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Following acute herpes simplex virus type 2 (HSV-2) infection, the virus undergoes an asymptomatic latent infection of sensory neurons of dorsal root ganglia (DRG). Chemical and physical stress cause intermittent virus reactivation from latently infected DRG and recurrent virus shedding in the genital mucosal epithelium causing genital herpes in symptomatic patients. While T cells appear to play a role in controlling virus reactivation from DRG and reducing the severity of recurrent genital herpes, the mechanisms for recruiting these T cells into DRG and the vaginal mucosa (VM) remain to be fully elucidated. The present study investigates the effect of CXCL9, CXCL10, and CXCL11 T-cell-attracting chemokines on the frequency and function of DRG- and VM-resident CD4+ and CD8+ T cells and its effect on the frequency and severity of recurrent genital herpes in the recurrent herpes guinea pig model. HSV-2 latent-infected guinea pigs were immunized intramuscularly with the HSV-2 ribonucleotide reductase 2 (RR2) protein (Prime) and subsequently treated intravaginally with the neurotropic adeno-associated virus type 8 expressing CXCL9, CXCL10, or CXCL11 chemokines to recruit CD4+ and CD8+ T cells into the infected DRG and VM (Pull). Compared to the RR2 therapeutic vaccine alone, the RR2/CXCL11 prime/pull therapeutic vaccine significantly increased the frequencies of functional tissue-resident and effector memory CD4+ and CD8+ T cells in both DRG and VM tissues. This was associated with less virus in the healed genital mucosal epithelium and reduced frequency and severity of recurrent genital herpes. These findings confirm the role of local DRG- and VM-resident CD4+ and CD8+ T cells in reducing virus shedding at the vaginal site of infection and the severity of recurrent genital herpes and propose the novel prime-pull vaccine strategy to protect against recurrent genital herpes.IMPORTANCEThe present study investigates the novel prime/pull therapeutic vaccine strategy to protect against recurrent genital herpes using the latently infected guinea pig model. In this study, we used the strategy that involves immunization of herpes simplex virus type 2-infected guinea pigs using a recombinantly expressed herpes tegument protein-ribonucleotide reductase 2 (RR2; prime), followed by intravaginal treatment with the neurotropic adeno-associated virus type 8 expressing CXCL9, CXCL10, or CXCL11 T-cell-attracting chemokines to recruit T cells into the infected dorsal root ganglia (DRG) and vaginal mucosa (VM) (pull). We show that the RR2/CXCL11 prime-pull therapeutic vaccine strategy elicited a significant reduction in virus shedding in the vaginal mucosa and decreased the severity and frequency of recurrent genital herpes. This protection was associated with increased frequencies of functional tissue-resident (TRM cells) and effector (TEM cells) memory CD4+ and CD8+ T cells infiltrating latently infected DRG tissues and the healed regions of the vaginal mucosa. These findings shed light on the role of tissue-resident and effector memory CD4+ and CD8+ T cells in DRG tissues and the VM in protection against recurrent genital herpes and propose the prime-pull therapeutic vaccine strategy in combating genital herpes.

Our sense of hearing is mediated by cochlear hair cells, of which there are two types organized in one row of inner hair cells and three rows of outer hair cells. Each cochlea contains 5-15 thousand terminally differentiated hair cells, and their survival is essential for hearing as they do not regenerate after insult. It is often desirable in hearing research to quantify the number of hair cells within cochlear samples, in both pathological conditions, and in response to treatment. Machine learning can be used to automate the quantification process but requires a vast and diverse dataset for effective training. In this study, we present a large collection of annotated cochlear hair-cell datasets, labeled with commonly used hair-cell markers and imaged using various fluorescence microscopy techniques. The collection includes samples from mouse, rat, guinea pig, pig, primate, and human cochlear tissue, from normal conditions and following in-vivo and in-vitro ototoxic drug application. The dataset includes over 107,000 hair cells which have been identified and annotated as either inner or outer hair cells. This dataset is the result of a collaborative effort from multiple laboratories and has been carefully curated to represent a variety of imaging techniques. With suggested usage parameters and a well-described annotation procedure, this collection can facilitate the development of generalizable cochlear hair-cell detection models or serve as a starting point for fine-tuning models for other analysis tasks. By providing this dataset, we aim to give other hearing research groups the opportunity to develop their own tools with which to analyze cochlear imaging data more fully, accurately, and with greater ease.

Prion diseases are transmissible, fatal neurologic diseases of mammals caused by the accumulation of mis-folded, disease associated prion protein (PrPd). Creutzfeldt-Jakob Disease (CJD) is the most common human prion disease and can occur by sporadic onset (sCJD) (~85% of CJD cases), genetic mutations in the prion protein gene (10–15%) or iatrogenic transmission (rare). PrPd is difficult to inactivate and many methods to reduce prion infectivity are dangerous, caustic, expensive, or impractical. Identifying viable and safe methods for decontamination of CJD exposed materials is critically important for medical facilities and research institutions. Previous research has shown that concentrated sodium hypochlorite (bleach) was effective at inactivation of CJD prions derived from brains of mice or guinea pigs. Unfortunately, human prions adapted to rodents may mis-fold differently than in humans, and the rodent adapted prions may not have the same resistance or susceptibility to inactivation present in bona fide CJD prions. To confirm that bleach was efficacious against human sourced CJD prions, we exposed different subtypes of sCJD-infected human brain homogenates to different concentrations of bleach for increasing exposure times. Initial and residual prion seeding activity following inactivation were measured using Real-Time Quaking Induced Conversion. In addition, we tested how passage of human sCJD into either transgenic mice that expressed human prion protein, or transmission of CJD to human cerebral organoids (CO), two common laboratory practices, may affect CJD prions' susceptibility to bleach inactivation. Our results show that bleach is effective against human sourced sCJD prions, and both treatment time and concentration of bleach were important factors for CJD inactivation. CJD derived from human brains, transgenic mouse brains or CO were all susceptible to inactivation with as low as a 10 percent bleach solution with a 30-minute exposure time or a 50 percent bleach solution with as little as a 1-minute exposure time. [ABSTRACT FROM AUTHOR]

Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus and the leading cause of infectious disease related birth defects worldwide. How the immune response modulates the risk of intrauterine transmission of HCMV after maternal infection remains poorly understood. Maternal T cells likely play a critical role in preventing infection at the maternal-fetal interface and limiting spread across the placenta, but concerns exist that immune responses to infection may also cause placental dysfunction and adverse pregnancy outcomes. This study investigated the role of CD4+ and CD8+ T cells in a guinea pig model of primary cytomegalovirus infection. Monoclonal antibodies specific to guinea pig CD4 and CD8 were used to deplete T cells in non-pregnant and in pregnant guinea pigs after mid-gestation. CD4+ T cell depletion increased the severity of illness, caused significantly elevated viral loads, and increased the rate of congenital guinea pig cytomegalovirus (GPCMV) infection relative to animals treated with control antibody. CD8+ T cell depletion was comparably well tolerated and did not significantly affect the weight of infected guinea pigs or viral loads in their blood or tissue. However, significantly more viral genomes and transcripts were detected in the placenta and decidua of CD8+ T cell depleted dams post-infection. This study corroborates earlier findings made in nonhuman primates that maternal CD4+ T cells play a critical role in limiting the severity of primary CMV infection during pregnancy while also revealing that other innate and adaptive immune responses can compensate for an absent CD8+ T cell response in α-CD8-treated guinea pigs. Author summary: Congenital cytomegalovirus infection is a leading cause of adverse pregnancy outcomes and preventable disability in children. Using guinea pigs, a well-established small animal model of congenital infection and intrauterine development, this study tested how depleting T cells affects the course of primary cytomegalovirus infections. Severe illness and high rates of congenital infection were observed when helper CD4+ T cells were depleted. The depletion of killer CD8+ T cells did not affect the severity of disease or the rate of congenital infection but did increase the amount of virus that was detected in the placenta. A greater understanding how an immune response can prevent the infection of the placenta and developing offspring is needed to inform vaccine and therapeutic development. This study not only describes a new reagent that can be used to study the guinea pig immune system but also sheds new light in how adaptive immunity regulates congenital viral infection. [ABSTRACT FROM AUTHOR]

