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Objectives: To assess healing of the canine lower eyelid without anatomical reconstruction. Materials and Methods: Retrospective case series of three client‐owned dogs with lower eyelid defects. These dogs that underwent debridement of lower eyelid wounds that were left to heal by secondary intention were assessed for anatomical, functional and aesthetic outcomes. Results: Two of the cases had previously undergone tumour resection with a lip‐to‐lid reconstruction and, following flap failure, developed a full thickness defect. The third dog presented with a traumatic laceration. Each dog lost approximately 70 to 90% of the lower eyelid margin. Two received topical antimicrobial eye drops after debridement, while the third dog required no further treatment. Follow‐up periods of 3 years, 15 months and 4 months were available. All owners were satisfied with the cosmetic outcome and provided pictures. One owner reported epiphora but no other ophthalmic complications occurred. Clinical Significance: The result of this small case series supports the notion that not all lower eyelid injuries or tumour resections require anatomical reconstruction. Selected cases can be left to heal by secondary intention with minimal post‐operative complications. [ABSTRACT FROM AUTHOR]

AIMS: To survey current anaesthesia practices for dogs and cats in small and mixed animal practices in New Zealand in order to improve anaesthesia education. METHODS: A questionnaire was sent to 440 small and mixed animal practices, including questions regarding the type of practice, preanaesthetic examination, anaesthetic drugs and management, anaesthetic machines, monitoring and topics of interest for continuing professional development. RESULTS: Responses were obtained from 113/440 (26%) practices, with 78 (69%) respondents from small and 35 (31%) from mixed animal practices. A preanaesthetic physical examination was carried out by >95% of respondents and premedication was usually given to dogs (112/113; 99%) and cats (95/113; 85%). Acepromazine was the preferred sedative for dogs and cats, with morphine or buprenorphine. Propofol and alfaxalone were the preferred induction agents, and isoflurane was preferred for maintenance in both dogs and cats. A venous catheter was usually placed for anaesthesia in dogs (59/113; 52%), but less so in cats (39/113; 35%). Perioperative fluid was administered at 10 mL/kg/hour by 62/110 (56%) respondents. Intubation was usually used for anaesthesia in dogs (111/112; 99%), and cats (87/112; 78%). Almost 40% of respondents usually administered supplementary oxygen if patients were not intubated. Local analgesia was used by 69/111 (88%) respondents sometimes or always if applicable. Morphine or buprenorphine, and meloxicam were common choices for post-operative analgesia after neuter surgery in dogs and cats. A semiclosed (non-rebreathing) system was used in animals weighing <10 kg, and a Mapleson E or F non-rebreathing circuit was used by 66/109 (61%) practices. Only 15/111 (14%) practices had a ventilator in their practice. A dedicated anaesthetist was usually used by 104/113 (92%) practices, and apnoea alarms, pulse oximeters, thermometers and oesophageal stethoscopes were the main monitoring devices available in practices. Loco-regional block, pain management, and anaesthetic drugs were the main topics of interest for continuing education. CONCLUSIONS AND CLINICAL RELEVANCE: Responses by the veterinarians taking part in this survey indicated that they had a reasonably good standard of anaesthetic practice. A physical examination was carried out preanaesthesia, and premedication including analgesia was routinely administered to most patients. A dedicated anaesthetist usually monitored patients and most respondents reported they had access to basic anaesthetic monitoring equipment. Areas where changes could lead to improved anaesthetic practice were increased use of I/V catheterisation, endotracheal intubation, and supplementary oxygen, and reduced I/V fluid rates. [ABSTRACT FROM PUBLISHER]

