) was found to be similar in children. The accuracy of eye movements is good on average for both saccades and vergence by the age of 4.5 years, and does not change with age; an exception is the variability of saccade amplitude, which is higher in children less than 8 years old. Taken together, the results indicate early maturation of brainstem structures controlling spatio-temporal aspects of saccades, vergence and their interaction.     

Inhibition of return in cue–target and target–target tasks

Inhibition of return (IOR), the term given for the slowing of a response to a target that appeared at the same location as a previously presented stimulus, has been studied with both target–target (TT; participants respond to each successive event) and cue–target (CT; participants only respond to the second of two events) tasks. Although both tasks have been used to examine the processes and characteristics of IOR, few studies have been conducted to understand if there are any differences in the processes that underlie the IOR that results from ignoring (CT paradigm) or responding to (TT paradigm) the first stimulus. The purpose of the present study was to examine the notion that IOR found in TT tasks represents “true” IOR whereas IOR found in CT tasks consist of both “true” IOR and response inhibition (Coward et al. in Exp Brain Res 155:124–128, 2004). Consistent with the pattern of effects found by Coward et al. (Exp Brain Res 155:124–128, 2004), IOR was larger in the CT task than in the TT task when a single detection response was required (Experiment 1). However, when participants completed one of two spatially-directed responses (rapid aiming movement to the location of the target stimulus), IOR effects from the CT and TT tasks were equal in magnitude (Experiment 2). Rather than CT tasks having an additional response inhibition component, these results suggest that TT tasks may show less of an inhibitory effect because of a facilitatory response repetition effect.     

In vitro and in vivo corrosion,cytocompatibility and mechanical properties of biodegradable Mg–Y–Ca–Zr alloys as implant materials

This study introduces a class of biodegradable Mg–Y–Ca–Zr alloys novel to biological applications and presents evaluations for orthopedic and craniofacial implant applications. Mg–Y–Ca–Zr alloys were processed using conventional melting and casting techniques. The effects of increasing Y content from 1 to 4 wt.% as well as the effects of T4 solution treatment were assessed. Basic material phase characterization was conducted using X-ray diffraction, optical microscopy and scanning electron microscopy. Compressive and tensile tests allowed for the comparison of mechanical properties of the as-cast and T4-treated Mg–Y–Ca–Zr alloys to pure Mg and as-drawn AZ31. Potentiodynamic polarization tests and mass loss immersion tests were used to evaluate the corrosion behavior of the alloys. In vitro cytocompatibility tests on MC3T3-E1 pre-osteoblast cells were also conducted. Finally, alloy pellets were implanted into murine subcutaneous tissue to observe in vivo corrosion as well as local host response through H&E staining. SEM/EDS analysis showed that secondary phase intermetallics rich in yttrium were observed along the grain boundaries, with the T4 solution treatment diffusing the secondary phases into the matrix while increasing the grain size. The alloys demonstrated marked improvement in mechanical properties over pure Mg. Increasing the Y content contributed to improved corrosion resistance, while solution-treated alloys resulted in lower strength and compressive strain compared to as-cast alloys. The Mg–Y–Ca–Zr alloys demonstrated excellent in vitro cytocompatibility and normal in vivo host response. The mechanical, corrosion and biological evaluations performed in this study demonstrated that Mg–Y–Ca–Zr alloys, especially with the 4 wt.% Y content, would perform well as orthopedic and craniofacial implant biomaterials.     

Links Between the Mother–Adolescent and Father–Adolescent Relationships and Adolescent Depression: A Genetically Informed Study