Masticatory myositis is an autoimmune neuromuscular disorder that affects the muscles of mastication. The affected individual has difficulties in opening or closing the mouth, pain, and swelling in the acute phase, and significant atrophy of the affected musculature in the chronic phase. A guinea pig (Cavia porcellus) with a history of chronic hyporexia, recurrent cheek teeth overgrowth, and loss of facial silhouette, was suspected of having masticatory myositis. The disease was confirmed by computed tomography and histopathological examination of muscle fragments. The patient was treated with a protocol involving corticosteroids and gabapentin, and occlusal correction procedures. [ABSTRACT FROM AUTHOR]

The (diphtheria, tetanus, and pertussis [acellular, component] [DTacP]) vaccine is a combined vaccine designed to prevent three potentially fatal diseases including pertussis, tetanus, and diphtheria in both children and adults. We utilized advanced technology to develop a novel DTacP vaccine that was previously unavailable in China. The nonclinical studies were performed to evaluate the immunogenicity, potential toxicity, and local tolerance of the vaccine in animal models. In the immunogenicity study, three batches of the vaccine were intraperitoneally administered to National Institutes of Health (NIH) mice, resulting in 100% seropositivity for all three batches. Additionally, antibody levels notably increased as the immunization dosage increased. In acute toxicity study, no mortality was observed among the animals during the 14‐day observation period, and no abnormalities in clinical signs were reported. Active systemic anaphylaxis assessment in guinea pigs showed no evidence of serious allergic reactions in the vaccine groups. In the repeat‐dose toxicity study, where five intramuscular doses were administered every 2 weeks, gross autopsy and histopathological examination revealed no vaccine‐related systemic pathological changes in rats, with dose site irritant reactions mostly recovered at the end of recovery period. In conclusion, the vaccine demonstrated good local and systemic tolerance, supporting its clinical development. We developed a novel DTacP vaccine that was previously unavailable in China and evaluated the immunogenicity, potential toxicity, and local tolerance of the vaccine in animal models. The seropositivity of vaccines reached 100% in mice. Acute toxicity study, active systemic anaphylaxis study, and repeat‐dose toxicity study showed no clinical signs abnormalities, and moderate irritant reactions were observed and mostly recovered at the end of recovery period. The DTacP vaccine demonstrated good local and systemic tolerance, supporting its clinical development. [ABSTRACT FROM AUTHOR]

The expansion of VapBC TA systems in M. tuberculosis has been linked with its fitness and survival upon exposure to stress conditions. Here, we have functionally characterized VapBC13 and VapBC26 TA modules of M. tuberculosis. We report that overexpression of VapC13 and VapC26 toxins in M. tuberculosis results in growth inhibition and transcriptional reprogramming. We have also identified various regulatory proteins as hub nodes in the top response network of VapC13 and VapC26 overexpression strains. Further, analysis of RNA protection ratios revealed potential tRNA targets for VapC13 and VapC26. Using in vitro ribonuclease assays, we demonstrate that VapC13 and VapC26 degrade serT and leuW tRNA, respectively. However, no significant changes in rRNA cleavage profiles were observed upon overexpression of VapC13 and VapC26 in M. tuberculosis. In order to delineate the role of these TA systems in M. tuberculosis physiology, various mutant strains were constructed. We show that in comparison to the parental strain, ΔvapBC13 and ΔvapBC26 strains were mildly susceptible to oxidative stress. Surprisingly, the growth patterns of parental and mutant strains were comparable in aerosol-infected guinea pigs. These observations imply that significant functional redundancy exists for some TA systems from M. tuberculosis. The ectopic expression of VapC13 and VapC26 results in transcriptional reprogramming of M. tuberculosis. Both, VapBC13 and VapBC26 TA systems are dispensable for infection in guinea pigs, suggesting a degree of functional redundancy in M. tuberculosis. [ABSTRACT FROM AUTHOR]

To compare the vibrational patterns of human and guinea pig cochleae accurately, we developed and validated a novel finite element model of the guinea pig, leveraging it to analyze vibrational patterns in the cochlea. This approach is mirrored in our examination of the human cochlear model, providing granular insights into the nuances of human bone conduction hearing. The comparative analysis reveals that the guinea pig cochlea mirrors human cochlear vibrational patterns, thus serving as an efficient proxy for exploring human cochlear function. The human mastoid and the upper region of the guinea pig's skull are recommended as the convenient and comparable sites for bone conduction stimulation. The cochlear vibration pattern encompasses a mix of rigid, rotational, and compressive motion. Significantly, the guinea pig model demonstrates robust agreement with existing experimental data and other studies, these findings are confirming the validity of the model. Our study delineates the distinct roles of the three vibration types across various frequency spectrums. At lower frequencies, rigid motion is the dominant mechanism, supplemented by rotational motion. However, at higher frequencies, the influence of rigid motion wanes, ceding prominence to rotational and compressive motions. This trend is consistently observed in both human and guinea pig models. [ABSTRACT FROM AUTHOR]

Objective: Human umbilical cord mesenchymal stem cells (hUCMSCs) hold significant promise across various clinical applications. Therefore, regulatory requirements necessitate a thorough investigation of the hUCMSCs safety before clinical trials and potential allergic reactions after transplantation. Methods: Abnormal toxicity test employed mice and guinea pigs dosed daily at 0.5×106 cells and 5×106 cells, respectively for 7 days. Acute toxicity test employed low, medium, and high doses of hUCMSCs injected into mice once, followed by observations for 23 days. In systemic allergy test, guinea pigs received low and high dose of hUCMSCs, with sensitization and excitation stages at day 14 and 21, respectively. Results: The abnormal toxicity test of hUCMSC injections revealed no abnormal reactions over a seven-day observation period, indicating the safety of this administration route. In acute toxicity studies, the high-dose hUCMSCs group resulted in fatalities due to pulmonary embolism. Conversely, the low-dose group exhibited no toxic reactions or deaths. The maximum tolerated dose was determined to be >2×107 cells/kg. Systemic active allergy test showed that high doses of hUCMSC intravenous injections did not induce allergic reactions. Conclusion: This research affirms hUCMSC injections meet safety standards for clinical cell therapy, emphasizing their safe and promising clinical utility. [ABSTRACT FROM AUTHOR]

Simple Summary: The demand for animal-assisted services (AAS) has increased in the past decades. The participation of supporting animals in complementary therapy for humans is a developing area. While dogs and horses are the most widely utilized species in AAS, several unconventional species have already been involved, although there is a lack of information about the effects of the stress they may experience. During the interventions, animals may experience stress that can potentially violate aspects of animal welfare. This review seeks to identify criteria for selecting unconventional animal species, such as guinea pigs, rabbits, farm animals, alpacas, donkeys, reptiles, aquarium fishes, and dolphins, for AAS, considering factors such as temperament, trainability, human–animal bond potential, stress measurement, and stress mitigation strategies. Despite the growing interest in AAS, our literature review underscores the scarcity of research exploring their effects on unconventional animal species, especially in stress measurement; therefore, more extensive studies should be conducted, for instance, measuring biochemical parameters, such as cortisol. The participation of animals during complementary therapy for humans is a developing area. Dogs and horses are the most frequent partner species in animal-assisted services, but several unconventional species have also been involved, although there is a lack of information about the stress they experience caused by AAS. We conducted a comprehensive literature search, analyzing 135 articles with the purpose of investigating the effects of AAS on unconventional species such as guinea pigs, rabbits, farm animals, alpacas, donkeys, reptiles, aquarium fishes, and dolphins. We found that the relevant articles emphasize investigating the impact of animal-assisted interventions on humans, and they generally report positive outcomes. Limited data is available concerning the potential consequences the interventions may have on the animals. Therefore, it is our conclusion that more extensive studies should be conducted to get adequate information on stress experienced by animals during AAS, such as the measurement of biochemical parameters such as cortisol. Hence, meeting animal welfare considerations in addition to human interests could serve as a basis for the recommended methodology for therapies. [ABSTRACT FROM AUTHOR]

