Multiple Family Research Articles

Coupling of zinc and GTP binding drives G-domain folding in Acinetobacter baumannii ZigA

COG0523 proteins, also known as nucleotide-dependent metallochaperones, are a poorly understood class of small P-loop G3E GTPases. Multiple family members play critical roles in bacterial pathogen survival during an infection as part of the adaptive response to host-mediated “nutritional immunity.” Our understanding of the structure, dynamics, and molecular-level function of COG0523 proteins, apart from the eukaryotic homolog, Zng1, remains in its infancy. Here, we use X-ray absorption spectroscopy to establish that Acinetobacter baumannii (Ab) ZigA coordinates ZnII using all three cysteines derived from the invariant CXCC motif to form an S3(N/O) coordination complex, a feature inconsistent with the ZnII-bound crystal structure of a distantly related COG0523 protein of unknown function from Escherichia coli, EcYjiA. The binding of ZnII and guanine nucleotides is thermodynamically linked in AbZigA, and this linkage is more favorable for the substrate GTP relative to the product GDP. Part of this coupling originates with nucleotide-induced stabilization of the G-domain tertiary structure as revealed by global thermodynamics measurements and hydrogen-deuterium exchange mass spectrometry (HDX-MS). HDX-MS also reveals that the HDX behavior of the G2 (switch 1) loop is highly sensitive to nucleotide status and becomes more exchange labile in the GDP (product)-bound state. Significant long-range perturbation of local stability in both the G-domain and the C-terminal domain define a candidate binding pocket for a client protein that appears sensitive to nucleotide status (GDP versus GTP). We place these new insights into the structure, dynamics, and energetics of intermolecular metal transfer into the context of a model for AbZigA metallochaperone function.

Detailed kinship estimation for detecting bias among breeding families in a reintroduced population of the endangered bagrid catfish Tachysurus ichikawai

AbstractIn the context of initiatives focused on captive breeding and reintroduction of endangered animal species, it is crucial to minimize any bias in reproductive success during the reintroduction phase in order to preserve genetic diversity. One population of Tachysurus ichikawai, a critically endangered bagrid catfish endemic to Japan, faces a threat from the construction of a dam. To address this, a captive breeding program followed by translocation is being implemented. Multiple breeding families are involved in this process; however, if there is a bias in reproductive success among them after release, it will result in a decline in genetic diversity. To ascertain potential biases of reproductive success among released individuals, we attempted to identify the familial lineage of individuals born at the release site. Due to the unavailability of samples from the released individuals themselves, we reconstructed the pedigree of three generations using distant kinship relationships, such as grandparent–grandchild and uncle–aunt–nephew–niece relationships, with data of 2230–5674 single‐nucleotide polymorphisms obtained from whole genome re‐sequence, and three different software. Our findings indicate no bias between lineages in the first year after reintroduction, but a significant bias in the second year, emphasizing the need for continuous management and monitoring of reintroduced populations. This study demonstrates that monitoring kinship after reintroduction can correct lineage bias, which is critical for the prompt restoration of genetic diversity.

The role of pyroptosis in viral infection.

Pyroptosis, also known as inflammatory necrosis, is a form of programmed cell death, which is an important natural immune response. Pyroptosis plays a major role in combating pathogenic infections. The mechanism of pyroptosis is distinct from other forms of cell death and is characterized by its dependence on inflammatory caspases (mainly caspases 1, 4, 5, and 11). Activation of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammatory vesicles is involved in caspase-1 activation and cleavage, which in turn triggers cleavage and multimerization of multiple gasdermin family members, including gasdermin-D (GSDMD). This further leads to cell perforation and cellular distension, causing cell membrane rupture, resulting in a massive efflux of cell contents, which triggers inflammatory reactions. In recent years, detailed study of viral diseases, has demonstrated that pyroptosis is closely associated with the development of viral diseases. This article focuses on the mechanism of pyroptosis and the connection between pyroptosis and viral infection.

Constructing Child-Friendly Community: The Path of Child-Friendly Construction of Community Childcare Service

With the development of society and the change of family structure, more and more families need childcare services to take care of their children. At present, there are some problems in community childcare services in China, such as insufficient supply of childcare services, low service quality and high price. The construction of child-friendly community is an important way to solve the problems of space, security and inclusiveness. It includes multi-layer platforms such as demand integration, resource landing, service supply, space construction and organization management, absorbs and allocates multiple forces, including government, social organizations, enterprises, voluntary forces, families and individuals, and integrates various resources to meet the differentiated and personalized childcare needs of community members. The establishment of a child-friendly community can improve the use efficiency of community childcare resources, provide a safe, healthy and happy environment for children to grow up, and promote children's all-round development.

