A multitope SARS-CoV-2 vaccine provides long-lasting B cell and T cell immunity against Delta and Omicron variants.

BackgroundThe Delta and Omicron variants of SARS-CoV-2 are currently responsible for breakthrough infections due to waning immunity. We report phase I/II trial results of UB-612, a multitope subunit vaccine containing S1-RBD-sFc protein and rationally designed promiscuous peptides representing sarbecovirus conserved helper T cell and cytotoxic T lymphocyte epitopes on the nucleocapsid (N), membrane (M), and spike (S2) proteins.MethodWe conducted a phase I primary 2-dose (28 days apart) trial of 10, 30, or 100 µg UB-612 in 60 healthy young adults 20 to 55 years old, and 50 of them were boosted with 100 µg of UB-612 approximately 7 to 9 months after the second dose. A separate placebo-controlled and randomized phase II study was conducted with 2 doses of 100 µg of UB-612 (n = 3,875, 18-85 years old). We evaluated interim safety and immunogenicity of phase I until 14 days after the third (booster) dose and of phase II until 28 days after the second dose.ResultsNo vaccine-related serious adverse events were recorded. The most common solicited adverse events were injection site pain and fatigue, mostly mild and transient. In both trials, UB-612 elicited respective neutralizing antibody titers similar to a panel of human convalescent sera. The most striking findings were long-lasting virus-neutralizing antibodies and broad T cell immunity against SARS-CoV-2 variants of concern (VoCs), including Delta and Omicron, and a strong booster-recalled memory immunity with high cross-reactive neutralizing titers against the Delta and Omicron VoCs.ConclusionUB-612 has presented a favorable safety profile, potent booster effect against VoCs, and long-lasting B and broad T cell immunity that warrants further development for both primary immunization and heterologous boosting of other COVID-19 vaccines.Trial RegistrationClinicalTrials.gov: NCT04545749, NCT04773067, and NCT04967742.FundingUBI Asia, Vaxxinity Inc., and Taiwan Centers for Disease Control, Ministry of Health and Welfare.

Volunteers' Demographics That Affect the Human-Dog Interaction During Walks in a Shelter.

Different people relate to dogs in different ways. We investigated differences between volunteers in their behavioural interactions with shelter dogs when they were walked on a leash. Cameras were used to record and quantify the behaviour of volunteers and a leash tension metre was used to measure pulling by both volunteers and shelter dogs. Effects of volunteers' age, body height, educational level, marital status, and experiences of living and working with dogs, and living with children, were examined. Older volunteers talked to the dogs more often during the walk than younger ones. Taller volunteers had reduced physical contact with dogs, and dogs pulled more frequently on the leash while walking with them. Volunteers with a postgraduate degree more frequently praised dogs and rewarded dogs with food and used more body language in the form of hand gestures and physical contact. Married and partnered volunteers more often praised dogs, while separated/divorced or widowed volunteers initiated more frequent physical contacts. Dogs pulled less when walking with volunteers who had experience of living with dogs, and these volunteers interacted with dogs using fewer verbal and body languages. Finally, those living with children more frequently communicated with dogs using body language (e.g., hand gestures and physical contact). We conclude that shelters should carefully consider volunteers' demographics when selecting them to walk dogs with various behavioural characteristics.

Dog Pulling on the Leash: Effects of Restraint by a Neck Collar vs. a Chest Harness.

Leash pulling is a concern for dog owners and can be detrimental to the health and welfare of dogs. Neck-collars and back-connection harnesses are popular restraint types. Harnesses have been proposed as a better and more considerate option for canine health and welfare. Anecdotally, dogs pull more when wearing a back-connection harness; however, there is no scientific evidence for this perception. This study aimed to investigate how strongly dogs pull on the lead to achieve a food treat or toy under restraint by a neck-collar versus a back-connection harness. A within-subject counterbalanced design was used for the study, involving 52 shelter dogs. A customised canine leash tension metre was connected to the collar or harness to record the pulling of the dogs, including measuring the maximal and mean leash tension, and the time spent pulling. In addition, dog behaviours were recorded using two cameras from two separate directions. The maximal and mean leash tension and the pulling time were greater under restraint by harness when attracting dogs with food treats. No significant difference between harness and collar was found in potential stress-related behaviours (e.g. tail and ear positions, lip-licking, and panting). However, dogs looked at the experimenter more often when restrained by harness than collar in the food treat attraction test. No significant difference was detected between harness and collar with respect to leash tension and stress-related behaviours in the toy attraction test. These findings suggest that dogs tend to pull stronger and more steadily when wearing a back-connection harness compared to a neck collar to reach the food treat but not the toy.