Adversity early in life can modify the trajectory for disease risk extending decades beyond the event. Preterm birth produces persistent cardiovascular alterations that may appear maladaptive in adulthood. We have previously hypothesized that those born preterm may exhibit cardiovascular vulnerability in the climate change context. Further, this vulnerability may be present as early as childhood. We aimed to identify the early signs of cardiovascular dysfunction at childhood‐equivalent age using our animal model of preterm birth. Using a whole‐body thermal stress test, guinea pigs aged 35‐d and 38‐d (equivalent to 8–10‐year‐old children) and born at term or preterm gestations were exposed to progressive hyper‐ (TC = 41.5°C) and hypo‐thermia (TC = 34°C; normothermia TC = 39°C). Comprehensive cardiovascular monitoring included ECG, blood pressure, microvascular perfusion, blood gas, and catecholamine profile, as well as skin and core body temperature. Preterm‐born animals exhibited attenuated vascular responses to hyperthermic stress, and a significant elevation in systolic blood pressure in response to hypothermic stress. Such responses are similar to those observed in elderly populations and indicate the presence of cardiovascular dysfunction. This is the first study to demonstrate the impact of preterm birth on the cardiovascular response to both heat and cold stress. Further, this dysfunction has been observed at an earlier age than that achievable using traditional stress testing techniques. The present findings warrant further investigation. [ABSTRACT FROM AUTHOR]

Diabetes (DM) patients have an increased risk (~50%) for sudden cardiac death (SCD), mostly as a result of ventricular arrhythmias. The molecular mechanisms involved remain partially defined. The potent proinflammatory lipid mediator leukotriene (LT) B4, is pathologically elevated in DM compared to nondiabetic patients, resulting in increased LTB4 accumulation in heart, leading to an increased risk for life‐threatening proarrhythmic signatures. We used electrophysiology, immunofluorescence, and confocal microscopy approaches to evaluate LTB4 cellular effects in guinea pig heart and ventricular myocytes. We have observed that LTB4 is increased in multiple mouse models (C57BL/6 J/Lepob/ob and PANIC‐ATTAC) of DM, promotes profound cellular arrhythmogenesis (spontaneous beats and early after depolarizations, EADs), and severely depresses the rapidly activating delayed rectifier K current (hERG1/IKr) density in HEK293 cells and guinea pig ventricular myocytes. We have further found that guinea pigs challenged with LTB4 displayed a significantly prolonged QT interval, and that this can be prevented with LTB4R inhibition, suggesting that preventing such LTB4R effects may be therapeutically beneficial in DM. Our data suggests that a further elucidation of LTB4 vulnerable substrates, and how this leads to ventricular arrhythmias, is likely to lead to continued improvements in management options, and the development of new therapies for prevention of SCD in DM patients. [ABSTRACT FROM AUTHOR]

Introduction: The herbal preparation STW 5 ameliorates functional dyspepsia partly by relaxing smooth muscle of the proximal stomach, thus improving gastric accommodation. We explored the unknown pathways responsible for this effect by testing targets known to modulate gastric smooth muscle relaxation. Methods: STW 5‐induced relaxation of smooth muscle strips from guinea pig gastric corpus before and after pharmacological interventions were recorded with force transducers in an organ bath. ORAI1 mRNA expression was tested in the proximal stomach. Key Results: Blockade of Ca2+‐activated K+ and Cl− channels, voltage‐gated L‐ or T‐type Ca2+ channels, TRPA1‐, TRPV1‐, adenosine or 5‐HT4 receptors, antagonizing ryanodine receptors, inhibiting cyclooxygenase or sarcoplasmic reticulum calcium ATPase did not affect STW 5‐evoked relaxation. Likewise, protein‐kinase A or G were not involved. However, the relaxation evoked by STW 5 was significantly reduced by phorbol‐12‐myristat‐13‐acetat, an activator of protein‐kinase C, by 2‐ aminoethyldiphenylborinate, an inhibitor of the IP3 receptor‐mediated Ca2+ release from the sarcoplasmic reticulum or by SKF‐96365, a nonselective store‐operated calcium entry (SOCE) blocker. Furthermore, the mixed TRPC3/SOCE inhibitor Pyr3, but not the selective TRPC3 blocker Pyr10, reduced the effect of STW 5. Finally, BTP2, a potent blocker of ORAI‐coupled SOCE, almost abolished STW 5‐evoked relaxation. Expression of ORAI1 could be demonstrated in the corpus/fundus. Conclusions & Inferences: STW 5 inhibited SOCE, most likely ORAI channels, which are modulated by IP3‐ and PKC‐dependent mechanisms. Our findings impact on the design of drugs to induce muscle relaxation and help identify phytochemicals with similar modes of actions to treat gastrointestinal disturbances. [ABSTRACT FROM AUTHOR]

Quinoline-related antimalarial drugs have been associated with cardiotoxicity risk, in particular QT prolongation and QRS complex widening. In collaboration with Medicines for Malaria Venture, we discovered novel plasmepsin X (PMX) inhibitors for malaria treatment. The first lead compounds tested in anesthetized guinea pigs (GPs) induced profound QRS widening, although exhibiting weak inhibition of NaV1.5-mediated currents in standard patch clamp assays. To understand the mechanism(s) underlying QRS widening to identify further compounds devoid of such liability, we established a set of in vitro models including CaV1.2, NaV1.5 rate-dependence, and NaV1.8 patch clamp assays, human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), and Langendorff-perfused isolated GP hearts. Six compounds were tested in all models including anesthetized GP, and 8 additional compounds were tested in vitro only. All compounds tested in anesthetized GP and isolated hearts showed a similar cardiovascular profile, consisting of QRS widening, bradycardia, negative inotropy, hypotension, and for some, QT prolongation. However, a left shift of the concentration–response curves was noted from in vitro to in vivo GP data. When comparing in vitro models, there was a good consistency between decrease in sodium spike amplitude in hiPSC-CM and QRS widening in isolated hearts. Patch clamp assay results showed that the QRS widening observed with PMX inhibitors is likely multifactorial, primarily due to NaV1.8 and NaV1.5 rate-dependent sodium blockade and/or calcium channel-mediated mechanisms. In conclusion, early de-risking of QRS widening using a set of different in vitro assays allowed to identify novel PMX inhibitors with improved cardiac safety profile. [ABSTRACT FROM AUTHOR]

Within drug development, high off-target promiscuity as well as potent cytotoxicity, are associated with a high attrition rate. We investigated the safety profile of novel plasmepsin X (PMX) inhibitors for the treatment of malaria. In our screening cascade, a total of 249 PMX compounds were profiled in a panel of in vitro secondary pharmacology assays containing 44 targets (SafetyScreen44 panel) and in a cytotoxicity assay in HepG2 cells using ATP as an endpoint. Six of the lead compounds were subsequently tested in a 7-d rat toxicology study, and/or in a cardiovascular study in guinea pigs. Overall, compounds with high cytotoxicity in HepG2 cells correlated with high promiscuity (off-target hit rate >20%) in the SafetyScreen44 panel and were associated with poor tolerability in vivo (decedents, morbidity, adverse clinical signs, or severe cardiovascular effects). Some side effects observed in rats or guinea pigs could putatively be linked with hits in the secondary pharmacological profiling, such as the M1 or M2 muscarinic acetylcholine receptor, opioid µ and/or κ receptors or hERG/CaV1.2/Na+ channels, which were common to >50% the compounds tested in vivo. In summary, compounds showing high cytotoxicity and high promiscuity are likely to be poorly tolerated in vivo. However, such associations do not necessarily imply a causal relationship. Identifying the targets that cause these undesirable effects is key for early safety risk assessment. A tiered approach, based on a set of in vitro assays, helps selecting the compounds with highest likelihood of success to proceed to in vivo toxicology studies. [ABSTRACT FROM AUTHOR]

Exotic animals have become popular pets, but there is little information about abandonment. Records of a network of foster homes for abandoned rabbits and rodents in Madrid (Spain) between 2008 and 2021 were analyzed. Data of 1024 animals were included, 46.4% were rabbits, 19.7% hamsters, 15.3% guinea pigs, 5.8% rats, 5.4% gerbils, 4.8% mice, and 2.6% chinchillas. Half of the animals (51.2%) were admitted with health issues, 41.3% had been abandoned, mostly in urban areas, 46.8% came from a local shelter, and 8.1% were relinquished by the owner. Only 12 animals were neutered and 8 were microchipped. The network of foster homes took care of 1009 animals (98.5%), 686 of them were adopted in an average time of 9.2 months, regardless of their health status, 15 animals died before fostering, and 323 died before adoption. Numerous rabbits and rodents are abandoned in urban areas in Madrid (Spain), very few of them are microchipped or neutered. Associations based on networks of foster homes for the adoption of abandoned rabbits and rodents can be effective, preserving animal welfare as effectively as shelters. [ABSTRACT FROM AUTHOR]