Mice lacking cyclophilin B, but not cyclophilin A, are protected from the development of NASH in a diet and chemical-induced model.

Cyclophilins are a diverse family of peptidyl-prolyl isomerases (PPIases) of importance in a variety of essential cellular functions. We previously reported that the pan-cyclophilin inhibitor drug reconfilstat (CRV431) decreased disease in mice under the western-diet and carbon tetrachloride (CCl4) non-alcoholic steatohepatitis (NASH) model. CRV431 inhibits several cyclophilin isoforms, among which cyclophilin A (CypA) and B (CypB) are the most abundant. It is not known whether simultaneous inhibition of multiple cyclophilin family members is necessary for the observed therapeutic effects or if loss-of-function of one is sufficient. Identifying the responsible isoform(s) would enable future fine-tuning of drug treatments. Features of human liver fibrosis and complete NASH can be reliably replicated in mice by administration of intraperitoneal CCl4 alone or CCl4 in conjunction with high sugar, high cholesterol western diet, respectively. Here we show that while wild-type (WT) and Ppia-/- CypA KO mice develop severe NASH disease features under these models, Ppib-/- CypB KO mice do not, as measured by analysis of picrosirius red and hematoxylin & eosin-stained liver sections and TNFα immuno-stained liver sections. Cyclophilin inhibition is a promising and novel avenue of treatment for diet-induced NASH. In this study, mice without CypB, but not mice without CypA, were significantly protected from the development of the characteristic features of NASH. These data suggest that CypB is necessary for NASH disease progression. Further investigation is necessary to determine whether the specific role of CypB in the endoplasmic reticulum secretory pathway is of significance to its effect on NASH development.

Microbial Interactions as a Sustainable Tool for Enhancing PGPR Antagonism against Phytopathogenic Fungi

Microbial interactions, which regulate the dynamics of eco- and agrosystems, can be harnessed to enhance antagonism against phytopathogenic fungi in agriculture. This study tests the hypothesis that plant growth-promoting rhizobacteria (PGPR) can also be potential biological control agents (BCAs). Antifungal activity assays against potentially phytopathogenic fungi were caried out using cultures and cell-free filtrates of nine PGPR strains previously isolated from agricultural soils. Cultures of Bacillus sp. BS36 inhibited the growth of Alternaria sp. AF12 and Fusarium sp. AF68 by 74 and 65%, respectively. Cell-free filtrates of the same strain also inhibited the growth of both fungi by 54 and 14%, respectively. Furthermore, the co-cultivation of Bacillus sp. BS36 with Pseudomonas sp. BS95 and the target fungi improved their antifungal activity. A subsequent metabolomic analysis using Fourier-transform ion cyclotron resonance mass spectrometry (FTICR-MS) identified fengycin- and surfactin-like lipopeptides (LPs) in the Bacillus sp. BS36 cell-free filtrates, which could explain their antifungal activity. The co-production of multiple families of LPs by Bacillus sp. BS36 is an interesting feature with potential practical applications. These results highlight the potential of the PGPR strain Bacillus sp. BS36 to work as a BCA and the need for more integrative approaches to develop biocontrol tools more accessible and adoptable by farmers.

Microtubule disruption synergizes with STING signaling to show potent and broad-spectrum antiviral activity.

The activation of stimulator of interferon genes (STING) signaling induces the production of type I interferons (IFNs), which play critical roles in protective innate immunity for the host to defend against viral infections. Therefore, achieving sustained or enhanced STING activation could become an antiviral immune strategy with potential broad-spectrum activities. Here, we discovered that various clinically used microtubule-destabilizing agents (MDAs) for the treatment of cancer showed a synergistic effect with the activation of STING signaling in innate immune response. The combination of a STING agonist cGAMP and a microtubule depolymerizer MMAE boosted the activation of STING innate immune response and showed broad-spectrum antiviral activity against multiple families of viruses. Mechanistically, MMAE not only disrupted the microtubule network, but also switched the cGAMP-mediated STING trafficking pattern and changed the distribution of Golgi apparatus and STING puncta. The combination of cGAMP and MMAE promoted the oligomerization of STING and downstream signaling cascades. Importantly, the cGAMP plus MMAE treatment increased STING-mediated production of IFNs and other antiviral cytokines to inhibit viral propagation in vitro and in vivo. This study revealed a novel role of the microtubule destabilizer in antiviral immune responses and provides a previously unexploited strategy based on STING-induced innate antiviral immunity.

