The severity of chronic histiocytic intervillositis is associated with gestational age and fetal weight.

INTRODUCTION: Chronic histiocytic intervillositis (CHI) is a rare histopathological lesion in the placenta that is associated with poor reproductive outcomes. The intervillous infiltrate consists mostly of maternal mononuclear cells and fibrin depositions, which are both indicators for the severity of the intervillous infiltrate. The severity of the intervillous infiltrate as well as the clinical outcomes of pregnancy differ between cases. Our objective is to determine the relation between the severity of the intervillous infiltrate and the clinical outcomes of CHI. METHODS: Cases of CHI were semi-quantitatively graded based on histopathological severity scores. Hereto, CD68 positive mononuclear cells were quantified, fibrin depositions visualized by both a PTAH stain and an immuohistochemical staining, and placental dysfunction was assessed via thrombomodulin staining. RESULTS: This study included 36 women with CHI. A higher CD68 score was significantly associated with a lower birthweight. Loss of placental thrombomodulin was associated with lower gestational age, lower birthweight, and a lower placenta weight. The combined severity score based on CD68 and PTAH was significantly associated with fetal growth restriction, and the joint score of CD68 and fibrin was associated with birthweight and placental weight. DISCUSSION: More severe intervillous infiltrates in CHI placentas is associated with a lower birth weight and placental weight. Furthermore, this study proposes thrombomodulin as a possible new severity marker of placental damage. More research is needed to better understand the pathophysiology of CHI.

Prospective experimental treatment of colorectal cancer patients based on organoid drug responses.

BACKGROUND: Organoid technology has recently emerged as a powerful tool to assess drug sensitivity of individual patient tumors in vitro. Organoids may therefore represent a new avenue for precision medicine, as this circumvents many of the complexities associated with DNA- or transcriptional-profiling. MATERIALS AND METHODS: The SENSOR trial was a single-arm, single-center, prospective intervention trial to evaluate the feasibility of patient-derived organoids to allocate patients for treatment with off-label or investigational agents. The primary endpoint was an objective response rate of ≥20%. Patients underwent a biopsy for culture before commencing their last round standard of care. Organoids were exposed to a panel of eight drugs and patients were treated after progression on standard-of-care treatment and when a clear signal of antitumor activity was identified in vitro. RESULTS: Sixty-one patients were included and we generated 31 organoids of 54 eligible patients. Twenty-five cultures were subjected to drug screening and 19 organoids exhibited substantial responses to one or more drugs. Three patients underwent treatment with vistusertib and three with capivasertib. Despite drug sensitivity of organoids, patients did not demonstrate objective clinical responses to the recommended treatment. CONCLUSIONS: Organoid technology had limited value as a tool for precision medicine in this patient population because a large fraction of patients could not undergo treatment or because the recommended treatment did not elicit an objective response. We identified several essential parameters, such as the culture success rate, clinical deterioration of patients during standard of care, and rational design of drug panels that need to be accounted for in organoid-guided clinical studies.

Decreased expression of ligands of placental immune checkpoint inhibitors in uncomplicated and preeclamptic oocyte donation pregnancies.

