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C.N.R. steam engine #6148, unknown location
No full textHandwritten on back: "C.N.R. #6148 Steam Engine"
Practical Synthesis of 6‑Amino-1-hydroxy-2,1-benzoxaborolane: A Key Intermediate of DNDI-6148
No full textVisceral leishmaniasis (VL), a parasitic, poverty-linked,
neglected
disease, is endemic across multiple regions of the world and fatal
if untreated. There is an urgent need for a better and more affordable
treatment for VL. DNDI-6148 is a promising drug candidate being evaluated
for the treatment of VL; however, the current process for producing
the key intermediate of DNDI-6148, 6-amino-1-hydroxy-2,1-benzoxaborolane,
is expensive and difficult to scale up. Herein, we describe two practical
approaches to synthesizing 6-amino-1-hydroxy-2,1-benzoxaborolane from
inexpensive and readily available raw materials. Starting with 4-tolunitrile,
the first approach is a five-step sequence involving a Hofmann rearrangement,
resulting in an overall yield of 40%. The second approach utilizes
2-methyl-5-nitroaniline as the starting material and features borylation
of aniline and continuous flow hydrogenation as the key steps, with
an overall yield of 46%. Both routes bypass the nitration of 1-hydroxy-2,1-benzoxaborolane,
which is challenging and expensive to scale. In particular, the second
approach is more practical and scalable because of the mild operating
conditions and facile isolation process
Scrapie prevalence in sheep of susceptible genotype is declining in a population subject to breeding for resistance
Get PDFAbstract Background Susceptibility of sheep to scrapie infection is known to be modulated by the PrP genotype of the animal. In the Netherlands an ambitious scrapie control programme was started in 1998, based on genetic selection of animals for breeding. From 2002 onwards EU regulations required intensive active scrapie surveillance as well as certain control measures in affected flocks. Here we analyze the data on genotype frequencies and scrapie prevalence in the Dutch sheep population obtained from both surveillance and affected flocks, to identify temporal trends. We also estimate the genotype-specific relative risks to become a detected scrapie case. Results We find that the breeding programme has produced a steady increase in the level of genetic scrapie resistance in the Dutch sheep population. We also find that a significant decline in the prevalence of scrapie in tested animals has occurred a number of years after the start of the breeding programme. Most importantly, the estimated scrapie prevalence level per head of susceptible genotype is also declining significantly, indicating that selective breeding causes a population effect. Conclusions The Dutch scrapie control programme has produced a steady rise in genetic resistance levels in recent years. A recent decline in the scrapie prevalence per tested sheep of susceptible prion protein genotype indicates that selective breeding causes the desired population effect.</p
Block Card 6148 Douglas Road
No full textThis image was produced by the Auditor's Office in Lucas County, Ohio for tax assessment purposes. Associated dates are approximate. Descriptive terms related to this photograph include: Ranch Style | 6148 Dougls Road (Toledo, Ohio) | Dwelling | Douglas Meadows Addition (Toledo, Ohio) | Greenwood Park area (Toledo, Ohio
Demographics of cattle movements in the United Kingdom
Get PDFBackground: The United Kingdom (UK) government has been recording the births, deaths, and movements of
cattle for the last decade. Despite reservations about the accuracy of these data, they represent a large and
valuable body of information about the demographics of the UK cattle herd and its contact structure. In this
article, a range of demographic data about UK cattle, and particularly their movements, are presented, as well as
yearly trends in the patterns of movements.
Results: A clear seasonal pattern is evident in the number of movements of cattle, as are the reductions in
movement volume due to foot and mouth disease outbreaks in 2001 and 2007. The distribution of ages of cattle at
their time of death is multimodal, and the impact of the over thirty months rule is marked. Most movements occur
between agricultural holdings, markets, and slaughterhouses, and there is a non-random pattern to the types of
holdings movements occur between. Most animals move only a short distance and a few times in their life. Most
movements between any given pair of holdings only occurred once in the last 10 years, but about a third occurred
between 2 and 10 times in that period. There is no clear trend to movement patterns in the UK since 2002.
