U kontekstu izlaganja razvoja instituta clausula rebus sic stantibus, premda u rimskom pravu nije postojao opći institut koji bi mu odgovarao, u romanistici se upućuje na remissio mercedis kod ...locatio fundi kao istaknuti primjer uvažavanja promijenjenih okolnosti od strane rimskih pravnika. Polazeći od općih karakteristika ugovora o zakupu te uređenja odgovornosti stranaka, u radu se analiziraju uređenje i argumentacija primjene instituta remissio mercedis iz perspektive promijenjenih okolnosti. Na temelju navedenoga, ispituje se u kojoj bi mjeri bila riječ o istoj liniji promišljanja o utjecaju izvanrednih vanjskih događaja na obveze ugovornih stranaka u rimskom pravu i u doktrini klauzule rebus sic stantibus.
In the context of studies concerned with the development of clausula rebus sic stantibus, although acknowledging the fact that this legal institute was not present in Roman law, some Romanists have pointed out the remissio mercedis in the lease of land (locatio fundi) as the prominent example when the change of circumstances influenced the obligations of parties in Roman law. Starting with the general characteristics of the contract of lease and the obligations of the parties, the authors analyze in the contral part of the paper the institute remissio mercedis and its basis, taking into account different opinions and arguments for its application. This is especially done from the viewpoint of changed circumstances, leading to the conclusion on the difference in the line of thought about the effects of changed circumstances in the Roman law remissio mercedis and in the medieval clausula rebus sic stantibus.
Male breast cancer (MBC) is rare and usually presents as a locally advanced disease. Stromal tumor-infiltrating lymphocytes (sTILs) are associated with a better response to neoadjuvant chemotherapy ...and improved prognosis in all molecular subtypes of female breast cancer, but their role in MBC is less clear. We studied sTILs and the expression of programmed cell death ligand 1 (PD-L1) and pan-TRK in MBC. We retrospectively studied 113 cases of MBC surgically treated between 1988 and 2015. The tumors were evaluated for histological type and grade, stage, intrinsic subtype and sTILs. We performed immunohistochemistry for PD-L1 (clone SP142) and pan-TRK (clone EPR17341) on tissue microarrays. Pan-TRK positive cases were further analyzed by next-generation sequencing. The median age was 69 years (range 60−77). Invasive carcinoma of no special type was found in 94.7% of cases, of which 53.1% were grade 2. Estrogen receptor was positive in 92% of the tumors, progesterone receptor in 85.8%, androgen receptor in 70.8%; 4.4% were human epidermal growth factor receptor 2 (HER2)-positive, and 55.8% HER2-low. 40.7% of tumors were luminal A and 51.3% luminal B, 4.4% HER2-enriched and 3.5% triple negative carcinoma. sTILs density was <50% in 96.4% of the tumors, >50% in 3.6% of the tumors. PD-L1 immune cell score >1% was found in 7.1% of the tumors (all of luminal subtype). A weak focal cytoplasmic pan-TRK staining was present in 8.8% but without NTRK fusion. Neither sTILs nor PD-L1 had statistically significant outcomes. Our findings suggest that a subset of MBC patients harbors an immunological environment characterized by increased sTILs with PD-L1 expression. These patients may potentially benefit from immune checkpoint inhibitor therapy. Frequent HER2-low may offer novel anti-HER2 treatment options.
Four new N
2
O
2
-donor macrocycles
mDo4R, mDo5R, mDo6R, mDo7R
(
mDo4R =
1,5-diaza-2,4:7,8:15,16- tribenzo-9,14-dioxa-cycloheptadecane,
mDo5R =
...1,5-diaza-2,4:7,8:16,17-tribenzo-9,15-dioxa-cyclooctadecane,
mDo6R =
1,5-diaza-2,4:7,8:17,18-tribenzo-9,16-dioxa-cyclononadecane;
mDo7R =
1,5-diaza-2,4:7,8:18,19-tribenzo-9,17-dioxa-cycloeicosane) were prepared by NaBH
4
reduction of appropriate macrocyclic Schiff bases in high yields. The compounds were characterized by means of FT-IR and NMR spectroscopy and elemental analysis. The crystal and molecular structure was determined for
mDo5R
and
mDo7R
. The molecular structure of
mDo5R
indicate large deviation from planarity, relatively large inner macrocyclic hole size (1.542–3.048 Å) and
exodentante
orientation of one nitrogen atom (N
2
) due to presence of intramolecular N–H⋯O hydrogen bond. In
mDo7R
both nitrogen atoms are
exodentante
and involved in intramolecular N–H⋯O hydrogen bond. The
mDo7R
molecules are quite planar with small values of puckering amplitude (1.329(2) Å, 1.355(2) Å and 1.433(2) Å). In the crystal structure of both compounds, molecules are primarily linked by weak C–H⋯
π
, C–H⋯N and C–H⋯O interactions. The metal cation extractability was determined for all compounds by UV–Vis spectrophotometry and all of compounds show affinity towards extraction of iron (III) and mercury (II) cations.
