The objective of this study was to validate standing and locomotion lameness scoring, mechanical nociceptive threshold testing, and behavioral profile tools for the diagnosis of naturally occurring ...lameness etiologies in pigs. A total of 55 crossbred gilts and sows obtained from a commercial farm were enrolled in the study; with sound pigs classified as controls (8) and the remainder as lame due to integumentary (20), musculoskeletal (15), and combinations of integumentary and musculoskeletal (12) etiologies. Standing and locomotion lameness, mechanical nociceptive threshold (MNT) test, pig-human interventions, and latency to complete an obstacle course were evaluated. Standing and locomotion lameness scoring systems, MNT, and pig behavior (latency) were capable of discriminating between animals with mild organic lameness and animals that were sound and may have utility on the farm for staff to use to identify and manage lame animals. In rare instances, the tools used here were able to discriminate between broad categories of lameness etiology.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Immune checkpoint inhibitors (ICIs) have emerged as active therapies for a variety of cancers. Cutaneous toxicities are common immune-related adverse events and patients will often be referred to ...dermatologists for evaluation.
Cutaneous adverse events to ICIs can have a variety of clinical presentations. Among the more common are eczematous, morbilliform, and lichenoid dermatoses, as well as vitiligo and pruritus. Less common adverse events include psoriasiform dermatoses, bullous disorders, and severe cutaneous adverse reactions, including Stevens–Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms. Because of the immunologic mechanism of ICIs, there are also a variety of rheumatologic adverse reactions with cutaneous manifestations, such as scleroderma, dermatomyositis, cutaneous lupus erythematosus, and various vasculitides. These cutaneous reactions often respond to topical or systemic steroids, although specific toxicities may have alternative treatments available.
As they become more widely prescribed, dermatologists will see an increasing number of patients with cutaneous adverse events caused by ICI therapies. Accurately diagnosing and treating these toxicities is paramount to achieving the most favorable outcomes for patients.
Why sequence all eukaryotes? Blaxter, Mark; Archibald, John M; Childers, Anna K ...
Proceedings of the National Academy of Sciences - PNAS,
01/2022, Letnik:
119, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Life on Earth has evolved from initial simplicity to the astounding complexity we experience today. Bacteria and archaea have largely excelled in metabolic diversification, but eukaryotes ...additionally display abundant morphological innovation. How have these innovations come about and what constraints are there on the origins of novelty and the continuing maintenance of biodiversity on Earth? The history of life and the code for the working parts of cells and systems are written in the genome. The Earth BioGenome Project has proposed that the genomes of all extant, named eukaryotes-about 2 million species-should be sequenced to high quality to produce a digital library of life on Earth, beginning with strategic phylogenetic, ecological, and high-impact priorities. Here we discuss why we should sequence all eukaryotic species, not just a representative few scattered across the many branches of the tree of life. We suggest that many questions of evolutionary and ecological significance will only be addressable when whole-genome data representing divergences at all of the branchings in the tree of life or all species in natural ecosystems are available. We envisage that a genomic tree of life will foster understanding of the ongoing processes of speciation, adaptation, and organismal dependencies within entire ecosystems. These explorations will resolve long-standing problems in phylogenetics, evolution, ecology, conservation, agriculture, bioindustry, and medicine.
Idiopathic normal pressure hydrocephalus (iNPH) is a neurological disorder that occurs in about 1% of individuals over age 60 and is characterized by enlarged cerebral ventricles, gait difficulty, ...incontinence, and cognitive decline. The cause and pathophysiology of iNPH are largely unknown. We performed whole exome sequencing of DNA obtained from 53 unrelated iNPH patients. Two recurrent heterozygous loss of function deletions in CWH43 were observed in 15% of iNPH patients and were significantly enriched 6.6‐fold and 2.7‐fold, respectively, when compared to the general population. Cwh43 modifies the lipid anchor of glycosylphosphatidylinositol‐anchored proteins. Mice heterozygous for CWH43 deletion appeared grossly normal but displayed hydrocephalus, gait and balance abnormalities, decreased numbers of ependymal cilia, and decreased localization of glycosylphosphatidylinositol‐anchored proteins to the apical surfaces of choroid plexus and ependymal cells. Our findings provide novel mechanistic insights into the origins of iNPH and demonstrate that it represents a distinct disease entity.
Synopsis
Idiopathic normal pressure hydrocephalus (iNPH) is a neurological disorder of aging characterized by enlarged cerebral ventricles, gait and balance difficulty, incontinence and cognitive impairment. The cause of iNPH is not known.