Oocyte donation (OD) pregnancies are characterized by a complete immunogenetic dissimilarity between mother and fetus, which requires enhanced immunoregulation compared to naturally conceived (NC) pregnancies. The trophoblast expresses co-inhibitory ligands crucial for regulation of the maternal T cell response. Therefore, we studied the role of placental immune checkpoint inhibitors for the establishment of fetal tolerance and their relation to the development of preeclampsia in OD compared to NC pregnancies. Placental tissue from uncomplicated OD (n = 21) and NC (n = 21) pregnancies, and OD (n = 9) and NC (n = 15) pregnancies complicated with preeclampsia were studied. Protein expression of co-inhibitory ligands PD-L1 and CD200 was double blind semi-quantitatively determined by immunohistochemistry. Messenger RNA expression of PD-L1, CD200 and indoleamine 2,3-dioxygenase (IDO) was determined using qPCR. Decreased PD-L1 and CD200 protein expression and increased IDO mRNA expression was observed in uncomplicated OD versus NC pregnancies (all p < 0.05). CD200 protein expression was positively correlated with PD-L1 expression in all groups, with the number of HLA total mismatches and with HLA class I mismatches in uncomplicated OD cases (all p < 0.05). Preeclamptic cases showed lower PD-L1 protein and CD200 protein and mRNA expression in OD compared to NC pregnancies (all p < 0.05). This study shows that signaling by co-inhibitory PD-L1 and CD200 and by immunosuppressive IDO is altered in the placenta of OD pregnancies, suggesting a contribution to the higher risk for preeclampsia. These insights provide future prospects in unraveling the immune paradox of oocyte pregnancy, which are applicable for better risk management and treatment of uncomplicated and preeclamptic pregnancies.

The N400 for brain computer interfacing: complexities and opportunities.

The N400 is an event related potential that is evoked in response to conceptually meaningful stimuli. It is for instance more negative in response to incongruent than congruent words in a sentence, and more negative for unrelated than related words following a prime word. This sensitivity to semantic content of a stimulus in relation to the mental context of an individual makes it a signal of interest for Brain Computer Interfaces. A complicating aspect is the number of factors that can affect the N400 amplitude. In this paper, we provide an accessible overview of this range of N400 effects, and survey the three main BCI application areas that currently exploit the N400: (1) exploiting the semantic processing of faces to enhance matrix speller performance, (2) detecting language processing in patients with Disorders of Consciousness, and (3) using semantic stimuli to probe what is on a user's mind. Drawing on studies from these application areas, we illustrate that the N400 can successfully be exploited for BCI purposes, but that the signal-to-noise ratio is a limiting factor, with signal strength also varying strongly across subjects. Furthermore, we put findings in context of the general N400 literature, noting open questions and identifying opportunities for further research.

[Collaboration on health in the neighbourhood: role for GPs? Experiences from the 'Prevention in the neighbourhood' project]. / Samenwerken aan gezondheid in de wijk: een rol voor de huisarts?

There are two reasons why general practitioners (GPs) should collaborate with others in their neighbourhood: social problems that translate into physical symptoms and addressing healthy lifestyles and prevention.

Identifying the Attended Speaker Using Electrocorticographic (ECoG) Signals.

People affected by severe neuro-degenerative diseases (e.g., late-stage amyotrophic lateral sclerosis (ALS) or locked-in syndrome) eventually lose all muscular control. Thus, they cannot use traditional assistive communication devices that depend on muscle control, or brain-computer interfaces (BCIs) that depend on the ability to control gaze. While auditory and tactile BCIs can provide communication to such individuals, their use typically entails an artificial mapping between the stimulus and the communication intent. This makes these BCIs difficult to learn and use. In this study, we investigated the use of selective auditory attention to natural speech as an avenue for BCI communication. In this approach, the user communicates by directing his/her attention to one of two simultaneously presented speakers. We used electrocorticographic (ECoG) signals in the gamma band (70-170 Hz) to infer the identity of attended speaker, thereby removing the need to learn such an artificial mapping. Our results from twelve human subjects show that a single cortical location over superior temporal gyrus or pre-motor cortex is typically sufficient to identify the attended speaker within 10 s and with 77% accuracy (50% accuracy due to chance). These results lay the groundwork for future studies that may determine the real-time performance of BCIs based on selective auditory attention to speech.

Habitat variation and wing coloration affect wing shape evolution in dragonflies.