Graphic Abstract
Synthesis and characterisation of secondary amine macrocycles derived from macrocyclic Schiff base analouges and metal picrate extraction studies
This study explores the Hydrothermal Carbonization (HTC) treatment of lignocellulosic biomass blends, delving into the influence of several key parameters: temperature, additive nature and dosage, ...residence time, and biomass composition. Rapeseeds, Pinus radiata sawdust, oat husks, and pressed olive served as the studied biomasses. One hundred twenty-eight experiments were conducted to assess the effects on mass yield (MY), energy yield (EY), higher heating value (HHV), and final ash content (ASH) by a Factorial Experimental Design. The derived model equations demonstrated a robust fit to the experimental data, averaging an R2 exceeding 0.94, affirming their predictive accuracy. The observed energy yield ranged between 65% and 80%, notably with sawdust and olive blends securing EY levels surpassing 70%, while rapeseed blends exhibited the highest HHV at 25 MJ/kg. Temperature emerged as the most influential factor, resulting in an 11% decrease in MY and a substantial 2.20 MJ/kg increase in HHV. Contrastingly, blend composition and additive presence significantly impacted ASH and EY, with all blends exhibiting increased ASH in the presence of additives. Higher initial hemicellulose and aqueous extractive content in raw biomass correlated proportionally with heightened HHV.
Most developing countries lack sufficient legal and management infrastructure to dispose of urban solid waste (USW). The continuous increase of USW generation requires evaluating different treatments ...for developing countries based on the life cycle assessment methodology to compare the environmental impact by reducing greenhouse gases and leachate. Hydrothermal carbonization (HTC) and gasification processes are presented as potential solutions for USW treatment due to their efficiency in producing energy for local requirements. This study aimed to compare both technologies for Temuco and Padre Las Casas cities in Southern Chile that show severe air pollution and USW management problems. The results indicated that gasification had a better environmental performance than HTC when the conversion of 1 ton of organic fraction USW was analyzed. However, since HTC achieved higher energy efficiency, it had a lower environmental impact than gasification, considering the production of 1 MWh. For a definitive choice of the technology to be used, it is necessary to compare other variables, including economic and social aspects, to provide a holistic perspective.
Weill-Marchesani syndrome (WMS) is a rare genetic disorder that affects the musculoskeletal system, the eye, and the cardiovascular system. Individuals with WMS present with short stature, joint ...contractures, thick skin, microspherophakia, small and dislocated lenses, and cardiac valve anomalies. WMS can be caused by recessive mutations in ADAMTS10 (WMS 1), ADAMTS17 (WMS 4), or LTBP2 (WMS 3), or by dominant mutations in fibrillin-1 (FBN1) (WMS 2); all genes encode secreted extracellular matrix (ECM) proteins. Individuals with WMS 4 due to ADAMTS17 mutations appear to have less severe cardiac involvement and present predominantly with the musculoskeletal and ocular features of WMS. ADAMTS17 is a member of the ADAMTS family of secreted proteases and directly binds to fibrillins. Here we report a novel pathogenic variant in ADAMTS17 that causes WMS 4 in an individual with short stature, brachydactyly, and small, spherical, and dislocated lenses. We provide biochemical and cell biological insights in the pathomechanisms of WMS 4, which also suggest potential biological functions for ADAMTS17. We show that the variant in ADAMTS17 prevents its secretion and we found intracellular accumulation of fibrillin-1 and collagen type I in patient-derived skin fibroblasts. In accordance, transmission electron microscopy revealed elastic fiber abnormalities, decreased collagen fibril diameters, and intracellular collagen accumulation in the dermis of the proband. Together, the data indicate a possible role for ADAMTS17 in the secretion of fibrillin-1 and collagen type I or in their early assembly in the pericellular matrix or the ECM.
