Bergerthorup2201

Rozanolixizumab is a fully humanised high-affinity anti-human neonatal Fc receptor (FcRn) monoclonal antibody (mAb) that accelerates the removal of circulating immunoglobulin G (IgG), including pathogenic IgG autoantibodies, via the natural lysosomal degradation pathway. The aim of this study was to develop a pharmacokinetic-pharmacodynamic (PK/PD) model characterising the effect of rozanolixizumab on IgG levels in cynomolgus monkeys, translate it into humans to support the first-in-human (FIH) rozanolixizumab clinical trial study design, and ultimately, develop a PK/PD model in humans. Simulations from the preclinical model were performed to predict IgG responses in humans and select clinically relevant doses in the FIH study. Good alignment was observed between predicted and observed reductions in IgG, which increased with increasing dose in the FIH study. The model successfully described the PK of the 4 and 7 mg/kg intravenous (IV) dose groups, although the PK was underpredicted for the 1 mg/kg IV dose group. Updating the model with subsequent human data identified parameters that deviated from preclinical assumptions. The updated PK/PD model was able to effectively characterise the PK FcRn-IgG non-linear system in response to rozanolixizumab in the FIH human data.

Hepatic ischemia reperfusion (HIR) injury, a common clinical complication of liver transplantation and resection, affects patient prognosis. RNF5 is an E3 ubiquitin ligase that plays important roles in endoplasmic reticulum stress, unfolded protein reactions, and inflammatory responses; however, its role in HIR is unclear.

RNF5 expression was significantly downregulated during HIR in mice and hepatocytes. Subsequently, RNF5 knockdown and overexpression cell lines were subjected to hypoxia-reoxygenation challenge. The results shown that RNF5 knockdown significantly increased hepatocyte inflammation and apoptosis, while RNF5 overexpression had the opposite effect. Furthermore, hepatocyte-specific RNF5 knockout and transgenic mice were established and subjected to HIR, and RNF5 deficiency markedly aggravated liver damage, cell apoptosis, and activated hepatic inflammatory responses. While hepatic RNF5 transgenic mice had the opposite effect compared with RNF5 knockout mice. Mechanistically, RNF5 interacted with PGAM5 and mediated the degradation of PGAM5 through K48-linked ubiquitination, thereby inhibiting the activation of ASK1 and its downstream JNK/p38. This eventually suppresses the inflammatory response and cell apoptosis in HIR.

We revealed that RNF5 protected against HIR via its interaction with PGAM5 to inhibit the activation of ASK1 and the downstream JNK/p38 signaling cascade. Our findings indicate that the RNF5-PGAM5 axis may be a promising therapeutic target for HIR.

We revealed that RNF5 protected against HIR via its interaction with PGAM5 to inhibit the activation of ASK1 and the downstream JNK/p38 signaling cascade. Our findings indicate that the RNF5-PGAM5 axis may be a promising therapeutic target for HIR.Intraportal (IP) islet cell transplants can restore metabolic control in type 1 diabetes patients, but limitations raise the need for establishing a functional beta cell mass (FBM) in a confined extrahepatic site. This study reports on function and composition of omental (OM) implants after placement of islet cell grafts with similar beta cell mass as in our IP-protocol (2-5.106 beta cells/kg body weight) on a scaffold. Four of seven C-peptide-negative recipients achieved low beta cell function (hyperglycemic clamp [HGC] 2-8 percent of controls) until laparoscopy, 2-6 months later, for OM-biopsy and concomitant IP-transplant with similar beta cell dose. This IP-transplant increased HGC-values to 15-40 percent. OM-biopsies reflected the composition of initial grafts, exhibiting varying proportions of endocrine-cell-enriched clusters with more beta than alpha cells and leucocyte pole, non-endocrine cytokeratin-positive clusters surrounded by leucocytes, and scaffold remnants with foreign body reaction. OM-implants on a polyglactin-thrombin-fibrinogen-scaffold presented larger endocrine clusters with infiltrating endothelial cells and corresponded to the higher HGC-values. No activation of cellular immunity to GAD/IA2 was measured post-OM-transplant. Establishment of a metabolically adequate FBM in omentum may require a higher beta cell number in grafts but also elimination of their immunogenic non-endocrine components as well as local conditioning that favors endocrine cell engraftment and function.Reliable partitioning of micrometeorologically measured evapotranspiration (ET) into evaporation (E) and transpiration (T) would greatly enhance our understanding of the water cycle and its response to climate change related shifts in local-to-regional climate conditions and rising global levels of vapor pressure deficit (VPD). While some methods on ET partitioning have been developed, their underlying assumptions make them difficult to apply more generally, especially in sites with large contributions of E. Here, we report a novel ET partitioning method using artificial neural networks (ANNs) in combination with a range of environmental input variables to predict daytime E from nighttime ET measurements. find more The study uses eddy covariance data from four restored wetlands in the Sacramento-San Joaquin Delta, California, USA, as well as leaf-level T data for validation. The four wetlands vary in their vegetation make-up and structure, representing a range of ET conditions. The ANNs were built with increasing complexity by adding the input variable that resulted in the next highest average value of model testing R2 across all sites. The order of variable inclusion (and importance) was VPD > gap-filled sensible heat flux (H_gf) > air temperature (Tair ) > friction velocity (u∗ ) > other variables. The model using VPD, H_gf, Tair , and u∗ showed the best performance during validation with independent data and had a mean testing R2 value of 0.853 (averaged across all sites, range from 0.728 to 0.910). In comparison to other methods, our ANN method generated T/ET partitioning results which were more consistent with CO2 exchange data especially for more heterogeneous sites with large E contributions. Our method improves the understanding of T/ET partitioning. While it may be particularly suited to flooded ecosystems, it can also improve T/ET partitioning in other systems, increasing our knowledge of the global water cycle and ecosystem functioning.

