X-linked hypophosphatemia (XLH) is the most common form of inherited rickets, resulting in short stature despite treatment with oral phosphate and active vitamin D. Detailed data of anthropometric parameters at birth, during infancy, and on the influence of an affected parent on outcome are lacking. In this prospective multicenter observational study, conducted from 1998 to 2023 in Germany, Austria, and Switzerland, body length, body weight, and head circumference were investigated in 198 children with XLH from birth until the age of 18 years, all being only on supplementation therapy. XLH newborns presented with disproportionate body shape characterized by decreased birth length relative to weight and head circumference with a 2.4-fold increased risk to be born small for gestational age (SGA). A positive family history for XLH was associated with lower anthropometric characteristics at birth. Body disproportion increased during 0–2 years old, resulting in significantly increased head circumference (+ 0.82 SD) and reduced body length (−2.00 SD) compared to healthy 2-year-old patients. Supplementation therapy failed to prevent progressive growth failure and reduced final height, regardless of whether treatment was started early due to an affected family member, which was associated with overall poor control of metabolic bone disease indicated by persistent hypophosphatemia and rising alkaline phosphatase z-score. XLH is associated with an increased risk for SGA and progressive disproportional body growth during infancy. Routine medical check-ups may soon use this unique growth pattern to identify children with XLH. Supplemental therapy fails to prevent progressive growth failure.
Population genetics and molecular anthropology have undergone remarkable methodological and conceptual development over the past two decades [...]
BACKGROUND/OBJECTIVES:Southeastern Europe and Croatia have served as a genetic crossroads between the Near East and Europe since prehistoric times, shaped by numerous and repeated migrations. By integrating 19 newly generated ancient genomes with 285 previously published ancient genomes from Croatia, we investigated patterns of maternal and paternal landscapes from the Neolithic, Bronze, and Iron Ages through to the Antiquity and medieval periods, as well as the modern Croatian population. METHODS:Ancient DNA extraction from human remains and library preparation were conducted in dedicated clean-room facilities, followed by high-throughput sequencing on the Illumina platform. Sequencing data were analyzed with established pipelines to determine mitochondrial and Y-chromosomal haplogroups and the genetic sex of individuals. RESULTS:New ancient data reveal a predominantly European maternal profile, dominated by haplogroups H, U, and HV0, whereas Y-chromosomal lineages are characterized by J subclades and R1a, with limited representation of R1b and the absence of I2a. When combined with published ancient Croatian genomes, the results reveal similar haplogroup diversity and patterns, as well as the expansion of mtDNA haplogroup H over time and a substantial increase in Y-chromosome R1a and I2a haplogroup frequency from the prehistoric to the modern period. CONCLUSIONS:Although the analyzed samples are heterogeneous and originate from different historical periods, their genetic signatures conform to the broader patterns expected for the region. In a wider context, the ancient Croatian mitochondrial data reveal stronger genetic persistence from prehistory to modern times, unlike paternal lineages, which show significantly higher divergence.
Herein, we report the design and synthesis of C6-substituted purine and 7-deazapurine isoxazole derivatives via 1,3-dipolar cycloaddition, followed by microwave-assisted Suzuki-Miyaura and Sonogashira cross-coupling reactions. Selected pyridine-isoxazole ligands were coordinated to fac-[Re(CO)5Cl], and the resulting Re(I) tricarbonyl complexes were characterized by UV-Vis, IR, NMR spectroscopy, and elemental analysis. The structure of complex 8aRe was confirmed by single-crystal X-ray diffraction analysis, revealing facial coordination of the carbonyl ligands and distorted octahedral geometry around the rhenium center. Antiproliferative activity of all compounds was evaluated across eight human cancer cell lines. Structure-activity relationship analysis demonstrated that arylalkynyl substitution at the C-6 position of purine and 7-deazapurine scaffolds significantly enhances antiproliferative potency, whereas directly arylated derivatives were largely inactive. Among the ligands, compound 6b emerged as the most potent, displaying low-micromolar IC50 values against pancreatic cancer Capan-1, T-cell leukemia DND-41, acute myeloid leukemia HL-60, and non-Hodgkin lymphoma Z-138 cell lines (IC50 = 1.5-2.1 mu M). Although these potencies are promising, selectivity toward nonmalignant cells remained moderate (SI = 3.7-4.8), indicating that further optimization is required. Rhenium coordination further increased antiproliferative activity but also reduced selectivity, with complex 8bRe showing consistent low-micromolar potency across the same cell lines (IC50 = 1.6-1.9 mu M, SI = 1.5-1.8). Molecular docking and in silico ADME analyses indicated favorable drug-like properties and suggested the STAT3 SH2 domain as a possible molecular target for both 6b and 8bRe, supporting their potential as promising lead compounds for selectivity improvement and further anticancer development.