Unveiling the dynamic expression of PR-1 during Musa spp. infection by Fusarium oxysporum fsp. Cubense: a cloning and characterization study.

Pathogen-related proteins (PR) are pivotal in plant defense, combating diverse biotic and abiotic stresses. While multiple gene families contribute to banana resistance against Fusarium oxysporum f sp. cubense (Foc), Pseudocercospora eumusae, and Pratylenchus coffeae, the significance of PR-1 genes in defense is paramount. Three PR-1 genes, up-regulated under diverse biotic stresses, were cloned from both resistant and susceptible cultivars of Foc, P. eumusae, and P. coffeae. Molecular characterization, phylogenetic analysis, and docking studies with the Foc TR4 CP gene were conducted. Through transcriptomic and real-time studies, three PR-1 genes (Ma02_g15050, Ma02_g15060, and Ma04_g34800) from Musa spp. were identified. These genes exhibited significant up-regulation in resistant cultivars when exposed to Foc, P. eumusae, and P. coffeae. Cloning of these genes was successfully performed from both resistant and susceptible cultivars of Foc race 1 and TR4, P. eumusae, and P. coffeae. Distinct characteristics were observed among the PR-1 genes, with groups 1 and 2 being acidic with signal peptides, and group 3 being basic without signal peptides. All cloned PR-1 proteins belonged to the CAP superfamily (PF00188). Phylogenetic analysis revealed clustering patterns for acidic PR-1 proteins, and KEGG orthology showed associations with vital pathways, including MAPK signaling, plant hormone signal transduction, and plant-pathogen interaction. Secondary and tertiary structure analyses confirmed sequence conservation across studied species. Docking studies explored interactions between the cerato-platanin (CP) gene from Foc TR4 and Ma02_g15060 from banana, suggesting the potential hindrance of PR-1 antifungal activity through direct interaction. The findings underscore the crucial role of cloned PR-1 genes in banana plant defense mechanisms against a broad spectrum of biotic stresses. These genes, especially those in groups 1 and 2, hold promise as candidates for developing stress-tolerant banana cultivars. The study provides valuable insights into the molecular aspects of banana defense strategies, emphasizing the potential applications of PR-1 genes in enhancing banana resilience.

Preliminary Impact of Group-Based Interventions on Stigma, Mental Health, and Treatment Adherence Among Adolescents Living with Human Immunodeficiency Virus in Uganda

To examine the preliminary impact of group cognitive behavioral therapy and multiple family group-based family strengthening to address HIV stigma and improve the mental health functioning of adolescents living with HIV in Uganda. We analyzed data from the Suubi4Stigma study, a 2-year pilot randomized clinical trial that recruited adolescents living with HIV (10-14 years) and their caregivers (n = 89 dyads), from 9 health clinics. We fitted separate three-level mixed-effects linear regression models to test the effect of the interventions on adolescent outcomes at 3 and 6 months post intervention initiation. The average age was 12.2 years and 56% of participants were females. Participants in the multiple family group-based family strengthening intervention reported lower levels of internalized stigma (mean difference = -0.008, 95% CI = -0.015, -0.001, P = .025) and depressive symptoms at 3 months (mean difference = -0.34, 95% CI = -0.53, -0.14, P < .001), compared with usual care. On the other hand, participants in the group cognitive behavioral therapy intervention reported lower levels of anticipated stigma at 3 months (mean difference =-0.039, 95% CI=-0.072, -0.006), P=.013) and improved self-concept at 6months follow-up (mean difference=0.04, 95% CI=0.01, 0.01, P=.025). Outcome trends from this pilot study provide compelling evidence to support testing the efficacy of these group-based interventions on a larger scale. The study is registered in the Clinical trials.gov database (Identifier #: NCT04528732).