•Pathogenic missense variant in ADAMTS17 causing Weill-Marchesani syndrome 4 results in lack of ADAMTS17 protein secretion.•Lack of ADAMTS17 secretion is assciated with co-retention of fibrillin-1 and collagen type I in the secretory pathway.•Subsequent alterations of the ECM may contribute to WMS 4 disease phenotype.•Patient skin shows altered collagen fibrils, intracellular collagen accumulation, and elastic fiber abnormalities.•Data suggest a possible role for ADAMTS17 in the secretion and/or deposition of several ECM proteins, including fibrillin-1 and collagen type I.
AURORA aims to study the processes of relapse in metastatic breast cancer (MBC) by performing multi-omics profiling on paired primary tumors and early-course metastases. Among 381 patients (primary ...tumor and metastasis pairs: 252 targeted gene sequencing, 152 RNA sequencing, 67 single nucleotide polymorphism arrays), we found a driver role for
and
somatic mutations. Metastases were enriched in
, and
mutations;
and
amplifications; and
deletions. An increase in clonality was observed in driver genes such as
and
. Intrinsic subtype switching occurred in 36% of cases. Luminal A/B to HER2-enriched switching was associated with
and/or
mutations. Metastases had lower immune score and increased immune-permissive cells. High tumor mutational burden correlated to shorter time to relapse in HR
/HER2
cancers. ESCAT tier I/II alterations were detected in 51% of patients and matched therapy was used in 7%. Integration of multi-omics analyses in clinical practice could affect treatment strategies in MBC. SIGNIFICANCE: The AURORA program, through the genomic and transcriptomic analyses of matched primary and metastatic samples from 381 patients with breast cancer, coupled with prospectively collected clinical data, identified genomic alterations enriched in metastases and prognostic biomarkers. ESCAT tier I/II alterations were detected in more than half of the patients.
.
The liver exhibits a remarkable capacity to regenerate following injury. Despite this unique attribute, toxic injury is a leading cause of liver failure. The temporal processes by which the liver ...senses injury and initiates regeneration remain unclear. Here, we developed a transgenic zebrafish model wherein hepatocyte-specific expression of uracil phosphoribosyltransferase (UPRT) enabled the implementation of SLAM-ITseq to investigate the nascent transcriptome during initiation of liver injury and regeneration. Using this approach, we identified a rapid metabolic transition from the fed to the fasted state that was followed by induction of the nuclear erythroid 2-related factor (Nrf2) antioxidant program. We find that activation of Nrf2 in hepatocytes is required to induce the pentose phosphate pathway (PPP) and improve survival following liver injury. Mechanistically, we demonstrate that inhibition of the PPP disrupts nucleotide biosynthesis to prevent liver regeneration. Together, these studies provide fundamental insights into the mechanism by which early metabolic adaptation to injury facilitates tissue regeneration.
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•Development of a SLAM-ITseq pipeline to identify nascent transcripts from hepatocytes•Liver injury causes Nrf2-dependent induction of the pentose phosphate pathway•G6PD is required for hepatocyte proliferation during regeneration•The Nrf2-driven pentose phosphate pathway is a metabolic dependency in regeneration
Tan et al. use a SLAM-ITseq approach to identify that liver injury stimulates Nrf2-dependent induction of genes in the pentose phosphate pathway (PPP). The Nrf2-driven PPP supports nucleotide biosynthesis to meet the metabolic demands of tissue growth during regeneration.
Adherence has emerged as a focal point and critical determinant of success for physical activity interventions. The term is used for both traditional and digital interventions, and for prescribed and ...nonprescribed activities. Many other terms for adherence are being used interchangeably, as there is no consensus on its precise conceptualization. This scoping review aimed to advance the definition of adherence to eHealth programs, specifically for the adult population with no specific health conditions. A total of 2983 papers, published between 1 January 2016 and 13 March 2022, were retrieved from different databases (including grey literature). Of those, 13 studies met the eligibility criteria and were included for review. The selected studies used a wide array of technologies and consisted mainly of exercise interventions. Most of the reviewed publications contemplated exercise adherence as a percentage of expected dose. Most (8 out of 13) studies neither assessed nor specified an expected use of the involved technology. Results suggest a need for homogeneity in the conceptualization of adherence to physical activity and exercise, including those interventions delivered digitally.
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