Two Ends of the Leash: Relations Between Personality of Shelter Volunteers and On-leash Walking Behavior With Shelter Dogs.

Human personality influences the way people interact with dogs. This study investigated the associations between the personality of animal shelter volunteers and behavior during on-leash walks with shelter dogs. Video recording and a canine leash tension meter were used to monitor the on-leash walking. Personality was measured in five dimensions (neurotic, extroverted, open, agreeable and conscientious) with the NEO Five-Factor Inventory (NEO-FFI). Neurotic volunteers pulled the leash harder and tended to interact with dogs using more body language; dogs being walked by neurotic volunteers in turn displayed more lip-licking and body shaking and were more likely to be rated as well-behaved. Extroverted volunteers were associated with stronger maximal leash tension at both the human and dog ends of the leash, and they praised the dog more, often in a high pitched voice. These volunteers eliciting more tail-wagging and body shaking by the dog. Extroverted volunteers were also more tolerant of different dog behaviors. Volunteers with personalities characterized by "openness to experiences" were less likely to verbally attract the attention of dogs, praise dogs and talk to them in a high-pitched voice; however, dogs walked by these volunteers were more likely to pull on the leash, and engaged in more lip-licking but less sniffing. "Agreeable" volunteers liked to verbally attract the attention of the dogs and more commonly initiated hand gestures and physical contact, causing the dogs to pull less frequently; dogs in these dyads displayed more gazing and lip-licking behaviors. Conscientious volunteers were less likely to pull the leash and tended to have more physical contact with the dogs but did not favor verbal communication and did not use a high pitched voice.

Do Canine Behavioural Assessments and Characteristics Predict the Human-Dog Interaction When Walking on a Leash in a Shelter Setting?

Inappropriate leash reactivity is one of the most common problems in shelter dogs, which negatively affects the health of dogs and reduces their adoptability. We explored 370 human-dog interactions, involving 74 volunteers and 111 dogs, in an animal shelter when volunteers walked shelter dogs on a leash, considering the effects of canine demographics and the results of the shelter's canine behavioural assessments. The interaction was video recorded and coded using ethograms, and a leash tension meter was used to measure the pull strength of dogs and handlers. Results showed that dogs that were more relaxed during the shelter assessment (i.e., when socialising with humans or being left alone in a new environment) were less reactive on the leash, with lower tension and pulling frequency. Moreover, socialised and relaxed dogs displayed more positive body language, such as tail in a high position, gazing at the handler, and exploring the environment. When walking with these dogs, volunteers utilised fewer verbal cues and body language during the walk. In addition to the canine behaviour assessment, there were correlations between canine demographics and the behavioural interaction and humans' perception. Finally, volunteers perceived the walk as less satisfactory when they needed to pull the leash harder during the walk. This research suggests that the RSPCA behavioural assessment may be useful in predicting the behaviour of shelter dogs when walked by volunteers.

Who Is Pulling the Leash? Effects of Human Gender and Dog Sex on Human-Dog Dyads When Walking On-Leash.

Previous studies have indicated that human gender and canine sex influences human-dog interactions. However, the majority of studies have considered the interaction when dogs were off-leash and the behavioural interactions when dogs are walked on a leash have not been addressed. This study investigated human-dog interactions when shelter volunteers take shelter dogs for an on-leash walk. Video records were made of 370 walks, involving 74 volunteers and 111 shelter dogs, and a leash tension meter was used to determine the pull strength of dogs and walkers. Human gender and canine sex had dyadic effects during the walk. Male dogs tended to pull more frequently and created increased leash tensions. Dogs displayed more stress related behaviours when interacting with men than women, with the signs being spending less time holding the tail in the high position, and more frequent gazing and lip-licking behaviours. Finally, there was a greater pre-disposition in women to use verbal commands, and language typically used with babies, while men were more inclined to have physical contact with dogs. This study's results may be used to match shelter dogs with appropriate men and women volunteers for walking exercise of the dog, and to improve potential dog socialisation efforts by shelters.

Behavioural Evaluation of a Leash Tension Meter Which Measures Pull Direction and Force during Human-Dog on-Leash Walks.