Mechanism of sturgeon intestinal inflammation induced by Yersinia ruckeri and the effect of florfenicol intervention

The mechanism by which Y. ruckeri infection induces enteritis in Chinese sturgeon remains unclear, and the efficacy of drug prevention and control measures is not only poor but also plagued with numerous issues. We conducted transcriptomic and 16 S rRNA sequencing analyses to examine the differences in the intestinal tract of hybrid sturgeon before and after Y. ruckeri infection and florfenicol intervention. Our findings revealed that Y. ruckeri induced the expression of multiple inflammatory factors, including il1β, il6, and various chemokines, as well as casp3, casp8, and multiple tumor necrosis factor family members, resulting in pathological injury to the body. Additionally, at the phylum level, the relative abundance of Firmicutes and Bacteroidota increased, while the abundance of Plesiomonas and Cetobacterium decreased at the genus level, altering the composition of the intestinal flora. Following florfenicol intervention, the expression of multiple apoptosis and inflammation-related genes was down-regulated, promoting tissue repair. However, the flora became further dysregulated, increasing the risk of infection. In conclusion, our analysis of the transcriptome and intestinal microbial composition demonstrated that Y. ruckeri induces intestinal pathological damage by triggering apoptosis and altering the composition of the intestinal microbiota. Florfenicol intervention can repair pathological damage, but it also exacerbates flora imbalance, leading to a higher risk of infection. These findings help elucidate the molecular mechanism of Y. ruckeri-induced enteritis in sturgeon and evaluate the therapeutic effect of drugs on intestinal inflammation in sturgeon.

Do Caregiver Perceptions of the Virtual More Than Words® Program Differ Based on Autistic Children's Attributes?

More Than Words® (MTW) is a caregiver-mediated intervention program led by a speech-language pathologist (SLP) who teaches caregivers strategies to support their autistic child's early social communication and play development. The program includes group sessions composed of multiple families with children of varying profiles. We explored whether caregiver experiences and perceived outcomes of the virtual MTW program differed depending on the child's age and social communication stage. As part of a program evaluation of virtual MTW delivered to over 2,000 families in Ontario, Canada, between 2020 and 2021, we randomly selected 31 families across four social communication stages and two age groups using stratified sampling (n = 4, in all but one subgroup). The Final Reflection and Evaluation form was analyzed both qualitatively and quantitatively, and a modified RE-AIM framework guided our analyses, including theme development. Child attributes did not appear to impact caregivers' experiences, but perceived child skill improvements varied by children's social communication stage. The majority of caregivers reported changes in how they interact with their child. Four themes emerged: (a) perceived child skill improvements differed by social communication stage, (b) caregivers gained new knowledge and strategies regardless of child attributes, (c) SLPs effectively managed families' individual needs, and (d) program components were appropriate for a variety of families. Findings suggest that the content taught in the MTW program was relevant for a variety of children, including those beyond the program's intended age of 5 years and under. Grouping families of children with varying profiles does not appear to negatively influence caregivers' experiences or perceived outcomes. https://doi.org/10.23641/asha.25237009.

Achieving Goals of Care Decisions in Chronic Critical Illness: A Multi-Institutional Qualitative Study

BACKGROUNDClinicians, patients, and families alike perceive a need to improve how goals of care (GOC) decisions occur in chronic critical illness (CCI) but little is currently known about this decision making process. RESEARCH QUESTIONHow do intensivists from various health systems facilitate decision-making about GOC for patients with CCI? What are barriers to, and facilitators of, this decision-making process? STUDY DESIGNAND METHODS: We conducted semi-structured interviews with a purposeful sample of intensivists from the United States and Canada using a ‘mental models’ approach adapted from decision science. We analyzed transcripts inductively using qualitative description. RESULTSWe interviewed 29 intensivists from six institutions. Participants across all sites described GOC decision-making in CCI as a complex, longitudinal, and iterative process that involved substantial preparatory work, numerous stakeholders, and multiple family meetings. Intensivists required considerable time to collect information on prior events and conversations, and to arrive at a prognostic consensus with other involved clinicians prior to meeting with families. Many intensivists stressed the importance of scheduling multiple family meetings to build trust and relationships prior to explicitly discussing GOC. Physician-identified barriers to GOC decision-making included one week staffing models, limited time and cognitive bandwidth, difficulty eliciting patient values, and interpersonal challenges with care team members or families. Potential facilitators included scheduled family meetings at regular intervals, greater interprofessional involvement in decisions, and consistent messaging from care team members. INTERPRETATIONIntensivists described a complex time and labor-intensive group process to achieve GOC decision-making in CCI. System-level interventions that improve how information is shared between clinicians and decrease logistical and relational barriers to timely and consistent communication are key to improving goals-of-care decision making in chronic critical illness.

