Osteopetrosis includes a group of inherited diseases in which inadequate bone resorption is caused by osteoclast dysfunction. Although molecular defects have been described for many animal models of osteopetrosis, the gene responsible for most cases of the severe human form of the disease (infantile malignant osteopetrosis) is unknown. Infantile malignant autosomal recessive osteopetrosis (MIM 259700) is a severe bone disease with a fatal outcome, generally within the first decade of life. Osteoclasts are present in normal or elevated numbers in individuals affected by autosomal recessive osteopetrosis, suggesting that the defect is not in osteoclast differentiation, but in a gene involved in the functional capacity of mature osteoclasts. Some of the mouse mutants have a decreased number of osteoclasts, which suggests that the defect directly interferes with osteoclast differentiation. In other mutants, it is the function of the osteoclast that seems to be affected, as they show normal or elevated numbers of non-functioning osteoclasts. Here we show that TCIRG1, encoding the osteoclast-specific 116-kD subunit of the vacuolar proton pump, is mutated in five of nine patients with a diagnosis of infantile malignant osteopetrosis. Our data indicate that mutations in TCIRG1 are a frequent cause of autosomal recessive osteopetrosis in humans.

Highlights SARS-CoV-2 was quantified (10 1 -10 4 copies 100 mL −1 ) in southeast Virginia wastewater. RT-ddPCR was optimized to quantify SARS-CoV-2 from wastewater. 5.5 and 7.6% recoveries were observed for BCoV and BRSV, respectively. Trends in SARS-CoV-2 are apparent at the facility and regional scaleover a 21-week study.

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This review aims to give an overview of current good practice in the prosecution of Lead Generation. It will assess experiences across the field as judged from the contents of the limited number of peer-review disclosures to date. It will also rely heavily on the experiences of the authors from many campaigns within this organisation. Its focus will be on the assembly of an appropriate compound collection for application in High Throughput Screening (HTS), the prosecution of HTS, the profiling of HTS output and, lastly the Hit-to-Lead optimisation of selected HTS output. Excluded from the scope are detailed aspects of library design [1], parallel synthesis [2], virtual library applications [3], virtual screening [4] and fragment screening [5] approaches, all of which have been the subject of recent reviews.