Background: Cell‐free DNA (cfDNA) comprises short, double‐stranded circulating DNA sequences released from damaged cells. In people, cfDNA concentrations correlate well with disease severity and tissue damage. No reports are available regarding cfDNA kinetics in dogs. Objectives/Hypothesis: Cell‐free DNA will have a short biological half‐life and would be able to stratify mild, moderate, and severe tissue injury. Our study aims were to determine the kinetics and biological half‐life of cfDNA and to contrast them with those of creatine kinase (CK). Animals: Three groups of 10 dogs undergoing open ovariohysterectomy, surgery for cranial cruciate ligament rupture (CCLR), or hemilaminectomy. Methods: Plasma for cfDNA and CK analysis was collected at admission, at induction of anesthesia, postsurgery (time 0) and at 6, 12, 24, 36, 48, 60, and 72 hours after surgery. Results: The biological half‐life of plasma cfDNA and CK were 5.64 hours (95% confidence interval [CI 95], 4.36–7.98 hours) and 28.7 hours (CI95, 25.3–33.3 hours), respectively. In the hemilaminectomy group, cfDNA concentrations differed significantly from admission at 6–12 hours after surgery. Creatine kinase activity differed among the surgical groups and reached a peak 6 hours after surgery. In the ovariohysterectomy and CCLR groups, plasma CK activity 72 hours after surgery did not differ from admission activity of the ovariohysterectomy group. In contrast, in the hemilaminectomy group, plasma CK activity after 72 hours did not return to the ovariohysterectomy group admission activity. Conclusions and Clinical Importance: Plasma CK activity has a longer biological half‐life than previously thought. In contrast to plasma CK activity, cfDNA has a short half‐life and could be a useful marker for peracute severe tissue injury. [ABSTRACT FROM AUTHOR]

Background: Each year, over 173,000 children and adolescents visit emergency departments due to sports and recreation related concussions, an increase of 60% over the last decade due to the rise in the number of children participating in sport. While numerous authors have sought to address the epidemiology of concussions across multiple age groups who participate in contact sports, a recent review of literature did not reveal a substantial amount of published articles that addressed the issue of subconcussive contact. Multiple tools have been developed to assess acute episodes of concussion. Among the assessment protocols many include an assessment of balance, short and long term memory recall, and balance. The Child-SCAT3 was designed specifically to evaluate concussions in children 5-12 years of age. Objective: The purpose of this study was to determine the effect of a season of subconcussive contact on Child-SCAT3 scores in 8-12 year old males compared to their age matched peers who participated in non-contact sports. A secondary purpose was to evaluate how scores of the sub- components of the Child-SCAT3 compare between contact and non-contact athletes. Design: A prospective cohort study was performed of 71 male athletes (58 football, 13 baseball) ages 8-12 (contact mean age 10.30 years, SD 1.20; non-contact mean age 10.03 years, SD 1.26) over the course of a season. Methods: Portions of The Child-SCAT3 were administered and scored in pre-adolescent athletes prior to and following a season of participation in football (contact sport group) and baseball (non-contact sport group). The outcome measures of interest included the portions related to Cognitive ability, Balance, and Coordination. Results: No statistically significant differences were found in group, time or time and group interaction for any of the utilized portions of the Child-SCAT3. Statistically significant differences were found between groups for preseason cognitive orientation and postseason immediate memory. Cognitive orientation and coordination were also found to be statistically significantly improved across both groups over the course of the season. Limitations: This study was potentially limited by the number of control subjects tested. Conclusions: A season of subconcussive contact in football was not detrimental to cognitive and balance scores on the Child-SCAT3. [ABSTRACT FROM AUTHOR]