Whole exome sequencing identified heterozygous damaging deletions in CWH43 in 15% of iNPH patients, and these deletions were statistically enriched when compared to the general population.
Mutant Cwh43 proteins fail to localize to the Golgi apparatus, which is where Cwh43 normally modifies the lipid anchor of glycosylphosphatidylinositol (GPI)‐anchored proteins.
Certain GPI‐anchored proteins (e.g. CD59) were no longer associated with lipid microdomains in human and mouse cells harboring iNPH‐associated CWH43 deletions.
Mice heterozygous or homozygous for CWH43 deletions displayed enlarged ventricles, gait and balance abnormalities, decreased cilia numbers and decreased expression of GPI‐anchored proteins on the apical surfaces of choroid plexus and ependymal cells.
Idiopathic normal pressure hydrocephalus (iNPH) is a neurological disorder of aging characterized by enlarged cerebral ventricles, gait and balance difficulty, incontinence and cognitive impairment. The cause of iNPH is not known.
Modern broilers are selected for fast growth and a large proportion of breast tissue, contributing to a top-heavy phenotype, leg disorders, and inactivity as birds reach market weight. Therefore, the ...objective was to motivate broilers to move through environmental enrichment. A total of 1,200 Ross 308 broilers were housed in pens of 30 for 6 wk: 600 birds were exposed to a novel laser enrichment device (LASER) and 600 were control. Each device projected 2 randomly moving red laser dots onto the floor 4 times/day for 4-min “laser periods.” Seven LASER and 7 control pens, with 5 focal birds/pen (n = 70), were randomly selected to be video-recorded day 0 to 8 and once weekly for the remainder of the trial. Videos were analyzed to measure broiler time-budget and behaviors such as latency to feed and distance walked during laser periods. Focal birds were gait scored weekly on-farm. A test of the human-approach paradigm was carried out on weeks 1 and 6 on all pens. LASER birds were more active on days 0, 1, 3, 4, 5, 7, and 8, moving 254% more on day 7 (P ≤ 0.05). Time spent active was increased in LASER treatment by 114% on week 2; 157% on week 3; 90% on week 4; and 82% on week 5. LASER birds spent more time at the feeder on days 0, 1, 2, 5, 8, and on weeks 1 and 5, with 84% more time at feeder than control on day 5 (P ≤ 0.05). LASER birds walked further during laser periods on day 0 to 8, reaching 646.5 cm greater (day 1), and on weeks 2, 3, 4, and 5, with an increase of 367.5 cm on week 2 (P ≤ 0.05). Over week 1 to 6, 60.54 ± 7.4% of focal birds in the laser treatment were at the feeder during or within 5 min following laser periods. The laser enrichment device was successful in stimulating broiler physical activity and feeding, and did not negatively impact walking ability.
Piglets are susceptible to hypothermia because they lack hair and energy reserves, have a large surface area to body weight ratio, and have poor body thermostability. Different heat sources are used ...on farm, but it is not known how long it takes half a litter to locate it and lie down. The objectives of this study were to determine 1) how long it took for ≥ 50% of piglets to locate and lie on- or under the supplemental heat source for ≥ 5 min after the birth of the last-born pig and, 2) how long this cohort of piglets laid on- or under the heat source. A total of 12 sows were enrolled in the study (parity 1 = 4; 3 = 2; 4 = 2; 5 = 2; and 7 = 2). The stall containing one sow and her litter was the experimental unit. Two treatments were compared: 1) Baby Pig Heat Mat-Single 48 (MAT) and 2) Poly Heat Lamp (LAMP). Temperature was 32°C for both heat source treatments. Sow and litter video recordings occurred continually over a 24-h period on the day of farrowing. Two measures were determined 1) how long it took for ≥ 50% of piglets to locate and lie on- or under the supplemental heat source for ≥ 5 min after the birth of the last-born pig (h:min), and 2) how long this cohort of piglets laid on- or under the heat source (min:sec). Lying was defined as either sternal or lateral recumbency with ≥ 75% of the piglet's body touching the heat mat or inside the lamp heat circle. Production records were used to verify farrowing date, total number of piglets born, and born alive. No cross fostering occurred during this study. All data will be presented descriptively. On average, sows assigned to the LAMP treatment took ~2 ½-h to farrow, and for sows assigned to the MAT ~3 ½-h, respectively. Piglets took between ~5-h (LAMP) and ~9-h (MAT) for ≥ 50% of piglets to locate and lie on- or under the supplemental heat source for ≥ 5 min after the birth of the last piglet. Cohort of piglets laid on- or under the heat source as follows, LAMP piglets spent ~29 mins lying and for MAT piglets ~42 mins, respectively. Average pre-weaning mortality was 11% (LAMP) and 18% (MAT). The MAT heat source used less energy than the LAMP (16 vs. 63 kWh) over the study duration. To the authors' knowledge, this is the first published study using a continuous sampling method to precisely examine a new measure (time needed for ≥ 50% of piglets to locate and lie on- or under the supplemental heat source for ≥ 5 min after the birth of the last-born piglet) and to determine how long this cohort of piglets laid on- or under the heat source. Our findings show an immense range in locating and lying under- or on the heat source. Therefore, we suggest that caretakers should assist all piglets to locate the heat source after farrowing is complete to improve piglet livability.