Habitats are spatially and temporally variable, and organisms must be able to track these changes. One potential mechanism for this is dispersal by flight. Therefore, we would expect flying animals to show adaptations in wing shape related to habitat variation. In this work, we explored variation in wing shape in relation to preferred water body (flowing water or standing water with tolerance for temporary conditions) and landscape (forested to open) using 32 species of dragonflies of the genus Trithemis (80% of the known species). We included a potential source of variation linked to sexual selection: the extent of wing coloration on hindwings. We used geometric morphometric methods for studying wing shape. We also explored the phenotypic correlation of wing shape between the sexes. We found that wing shape showed a phylogenetic structure and therefore also ran phylogenetic independent contrasts. After correcting for the phylogenetic effects, we found (i) no significant effect of water body on wing shape; (ii) male forewings and female hindwings differed with regard to landscape, being progressively broader from forested to open habitats; (iii) hindwings showed a wider base in wings with more coloration, especially in males; and (iv) evidence for phenotypic correlation of wing shape between the sexes across species. Hence, our results suggest that natural and sexual selection are acting partially independently on fore- and hindwings and with differences between the sexes, despite evidence for phenotypic correlation of wing shape between males and females.

Stress-reducing effects of indoor plants in the built healthcare environment: the mediating role of perceived attractiveness.

OBJECTIVE: Natural elements in the built healthcare environment have shown to hold potential stress-reducing properties. In order to shed light on the underlying mechanism of stress-reducing effects of nature, the present study investigates whether the stress-reducing effects of indoor plants occur because such an environment is perceived as being more attractive. METHOD: A single-factor between-subjects experimental design (nature: indoor plants vs. no plants) was used in which participants (n=77) were presented with a scenario describing hospitalization with a possible legionella diagnosis. The study was conducted from March to May 2007 in the Netherlands. Subsequently, they were exposed to a photo of a hospital room. In this room were either indoor plants, or there was a painting of an urban environment on the wall. Afterwards, perceived stress and the perceived attractiveness of the hospital room were measured. RESULTS: Participants exposed to the hospital room with indoor plants reported less stress than those in the control condition. Mediation analysis confirmed that indoor plants in a hospital room reduce feelings of stress through the perceived attractiveness of the room. CONCLUSION: This study confirms the stress-reducing properties of natural elements in the built healthcare environment. It also sheds light on the underlying mechanism causing this stress-reduction.

Come talk with me: improving communication between nursing assistants and nursing home residents during care routines.

PURPOSE: We examined the effects of communication skills training and the use of memory books by certified nursing assistants (CNAs) on verbal interactions between CNAs (n = 64) and nursing home residents (n = 67) during care routines. DESIGN AND METHODS: CNAs were taught to use communication skills and memory books during their interactions with residents with moderate cognitive impairments and intact communication abilities. A staff motivational system was used to encourage performance and maintenance of these skills. Formal measures of treatment implementation were included. RESULTS: Results were compared with those for participants on no-treatment control units. Trained CNAs talked more, used positive statements more frequently, and tended to increase the number of specific instructions given to residents. Changes in staff behavior did not result in an increase in total time giving care to residents. Maintenance of CNA behavior change was found 2 months after research staff exited the facility. Although an increase was found in positive verbal interactions between CNAs and residents on intervention units, other changes in resident communication were absent. IMPLICATIONS: Nursing staff can be trained to improve and maintain communication skills during care without increasing the amount of time delivering care. The methodological advantages of including measures to assess treatment implementation are discussed.

NMR structure of cysteinyl-phosphorylated enzyme IIB of the N,N'-diacetylchitobiose-specific phosphoenolpyruvate-dependent phosphotransferase system of Escherichia coli.