Undernormoxic conditions in vitro, isolated pulmonary arteries from broilers exhibit reduced endothelium-dependent relaxation responses when compared with Leghorns. In vivo, hypoxia increases the susceptibility of broiler chickens to pulmonary hypertension syndrome (PHS), whereas Leghorns are considered resistant to PHS. Because L-arginine supplementation decreases the incidence of PHS in vivo and improves the relaxation responses of broiler isolated pulmonary arteries in vitro, we hypothesized that in vitro hypoxia would further reduce the relaxation responses of broilers to endothelium-derived nitric oxide (EDNO)-dependent vasodilators and that L-arginine supplementation would alleviate this impairment. As a test of this hypothesis, pulmonary arteries from broiler and Leghorn chickens were isolated and exposed to normoxia or hypoxia in the presence or absence of L-arginine while their constriction and relaxation responses to vasoactive compounds were recorded. In broilers, hypoxia did not affect the constriction responses of isolated pulmonary arteries but decreased EDNO-dependent acetylcholine-induced relaxation responses. In contrast, in Leghorns hypoxia increased endothelin-1-induced vasoconstriction responses only to the lowest concentration of acetylcholine used. L-Arginine supplementation augmented the relaxation responses to acetylcholine in broilers and Leghorns under normoxia but failed to augment them under hypoxia. Relaxation responses to the NO donor, sodium nitroprusside, were not affected by hypoxia in Leghorns but were increased by hypoxia in broilers. These results suggest that the increased incidence of PHS in broiler chickens reared under hypoxia may be associated with a hypoxia-induced reduction in the synthesis or activity of EDNO in the pulmonary circulation. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system (RAS) is increasingly being recognized to play a role in the tumor microenvironment, promoting tumor growth. Studies blocking a single part of the RAS have shown mixed results, possibly due to the existence of different bypass pathways and redundancy within the RAS. As such, multimodal blockade of the RAS has been developed to exert more complete inhibition of the RAS. The aim of the present study was to assess the safety of multimodal RAS blockade in dogs. Five dogs (four with appendicular osteosarcoma, one with oral malignant melanoma) were treated with atenolol, benazepril, curcumin, meloxicam, and metformin. The dogs underwent clinical examination, blood pressure measurement, and hematology and serum biochemistry tests performed at 0, 1, 3, 6, 9, and 12 weeks, then every 3 months thereafter. End-of-life decisions were made by the owners. None of the dogs developed hypotension. One dog had intermittent vomiting during the 64 weeks it was on the trial. One dog had a one-off increase in serum SDMA(symmetrical dimethylarginine) concentration. Dogs were euthanized at weeks 3 (osteosarcoma), 10 (osteosarcoma), 17 (osteosarcoma), and 26 (oral malignant melanoma), and one dog was still alive at the end of the trial at 64 weeks (osteosarcoma). This is the first assessment of multimodal blockade of the RAS in dogs, and the results suggest it causes only mild adverse effects in some animals. The efficacy of the treatment was not assessed due to the small number of dogs. This pilot study allows for future larger studies assessing multimodal RAS blockade for the treatment of canine cancer.

In contrast to prevalent strategies which make use of β-sheet mimetics to block Aβ fibrillar growth, in this study, we designed a series of sulfonyl-γ-AApeptide helices that targeted the crucial α-helix domain of Aβ13-26 and stabilized Aβ conformation to avoid forming the neurotoxic Aβ oligomeric β-sheets. Biophysical assays such as amyloid kinetics and TEM demonstrated that the Aβ oligomerization and fibrillation could be greatly prevented and even reversed in the presence of sulfonyl-γ-AApeptides in a sequence-specific and dose-dependent manner. The studies based on circular dichroism, Two-dimensional nuclear magnetic resonance spectroscopy (2D-NMR) spectra unambiguously suggested that the sulfonyl-γ-AApeptide Ab-6 could bind to the central region of Aβ 42 and induce α-helix conformation in Aβ. Additionally, Electrospray ionisation-ion mobility spectrometry-mass spectrometry (ESI-IMS-MS) was employed to rule out a colloidal mechanism of inhibitor and clearly supported the capability of Ab-6 for inhibiting the formation of Aβ aggregated forms. Furthermore, Ab-6 could rescue neuroblastoma cells by eradicating Aβ-mediated cytotoxicity even in the presence of pre-formed Aβ aggregates. The confocal microscopy demonstrated that Ab-6 could still specifically bind Aβ 42 and colocalize into mitochondria in the cellular environment, suggesting the rescue of cell viability might be due to the protection of mitochondrial function otherwise impaired by Aβ 42 aggregation. Taken together, our studies indicated that sulfonyl-γ-AApeptides as helical peptidomimetics could direct Aβ into the off-pathway helical secondary structure, thereby preventing the formation of Aβ oligomerization, fibrillation and rescuing Aβ induced cell cytotoxicity., Competing Interests: Competing interests statement:The authors declare no competing interest.