Leash tension forces exerted by dog and handler during walks affect their welfare. We developed a novel ambulatory measurement device using a load cell and a tri-axial accelerometer to record both the tension and direction of forces exerted on the leashes. Data were relayed telemetrically to a laptop for real time viewing and recording. Larger and heavier dogs exerted higher leash tension but had a lower pulling frequency than their smaller and lighter conspecifics. This pattern was observed in the reactional forces of handlers. Young dogs pulled more frequently during walks, which was also mirrored in handlers' pulling. Well-behaved dogs created lower leash tension, but handlers did not respond with lower forces. This novel method of recording leash tension will facilitate real-time monitoring of the behaviour of dogs and their handlers during walks.

Socioeconomic Influences on Reports of Canine Welfare Concerns to the Royal Society for the Prevention of Cruelty to Animals (RSPCA) in Queensland, Australia.

Human-dog relationships are an important contributor to the welfare of dogs, but little is known about the importance of socioeconomic status of the dogs' owners. We conducted a retrospective study of canine welfare complaints, using Australian government statistics on the socioeconomic status of the inhabitants at the location of the alleged welfare issue. The socioeconomic score of inhabitants at the relevant postcode was assumed to be that of the plaintiff. Our dataset included 107,597 complaints that had been received by RSPCA Queensland between July 2008 and June 2018, each with the following information: the number of dogs involved, dog(s) age, breed(s), suburb, postcode, date received, and complaint code(s) (describing the type of complaint). The median index score for relative social advantage of the locations where the alleged welfare concern occurred was less than the median score for the population of Queensland, suggesting that welfare concerns in dogs were more commonly reported in areas with inhabitants of low socioeconomic status. It was also less if the dog being reported was not of a recognised breed, compared to dogs of recognised breeds. Dogs reported to be in the gundog breed group were in the most socioeconomically advantaged postcodes, followed by toy, hound, non-sporting, working dog, terrier, and utility breed groups. Reports of alleged cruelty, insufficient food and/or water, a dog being not exercised or being confined/tethered, failure to provide shelter or treatment, overcrowding, a dog being in poor condition or living in poor conditions were most likely to be made in relation to dogs in low socioeconomic postcodes. Reports of dogs being left in a hot vehicle unattended were more likely to be made in relation to dogs in high socioeconomic postcodes. It is concluded that both canine welfare complaints and dogs in specific breed groups appear to be related to the owner's socioeconomic status. This study may be used to improve public awareness and to tailor educational campaigns toward different populations.

Breed Group Effects on Complaints about Canine Welfare Made to the Royal Society for the Prevention of Cruelty to Animals (RSPCA) Queensland, Australia.

Cruelty- and neglect-related canine welfare concerns are important welfare and social issues. Dog breed has been identified as a risk factor for bad welfare, and yet its role in different types of canine welfare concerns has not been fully investigated. We conducted a retrospective study of 107,597 dog welfare complaints received by RSPCA Queensland from July 2008 to June 2018. The breed of the dog involved in the incident was either recorded as stated by the complainant or by the inspector attending the case. Dog breed was divided into groups following the Australian National Kennel Club nomenclature. Dogs of a non-recognised breed were more likely to be reported in welfare complaints than recognised breed dogs. Recognised breed dogs had a greater risk of being reported with poisoning, lack of veterinary support, abuse and being left unattended in a hot vehicle; while non-recognised breed dogs had greater risk of being reported with insufficient shelter, exercise and food/water, as well as overcrowding and abandonment. Utility breeds, terriers and working dogs were most likely to be reported, while toy, non-sporting breeds and gundogs were least likely to be reported. Common complaint types for utility dogs were: insufficient food/water, shelter and exercise, and poor living conditions; for terriers: abandonment, intentional abuses and killing or injuring another animal; for working dogs: insufficient food/water, shelter and exercise; for toy dogs: lack of veterinary care, overcrowding and staying in a hot vehicle alone; for non-sporting dogs: lack of veterinary care, being left in a hot vehicle unattended and poor body conditions; and for hounds: killing or injuring another animal, intentional abuses and poor body conditions. Breed groups rather than breeds may be the best method of breed identification in a public reporting system as they group similar breeds together, and as our research shows, they relate to types of animal welfare complaints. Understanding the relationship between breed group and canine welfare complaints may help authorities improve public education programs and inform decision-making around which breed a new owner should choose.