The determination by NMR of the solution structure of the phosphorylated enzyme IIB (P-IIB(Chb)) of the N,N'-diacetylchitobiose-specific phosphoenolpyruvate-dependent phosphotransferase system of Escherichia coli is presented. Most of the backbone and side-chain resonances were assigned using a variety of mostly heteronuclear NMR experiments. The remaining resonances were assigned with the help of the structure calculations.NOE-derived distance restraints were used in distance geometry calculations followed by molecular dynamics and simulated annealing protocols. In addition, combinations of ambiguous restraints were used to resolve ambiguities in the NOE assignments. By combining sets of ambiguous and unambiguous restraints into new ambiguous restraints, an error function was constructed that was less sensitive to information loss caused by assignment uncertainties. The final set of structures had a pairwise rmsd of 0.59 A and 1.16 A for the heavy atoms of the backbone and side-chains, respectively. Comparing the P-IIB(Chb) solution structure with the previously determined NMR and X-ray structures of the wild-type and the Cys10Ser mutant shows that significant differences between the structures are limited to the active-site region. The phosphoryl group at the active-site cysteine residue is surrounded by a loop formed by residues 10 through 16. NOE and chemical shift data suggest that the phosphoryl group makes hydrogen bonds with the backbone amide protons of residues 12 and 15. The binding mode of the phosphoryl group is very similar to that of the protein tyrosine phosphatases. The differences observed are in accordance with the presumption that IIB(Chb) has to be more resistant to hydrolysis than the protein tyrosine phosphatases. We propose a proton relay network by which a transfer occurs between the cysteine SH proton and the solvent via the hydroxyl group of Thr16.

Change in cervical length after cerclage as a predictor of preterm delivery.

OBJECTIVE: To determine whether the degree of cervical lengthening after cerclage and whether serial follow-up measurements of cervical length after cerclage are predictive of pregnancy outcome. METHODS: Eighty women whose primary physician determined that a prophylactic (n = 50) or urgent cerclage (n = 30) was indicated had transvaginal ultrasonographic evaluation before and after cerclage. Thereafter, most women had three additional transvaginal ultrasound examinations until 32 weeks' gestation. At each examination, the mean of three measurements was calculated. Statistical analyses were done by t test, analysis of variance, and logistic regression, with significance set at P <.05. RESULTS: The mean +/- standard deviation precerclage cervical length was 27.2 +/- 10.3 mm and after cerclage was 34.1 +/- 9.9 mm (n = 80, P <.001, paired t test). No significant association was found (r = -0.26) between the difference in cervical length (postcerclage - precerclage lengths) and pregnancy outcome. Patients with a prophylactic cerclage had a mean cervical length that was consistently longer in patients delivering at term compared with those who delivered preterm at 20 to 32 weeks' gestation. In the urgent cerclage group a significant difference in cervical length between those who delivered at term compared with preterm was evident only at 28 to 32 weeks. CONCLUSION: The increase in cervical length after cerclage is not predictive of term delivery. Serial cervical length measurements in the late second or early third trimester predict preterm birth but could provide earlier warning in patients with a prophylactic cerclage than in patients with urgent cerclage.

Age, luminance, and print legibility in homes, offices, and public places.

Field studies were conducted in homes, offices, and public places with younger and older adults to determine how legibility performance (in a proofreading and phone book search) changes with age and luminance. Homes and public places generally exhibited much lower than recommended luminance values for reading. Older adults had higher light levels in their homes than did younger adults at reading locations. Older adults performed less quickly than did younger adults on most legibility tasks. Adding light helped younger and older adults equally for most legibility tasks (in homes and public places), though increased luminance differentially improved the performance of older office workers. In response to feedback about low light levels, nearly 60% of building managers in public places indicated in a 6-month follow-up that they had improved lighting or were planning to do so. Actual or potential applications of this work include setting luminance guidelines for adults and identifying barriers to lighting changes.

The structure in solution of the b domain of protein disulfide isomerase.

