Notes

Dual-Wavelength Gated oxo-Diels-Alder Photoligation.
Dominant loss-of-function mutations in the gene encoding the lysosomal protein, progranulin, cause 5-10% of frontotemporal dementia cases. As progranulin undergoes secretion and endocytosis, a small number of progranulin-expressing cells can potentially supply the protein to the entire central nervous system. Thus, gene therapy is a promising treatment approach.

We evaluated adeno-associated viral vector administration into the cerebrospinal fluid as a minimally invasive approach to deliver the granulin gene to the central nervous system in a murine disease model and nonhuman primates.

In progranulin-deficient mice, vector delivery into the lateral cerebral ventricles increased progranulin levels in the cerebrospinal fluid and normalized histological and biochemical markers of progranulin deficiency. A single vector injection into the cisterna magna of nonhuman primates achieved CSF progranulin concentrations up to 40-fold higher than those of normal human subjects and exceeded CSF progranulin levels of successfully treated mice. Animals treated with an adeno-associated virus serotype 1 vector exhibited progranulin expression fivefold higher than those treated with an AAV5 vector or the AAV9 variant, AAVhu68, apparently due to remarkably efficient transduction of ependymal cells. Progranulin expression mediated by adeno-associated viral vectors was well tolerated in nonhuman primates with no evidence of dose-limiting toxicity, even at vector doses that induced supraphysiologic progranulin expression.

These findings support the development of AAV1-based gene therapy for frontotemporal dementia caused by progranulin deficiency.
These findings support the development of AAV1-based gene therapy for frontotemporal dementia caused by progranulin deficiency.
Variation in host attributes that influence their contact rates and infectiousness can lead some individuals to make disproportionate contributions to the spread of infections. Understanding the roles of such 'superspreaders' can be crucial in deciding where to direct disease surveillance and controls to greatest effect. In the epidemiology of bovine tuberculosis (bTB) in Great Britain, it has been suggested that a minority of cattle farms or herds might make disproportionate contributions to the spread of Mycobacterium bovis, and hence might be considered 'superspreader farms'.

We review the literature to identify the characteristics of farms that have the potential to contribute to exceptional values in the three main components of the farm reproductive number - R
contact rate, infectiousness and duration of infectiousness, and therefore might characterize potential superspreader farms for bovine tuberculosis in Great Britain.

Farms exhibit marked heterogeneity in contact rates arising from between-farm trading of cattle. A minority of farms act as trading hubs that greatly augment connections within cattle trading networks. Herd infectiousness might be increased by high within-herd transmission or the presence of supershedding individuals, or infectiousness might be prolonged due to undetected infections or by repeated local transmission, via wildlife or fomites.

Targeting control methods on putative superspreader farms might yield disproportionate benefits in controlling endemic bovine tuberculosis in Great Britain. However, real-time identification of any such farms, and integration of controls with industry practices, present analytical, operational and policy challenges.
Targeting control methods on putative superspreader farms might yield disproportionate benefits in controlling endemic bovine tuberculosis in Great Britain. However, real-time identification of any such farms, and integration of controls with industry practices, present analytical, operational and policy challenges.The fore- and hindlimbs of birds are specialized to perform different functions. Merbarone supplier The growth patterns of limb bones and their relationship with the ontogeny of locomotion are critical to our understanding of variation in morphological, physiological and life-history traits within and among species. Unfortunately, the ontogenetic development of limb bones has not been well explored, especially in altricial birds. In this study, we sampled the entire measurements of the pigeon (Columba livia) of individual skeletons, to investigate the ontogenetic allometry of limb bones by reduced major axis regression. The ulna and humerus were found to be positively allometric in relation to body mass, with the ulna growing more rapidly than the humerus. Together with previous data, this suggests that strong positive allometric growth in forelimb bones could be a common trend among diverse Carinatae groups. Hindlimb was dominated by positive allometry, but was variable in the growth of the tarsometatarsus which included three allometric patterns. A greater dorsoventral diameter in the midsection of the humerus and ulna confers superior bending resistance and is ideal for flapping/gliding flight. Shape variation in the midsection of different hindlimb components reflects different mechanical loading, and the markedly inverse trend between the tibiotarsus and tarsometatarsus before 28 days of age also suggests loading change before fledging. Before fledging, the growth of the leg bones was prior to that of the wing bones. This kind of asynchronous development of the fore- and hindlimbs was associated with the establishment and improvement of different functions, and with shifts in the importance of different functions over time.The increased use of big data in the medical field has shifted the way in which biomedical research is designed and carried out. The novelty of techniques and methods brought by big data research brings new challenges to institutional review boards (IRBs). Yet it is unclear if IRBs should be the responsible oversight bodies for big data research and, if so, which criteria they should use. A large but heterogenous set of ethics guidelines and normative responses have emerged to address these issues. In this study, we conducted a scoping review of soft-law documents and guidelines with the aim of assessing ongoing normative efforts that are proliferating in this domain. We also synthesize a set of recurrent guidelines that could work as a baseline to create a harmonized process for big data research ethics.
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