A Retrospective Analysis of Complaints to RSPCA Queensland, Australia, about Dog Welfare.

Animal neglect and cruelty are important welfare and social issues. We conducted an epidemiological study of dog welfare complaints and identified risk factors. The retrospective study included 107,597 dog welfare complaints received by RSPCA Queensland from July 2008 to June 2018. The risk factors considered were the age of dogs and the year of being reported. The number of complaints received each year increased by 6.2% per year. The most common complaints were poor dog body conformation, insufficient food and/or water, dogs receiving inadequate exercise, and dogs being confined or tethered. Increasing numbers were most evident for poor living conditions and leaving dogs in a hot vehicle unattended, both of which may have resulted from increasing public awareness. The majority of complaints were neglect-related rather than related to deliberate cruelty. Compared with puppies, adult dogs were more likely to be reported to have been poisoned, left unattended in a hot car or abandoned, as well as to have had inadequate exercise and shelter. Reported puppies were more likely to be alleged to have experienced cruelty, lack of veterinary support, overcrowding, poor living and health conditions, and inappropriate surgery. In conclusion, animal neglect was the most commonly reported welfare concern in dogs. Due to an assumed increasing public awareness of some types of cruelty, the trends of reported concerns differed. Adult dogs and puppies were reported to be involved in different types of welfare concerns. Strategies to address cruelty to dogs can be informed by an understanding of risk factors and trends in types of cruelty.

Intratumoral heterogeneity of the therapeutical response to gemcitabine and metformin.

Cancer heterogeneity and microenvironmental aspects within a tumor are considered key factors influencing resistance of carcinoma cells to distinct chemotherapeutical agents. We evaluated a high concentration of metformin in combination with gemcitabine on a syngeneic orthotopic mouse model using 6606PDA cells. We observed reduced tumor size and reduced cancer cell proliferation after three weeks of chemotherapy with either compound and noticed an additive effect between gemcitabine and metformin on tumor weight. Interestingly, distinct areas of the carcinoma responded differently to either compound. Metformin inhibited the proliferation of cancer cells close to the desmoplastic reaction, whereas gemcitabine inhibited the proliferation of cancer cells mainly 360-570 µm distant to the desmoplastic reaction. Indeed, co-culture of pancreatic stellate cells with 6606PDA, 7265PDA or MIA PaCa-2 cells increased gemcitabine resistance. Metformin resistance, however, was increased by high glucose concentration in the medium. Other factors such as hypoxia or the pH of the medium had no influence on gemcitabine or metformin induced inhibition of cancer cell proliferation. These data demonstrate a spatial heterogeneity in drug resistance within pancreatic adenocarcinomas and that microenvironmental aspects such as supply of glucose and the presence of pancreatic stellate cells regulate cancer cell sensitivity towards metformin or gemcitabine.

Prophylactic and abundant intake of α-lipoic acid causes hepatic steatosis and should be reconsidered in usage as an anti-aging drug.

The majority of research has suggested that α-lipoic acid (ALA) is a potential therapeutic agent for chronic diseases associated with oxidative stress, including atherosclerosis, diabetes, and neurodegeneration. Therefore, a nutritional supplementation with ALA is recommended although the effects of a short- and long-term intake of ALA on central organs in healthy individuals are not studied in detail yet. Therefore, liver tissue of 4 and 74 weeks ALA-treated healthy C57BL6/J mice with respect to lipid metabolism was analyzed. In doing so, it was shown that short-term and long-term ALA treatment caused a marked increase of ß-oxidation, as indicated by a significant rise of mRNA expression of fgf21, pparα, and its target genes, for example, acox1, cpt1α, and cpt2, as well as of Fgf21 plasma concentration. Glycolytic activity, as assessed by pklr1 mRNA expression and pyruvate kinase activity, was also found increased. In addition, it was shown that both short- and long-term ALA treatment increased cholesterol content, induced systemic triglyceridemia, and enhanced rxrα and lxrα mRNA expression. Despite the fact that short-term ALA intake reduced lipogenesis, as given by significant declines of fas and srebp1c mRNA expression, and that a long-term ALA intake induced a significant rise of these lipogenic genes, both treatment regimen caused fat accumulation. This, however, was more pronounced upon long-term ALA intake, leading to hepatic steatosis and liver injury, as indicated by increased inflammation and disruption of the general hepatic architecture. In summary, the prophylactic and abundant use of ALA under healthy conditions should be considered with caution.