The purpose of this study was to functionalize an ovine stretched cheese belonging to 'Vastedda' typology with red grape pomace powder (GPP) of Nero d'Avola cultivar and to characterize the microbiological, physicochemical, phenolic profile and sensory characteristics of the final cheeses.

Before cheeses production, GPP was characterized for its microbiological profile, antibacterial activity and polyphenolic content. No colonies of bacteria and yeasts were detected in the GPP. GPP showed a large inhibition spectrum against spoilage and pathogenic bacteria. Three classes of polyphenolic compounds belonging to flavan-3-ols, flavonol and phenolic acids were identified. Two cheeses [0 and 1% (w w

) of GPP] were produced with pasteurized ewe's milk and commercial starter cultures. Plate counts and randomly amplified polymorphic DNA analysis demonstrated the ability of the starter strains to drive the fermentation process in the presence of GPP. GPP enrichment resulted in an increase of protein, phenolic compounds, sensory traits and reduced fat.

GPP addition to cheese represents an optimal strategy for the valorization of winemaking by-products and to obtain polyphenol-enriched cheese.

This study allowed to achieve an ovine cheese with specific physicochemical, nutraceutical and sensorial characteristics able to enlarge the functional dairy product portfolio.

This study allowed to achieve an ovine cheese with specific physicochemical, nutraceutical and sensorial characteristics able to enlarge the functional dairy product portfolio.Climate warming in recent decades has negatively impacted forest health in the western United States. Here, we report on potential early warning signals (EWS) for drought-related mortality derived from measurements of tree-ring growth (ring width index; RWI) and carbon isotope discrimination (∆13 C), primarily focused on ponderosa pine (Pinus ponderosa). Sampling was conducted in the southern Sierra Nevada Mountains, near the epicenter of drought severity and mortality associated with the 2012-2015 California drought and concurrent outbreak of western pine beetle (Dendroctonus brevicomis). At this site, we found that widespread mortality was presaged by five decades of increasing sensitivity (i.e., increased explained variation) of both tree growth and ∆13 C to Palmer Drought Severity Index (PDSI). We hypothesized that increasing sensitivity of tree growth and ∆13 C to hydroclimate constitute EWS that indicate an increased likelihood of widespread forest mortality caused by direct and indirect effects of drouaid in forecasting of forest responses to continued climate warming.

To stimulate obstetric centers to start training in breech counseling and selection and performing vaginal breech deliveries.

The different steps that were needed to roll out a breech program, are described the "walking" epidural (PIEB protocol), the breech consultation with a structured counseling tool, and training of the whole team (gynecologists, midwives, anesthesiologists, and pediatricians). We describe below the results of 111 women who were counseled at the breech consultation, in the period May 2019 to August 2021.

In all, 86.5% of patients (n= 96) with a singleton term breech met the criteria for a vaginal breech delivery; 77% of this group (n= 74) accepted a planned vaginal breech delivery. Of this group, 54% (n=40) had a successful vaginal breech delivery, 27% (n=20) ended up in a secondary cesarean section, and 19% (n=14) had a planned cesarean section.

We were able to roll out a successful breech program, including vaginal breech delivery, in a safe way. The breech consultation is the most essential part of the process. Training of the whole team is mandatory. The results of the first 2 years are encouraging to continue this program.

We were able to roll out a successful breech program, including vaginal breech delivery, in a safe way. The breech consultation is the most essential part of the process. Training of the whole team is mandatory. The results of the first 2 years are encouraging to continue this program.

To analyze a case of heavy uterine bleeding in adolescence caused by an arteriovenous malformation (AVM) in Hanoi Obstetrics and Gynecology Hospital, Vietnam.

We observed a case of a 14-year-old girl, without vaginal sexual intercourse experience, having heavy uterine bleeding caused by AVM. She underwent a laparoscopic operation at the hospital for vascular lesions in the uterine anterior wall, which caused an internal hemorrhage of 1500ml blood loss into the peritoneal cavity. Three years later, this patient was hospitalized twice for massive vaginal bleeding.

Results of ultrasound and magnetic resonance imaging indicated a uterine intramural mass with enlarged vessels connecting to the endometrial cavity. A pelvic digital subtraction angiography was performed and showed profuse bleeding from a ruptured branch of the left uterine artery. This artery was embolized at Bach Mai hospital and the bleeding was stopped. The patient had stable health and normal menstrual periods after 4months of follow up.

Abnormal mass with dilated vessels in the myometrium in a patient experiencing heavy uterine bleeding is an exclusive sign of uterine vascular malformation and can be treated by angioembolization.