This study examined the unique roles of support and conflict in the relationship with the mother and the father in predicting changes in adolescents’ depressive symptoms over a 1-year period. Potential moderating effects of genetic factors (Gene × Environment interaction) and sex were also investigated. This study utilized a design of twins raised in the same family, based on a sample of 121 monozygotic and 88 dizygotic same-sex twin pairs (418 individuals; 52.2% girls) assessed in Grade 8 (M = 14.09, SD = .29) and in Grade 9 (M = 15.07, SD = .26). Depressive symptoms and the parent–adolescent relationship quality were measured with self-report questionnaires. Multilevel regressions revealed that a lack of support in the father–adolescent relationship predicted increased depressive symptoms among all adolescents, whereas conflict in the father–adolescent relationship predicted increased depressive symptoms more strongly as adolescents’ genetic vulnerability for depressive symptoms increased. Moreover, a high level of support in the relationship with the mother predicted increased depressive symptoms in boys—but not girls—with a high genetic risk for such problems. In line with a diathesis-stress model of psychopathology, these findings suggest that relationship quality with both parents might impact girls’ and boys’ depressive symptoms but that these associations depend to some extent on adolescents’ genetic vulnerabilities.     

Obsessive–compulsive disorder and gut microbiota dysregulation

Obsessive–compulsive disorder (OCD) is a debilitating disorder for which the cause is not known and treatment options are modestly beneficial. A hypothesis is presented wherein the root cause of OCD is proposed to be a dysfunction of the gut microbiome constituency resulting in a susceptibility to obsessional thinking. Both stress and antibiotics are proposed as mechanisms by which gut microbiota are altered preceding the onset of OCD symptomology. In this light, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) leading to episodic OCD is explained not by group A beta-hemolytic streptococcal infections, but rather by prophylactic antibiotics that are administered as treatment. Further, stressful life events known to trigger OCD, such as pregnancy, are recast to show the possibility of altering gut microbiota prior to onset of OCD symptoms. Suggested treatment for OCD would be the directed, specie-specific (re)introduction of beneficial bacteria modifying the gut microbiome, thereby ameliorating OCD symptoms. Special considerations should be contemplated when considering efficacy of treatment, particularly the unhealthy coping strategies often observed in patients with chronic OCD that may need addressing in conjunction with microbiome remediation.     

DeFries–Fulker and Pearson–Aitken Model-fitting Analyses of Reading Performance Data from Selected and Unselected Twin Pairs

Although a comparison of concordance rates for deviant scores in identical and fraternal twin pairs can provide prima facie evidence for a genetic etiology, information is not fully utilized when continuous measures are analyzed in a dichotomous manner. Thus, DeFries and Fulker (Behav Genet 15:467–473, 1985; Acta Genet Med Gemellol, 37:205–216, 1988) developed a regression-based methodology (DF analysis) to assess genetic etiology in both selected and unselected twin samples. While the DF analysis is a very versatile and relatively powerful statistical approach, it is not easily extended to the multivariate case. In contrast, structural equation models may be readily extended to analyze multivariate data sets (Neale and Cardon, Methodology for genetic studies of twins and families, 1992). However, such methodologies may yield biased estimates of additive genetic, shared environmental, and non-shared environmental influences when multivariate models are fitted to selected twin data. Therefore, the Pearson–Aitken (PA) selection formula (Aitken, Proc Edinburgh Math Soc B, 4:106–110, 1934) was used to analyze reading performance data from twins with reading difficulties (selected sample) and a population of normally-achieving twin pairs (control sample). As a comparison, DF models were also fitted to these same data sets. In general, resulting estimates of additive genetic, shared environmental, and non-shared environmental influences were similar when the DF and PA models were fitted to the data. However, the PA selection formula may be more readily generalized to the multivariate case. Edited by Hermine Maes.     