The role of the renin-angiotensin system (RAS) in cancer growth and progression is well recognized in humans. However, studies on RAS inhibition with a single agent have not shown consistent anticancer effects, potentially due to the neoplastic cells utilizing alternative pathways for RAS activation. To achieve more complete RAS inhibition, multimodal therapy with several medications that simultaneously block multiple steps in the RAS has been developed for use in humans. In the present study, the safety of multimodal RAS inhibition using atenolol, benazepril, metformin, curcumin, and meloxicam was assessed in six cats with squamous cell carcinomas. Cats were treated for 8 weeks, with blood pressure measured and blood sampled five times during the treatment period. None of the cats developed hypotension, azotemia, or increased serum liver enzyme concentrations. The packed cell volume of one cat decreased to just below the reference range during treatment. One cat was reported to have increased vomiting, although this occurred infrequently. One cat was withdrawn from the study due to difficulties administering the medications, and another cat died of an unrelated cause. Two cats were euthanatized during the study period due to cancer progression. Two cats completed the 8-week study period. One was subsequently euthanized due to cancer progression while the other cat is still alive 32 weeks after entering the study and is still receiving the multimodal blockade of the RAS. This is the first evaluation of multimodal blockade of the RAS in veterinary species. The study showed that the treatment is safe, with only mild adverse effects observed in two treated cats. Due to the small number of cats, the efficacy of treatment could not be evaluated. However, evidence from human studies suggests that a multimodal blockade of RAS could be a safe and cost-effective treatment option for cancer in cats.

Peptidomimetics have gained great attention for their function as protein-protein interaction (PPI) inhibitors. Herein, we report the design and investigation of a series of right-handed helical heterogeneous 1:1 α/Sulfono-γ-AA peptides as unprecedented inhibitors for p53-MDM2 and p53-MDMX. The most potent helical heterogeneous 1:1 α/Sulfono-γ-AA peptides were shown to bind tightly to MDM2 and MDMX, with K d of 19.3 and 66.8 nM, respectively. Circular dichroism spectra, 2D-NMR spectroscopy, and the computational simulations suggested that these helical sulfono-γ-AA peptides could mimic the critical side chains of p53 and disrupt p53/MDM2 PPI effectively. It was noted that these 1:1 α/Sulfono-γ-AA peptides were completely resistant to proteolytic degradation, boosting their potential for biomedical applications. Furthermore, effective cellular activity is achieved by the stapled 1:1 α/Sulfono-γ-AA peptides, evidenced by significantly enhanced p53 transcriptional activity and much more induced level of MDM2 and p21. The 1:1 α/Sulfono-γ-AA peptides could be an alternative strategy to antagonize a myriad of PPIs.