Statistical modelling under differential privacy constraints: a case study in fine-scale geographical analysis with Australian Bureau of Statistics TableBuilder data

ABSTRACT Consistent with the principles of differential privacy protection, the Australian Bureau of Statistics artificially perturbs all count data from the Australian Census prior to its release to researchers through the TableBuilder platform. This perturbation involves the addition of random noise to every non-zero cell count followed by the suppression of small values to zero. A consequent problem encountered by researchers working with geographical TableBuilder outputs is that the aggregate sums of cell counts over fine-scale units are often much lower than the direct query totals of their coarser enclosing units. Hierarchical Bayesian modelling is here proposed as a powerful methodology for achieving consistent multi-scale statistical reconstructions suitable for downstream spatial modelling. The utility of this framework is demonstrated for the toy problem of reconstructing Multiple Family Household counts by Mesh Block in the Perth Greater Capital City area.

Black adolescents' disclosure and advice‐seeking: Making choices between parents and adult relatives

AbstractObjectiveThis study examined Black adolescents' decision‐making processes around disclosure and advice‐seeking with their primary caregivers and nonparental adult relatives.BackgroundFew studies have examined youths' decision‐making in the support process or how multiple dyadic youth–adult familial relationships concurrently function to support youths' needs. Consideration of multiple dyadic relationships facilitates a more comprehensive understanding of how Black adolescents use familial resources to meet their support needs.MethodInterview data from 24 youth, their primary caregivers, and one nonparental adult relative with whom youth reported having a strong relational bond (n = 72 individuals) were analyzed to investigate who youth were deciding to confide in and what information youth were choosing to share with these adults.ResultsBlack adolescents often disclosed and sought advice from their primary caregivers either exclusively or in conjunction with nonparental adult relatives across most domains of disclosure and advice‐seeking. Family issues was one topic that youth would almost exclusively discuss with their nonparental adult relatives.ConclusionFindings suggest that youths' decision to confide may be topic dependent rather than based on a general disposition among youth for whom they share most of their concerns.ImplicationsUnderstanding youths' disclosure and advice‐seeking across multiple close family relationships may inform interventions aimed to promote Black adolescents' support seeking.

Distinct structural variants and repeat landscape shape the genomes of the ancient grapes Aglianico and Falanghina

Mounting evidence recognizes structural variations (SVs) and repetitive DNA sequences as crucial players in shaping the existing grape phenotypic diversity at intra- and inter-species levels. To deepen our understanding on the abundance, diversity, and distribution of SVs and repetitive DNAs, including transposable elements (TEs) and tandemly repeated satellite DNA (satDNAs), we re-sequenced the genomes of the ancient grapes Aglianico and Falanghina. The analysis of large copy number variants (CNVs) detected candidate polymorphic genes that are involved in the enological features of these varieties. In a comparative analysis of Aglianico and Falanghina sequences with 21 publicly available genomes of cultivated grapes, we provided a genome-wide annotation of grape TEs at the lineage level. We disclosed that at least two main clusters of grape cultivars could be identified based on the TEs content. Multiple TEs families appeared either significantly enriched or depleted. In addition, in silico and cytological analyses provided evidence for a diverse chromosomal distribution of several satellite repeats between Aglianico, Falanghina, and other grapes. Overall, our data further improved our understanding of the intricate grape diversity held by two Italian traditional varieties, unveiling a pool of unique candidate genes never so far exploited in breeding for improved fruit quality.

Evolutionary history influences the microbiomes of a female symbiotic reproductive organ in cephalopods.

