Evaluation of impact of land use and landscape metrics on surface water quality in the northeastern part along Lake Tanganyika, Africa.

As the second deepest lake in Africa, Lake Tanganyika plays an important role in supplying fish protein for the catchment's residents and is irreplaceable in global biodiversity. However, the lake's water environment is threatened by socioeconomic development and rapid population growth along the lake. This study analyzed the spatial scale effects and seasonal dependence of land use types and landscape metrics on water quality in 16 sub-basins along northeastern Lake Tanganyika at different levels of urbanization. The results revealed that land use types had a higher influence on water quality in urban areas than that in rural areas; the explanatory variance in the urban area was 0.78-0.96, while it was 0.21-0.70 in the rural area. The explanatory ability of land use types on water quality was better at the buffer scale than at the sub-watershed scale, and the 500 m buffer scale had the highest explanatory ability in the urban area and rural area both in the rainy season and dry season, and artificial surface and arable land were the main contributing factors. And this phenomenon was more obvious in dry season than in rainy season. We identified that CONTAG was the key landscape metric in urban area and was positively correlated with nutrient variables, indicating that water quality degraded in less fragmented landscapes. The sub-watershed scale had the highest explained ability, while in rural area, the 1500 m buffer scale had the highest explained ability and IJI had the highest explanatory variance, which had a negative effect on water quality. Research on the relationship between land use and water quality would help assess the water quality in the unmonitored watershed as monitoring is expensive and time-consuming in low-income area. This knowledge would provide guideline to watershed managers and policymakers to prioritize the future land use development within Lake Tanganyika basin.

ALPK1 hotspot mutation as a driver of human spiradenoma and spiradenocarcinoma.

Spiradenoma and cylindroma are distinctive skin adnexal tumors with sweat gland differentiation and potential for malignant transformation and aggressive behaviour. We present the genomic analysis of 75 samples from 57 representative patients including 15 cylindromas, 17 spiradenomas, 2 cylindroma-spiradenoma hybrid tumors, and 24 low- and high-grade spiradenocarcinoma cases, together with morphologically benign precursor regions of these cancers. We reveal somatic or germline alterations of the CYLD gene in 15/15 cylindromas and 5/17 spiradenomas, yet only 2/24 spiradenocarcinomas. Notably, we find a recurrent missense mutation in the kinase domain of the ALPK1 gene in spiradenomas and spiradenocarcinomas, which is mutually exclusive from mutation of CYLD and can activate the NF-κB pathway in reporter assays. In addition, we show that high-grade spiradenocarcinomas carry loss-of-function TP53 mutations, while cylindromas may have disruptive mutations in DNMT3A. Thus, we reveal the genomic landscape of adnexal tumors and therapeutic targets.

Intrinsic Clearance Assay Incubational Binding: A Method Comparison.

The fraction of unbound drug (fuinc) in in vitro intrinsic clearance (CLint) incubation is an important parameter in the pursuit of accurate clearance predictions and is often predicted using algorithms based on drug lipophilicity measures. However, analysis of an AstraZeneca database suggests that simple lipophilicity alone is a relatively poor predictor of fuinc measured using equilibrium dialysis. He fuinc value can also be measured directly in CLint assays using multiple concentrations of hepatocytes or microsomal protein. Since this approach informs of the unbound drug concentration in the assay used to predict in vivo clearance, it should be considered the gold standard method. As a starting point for building better predictive algorithms we aimed to determine if equilibrium dialysis really is an appropriate assay for assessing fuinc Employing a large number of compounds with a wide range of lipophilicities, experiments were performed to measure fuinc using rat hepatocytes (RH) and human liver microsomes (HLM) in both assay formats. A high percentage (94% and 93% for HLM and RH, respectively) of the fuinc values were within 2-fold when the compound distribution coefficient describing the ratio of compound concentration in octanol and pH 7.4 buffer when the test system is at equilibrium (lipophilicity measure) (logD7.4) values were less than 3.5. However, with logD7.4 values greater than these, the agreement was considerably worse. Additional experimental data generated indicated that this discrepancy was likely due to failings in the direct method when drug binding is high. Thus, we conclude that unbound CLint can be indeed calculated indirectly by incorporating equilibrium dialysis data with measured CLint but that simple lipophilicity descriptors alone may be inadequate for predicting fuinc.