Lowering the levels of the cellular prion protein (PrPC) is widely considered a promising strategy for the treatment of prion diseases. Building on work that established immediate spatial proximity of PrPC and Na+, K+-ATPases (NKAs) in the brain, we recently showed that PrPC levels can be reduced by targeting NKAs with their natural cardiac glycoside (CG) inhibitors. We then introduced C4'-dehydro-oleandrin as a CG with improved pharmacological properties for this indication, showing that it reduced PrPC levels by 84% in immortalized human cells that had been differentiated to acquire neural or astrocytic characteristics. Here we report that our lead compound caused cell surface PrPC levels to drop also in other human cell models, even when the analyses of whole cell lysates suggested otherwise. Because mice are refractory to CGs, we explored guinea pigs as an alternative rodent model for the preclinical evaluation of C4'-dehydro-oleandrin. We found that guinea pig cell lines, primary cells, and brain slices were responsive to our lead compound, albeit it at 30-fold higher concentrations than human cells. Of potential significance for other PrPC lowering approaches, we observed that cells attempted to compensate for the loss of cell surface PrPC levels by increasing the expression of the prion gene, requiring daily administration of C4'-dehydro-oleandrin for a sustained PrPC lowering effect. Regrettably, when administered systemically in vivo, the levels of C4'-dehydro-oleandrin that reached the guinea pig brain remained insufficient for the PrPC lowering effect to manifest. A more suitable preclinical model is still needed to determine if C4'-dehydro-oleandrin can offer a cost-effective complementary strategy for pushing PrPC levels below a threshold required for long-term prion disease survival. [ABSTRACT FROM AUTHOR]

Background: Rabbits are herbivores with a distinctive digestive strategy that differs significantly from other caecal fermenters (e.g., horses, guinea pigs) and ruminants. In view of this, the current study aimed to highlight distinctive histological and morphometric features of the caecal mucosa in adult rabbits that accentuate its major role in digestion. The caecal and jejunal samples were harvested from five 1-year-old domestic rabbits and processed by regular paraffin-embedding histological technique followed by Goldner's trichrome staining. A comprehensive morphological and morphometrical analysis of the jejunal mucosa vs. caecal mucosa was performed. Results: Microscopically, as in the case of the jejunal mucosa, the caecal mucosa presents long and often branched finger-like villi covered by a simple columnar epithelium mostly made of enterocytes with a prominent microvillous brush border. Besides, the caecal villi include a lacteal along with the villous muscle. Statistically, except for villus length, all the parameters assessed in the caecal mucosa, including villus width, villus count, thickness of the brush border and enterocyte/goblet cells ratio, revealed a high grade of similarities with the jejunal villi. Conclusions: According to the obtained results, the caecal mucosa in adult domestic rabbits includes unique features, namely caecal villi, structures infrequently presented in the large intestine of other adult mammals. Those structures once more emphasize the major role of the caecum not only in fermentation but also subliminally in local absorption. To our knowledge, this is the first reliable microanatomical and morphometric report of caecal villi in adult domestic rabbits. [ABSTRACT FROM AUTHOR]

Updates of SARS-CoV-2 vaccines are required to generate immunity in the population against constantly evolving SARS-CoV-2 variants of concerns (VOCs). Here we describe three novel in-silico designed spike-based antigens capable of inducing neutralising antibodies across a spectrum of SARS-CoV-2 VOCs. Three sets of antigens utilising pre-Delta (T2_32), and post-Gamma sequence data (T2_35 and T2_36) were designed. T2_32 elicited superior neutralising responses against VOCs compared to the Wuhan-1 spike antigen in DNA prime-boost immunisation regime in guinea pigs. Heterologous boosting with the attenuated poxvirus - Modified vaccinia Ankara expressing T2_32 induced broader neutralising immune responses in all primed animals. T2_32, T2_35 and T2_36 elicited broader neutralising capacity compared to the Omicron BA.1 spike antigen administered by mRNA immunisation in mice. These findings demonstrate the utility of structure-informed computationally derived modifications of spike-based antigens for inducing broad immune responses covering more than 2 years of evolved SARS-CoV-2 variants. [ABSTRACT FROM AUTHOR]

To evaluate the changes of choroidal thickness (CT) and blood flow related to myopia, and its effects of vascular endothelial growth factor (VEGFA) on choroidal vessels in myopia. Subjects were included and divided into emmetropia (EM), non-high myopia (Non-HM) and high myopia (HM) groups. we measured choroidal thickness (CT), choriocapillaris vessel density (VD), and VEGFA content in tears in humans (137 subjects for CT, VD and 84 for tear) and detected the role of VEGFA in the choroid in form-deprivation myopia (FDM) in guinea pigs. Twenty-four guinea pigs were divided into control and FDM groups, and the expression changes of choroidal vessels and VEGFA were observed and compared using immunohistochemistry and Western blotting. Twenty-one guinea pigs were divided into control, FDM + Vehicle and FDM + Conbercept groups. The changes of diopter, axis length and choroidal vessels after intravitreal injection of Conbercept were observed. There were significant differences in CT and VD among the three groups (p < 0.05). VEGFA levels in tears were significantly lower in the myopic groups, with a decreasing trend from EM to Non-HM to HM. The choroidal vascular area fraction of FDM decreased compared to the control group. FDM guinea pigs exhibited reduced choroidal vasculature and significant downregulation of VEGFA expression. Following intravitreal injection of conbercept, the FDM + Conbercept group showed greater myopia, longer axial length, and lower choroidal vascular area fraction compared to the control group. VEGFA may participate in the regulation of choroidal blood vessels and blood flow in the progression of myopia. The reduction in VEGFA may accelerates the progression of myopia. [ABSTRACT FROM AUTHOR]

Trachyspermum ammi is widely used among the people in the Arabian Peninsula to treat general respiratory problems including bronchoconstriction. In this study, the fruit extracts and its fractions and purely isolated components obtained from the T. ammi were investigated for their possible bronchodilator potential in an ex vivo model using guinea pig trachea. It was observed that the ethanol extract (TAT) of the plant and its hexane (TAH) and chloroform (TAC) extract fractions completely inhibited carbachol (CCh, 1 µM)-induced contractions at a concentration of 1 mg/mL. As a result of the biological activity-guided purification studies of the chloroform extract (TAC), in which the highest activity was observed, eight sub-fractions were obtained between A-H. Of these, fractions A, D, G were found to have significant activity for tracheal relaxation with 100%, 55 ± 5% and 31 ± 3%, respectively, while the other five fractions were found not to have any activity. Three monoterpene compounds were isolated from the fractions with high activity and their structures were determined by 1D and 2D NMR and mass spectrometric techniques as well as by simple chemical derivatization. In this study, it was determined that the bronchodilator effect of compound 1 (thymol) was demonstrated by the activation of different subtypes of K+ channels. Reported data herein, demonstrated the scientific justification for the traditional use of T. ammi species against asthma and bronchitis. [ABSTRACT FROM AUTHOR]

Background: The Sunda porcupine, or the Javan porcupine (Hystrix javanica), is a rodent native to Indonesia. Although information about its conservation status is available, the hematological profile is limited. The normal hematological profile of an animal is essential as a basic health indicator to determine the initial state of a pathological process of a disease. Since the hematological profile can provide significant evidence regarding the health status of the species, the Sunda Porcupine's hematological profile can benefit conservation initiatives. Therefore, hematological evaluation of these porcupines can play a role in conservation initiatives, breeding strategies, and the prevention of zoonotic diseases. Aim: This research revealed the routine blood evaluation and white blood cell (WBC) morphological features of the free-ranging Sunda porcupine (H. javanica). Methods: Blood samples from four free-range individuals captured Sunda porcupine (H. javanica) were obtained intracardially for routine hematological evaluation and WBC staining for morphological identification. The profiles were then analyzed descriptively. Results: Hematology profile averages were generally 4.04 × 106/Ul for RBC; Hemoglobin was in 12.83 g/dl; Hematocrit by 37.8%; MCV 107.1 fl; MCH 31.80 pg; MCHC 31.23 g/dl; while WBC and platelet (PLT) were at 9.67 × 10³/µl and 503.00 × 10³/µl, respectively. Conclusion: The morphology of red blood cells, WBCs, and the hematological profile of the Javan hedgehog is not much different from that of other mammals such as crested porcupines, ferrets, and guinea pigs. Until now, there has been limited research on the hematology of Sunda porcupines, which has led to a limited understanding of their health status. We anticipate that the findings of this study will serve as a diagnostic instrument for evaluating the health condition of Sunda porcupine and serve as a benchmark. [ABSTRACT FROM AUTHOR]