Many female squids and cuttlefishes have a symbiotic reproductive organ called the accessory nidamental gland (ANG) that hosts a bacterial consortium involved with egg defense against pathogens and fouling organisms. While the ANG is found in multiple cephalopod families, little is known about the global microbial diversity of these ANG bacterial symbionts. We used 16S rRNA gene community analysis to characterize the ANG microbiome from different cephalopod species and assess the relationship between host and symbiont phylogenies. The ANG microbiome of 11 species of cephalopods from four families (superorder: Decapodiformes) that span seven geographic locations was characterized. Bacteria of class Alphaproteobacteria, Gammaproteobacteria, and Flavobacteriia were found in all species, yet analysis of amplicon sequence variants by multiple distance metrics revealed a significant difference between ANG microbiomes of cephalopod families (weighted/unweighted UniFrac, Bray-Curtis, P = 0.001). Despite being collected from widely disparate geographic locations, members of the family Sepiolidae (bobtail squid) shared many bacterial taxa including (~50%) Opitutae (Verrucomicrobia) and Ruegeria (Alphaproteobacteria) species. Furthermore, we tested for phylosymbiosis and found a positive correlation between host phylogenetic distance and bacterial community dissimilarity (Mantel test r = 0.7). These data suggest that closely related sepiolids select for distinct symbionts from similar bacterial taxa. Overall, the ANGs of different cephalopod species harbor distinct microbiomes and thus offer a diverse symbiont community to explore antimicrobial activity and other functional roles in host fitness.IMPORTANCEMany aquatic organisms recruit microbial symbionts from the environment that provide a variety of functions, including defense from pathogens. Some female cephalopods (squids, bobtail squids, and cuttlefish) have a reproductive organ called the accessory nidamental gland (ANG) that contains a bacterial consortium that protects eggs from pathogens. Despite the wide distribution of these cephalopods, whether they share similar microbiomes is unknown. Here, we studied the microbial diversity of the ANG in 11 species of cephalopods distributed over a broad geographic range and representing 15-120 million years of host divergence. The ANG microbiomes shared some bacterial taxa, but each cephalopod species had unique symbiotic members. Additionally, analysis of host-symbiont phylogenies suggests that the evolutionary histories of the partners have been important in shaping the ANG microbiome. This study advances our knowledge of cephalopod-bacteria relationships and provides a foundation to explore defensive symbionts in other systems.

Feasibility and Acceptability of Group-Based Stigma Reduction Interventions for Adolescents Living with HIV and Their Caregivers: The Suubi4Stigma Randomized Clinical Trial (2020-2022).

This study examined the feasibility and acceptability of two group-based interventions: group-cognitive behavioral therapy (G-CBT) and a family-strengthening intervention delivered via multiple family group (MFG-FS), to address HIV stigma among adolescents living with HIV (ALHIV) and their caregivers. A total of 147 adolescent -caregiver dyads from 9 health clinics situated within 7 political districts in Uganda were screened for eligibility. Of these, 89 dyads met the inclusion criteria and provided consent to participate in the study. Participants were randomized, at the clinic level, to one of three study conditions: Usual care, G-CBT or MFG-FS. The interventions were delivered over a 3-month period. While both adolescents and their caregivers attended the MFG-FS sessions, G-CBT sessions were only attended by adolescents. Data were collected at baseline, 3 and 6-months post intervention initiation. The retention rate was 94% over the study period. Across groups, intervention session attendance ranged between 85 and 92%, for all sessions. Fidelity of the intervention was between 85 and 100%, and both children and caregivers rated highly their satisfaction with the intervention sessions. ALHIV in Uganda, and most of sub-Saharan Africa, are still underrepresented in stigma reduction interventions. The Suubi4Stigma study was feasible and acceptable to adolescents and their caregivers -supporting testing the efficacy of the interventions in a larger trial.

The Inhibition of Serine Proteases by Serpins Is Augmented by Negatively Charged Heparin: A Concise Review of Some Clinically Relevant Interactions.

Serine proteases are members of a large family of hydrolytic enzymes in which a particular serine residue in the active site performs an essential role as a nucleophile, which is required for their proteolytic cleavage function. The array of functions performed by serine proteases is vast and includes, among others, the following: (i) the ability to fight infections; (ii) the activation of blood coagulation or blood clot lysis systems; (iii) the activation of digestive enzymes; and (iv) reproduction. Serine protease activity is highly regulated by multiple families of protease inhibitors, known collectively as the SERine Protease INhibitor (SERPIN). The serpins use a conformational change mechanism to inhibit proteases in an irreversible way. The unusual conformational change required for serpin function provides an elegant opportunity for allosteric regulation by the binding of cofactors, of which the most well-studied is heparin. The goal of this review is to discuss some of the clinically relevant serine protease-serpin interactions that may be enhanced by heparin or other negatively charged polysaccharides. The paired serine protease-serpin in the framework of heparin that we review includes the following: thrombin-antithrombin III, plasmin-anti-plasmin, C1 esterase/kallikrein-C1 esterase inhibitor, and furin/TMPRSS2 (serine protease Transmembrane Protease 2)-alpha-1-antitrypsin, with the latter in the context of COVID-19 and prostate cancer.