Complexity and dynamics of host–fungal interactions

Pathologies attributable to fungal infections represent a growing concern in both developed and developing countries. Initially discovered as opportunistic pathogens of immunocompromised hosts, fungi such as Candida albicans are now being placed at the centre of a more complex and dynamic picture in which the outcome of an infection is the result of an intricate network of molecular interactions between the fungus, the host and the commensal microflora co-inhabiting various host niches, and especially the gastrointestinal (GI) tract. The complexity of the host-fungal interaction begins with the numerous pathogen-associated molecular patterns (PAMPs) present on the fungal cell wall that are recognized by multiple pathogen-recognition receptors (PRRs), expressed by several types of host cells. PAMP-PRR interactions elicit a variety of intracellular signalling pathways leading to a wide array of immune responses, some of which promote fungal clearance while others contribute to pathogenesis. The picture is further complicated by the fact that numerous commensal bacteria normally co-inhabiting the host's GI tract produce molecules that either directly modulate the survival and virulence of commensal fungi such as C. albicans or indirectly modulate the host's antifungal immune responses. On top of this complexity, this host-microbiome-fungal interaction exhibits features of a dynamic system, in which the same fungi can easily switch between different morphological forms presenting different PAMPs at different moments of time. Furthermore, fungal pathogens can rapidly accumulate genomic alterations that further modify their recognition by the immune system, their virulence and their resistance to antifungal compounds. Thus, based on available molecular data alone, it is currently difficult to construct a coherent model able to explain the balance between commensalism and virulence and to predict the outcome of a fungal infection. Here, we review current advances in our understanding of this complex and dynamic system and propose new avenues of investigation to assemble a more complete picture of the host-fungal interaction, integrating microbiological and immunological data under the lens of systems biology and evolutionary genomics.     

HLA-G and mother–child perinatal HIV transmission

Transplacental passage is a well-known phenomenon in HIV infection and immune responses at the maternal-fetal interface play a critical role in perinatal mother-to-child HIV transmission (MCHT). The high expression of HLA-G at the maternal-fetal interface and its role in mediating immune tolerance suggest that it could play an important role in MCHT. We investigated the role of HLA-G polymorphism in perinatal HIV transmission in 348 ART naïve mother–child pairs enrolled in a mother–child HIV transmission cohort, established in Nairobi, Kenya in 1986.     

Hypersensitivity reactions and anaphylaxis to checkpoint inhibitor–monoclonal antibodies and desensitization

ObjectiveTo review type 1 hypersensitivity reactions and anaphylaxis to checkpoint inhibitor–monoclonal antibodies and its management with drug desensitization.Data SourcesEnglish-language literature on MEDLINE regarding hypersensitivity, anaphylaxis, and checkpoint inhibitor–monoclonal antibodies.Study SelectionsReferences were selected based on relevance, novelty, robustness, and applicability.ResultsThere are well-known tissue toxicities associated to checkpoint inhibitors, but hypersensitivity reactions and anaphylaxis have been underreported. The presentation of these reactions is based on clinical phenotypes with underlying endotypes identified by specific biomarkers. Drug desensitizations have been successfully applied to checkpoint inhibitor drugs to allow patients with cancer to receive first-line therapies. This review provides current best practices for the recognition and diagnosis of hypersensitivity reactions and anaphylaxis to checkpoint inhibitors and their management using drug desensitization.ConclusionHypersensitivity reactions and anaphylaxis have been identified as potential adverse effects induced by checkpoint inhibitor–monoclonal antibodies. Drug desensitization is a safe and effective treatment option for patients who experience hypersensitivity reactions in need of these monoclonal antibodies to improve cancer outcomes.     

Microstructural and mechanical differences between digested collagen–fibrin co-gels and pure collagen and fibrin gels

Collagen and fibrin are important extracellular matrix (ECM) components in the body, providing structural integrity to various tissues. These biopolymers are also common scaffolds used in tissue engineering. This study investigated how co-gelation of collagen and fibrin affected the properties of each individual protein network. Collagen–fibrin co-gels were cast and subsequently digested using either plasmin or collagenase; the microstructure and mechanical behavior of the resulting networks were then compared with the respective pure collagen or fibrin gels of the same protein concentration. The morphologies of the collagen networks were further analyzed via three-dimensional network reconstruction from confocal image z-stacks. Both collagen and fibrin exhibited a decrease in mean fiber diameter when formed in co-gels compared with the pure gels. This microstructural change was accompanied by an increased failure strain and decreased tangent modulus for both collagen and fibrin following selective digestion of the co-gels. In addition, analysis of the reconstructed collagen networks indicated the presence of very long fibers and the clustering of fibrils, resulting in very high connectivities for collagen networks formed in co-gels.