Hepatic bile acid accretion correlates with cholestatic liver injury and therapeutic response in knockout mice with a humanized bile acid composition.

knockout (KO) mice lack the liver enzyme responsible for synthesis of 6-hydroxylated muricholate bile acid species and possess a more hydrophobic human-like bile acid composition. KO mice develop cholestatic liver injury that can be prevented by the administration of an ileal bile acid transporter (IBAT) inhibitor. In this study, we investigated the potential of an ileal bile acid transporter (IBAT) inhibitor (SC-435) and steroidal farnesoid X receptor (FXR) agonist (cilofexor) to modulate established hepatobiliary injury and the consequent relationship of intrahepatic bile acid content and hydrophobicity to the cholestatic liver injury phenotype.

Validation of the Coping With Discrimination Scale among Arab/Middle Eastern North African Americans.

Objectives: Arab/Middle Eastern North African (MENA) Americans experience high levels of discrimination, which is associated with greater engagement in coping strategies to alleviate the stress. The Coping with Discrimination Scale (CDS; Wei, Alvarez, et al., 2010) remains one of the only measures that assesses responses to discrimination.

BiliQML: a supervised machine-learning model to quantify biliary forms from digitized whole slide liver histopathological images.

The progress of research focused on cholangiocytes and the biliary tree during development and following injury is hindered by limited available quantitative methodologies. Current techniques include two-dimensional standard histological cell-counting approaches, which are rapidly performed, error prone, and lack architectural context or three-dimensional analysis of the biliary tree in opacified livers, which introduce technical issues along with minimal quantitation. The present study aims to fill these quantitative gaps with a supervised machine-learning model (BiliQML) able to quantify biliary forms in the liver of anti-keratin 19 antibody-stained whole slide images.

Microsecond dynamics control the HIV-1 Envelope conformation.

The HIV-1 Envelope (Env) glycoprotein facilitates host cell fusion through a complex series of receptor-induced structural changes. Although remarkable progress has been made in understanding the structures of various Env conformations, microsecond timescale dynamics have not been studied experimentally. Here, we used time-resolved, temperature-jump small-angle x-ray scattering to monitor structural rearrangements in an HIV-1 Env SOSIP ectodomain construct with microsecond precision.

A molecular dynamics study of cell-penetrating peptide transportan-10 (TP10): Binding, folding and insertion to transmembrane state in zwitterionic membrane.

Transportan 10 (TP10) is a 21-residue, cationic, α-helical cell-penetrating peptide that can be used as a delivery vector for various bioactive molecules. Based on recent confocal microscopy studies, it is believed that TP10 can translocate across neutral lipid membrane passively, possibly as a monomer, without the formation of permanent pore. Here, we performed extensive molecular dynamics (MD) simulations of TP10W (Y3W variant of TP10) to find the microscopic details of binding, folding and insertion of TP10W to transmembrane state in POPC bilayer.

The Impact of Acupuncture on Self-Perceived Stress and ADHD Core Symptomatology in an Adult, Atomoxetine-taking ADHD Participant. Insights from an In-depth Single Case Study.

Background: Attention Deficit Hyperactivity Disorder (ADHD) includes inattention, hyperactivity, and impulsivity as core symptoms and is associated with increased self-perceived stress.

Primary Study Objective: This article evaluates the impact of acupuncture (provided in addition to regular pharmacological treatment with Atomoxetine) on self-perceived stress and ADHD core symptomatology, compared to atomoxetine (ATX) alone.

Methods/design: In-depth single case study, involving a mixed methods approach with questionnaires and interviews was used.

Microsecond dynamics control the HIV-1 envelope conformation.

The HIV-1 Envelope (Env) glycoprotein facilitates host cell fusion through a complex series of receptor-induced structural changes. Although significant progress has been made in understanding the structures of various Env conformations and transition intermediates that occur within the millisecond timescale, faster transitions in the microsecond timescale have not yet been observed. In this study, we employed time-resolved, temperature-jump small angle X-ray scattering to monitor structural rearrangements in an HIV-1 Env ectodomain construct with microsecond precision.

Liver-restricted deletion of the biliary atresia candidate gene Pkd1l1 causes bile duct dysmorphogenesis and ciliopathy.

Background And Aims: A recent multicenter genetic exploration of the biliary atresia splenic malformation syndrome identified mutations in the ciliary gene PKD1L1 as candidate etiologic contributors. We hypothesized that deletion of Pkd1l1 in developing hepatoblasts would lead to cholangiopathy in mice.

Approach And Results: CRISPR-based genome editing inserted loxP sites flanking exon 8 of the murine Pkd1l1 gene.

Doxorubicin for treatment of histiocytic sarcoma in dogs: 31 cases (2003-2017).

Objective: To evaluate the efficacy of doxorubicin for treatment of histiocytic sarcoma (HS) in dogs, whether administered as the sole treatment or as an adjunct to surgery or radiation therapy.

Animals: 31 client-owned dogs with localized or disseminated HS examined between 2003 and 2017.

Procedures: Medical records were reviewed retrospectively, and data were collected.

Ileal bile acid transporter inhibition in Cyp2c70 KO mice ameliorates cholestatic liver injury.

Cyp2c70 is the liver enzyme in rodents responsible for synthesis of the primary 6-hydroxylated muricholate bile acid (BA) species. Cyp2c70 KO mice are devoid of protective, hydrophilic muricholic acids, leading to a more human-like BA composition and subsequent cholestatic liver injury. Pharmacological inhibition of the ileal BA transporter (IBAT) has been shown to be therapeutic in cholestatic models.