Angiosperm-wide analysis of fruit and ovary evolution aided by a new nuclear phylogeny supports association of the same ovary type with both dry and fleshy fruits.

Fruit functions in seed protection and dispersal and belongs to many dry and fleshy types, yet their evolutionary pattern remains unclear in part due to uncertainties in the phylogenetic relationships among several orders and families. Thus we used nuclear genes of 502 angiosperm species representing 231 families to reconstruct a well supported phylogeny, with resolved relationships for orders and families with previously uncertain placements. Using this phylogeny as a framework, molecular dating supports a Triassic origin of the crown angiosperms, followed by the emergence of most orders in the Jurassic and Cretaceous and their rise to ecological dominance during the Cretaceous Terrestrial Revolution. The robust phylogeny allowed an examination of the evolutionary pattern of fruit and ovary types, revealing a trend of parallel carpel fusions during early diversifications in eudicots, monocots, and magnoliids. Moreover, taxa in the same order or family with the same ovary type can develop either dry or fleshy fruits with strong correlations between specific types of dry and fleshy fruits; such associations of ovary, dry and fleshy fruits define several ovary-fruit "modules" each found in multiple families. One of the frequent modules has an ovary containing multiple ovules, capsules and berries, and another with an ovary having one or two ovules, achenes (or other single-seeded dry fruits) and drupes. This new perspective of relationships among fruit types highlights the closeness of specific dry and fleshy fruit types, such as capsule and berry, that develop from the same ovary type and belong to the same module relative to dry and fleshy fruits of other modules (such as achenes and drupes). Further analyses of gene families containing known genes for ovary and fruit development identified phylogenetic nodes with multiple gene duplications, supporting a possible role of whole-genome duplications, in combination with climate changes and animal behaviors, in angiosperm fruit and ovary diversification.

Multiple Sclerosis and Family Planning: A Survey Study of the Patient Experience.

Multiple sclerosis (MS) commonly affects women in their childbearing years, necessitating discussion between patients and their MS treatment team around the issues of family planning, pregnancy, and postpartum experiences. This study assessed the impact of a diagnosis of MS on women's reproductive decision-making and on their perception of counseling received surrounding pregnancy. It also sought to evaluate trends in pregnancy and postpartum experiences and determine whether experiences differed by race, ethnicity, and zip code. Women with an MS diagnosis seen at the University of Virginia MS Clinic or at Virginia Commonwealth University (VCU) MS Clinic were invited to participate in a survey study. MS disease and pregnancy history, and, when appropriate, reasons for pregnancy avoidance were collected. Respondents who had >1 pregnancy following MS diagnosis were asked to evaluate the counseling they received from medical professionals and to share their pregnancy experiences including complications during pregnancy, delivery outcomes, and postpartum experience including breastfeeding. Of the 280 respondents, 76.6% were currently receiving MS specialty care. Most of them (79.3%) had not been pregnant following MS diagnosis. Of them, 20.1% indicated that this decision was driven by MS-related concerns: MS worsening with pregnancy (47%); ability to care for child secondary to MS (35%); passing MS onto child (19%); stopping disease-modifying therapies to attempt pregnancy (14%); lack of knowledge about options for pregnancy and MS (9%). Women with a more recent estimated decade of pregnancy were more likely to report neurologist counseling regarding MS and pregnancy (pregnancy before 2000: 40%, 2000-2010: 64.7%, 2010- present: 83.3%; χ2 0.020). Breastfeeding initiation was reported in 71.4% of postdiagnosis pregnancies (median duration 6 months, interquartile range 1.75-11). Over the past few decades, women with MS have received a wide range of evolving guidance surrounding family planning, pregnancy, and postpartum care. Survey data suggest improvements in MS/pregnancy counseling and medical management in recent years, which may be driven by an increase in research in the field. There remains an important need and opportunity to improve counseling of women with MS who are considering pregnancy.