Conclusions: Despite a substantial number of regulatory interventions during the last decade, movement patterns
show no clear trend since 2002. The observed patterns in the repeatability of movements, the types of holdings
involved in movements, the distances and frequencies of cattle movements, and the batch sizes involved give an
insight into the structure of the UK cattle industry, and could act as the basis for a predictive model of livestock
movements in the UK
Effect of abrupt weaning at housing on leukocyte distribution, functional activity of neutrophils, and acute phase protein response of beef calves
Get PDFpeer-reviewedBackground: Sixteen, spring-born, single suckled, castrated male calves of Limousin × Holstein-Friesian and Simmental × Holstein-Friesian dams respectively, were used to investigate the effect of weaning on total leukocyte and differential counts, neutrophil functional activity, lymphocyte immunophenotypes, and acute phase protein response. Calves grazed with their dams until the end of the grazing season when they were housed in a slatted floor shed. On the day of housing, calves were assigned to a treatment, (i) abruptly weaned (W: n = 8) or (ii) non-weaned (controls) (C: n = 8). Weaned calves were housed in pens without their dams, whereas non-weaned (control) calves were housed with their dams. Blood was collected on day -7, 0 (housing), 2, 7, and 14 to determine total leukocyte and differential counts and concentration of fibrinogen and haptoglobin. Lymphocyte immunophenotypes were characterised using selected surface antigens (CD4+, CD8+, WC1+ (γδ T cells), MHC Class II+ lymphocytes), and the functional activities of neutrophils (surface expression of L-selectin (CD62L), phagocytic and oxidative burst activity) were investigated using flow cytometry. Results: Treatment × sampling time interactions (P 0.05) in C. On d 2, percentage WC1+ lymphocytes decreased (P 0.05) for monocyte, eosinophil, and basophil counts, percentage G1+ neutrophils, or percentage oxidative burst positive neutrophils. Conclusions: Abrupt weaning resulted in increased neutrophil counts and impaired trafficking and phagocytic function. Together with the changes in lymphocyte subsets, the results suggest that there was a greater transitory reduction in immune function at housing in abruptly weaned than non-weaned beef calves.Teagasc Walsh Fellowship; John and Pat Hume
Scholarship, National University of Ireland, Maynooth (E. M. Lynch
DNDI-6148: A Novel Benzoxaborole Preclinical Candidate for the Treatment of Visceral Leishmaniasis
No full textVisceral leishmaniasis
(VL) is a parasitic disease endemic across
multiple regions of the world and is fatal if untreated. Current therapies
are unsuitable, and there is an urgent need for safe, short-course,
and low-cost oral treatments to combat this neglected disease. The
benzoxaborole chemotype has previously delivered clinical candidates
for the treatment of other parasitic diseases. Here, we describe the
development and optimization of this series, leading to the identification
of compounds with potent in vitro and in
vivo antileishmanial activity. The lead compound (DNDI-6148)
combines impressive in vivo efficacy (>98% reduction
in parasite burden) with pharmaceutical properties suitable for onward
development and an acceptable safety profile. Detailed mode of action
studies confirm that DNDI-6148 acts principally through the inhibition
of Leishmania cleavage and polyadenylation specificity
factor (CPSF3) endonuclease. As a result of these studies and its
promising profile, DNDI-6148 has been declared a preclinical candidate
for the treatment of VL
Effect of pre-weaning concentrate supplementation on peripheral distribution of leukocytes, functional activity of neutrophils, acute phase protein and behavioural responses of abruptly weaned and housed beef calves
Get PDFpeer-reviewedBackground: The effect of pre-weaning concentrate supplementation on peripheral distribution of leukocytes, functional activity of neutrophils, acute phase protein response, metabolic and behavioural response, and performance of abruptly weaned and housed beef calves was investigated. Calves were grazed with their dams until the end of the grazing season when they were weaned and housed (day (d) 0) in a concrete slatted floor shed, and offered grass silage ad libitum plus supplementary concentrates. Twenty-six days prior to weaning and housing, 20 singled suckled, pure-bred Simmental male (non-castrated), (n = 10, m) and female (n = 10, f) calves were assigned to one of two treatments (i) concentrate supplement (CS: n = 10 (5 m and 5 f), mean age (s.d.) 201 (12.8) d, mean weight (s.d.) 258 (20.2) kg) or (ii) no concentrate supplement (controls) (NCS: n = 10, (5 m and 5 f), mean age (s.d.) 201 (13.4) d, mean weight (s.d.) 257 (19.6) kg) pre-weaning. Results: There was a treatment × sampling time interaction (P 0.05) from d 0. On d 2, WC1+ lymphocytes decreased (P 0.05) from pre-weaning baseline. On d 2, the increase in concentration of globulin was greater (P < 0.05) in CS compared with NCS, and subsequently there was no difference between treatments. Pre-weaning ADG was 1.07 (s.e.m.) (0.26) kg and 0.99 (s.e.m.) (0.26) kg for CS and NCS, respectively. Post-weaning, CS calves spent more time lying compared with NCS calves. Conclusions: Calves supplemented with concentrate prior to weaning had a lesser reduction in WC1+ lymphocytes, increased percentage CD4+ lymphocytes and concentration of total protein, and spent more time lying post-weaning, compared with non-supplemented calves
Safety, tolerability and pharmacokinetics of DNDI‐6148, a novel agent for leishmaniasis: A randomized, controlled, single ascending dose study in healthy participants
Get PDFAim: The benzoxaborole derivative DNDI‐6148 is an antiparasitic agent with activity against multiple Leishmania protozoan species, including L. infantum and L. donovani , which cause visceral leishmaniasis. We investigated the safety, tolerability and pharmacokinetics of single oral doses of DNDI‐6148 in a randomized, parallel‐group, placebo‐controlled, first‐in‐human study in 64 healthy participants. Methods: Eight cohorts of eight participants each were enrolled. DNDI‐6148, formulated as a suspension in ORA‐Sweet® was administered orally as single 10–380 mg doses. Pharmacokinetics (PK) and safety were assessed for four (cohorts receiving 10–80 mg DNDI‐6148) or six (cohorts receiving 160–380 mg DNDI‐6148) days after dosing. Results: Sixteen adverse events (AEs) were experienced by 13 participants (20.3%), all mild or moderate in severity and resolved by the end of the study. No AE led to any participant withdrawal, and no fatal or serious AEs were reported. DNDI‐6148 was relatively slowly absorbed (tmax ranging between 3 and 12 h) under fasting conditions, with increase in plasma concentrations modestly sub‐proportional to dose. The mean half‐life was between 12.80 and 25.42 h. The fraction of the dose excreted by the kidneys as unchanged DNDI‐6148 was below 0.2%. Trace amounts of three metabolites (formed by oxidation, deboronation, dehydrogenation of DNDI‐6148) were detected in plasma. Conclusion: After a single administration of up to 380 mg by oral route, DNDI‐6148 had an acceptable safety and tolerability profile and a favourable PK profile. These data support further clinical development
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