Myocardial sleeves of the pulmonary veins (PV) extending from the left atrium (LA) are the major source of ectopic activity causing atrial arrhythmias. The structural and electrophysiological characteristics of the PV myocardium differ from those of the LA. The mechanical activity of cardiomyocytes (CM) impacts cardiac excitation-contraction coupling, however, the mechanical function of PV CM has not been studied yet. We compared the characteristics of the actin-myosin interaction and sarcomere length (SL) dynamics in mechanically non-loaded single CM between the PV and LA in the guinea pig heart. We found that the functional properties of myosin from the PV and LA are not different, while the phosphorylation levels of sarcomeric proteins in the PV and LA are different. End-diastolic SL, sarcomere shortening amplitude, and velocities of sarcomere shortening and relengthening of PV and LA CM do not differ, while PV CM are longer and thinner than LA CM. The amplitude of sarcomere shortening increased with an increase in CM length in the LA but not in the PV. We assume that an absence of correlation between the morphometric parameters of CM and the amplitude of sarcomere shortening together with the electrophysiological features of the PV myocardium may contribute to the occurrence and development of atrial fibrillation. [ABSTRACT FROM AUTHOR]

Background: Serving as a reservoir, the gastric fundus can expand significantly, with an initial receptive and a following adaptive relaxation, controlled by extrinsic and intrinsic reflex circuits, respectively. We hypothesize that mechanosensitive enteric neurons (MEN) are involved in the adaptive relaxation, which is initiated when a particular gastric volume and a certain stretch of the stomach wall is reached. To investigate whether the responsiveness of MEN in the gastric fundus is dependent on tissue stretch, we performed mechanical stimulations in stretched versus ganglia "at rest". Methods: Responses of myenteric neurons in the guinea pig gastric fundus were recorded with membrane potential imaging using Di‐8‐ANEPPS. MEN were identified by small‐volume intraganglionic injection in ganglia stretched to different degrees using a self‐constructed stretching tool. Immunohistochemical staining identified the neurochemical phenotype of MEN. Hexamethonium and capsaicin were added to test their effect on recruited MEN. Key Results: In stretched compared to "at rest" ganglia, significantly more MEN were activated. The change in the ganglionic area correlated significantly with the number of additional recruited MEN. The additional recruitment of MEN was independent from nicotinic transmission and the ratio of active MEN in stretched ganglia shifted towards a nitrergic phenotype. Conclusion and Inferences: The higher number of active MEN with increasing stretch of the ganglia and their greater share of nitrergic phenotype might indicate their contribution to the adaptive relaxation. Further experiments are necessary to address the receptors involved in mechanotransduction. [ABSTRACT FROM AUTHOR]

Guinea pigs in intensive production generates an imperative necessity of physio-pathological bases for diagnosing their state of welfare, health, and production; those which are available for this species are referred to as laboratory or companion animal. The aim of this research is to determine changes in hematological and blood metabolites profiles in relation to age of Cavia porcellus reared in intensive system at 660 masl in humid tropic. For this purpose, forty 15-120 days old guinea pig in healthy conditions from the inti x Peru lines born in the humid tropic were used and the evaluation ages were 15-21, 22-35, 36-60 and 61-120 days. Blood samples were obtained by puncture of the cephalic vein; profiles of erythrocytes (RBC), total leucocytes (WBC), lymphocytes, granulocytes, hematocrit, hemoglobin, MCV, MCH and MCHC indices were determined. In serum, profiles of glucose, total protein (TP), albumin, total cholesterol (TC), triglycerides, total bilirubin (TB), and direct bilirubin (DB), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined. Hemoglobin profile, MCH and MCHC indices increased as age increased (p < 0;05) and the erythrocytes, leucocytes, hematocrit, hemoglobin profiles and MCV, MCH, MCHC indices showed the narrower interval ranges in the 15-35- and 61-120-days old guinea pigs. Profiles of TP, DB and AST showed increase with age (p < 0;05) and the DB, AST, ALT, and TC profiles showed the narrower interval range at 36-120 days old. The hematological and blood metabolites profiles of guinea pigs raised in intensive system in humid tropical conditions show significant changes with production age. [ABSTRACT FROM AUTHOR]

Background: Preserving residual hearing after cochlear implant (CI) surgery remains a crucial challenge. The application of dexamethasone (DEX) has been proven to positively affect residual hearing. To deliver DEX in a localized and controlled way, a round window niche implant (RNI), allowing drug diffusion via the round window membrane into the cochlea, may be used. To prove this concept, an RNI for guinea pigs as a CI-trauma model was manufactured by molding and tested for its drug release in vitro and biological effects in vivo. Methods: The RNIs were molded using silicone containing 10% DEX. Release was analyzed over time using high-performance liquid chromatography (HPLC). Fourteen adult guinea pigs were randomly assigned to two groups (CI or CI + RNI group). All animals received a unilateral CI electrode insertion trauma followed by CI insertion. The CI + RNI group was additionally implanted with an RNI containing 10% DEX. Animals were followed up for 4 weeks. Acoustically evoked auditory brainstem response and impedance measurement, micro-computed tomography (µCT) imaging, and histology were performed for evaluation. Results: DEX was released for more than 250 days in vitro, with an initial burst followed by a slower release over time. Comparing the hearing threshold shift (from day 0 to day 28) of the CI and CI + RNI groups, significant differences were observed at 32 and 40 kHz. The impedance shift at basal contacts was lower in the CI + RNI group than in the CI group. Moreover, the fibrosis in the lower basal turn was reduced in the CI + RNI group in contrast to the CI group. Conclusions: The RNI containing 10% DEX has anti-inflammatory potential concerning fibrosis inhibition and has beneficial effects on hearing preservation at high frequencies. [ABSTRACT FROM AUTHOR]

There are four genogroups and 18 genotypes of human sapoviruses (HuSaVs) responsible for acute gastroenteritis. To comprehend their antigenic and virological differences, it is crucial to obtain viral stocks of the different strains. Previously, we utilized the human duodenum-derived cell line HuTu80, and glycocholate, a conjugated bile acid, to replicate and propagate GI.1, GI.2, and GII.3 HuSaVs (H. Takagi et al., Proc Natl Acad Sci U S A 117:32078–32085, 2020, https://10.1073/pnas.2007310117). First, we investigated the impact of HuTu80 passage number on HuSaV propagation. Second, we demonstrated that taurocholate improved the initial replication success rate and viral RNA levels in fecal specimens relative to glycocholate. By propagating 15 HuSaV genotypes (GI.1–7, GII.1–5, −8, and GV.1–2) and accomplishing preparation of viral stocks containing 1.0 × 109 to 3.4 × 1011 viral genomic copies/mL, we found that all strains required bile acids for replication, with GII.4 showing strict requirements for taurocholate. The deduced VP1 sequences of the viruses during the scale-up of serial passaged virus cultures were either identical or differed by only two amino acids from the original sequences in feces. In addition, we purified virions from nine strains of different genotypes and used them as immunogens for antiserum production. Enzyme-linked immunosorbent assays (ELISAs) using rabbit and guinea pig antisera for each of the 15 strains of different genotypes revealed distinct antigenicity among the propagating viruses across genogroups and differences between genotypes. Acquisition of biobanked viral resources and determination of key culture conditions will be valuable to gain insights into the common mechanisms of HuSaV infection. IMPORTANCE The control of human sapovirus, which causes acute gastroenteritis in individuals of all ages, is challenging because of its association with outbreaks similar to those caused by human norovirus. The establishment of conditions for efficient viral propagation of various viral strains is essential for understanding the infection mechanism and identifying potential control methods. In this study, two critical factors for human sapovirus propagation in a conventional human duodenal cell line were identified, and 15 strains of different genotypes that differed at the genetic and antigenic levels were isolated and used to prepare virus stocks. The preparation of virus stocks has not been successful for noroviruses, which belong to the same family as sapoviruses. Securing virus stocks of multiple human sapovirus strains represents a significant advance toward establishing a reliable experimental system that does not depend on limited virus-positive fecal material. [ABSTRACT FROM AUTHOR]