Protein disulfide isomerase (PDI) is a multifunctional protein of the endoplasmic reticulum, which catalyzes the formation, breakage and rearrangement of disulfide bonds during protein folding. It consists of four domains designated a, b, b and a. Both a and a domains contains an active site with the sequence motif -Cys-Gly-His-Cys-involved directly in thiol-disulfide exchange reactions. As expected these domains have structures very similar to the ubiquitous redox protein thioredoxin. A low-resolution NMR structure of the b domain revealed that this domain adopts a fold similar to the PDI a domain and thioredoxin [Kemmink, J., Darby, N.J., Dijkstra, K., Nilges, M. and Creighton, T.E. (1997) Curr. Biol. 7, 239-245]. A refined ensemble of solution structures based on the input of 1865 structural restraints shows that the structure of PDI b is well defined throughout the complete protein except for about 10 residues at the C-terminus of the sequence. 15N relaxation data show that these residues are disordered and not part of this structural domain. Therefore the domain boundaries of PDI can now be fixed with reasonable precision. Structural comparison of the PDI b domain with thioredoxin and PDI a reveals several features important for thiol-disulfide exchange activity.

The signal transducer gp130: solution structure of the carboxy-terminal domain of the cytokine receptor homology region.

The transmembrane glycoprotein gp130 is the common signal transducing receptor subunit of the interleukin-6-type cytokines. It is a member of the cytokine-receptor superfamily predicted to consist of six domains in its extracellular part. The second and third domain constitute the cytokine-binding module defined by a set of four conserved cysteines and a WSXWS motif, respectively. The three-dimensional structure of the carboxy-terminal domain of this region was determined by multidimensional NMR. The domain consists of seven beta-strands constituting a fibronectin type III-like topology. The structure reveals that the WSDWS motif of gp130 is part of an extended tryptophan/arginine zipper which modulates the conformation of the CD loop.

Cervical length in uncomplicated pregnancy: A study of sociodemographic predictors of cervical changes across gestation.

OBJECTIVE: We conducted this study to evaluate sociodemographic factors associated with changes in the length of the cervix across gestation in pregnancies that resulted in term deliveries. STUDY DESIGN: This study is an observational cohort design of sonographically determined cervical length measured at 3- to 4-week intervals in 125 women with a singleton pregnancy between 20 and 32 weeks gestation. We developed a structured questionnaire to collect psychosocial and sociodemographic characteristics. We used bivariate analysis, analysis of variance, and regression analysis to study variation in cervical length. RESULTS: Overall, cervical length decreased minimally as gestational age progressed. However, among black women cervical length decreased significantly with increasing gestational age (P =.006). In addition, high psychosocial stress was associated with significantly shorter cervices later in gestation, independent of race (P =.003). Finally, women whose occupations involved skilled manual labor had shorter cervices (P =.02). CONCLUSIONS: Women who are black, under stress, or working as skilled manual laborers demonstrate significant shortening of the cervix during gestation. Given that a shorter cervix predisposes to preterm delivery, our findings provide new insights into the well-described association of these psychosocial and sociodemographic factors with an increased risk of preterm delivery.

Role of aromatic amino acids in carbohydrate binding of plant lectins: laser photo chemically induced dynamic nuclear polarization study of hevein domain-containing lectins.

Carbohydrate recognition by lectins often involves the side chains of tyrosine, tryptophan, and histidine residues. These moieties are able to produce chemically induced dynamic nuclear polarization (CIDNP) signals after laser irradiation in the presence of a suitable radical pair-generating dye. Elicitation of such a response in proteins implies accessibility of the respective groups to the light-absorbing dye. In principle, this technique is suitable to monitor surface properties of a receptor and the effect of ligand binding if CIDNP-reactive amino acids are affected. The application of this method in glycosciences can provide insights into the protein-carbohydrate interaction process, as illustrated in this initial study. It focuses on a series of N-acetylglucosamine-binding plant lectins of increasing structural complexity (hevein, pseudohevein, Urtica dioica agglutinin and wheat germ agglutinin and its domain B), for which structural NMR- or X-ray crystallographic data permit a decision of the validity of the CIDNP method-derived conclusions. On the other hand, the CIDNP data presented in this study can be used for a rating of our molecular models of hevein, pseudohevein, and domain B obtained by various modeling techniques. Experimentally, the shape and intensity of CIDNP signals are determined in the absence and in the presence of specific glycoligands. When the carbohydrate ligand is bound, CIDNP signals of side chain protons of tyrosine, tryptophan, or histidine residues are altered, for example, they are broadened and of reduced intensity or disappear completely. In the case of UDA, the appearance of a new tryptophan signal upon ligand binding was interpreted as an indication for a conformational change of the corresponding indole ring. Therefore, CIDNP represents a suitable tool to study protein-carbohydrate interactions in solution, complementing methods such as X-ray crystallography, high-resolution multidimensional nuclear magnetic resonance, transferred nuclear Overhauser effect experiments, and molecular modeling.