Foldamers have defined and predictable structures, improved resistance to proteolytic degradation, enhanced chemical diversity, and are versatile in their mimicry of biological molecules, making them promising candidates in biomedical and material applications. However, as natural macromolecules exhibit endless folding structures and functions, the exploration of the applications of foldamers remains crucial. As such, it is imperative to continue to discover unnatural foldameric architectures with new frameworks and molecular scaffolds. To this end, we recently developed a new class of peptidomimetics termed ″γ-AApeptides", oligomers of γ-substituted- N -acylated- N -aminoethyl amino acids, which are inspired by the chiral peptide nucleic acid backbone. To date γ-AApeptides have been shown to be resistant to proteolytic degradation and possess limitless potential to introduce chemically diverse functional groups, demonstrating promise in biomedical and material sciences. However, the structures of γ-AApeptides were initially unknown, rendering their rational design for the mimicry of a protein helical domain impossible in the beginning, which limited their potential development. To our delight, in the past few years, we have obtained a series of crystal structures of helical sulfono-γ-AApeptides, a subclass of γ-AApeptides. The single-crystal X-ray crystallography indicates that sulfono-γ-AApeptides fold into unprecedented and well-defined helices with unique helical parameters. On the basis of the well-established size, shape, and folding conformation, the design of sulfono-γ-AApeptide-based foldamers opens a new avenue for the development of alternative unnatural peptidomimetics for their potential applications in chemistry, biology, medicine, materials science, and so on.In this Account, we will outline our journey on sulfono-γ-AApeptides and their application as helical mimetics. We will first briefly introduce the design and synthetic strategy of sulfono-γ-AApeptides and then describe the crystal structures of helical sulfono-γ-AApeptides, including left-handed homogeneous sulfono-γ-AApeptides, right-handed 1:1 α/sulfono-γ-AA peptide hybrids, and right-handed 2:1 α/sulfono-γ-AA peptide hybrids. After that, we will illustrate the potential of helical sulfono-γ-AApeptides for biological applications such as the disruption of medicinally relevant protein-protein interactions (PPIs) of BCL9-β-catenin and p53-MDM2/MDMX as well as the mimicry of glucagon-like peptide 1 (GLP-1). In addition, we also exemplify their potential application in material science. We expect that this Account will shed light on the structure-based design and function of helical sulfono-γ-AApeptides, which can provide a new and alternative way to explore and generate novel foldamers with distinctive structural and functional properties.

Through our continuous effort in developing a new class of foldamers, we have both designed and synthesized homogenous sulfono-γ-AApeptides using tetraphenylethylene (TPE) moieties attached to the backbone as luminogenic sidechains. Based on previous crystal structures, we have found that these foldamers adopted a left-handed 4 14 -helix. Due to the constraint of the helical scaffold, the rotation of the TPE moieties were restricted, leading to fluorescent emissive properties with high quantum yields not only at the aggregate state but also in solution. Investigation of the relationship between the structure and fluorescence behavior reveals that emission was induced by the combined effect of the aggregation-induced emission (AIE) and the rotated restriction from the backbone. Furthermore, as the packing mode of the luminogens could be precisely adjusted by the helical backbone, these foldamers were found to be circularly polarizable with relatively large luminescence dissymmetry factor ( g lum ). Interestingly, possessing cationic amphipathic structures similar to that of host-defense peptides (HDPs), these sulfono-γ-AApeptides were able to inhibit the growth of Gram-positive bacteria methicillin-resistant S. aureus (MRSA) through membrane interactions., Competing Interests: The authors declare no conflict of interest.

Over the past few decades, the emergence of antibiotic resistance developed by life-threatening bacteria has become increasingly prevalent. Thus, there is an urgent demand to develop novel antibiotics capable of mitigating this trend. Herein, we report a series of dimeric γ-AApeptide derivatives as potential antibiotic agents with limited toxicity and excellent selectivity against Gram-positive strains. Among them, compound 2 was identified to have the best MICs without inducing drug resistance, even after exposure to MRSA for 20 passages. Time-kill kinetics and mechanistic studies suggested that 2 could mimic host-defense peptides (HDPs) and rapidly eradicate MRSA within 2 hours through disturbing the bacteria membrane. Meanwhile, biofilm formation was successfully inhibited even at a low concentration. Taken together, these results suggested the great potential of dimeric γ-AApeptide derivatives as antibacterial agents., (Copyright © 2020 Wang, Gao, Sang, Odom, Zheng, Shi, Xu, Cao and Cai.)

Existing long α-helix mimicking necessitates the retention of most natural amino acid residues to maintain their biological activity. Here, we report the exploration of helical sulfono-γ-AApeptides with entire unnatural backbones for their ability to structurally and functionally mimic glucagon-like peptide 1 (GLP-1). Our findings suggest that efficient construction of novel GLP-1 receptor (GLP-1R) agonists could be achieved with nanomolar potencies. In addition, the resulting sulfono-γ-AApeptides were also proved to display remarkable stability against enzymatic degradation compared to GLP-1, augmenting their biological potential. This alternative strategy of α-helix mimicking, as a proof of concept, could provide a new paradigm to prepare GLP-1R agonists., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)