Pulmonary surfactant serves as a barrier to respiratory epithelium but can also regulate airway smooth muscle (ASM) tone. Surfactant (SF) relaxes contracted ASM, similar to β2‐agonists, anticholinergics, nitric oxide, and prostanoids. The exact mechanism of surfactant relaxation and whether surfactant relaxes hyperresponsive ASM remains unknown. Based on previous research, relaxation requires an intact epithelium and prostanoid synthesis. We sought to examine the mechanisms by which surfactant causes ASM relaxation. Organ bath measurements of isometric tension of ASM of guinea pigs in response to exogenous surfactant revealed that surfactant reduces tension of healthy and hyperresponsive tracheal tissue. The relaxant effect of surfactant was reduced if prostanoid synthesis was inhibited and/or if prostaglandin E2‐related EP2 receptors were antagonized. Atomic force microscopy revealed that human ASM cells stiffen during contraction and soften during relaxation. Surfactant softened ASM cells, similarly to the known bronchodilator prostaglandin E2 (PGE2) and the cell softening was abolished when EP4 receptors for PGE2 were antagonized. Elevated levels of PGE2 were found in cultures of normal human bronchial epithelial cells exposed to pulmonary surfactant. We conclude that prostaglandin E2 and its EP2 and EP4 receptors are likely involved in the relaxant effect of pulmonary surfactant in airways. [ABSTRACT FROM AUTHOR]

Trixacarus caviae is a sarcoptic mange mite infesting guinea pigs. Infestation in immunosuppressed animals produces severe dermatological problems, including alopecia, intense pruritus, hyperkeratosis and non‐dermatological issues (e.g., seizures). Treatment options are limited and include topical application of macrocyclic lactones or amitraz or injectable administration of ivermectin or doramectin. Considering the severity of the disease and the challenging treatment, the present paper aimed to determine the efficacy of oral afoxolaner in a severe case of infestation with T. caviae in a pet guinea pig. One female guinea pig was referred to the New Companion Animal Clinic due to severe dermatological problems. A clinical evaluation was done, and skin scrapings were collected and examined under the microscope. Small mites were detected and morphologically identified as T. caviae. The animal was treated with a single oral dose of 2.50 mg/kg afoxolaner, and the lesions, presence/absence of mites and intensity of pruritus were evaluated periodically until 2 months post‐treatment. A week after the medication, the lesions were milder, but pruritus was still present and was attributed to the healing process. Further examinations showed significant improvement with the complete remission of clinical signs and no mites at the microscopic examination after 4 weeks. Afoxolaner was safe and effective in this guinea pig for the treatment of T. caviae mange with no repetition needed. [ABSTRACT FROM AUTHOR]

Myopia represents a widespread global public health concern influenced by a combination of environmental and genetic factors. The prevailing theory explaining myopia development revolves around scleral extracellular matrix (ECM) remodeling, characterized by diminished Type I collagen (Col-1) synthesis and increased degradation, resulting in scleral thinning and eye axis elongation. Existing studies underscore the pivotal role of scleral hypoxia in myopic scleral remodeling. This study investigates the peroxidase-like activity and catalytic performance of octahedral Palladium (Pd) nanocrystals, recognized as nanozymes with antioxidative properties. We explore their potential in reducing oxidative stress and alleviating hypoxia in human scleral fibroblasts (HSF) and examine the associated molecular mechanisms. Our results demonstrate the significant peroxidase-like activity of Pd nanocrystals. Furthermore, we observe a substantial reduction in oxidative stress in HSF under hypoxia, mitigating cellular damage. These effects are linked to alterations in Nrf-2/Ho-1 expression, a pathway associated with hypoxic stress. Importantly, our findings indicate that Pd nanocrystals contribute to attenuated scleral matrix remodeling in myopic guinea pigs, effectively slowing myopia progression. This supports the hypothesis that Pd nanocrystals regulate myopia development by controlling oxidative stress associated with hypoxia. Based on these results, we propose that Pd nanocrystals represent a novel and potential treatment avenue for myopia through the modulation of scleral matrix remodeling. This study introduces innovative ideas and directions for the treatment and prevention of myopia. [Display omitted] • Pd nanocrystals exhibit peroxidase-like activity, modulating hypoxia in sclera. • Decreased oxidative stress in HSF linked to upregulated Nrf-2/Ho-1 pathway. • Pd treatment attenuates scleral ECM remodeling, slowing myopia progression. • In vivo study shows Pd reduces axial length, improves myopia in guinea pigs. • Potential novel therapeutic approach for myopia treatment via Pd nanocrystals. [ABSTRACT FROM AUTHOR]

Caseous lymphadenitis (CLA) is a chronic and subclinical bacterial disease of ruminants caused by Corynebacterium pseudotuberculosis (C. pseudotuberculosis) infection. Until 2014, there were no reports of CLA outbreaks in South Korea; however, the prevalence of CLA cases has steadily increased. In this study, we used recently obtained field isolates to develop the first inactivated CLA vaccine in South Korea and evaluated it in various animal models. The inactivated vaccine was evaluated for virulence and effectiveness. Mice were tested for virulence and immunization challenges, and guinea pigs and Korean Native Black Goats (KNBGs) evaluated various vaccine concentrations to determine the optimal dose and effectiveness. In the case of KNBGs, clinical symptoms were not observed after vaccination. In addition, CLA-specific IgG was detected at a significantly (p < 0.05) high level and was maintained. In histopathological evaluations, inflammation was predominantly observed in the prefemoral lymph nodes in the non-vaccinated+CHAL group. The genetic diversity of C. pseudotuberculosis, which has become widespread in South Korea, is less than 0.5% our vaccine is expected to prevent infection by a wide range of strains effectively. In summary, our CLA vaccine can potentially prevent CLA and foster the growth of South Korea's domestic KNBG industry. [ABSTRACT FROM AUTHOR]

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BACKGROUND: In Brugada syndrome (BrS), phase 2 re-excitation/re-entry (P2R) induced by the transient outward potassium current (Ito) is a proposed arrhythmia mechanism; yet, the most common genetic defects are loss-of-function sodium channel mutations. OBJECTIVES: The authors used computer simulations to investigate how sodium channel dysfunction affects P2R-mediated arrhythmogenesis in the presence and absence of Ito. METHODS: Computer simulations were carried out in 1-dimensional cables and 2-dimensional tissue using guinea pig and human ventricular action potential models. RESULTS: In the presence of Ito sufficient to generate robust P2R, reducing sodium current (INa) peak amplitude alone only slightly potentiated P2R. When INa inactivation kinetics were also altered to simulate reported effects of BrS mutations and sodium channel blockers, however, P2R occurred even in the absence of Ito. These effects could be potentiated by delaying L-type calcium channel activation or increasing ATP-sensitive potassium current, consistent with experimental and clinical findings. INa-mediated P2R also accounted for sex-related, day and night-related, and fever-related differences in arrhythmia risk in BrS patients. CONCLUSIONS: Altered INa kinetics synergize powerfully with reduced INa amplitude to promote P2R-induced arrhythmias in BrS in the absence of Ito, establishing a robust mechanistic link between altered INa kinetics and the P2R-mediated arrhythmia mechanism.

Abstract Background Guinea pigs exhibit numerous physiological similarities to humans, yet the details of their preimplantation embryonic development remain largely unexplored. Results To address this, we conducted single-cell sequencing on the transcriptomes of cells isolated from the zygote stage through preimplantation stages in guinea pigs. This study identified seven distinct cell types within guinea pig preimplantation embryos and pinpointed the timing of zygotic gene activation (ZGA). Trajectory analysis revealed a bifurcation into two lineage-specific branches, accompanied by alterations in specific pathways, including oxidative phosphorylation and vascular endothelial growth factor (VEGF). Additionally, co-expressed gene network analysis highlighted the most enriched functional modules for the epiblast (EPI), primitive endoderm (PrE), and inner cell mass (ICM). Finally, we compared the similarities and differences between human and guinea pig epiblasts (EPIs). Conclusion This study systematically constructs a cell atlas of guinea pig preimplantation embryonic development, offering fresh insights into mammalian embryonic development and providing alternative experimental models for studying human embryonic development.