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Respiratory syncytial virus (RSV) is a common cause of acute lower respiratory tract infection in infants, older adults and the immunocompromised. Effective directly acting antivirals are not yet ...available for clinical use. To address this, we screen the ReFRAME drug-repurposing library consisting of 12,000 small molecules against RSV. We identify 21 primary candidates including RSV F and N protein inhibitors, five HSP90 and four IMPDH inhibitors. We select lonafarnib, a licensed farnesyltransferase inhibitor, and phase III candidate for hepatitis delta virus (HDV) therapy, for further follow-up. Dose-response analyses and plaque assays confirm the antiviral activity (IC
: 10-118 nM). Passaging of RSV with lonafarnib selects for phenotypic resistance and fixation of mutations in the RSV fusion protein (T335I and T400A). Lentiviral pseudotypes programmed with variant RSV fusion proteins confirm that lonafarnib inhibits RSV cell entry and that these mutations confer lonafarnib resistance. Surface plasmon resonance reveals RSV fusion protein binding of lonafarnib and co-crystallography identifies the lonafarnib binding site within RSV F. Oral administration of lonafarnib dose-dependently reduces RSV virus load in a murine infection model using female mice. Collectively, this work provides an overview of RSV drug repurposing candidates and establishes lonafarnib as a bona fide fusion protein inhibitor.
Viruses interact with numerous host factors to facilitate viral replication and to dampen antiviral defense mechanisms. We currently have a limited mechanistic understanding of how SARS-CoV-2 binds ...host factors and the functional role of these interactions. Here, we uncover a novel interaction between the viral NSP3 protein and the fragile X mental retardation proteins (FMRPs: FMR1, FXR1-2). SARS-CoV-2 NSP3 mutant viruses preventing FMRP binding have attenuated replication in vitro and reduced levels of viral antigen in lungs during the early stages of infection. We show that a unique peptide motif in NSP3 binds directly to the two central KH domains of FMRPs and that this interaction is disrupted by the I304N mutation found in a patient with fragile X syndrome. NSP3 binding to FMRPs disrupts their interaction with the stress granule component UBAP2L through direct competition with a peptide motif in UBAP2L to prevent FMRP incorporation into stress granules. Collectively, our results provide novel insight into how SARS-CoV-2 hijacks host cell proteins and provides molecular insight into the possible underlying molecular defects in fragile X syndrome.
Synopsis
The SARS-CoV-2 NSP3 protein binds directly to fragile X mental retardation proteins (FMRPs) to support viral replication. NSP3 binding disrupts FMRP interaction with the stress granule protein UBAP2L, thereby preventing FMRP localization to these structures.
The SARS-CoV-2 NSP3 protein binds to the KH domains of FMRPs through a short peptide motif.
Engineered SARS-CoV-2 viruses unable to bind FMRPs have reduced replication.
NSP3 binding to FMRPs disrupts their localization to stress granules through competition with UBAP2L.
The SARS-CoV-2 NSP3 protein binds directly to fragile X mental retardation proteins (FMRPs) to support viral replication. NSP3 binding disrupts FMRP interaction with the stress granule protein UBAP2L, thereby preventing FMRP localization to these structures.
A global international initiative, such as the Earth BioGenome Project (EBP), requires both agreement and coordination on standards to ensure that the collective effort generates rapid progress ...toward its goals. To this end, the EBP initiated five technical standards committees comprising volunteer members from the global genomics scientific community: Sample Collection and Processing, Sequencing and Assembly, Annotation, Analysis, and IT and Informatics. The current versions of the resulting standards documents are available on the EBP website, with the recognition that opportunities, technologies, and challenges may improve or change in the future, requiring flexibility for the EBP to meet its goals. Here, we describe some highlights from the proposed standards, and areas where additional challenges will need to be met.
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