Clodronate inhibits alloimmunization against distinct red blood cell alloantigens in mice.

Background: Alloimmunization can be a significant barrier to red blood cell (RBC) transfusion. While alloantigen matching protocols hold promise in reducing alloantibody formation, transfusion-dependent patients can still experience RBC alloimmunization and associated complications even when matching protocols are employed. As a result, complementary strategies capable of actively preventing alloantibody formation following alloantigen exposure are warranted.

HIV-1 Envelope Conformation, Allostery, and Dynamics.

The HIV-1 envelope glycoprotein (Env) mediates host cell fusion and is the primary target for HIV-1 vaccine design. The Env undergoes a series of functionally important conformational rearrangements upon engagement of its host cell receptor, CD4. As the sole target for broadly neutralizing antibodies, our understanding of these transitions plays a critical role in vaccine immunogen design.

The Impact of the Tertiary Survey in an Established Trauma Program.

Introduction: The trauma tertiary survey (TTS) was first described in 1990 and is recognized as an essential practice in trauma care. The TTS remains effective in detecting secondary injuries in the modern era.

Methods: Trauma patients discharged between August 1, 2016, and December 31, 2016, were identified in our trauma registry.

Rectal foreign bodies: national outcomes after the operating room.

Purpose: Rectal foreign bodies can pose a unique problem to the acute care surgeon or emergency room physician. Little data exists on the patient with such a diagnosis, outside of case reports, and institutional cohorts. This study describes demographics and outcomes for this patient population.

Ketoacidosis in Euglycemic Patients With Type 2 Diabetes After Abdominal Surgery.

Diabetic ketoacidosis is defined as hyperglycemia >250 mg/dL with metabolic acidosis of arterial pH <7.3, serum bicarbonate <18 mEq/L with positive urine and serum ketones and an anion gap >10. Euglycemic ketoacidosis has been reported in patients with type 2 diabetes and in patients with type 1 diabetes.

Anemia induces gut inflammation and injury in an animal model of preterm infants.

Background: While very low birth weight (VLBW) infants often require multiple red blood cell transfusions, efforts to minimize transfusion-associated risks have resulted in more restrictive neonatal transfusion practices. However, whether restrictive transfusion strategies limit transfusions without increasing morbidity and mortality in this population remains unclear. Recent epidemiologic studies suggest that severe anemia may be an important risk factor for the development of necrotizing enterocolitis (NEC).

Landscape and local site variables differentially influence pollinators and pollination services in urban agricultural sites.

Urbanization has detrimental effects on biodiversity and ecosystem functioning, as agricultural and semi-natural habitats are converted into landscapes dominated by built features. Urban agricultural sites are a growing component of urban landscapes and have potential to serve as a source of biodiversity conservation and ecosystem service provisioning in urban areas. In 19 urban agricultural sites, we investigated how surrounding land cover and local site variables supported bees and pollination services.

Marginal Zone B Cells Induce Alloantibody Formation Following RBC Transfusion.

Red blood cell (RBC) alloimmunization represents a significant immunological challenge for some patients. While a variety of immune constituents likely contribute to the initiation and orchestration of alloantibodies to RBC antigens, identification of key immune factors that initiate alloantibody formation may aid in the development of a therapeutic modality to minimize or prevent this process. To define the immune factors that may be important in driving alloimmunization to an RBC antigen, we determined the specific immune compartment and distinct cells that may initially engage transfused RBCs and facilitate subsequent alloimmunization.

Complement serves as a switch between CD4+ T cell-independent and -dependent RBC antibody responses.

RBC alloimmunization represents a significant immunological challenge for patients requiring lifelong transfusion support. The majority of clinically relevant non-ABO(H) blood group antigens have been thought to drive antibody formation through T cell-dependent immune pathways. Thus, we initially sought to define the role of CD4+ T cells in formation of alloantibodies to KEL, one of the leading causes of hemolytic transfusion reactions.

Antibody-mediated immune suppression by antigen modulation is antigen-specific.

Alloantibodies developing after exposure to red blood cell (RBC) alloantigens can complicate pregnancy and transfusion therapy. The only method currently available to actively inhibit RBC alloantibody formation is administration of antigen-specific antibodies, a phenomenon termed antibody-mediated immune suppression (AMIS). A well-known example of AMIS is RhD immune globulin prophylaxis to prevent anti-D formation in RhD individuals.

Harvesting effects on wild bee communities in bioenergy grasslands depend on nesting guild.

Conversion of annual crops to native perennial grasslands for bioenergy production may help conserve wild bees by enhancing nest and food resources. However, bee response to the disturbance of biomass harvesting may depend on their nesting location, thus their vulnerability to nest destruction, and the response of the forb community on which they forage. Moreover, because bees have long foraging ranges, effects of local harvesting may depend on the amount of natural habitat in the surrounding landscape.

Coupling between an electrostatic network and the Zn binding site modulates Hv1 activation.

The voltage sensor (VS) domain in Hv1 proton channels mediates a voltage-dependent and H-selective "aqueous" conductance (G) that is potently modulated by extracellular Zn Although two conserved His residues are required for Zn effects on G gating, the atomic structure of the Zn coordination site and mechanism by which extracellular Zn stabilizes a closed-state conformation remain unknown. Here we use His mutagenesis to identify residues that increase Zn potency and are therefore likely to participate in first solvation shell interactions with Zn Experimental Zn-mapping data were then used to constrain the structure of a new resting-state Hv1 model (Hv1 F). Molecular dynamics (MD) simulations show how protein and water atoms directly contribute to octahedral Zn coordination spheres in Zn-bound and -unbound Hv1 F models.