The purpose of the research is to investigate subacute cutaneous toxicity in rats, allergenic properties in guinea pigs and tolerance of increased doses of drugs based on imidacloprid, moxidectin and pyriproxyfen by dogs and cats of different age groups.Materials and methods. Toxicological studies (subacute cutaneous toxicity, study of allergenic properties) were conducted in the vivarium of the All-Russian Research Institute of Plant Protection, a branch of the Federal Scientific Center for Experimental Veterinary Medicine of the Russian Academy of Sciences, on male rats and guinea pigs. Experiments on the tolerance of drugs by target animal species (dogs, cats) were conducted in the Podolsk department of the All-Russian Research Institute of Plant Protection. The choice of doses, frequency and methods of administration of the studied drugs were determined in accordance with the Guidelines for Experimental (Preclinical) Study of New Pharmacological Substances. All doses were calculated for the drug taking into account the density (1.08 g/cm3).Results and discussion. When studying the acute cutaneous toxicity of the drug on rats, LD50 exceeded the maximum possible dose of 10 000 mg/kg (hazard class 4 according to GOST 12.1.007-76). In a subacute experiment on rats, it was established that doses of 1000 and 500 mg/kg are ineffective (safe), the threshold and toxic doses could not be established. These drugs, when treating animals 8 times with an interval of 3 days in a three- and five-fold increase in the maximum therapeutic dose during the experimental period, did not have a negative effect on the general condition of the animals, their physiological status and behavior; no statistically significant changes in the morphological and biochemical parameters of the blood, physicochemical parameters of urine were noted in animals from the experimental groups compared to the control. However, in one adult dog from the second experimental group, which was used a five-fold increase in the maximum therapeutic dose of the drug, depression was noted on the 20th day of the experiment. The physiological state of the animal returned to normal within 24 hours voluntarily without the use of symptomatic therapy.

The purpose of the research is to evaluate some toxicological parameters of antiparasitic selamectin-based drug.Materials and methods. The study drug is a solution for external use, 1 mL of which contains the active component selamectin (120 mg), as well as additives. The experiments used a total of 66 white outbred male rats, 42 white outbred male mice and 3 guinea pigs. The parameters of acute oral toxicity (in mice and rats), acute dermal toxicity (in rats), and dermal and mucous membrane irritation (in rats and guinea pigs) of antiparasitic selamectin-based drug were evaluated. LD50 was calculated and the irritation of the drug was evaluated using established procedures in toxicology.Results and discussion. The maximum tolerated dose of the selamectin-based drug was 2550 mg/kg in the mice and 4250 mg/kg in the rats. The absolutely lethal dose for the mice and the rats was 6800 and 8500 mg/kg, respectively. It was established that the drug belonged to hazard class 3 (moderately hazardous substances) when administered intragastrically to the animals: LD50 for the mice was 4816.7 mg/kg, and LD50 for the rats was 6091.7 mg/kg. In determining acute dermal toxicity in the rats, the drug was classified as hazard class 4 (low-hazardous substances): LD50 more than 8500 mg/kg. The drug irritant effect on the skin of the rats at doses of 4250, 6375 and 8500 mg/kg was not established. The drug had a mild effect on the mucous membrane of the eyes of the guinea pigs with its recovery to normal within 24 hours.

PURPOSE: We previously reported differential gene expression of the bone morphogenetic protein 2 (Bmp2) in guinea pig retinal pigment epithelium (RPE) after 1 day of hyperopic defocus, imposed with a negative contact lens (CLs). The study reported here sought to obtain insights into the temporal profiles of gene expression changes in Bmp2, as well as those of two closely related genes, the inhibitor of DNA binding 3 (Id3) and Noggin (Nog), both during myopia induction and when the CL treatment was terminated to allow recovery from induced myopia. METHODS: To induce myopia, 2-week-old pigmented guinea pigs (New Zealand strain, n = 8) wore monocular -10 diopter (D) rigid gas-permeable (RGP) CLs for one week, while the other eye served as a control. Ocular measurements were made at baseline, 3 days, and 7 days after the initiation of CL wear, with treatment then being terminated and additional measurements being made after a further 3 days, 1 week, and 2 weeks. Spherical equivalent refractive errors (SERs), axial length (AL), choroidal thickness (ChT), and scleral thickness (ScT) data were collected using retinoscopy, optical biometry (Lenstar), and spectral domain optical coherence tomography (SD-OCT), respectively. RPE samples were collected from both eyes of the guinea pigs after either 1 day or 1 week of CL wear or 1 day or 2 weeks after its termination, and RNA was subsequently isolated and subjected to quantitative real-time PCR (qRT-PCR) analyses, targeting the Bmp2, Id3, and Nog genes. RESULTS: Mean interocular differences (treated-control) in AL and SER were significantly different from baseline after 3 and 7 days of CL wear, consistent with induced myopia (p < 0.001 for all cases). Termination of CL wear resulted in the normalization (i.e., recovery) of the ALs and SERs of the treated eyes within 7 days, and the earlier significant ChT thinning with CL wear (p = 0004, day 7) was replaced by rapid thickening, which remained significant on day 7 (p = 0.009) but had normalized by day 14. The ChT changes were much smaller in magnitude than the AL changes in both phases. Interocular differences in the ScT showed no significant changes. The Bmp2 and Id3 genes were both significantly downregulated with CL wear, after 1 day (p = 0.012 and 0.016) and 7 days (p = 0.002 and 0.005), while Bmp2 gene expression increased and Nog gene expression decreased after the termination of CL wear, albeit transiently, which was significant on 1 day (p = 0.004 and 0.04) but not 2 weeks later. No change in Id3 gene expression was observed over the latter period. Conclusions: The above patterns of myopia induction and recovery validate this negative RGP-CL model as an alternative to traditional spectacle lens models for guinea pigs. The defocus-driven, sign-dependent changes in the expression of the Bmp2 gene in guinea pig RPE are consistent with observations in chicks and demonstrate the important role of BMP2 in eye growth regulation.

BACKGROUND: Our previous studies have found that poly(vinylidene fluoride) bionic periosteum prepared by electrospinning has good cytocompatibility, but its biocompatibility is unknown. OBJECTIVE: To evaluate the biocompatibility of poly(vinylidene fluoride) bionic periosteum doped with Zn2+ and Mg2+. METHODS: Poly(vinylidene fluoride), poly(vinylidene fluoride) bionic periosteum doped with 1% Zn2+, doped with 1% Mg2+, and doped with 1% (Zn2++Mg2+) were prepared by electrospinning to make bionic periosteum extract. SD rats were selected as the experimental subjects for hemolysis test, short-term systemic toxicity test, and heat source test. Guinea pigs were selected as the experimental subjects for skin sensitization test. The biocompatibility of bionic periosteum of four groups was tested. RESULTS AND CONCLUSION: (1) The hemolysis test results showed that the hemolysis rates of 1% Zn2+ poly(vinylidene fluoride), 1% Mg2+ poly (vinylidene fluoride), 1% Zn2++1% Mg2+ poly(vinylidene fluoride) bionic periosteum and poly(vinylidene fluoride) extract were (0.130±0.013)%, (0.149±0.020)%, (0.466±0.018)%, and (0.037±0.018)%, respectively, which met the hemocompatibility standard of biomaterials. (2) The results of short-term systemic toxicity test showed that the four groups of bionic periosteal extract had no toxic signs such as body mass reduction, food intake changes, and dyspnea in SD rats, and had no toxic effects on major organs of rats. (3) Heat source test results showed that after intervention with poly(vinylidene fluoride) bionic periosteum doped with 1% Zn2+, doped with 1% Mg2+, and doped with 1% (Zn2++Mg2+), and poly(vinylidene fluoride) bionic periosteum extract, the elevated body temperature values of SD rats were (0.133±0.058), (0.100±0.010), (0.300±0.010), and (0.300±0.017)°C, respectively. All were less than 0.6 °C, and the total temperature increase was less than 1.4*#176;C. (4) The results of skin sensitization test showed that no erythema or edema was observed under the skin of guinea pigs after the intervention of bionic periosteum extract of four groups. (5) The results showed that poly(vinylidene fluoride) and poly(vinylidene fluoride) bionic periosteum doped with Zn2+ and Mg2+ had good biocompatibility. [ABSTRACT FROM AUTHOR]

The Asian tiger mosquito, Aedes albopictus (Skuse) (Diptera: Culicidae), is a global vector of dengue, chikungunya and zika viruses. With extreme adaptability of survival as diapause eggs, this mosquito has invaded and established in temperate climatic zones. The diapause eggs are specially programmed to overcome the harsh winter conditions in temperate habitats. In the laboratory, diapausing females are reared from early larval instars under short‐day conditions (21°C and 16D:8 L photoperiods). Aedes albopictus is normally fed on Guinea pigs for the rearing of diapause mosquitoes which requires ethical approval from the animal use committee and costly arrangements. Therefore, the present study was conducted to find whether bovine serum albumin protein (10%) with sucrose (5%) solution (SAP‐10) offered through a membrane‐free feeding system would result in an alternative diet for the production of diapause eggs in comparison to blood‐feeding. This feeding system shows a considerable rate of engorgement of diapausing females under short‐day conditions and produced 30.8 diapause eggs/female in comparison to blood‐feeding on a guinea pig (40.9 eggs/female). The diapause rate of viable eggs for the SAP‐10 diet (95.28%) was similar to the blood‐feeding (96.32%). The findings suggest that the present diet feeding system is a promising tool for the rearing of diapause Ae. albopictus mosquitoes under short‐day conditions. Further studies are suggested to evaluate the physiological and developmental aspects of mosquitoes reared on the diet. [ABSTRACT FROM AUTHOR]