The folding catalyst protein disulfide isomerase is constructed of active and inactive thioredoxin modules.

BACKGROUND: Protein disulfide isomerase (PDI), a multifunctional protein of the endoplasmic reticulum, catalyzes the formation, breakage and rearrangement of disulfide bonds during protein folding. Dissection of this protein into its individual domains has confirmed the presence of the a and a' domains, which are homologous to thioredoxin, having related structures and activities. The a and a' domains both contain a -Cys-Gly-His-Cys- active-site sequence motif. The remainder of the molecule consists primarily of two further domains, designated b and b' which are thought to be sequence repeats on the basis of a limited sequence similarity. The functions of the b and b' domains are unknown and, until now, the structure of neither domain was known. RESULTS: Heteronuclear nuclear magnetic resonance (NMR) methods have been used to determine the global fold of the PDI b domain. The protein has an alpha/beta fold with the order of the elements of secondary structure being beta1-alpha1-beta2-alpha2-beta3-alpha3-beta4-beta5+ ++-alpha4. The strands are all in a parallel arrangement with respect to each other, except for beta4 which is antiparallel. The arrangement of the secondary structure elements of the b domain is identical to that found in the a domain of PDI and in the ubiquitous redox protein thioredoxin; the three-dimensional folding topology of the b domain is also very similar to that of these proteins. CONCLUSIONS: Our determination of the global fold of the b domain of PDI by NMR reveals that, like the a domain, the b domain contains the thioredoxin motif, even though the b domain has no significant amino-acid sequence similarities to any members of the thioredoxin family. This observation, together with indications that the b' domain adopts a similar fold, suggests that PDI consists of active and inactive thioredoxin modules. These modules may have been adapted during evolution to provide PDI with its complete spectrum of enzymatic activities.

The NMR side-chain assignments and solution structure of enzyme IIBcellobiose of the phosphoenolpyruvate-dependent phosphotransferase system of Escherichia coli.

The assignment of the side-chain NMR resonances and the determination of the three-dimensional solution structure of the C10S mutant of enzyme IIBcellobiose (IIBcel) of the phosphoenolpyruvate-dependent phosphotransferase system of Escherichia coli are presented. The side-chain resonances were assigned nearly completely using a variety of mostly heteronuclear NMR experiments, including HCCH-TOCSY, HCCH-COSY, and COCCH-TOCSY experiments as well as CBCACOHA, CBCA(CO)NH, and HBHA(CBCA)(CO)NH experiments. In order to obtain the three-dimensional structure, NOE data were collected from 15N-NOESY-HSQC, 13C-HSQC-NOESY, and 2D NOE experiments. The distance restraints derived from these NOE data were used in distance geometry calculations followed by molecular dynamics and simulated annealing protocols. In an iterative procedure, additional NOE assignments were derived from the calculated structures and new structures were calculated. The final set of structures, calculated with approximately 2000 unambiguous and ambiguous distance restraints, has an rms deviation of 1.1 A on C alpha atoms. IIBcel consists of a four stranded parallel beta-sheet, in the order 2134. The sheet is flanked with two and three alpha-helices on either side. Residue 10, a cysteine in the wild-type enzyme, which is phosphorylated during the catalytic cycle, is located at the end of the first beta-strand. A loop that is proposed to be involved in the binding of the phosphoryl-group follows the cysteine. The loop appears to be disordered in the unphosphorylated state.