An individual's energetic demands and hence metabolic rate can strongly change during adolescence, a phase characterized by profound morphological, physiological, and endocrine changes. Glucocorticoid hormones (e.g. cortisol) are released in response to hypothalamic–pituitary–adrenal–axis activity, modulate several metabolic processes, and can also be linked to increased metabolic rate. In domestic guinea pigs (Cavia aperea f. porcellus) housed in same-sex groups, cortisol concentrations increase during adolescence in males but remain stable in females, which was suggested to be related to different energetic demands by age. We therefore measured metabolic rate through oxygen (O2) consumption over 2.5 h in male and female guinea pigs housed in same-sex groups during adolescence at ages of 60, 120, and 180 days, which was paralleled by analyses of saliva cortisol concentrations before and after the measurement. The statistical analyses involved whole body metabolic rate (ml O2/h), body mass-corrected metabolic rate (ml O2/h/kg), and body mass-independent metabolic rate (ml O2/h statistically corrected for body mass). We found increasing cortisol concentrations with age in males only, but none of the three metabolic rate analyses revealed a sex difference by age. On the individual level, repeatability across ages was found in metabolic rate as well as in body mass and cortisol concentrations after the measurement, but not in "basal" cortisol concentrations. Our results suggest no sex-specific changes in metabolic rate and hence equal energetic demands in male and female guinea pigs during adolescence. Moreover, metabolic rate clearly represents a highly stable physiological trait already early in a guinea pig's life irrespective of rather fluctuating cortisol concentrations. [ABSTRACT FROM AUTHOR]

In the absence of local studies, the current study was conducted in four villages located in the province of Cajabamba (Cajamarca, Peru) to demonstrate and determine the point prevalence of enteric nematodes in guinea pigs (Cavia porcellus) raised in a family-commercial breeding system. A total of 384 faecal samples were collected from guinea pigs and processed using the Sheather Sugar method. The eggs of P. uncinata, Trichuris spp., and Capillaria spp. were identified in guinea pigs from all four villages, resulting in an overall prevalence of 66.15±4.73%. Among the villages, the highest prevalence was observed in Naranjos, with a prevalence of 78.16±8.68% (68 out of 87 guinea pigs). This was followed by Malcas with a prevalence of 67.24±8.54% (78 out of 116 guinea pigs), Ogosgón-Paucamonte with a prevalence of 64.08±9.27% (66 out of 103 guinea pigs), and La Esperanza with a prevalence of 53.85±11.06% (42 out of 78 guinea pigs). Furthermore, it was found that 66.54±5.80% of guinea pigs had a single nematode, 28.35±5.54% had two nematodes, and 5.12±2.71% had three nematodes. Thus, the presence of enteric nematodes in guinea pigs raised in a family-commercial breeding system from four villages in the Cajabamba district was established. [ABSTRACT FROM AUTHOR]

AIM: To avoid the problem of retinal dissection in guinea pig large eyeball tissue sections, different methods were used to optimize the fixation effect of the posterior pole of the eyeball.METHODS: A total of 75 normal guinea pigs(2 weeks old)were randomly divided into 5 large groups. Group A(1-3 small groups), the entire eyeball was fixed with FAS, Davidson fixative 1(D1), and Davidson fixative 2(D2)for 24 h; group B(4-6 small groups), the entire eyeball was fixed with FAS, D1, and D2 for 1 h, then cut the cornea and fix it in their respective fixatives for 2 h; group C(7-9 small groups), the eyeball was fixed in FAS, D1, and D2 for 1 h, divided into left and right halves along the direction of the optic nerve, and then placed them in their respective fixation solutions for 2 h; group D(10-12 small groups), after fixation for 3 h in FAS, D1, and D2, the eyeball was divided into left and right halves along the optic nerve direction; group E(13-15 small groups), the cornea was cut after fixation for 3 h in FAS, D1, and D2. Hematoxylin-eosin(HE)staining was used to compare the fixation effect on posterior eyeball in each group.RESULTS: After fixation, the surface of the eyeballs in groups, 1-6 and 11-15 was smooth and round, with a transparent and bright color. In groups 7-10, the eyeballs were sunken, wrinkled, and deformed. The HE staining showed that the eyeball morphology of groups 1, 5, 6, 14, and 15 was significantly better than the other groups, with a regular internal tissue structure. The eyeballs of the other groups were sunken and wrinkled, and the internal tissue was curled and tangled, with severe retinal detachment. In groups 1, 5, 6, 14, and 15, the retina, choroid, and sclera tissues of group 14 were closely connected, without obvious retinal detachment, rupture, or curling. The tissue structure was clear and visible, and the cells were arranged neatly.CONCLUSION: The fixation effect of cutting the cornea after fixing guinea pig eyeball with D1 fixative for 3 h is the most ideal, and this operation method is simple and suitable for studying the related structures of the posterior pole of the eye.

Introduction: Obesity and overweight are major global health challenges. One of the bad effects of noise that has been recently expressed is the effect of noise on obesity. This study aimed to investigate the effect of high-frequency noise exposure on obesity, food intake, and abdominal visceral fat in adult male guinea pigs. Material and Methods: The animals in this study were 24 adult male guinea pigs randomly divided into 3 groups (control and two case groups). Each case group was separately exposed to high- frequency white noise with sound pressure levels in 65 dB and 85 dB for 5 days per week in 30 days. The food intake was measured daily. The weight of animals was measured at the start and on days 6, 12, 18, 24, and at the end of exposure period. The abdominal visceral fat was extracted and weighted at the end of the study period. The data were assessed using SPSS V.22 software. Results: ANOVA analysis showed that exposure to high-frequency noise at 65dB and 85dB had a significant effect on weight gain, food intake, and abdominal visceral fat weight (P-value< 0.05) which in the group exposed to the noise with 65 dB was more than other groups. Conclusion: Based on this study, exposure to high-frequency noise may be an effective factor in obesity and increasing abdominal visceral fat. Further studies are needed to investigate the mechanism affecting weight status following noise exposure.

The paper reports on the research into the immunotherapeutic properties of a conjugate based on BCG antigens with betulonic acid after experimental infection of guinea pigs with Mycobacterium scrofulaceum culture, belonging to nontuberculosis mycobacteria type II according to the Runyon classification. Fifteen guinea pigs were used for the experimental purposes, divided into 3 groups. Mycobacterium scrofulaceum was subcutaneously injected into animals of Groups 1 and 2 (n = 10) at a dose of 5 mg. Fourteen days later, a conjugate based on BCG antigens with betulonic acid was subcutaneously injected into animals of Group 2 (n = 5) at a dose of 500 µg/mL of protein. Five intact animals were used as controls. During the experiment, neutrophil bactericidal activity was assessed, and histopathological examination of inguinal lymph nodes was done. The experiment showed that the inoculation of Mycobacterium scrofulaceum into guinea pigs activates cationic proteins and neutrophil myeloperoxidase, and on experiment day 42 (preceded by mycobacteria withdrawal from the body) their concentration reduced to the level of the control group. The vaccine administration induced a more active intracellular phagocyte metabolism during the entire observation period, which resulted in the elimination of nontuberculosis mycobacteria in animals as early as day 7 after treatment with the conjugate. The elimination was confirmed by the absence of mycobacterial antigen in blood smears tested in indirect immunofluorescence, as well as by histopathological changes in inguinal lymph nodes demonstrated as a reduction of germinal centers within lymphoid follicles.

ABSTRACT: A study was undertaken to evaluate the skin sensitization and acute dermal irritation of Mesoporous antibacterial bioactive glass microsphere impregnated non-woven surgical cotton gauze (MABGmscg) dressings on shaved rabbits and guinea pigs. This study complied with guidelines 404 and 406 of the Organization for Economic Co-operation and Development (OECD). In the dermal irritation test, three different MABGmscg dressings were applied to the shaved skin of rabbits at three separate sites for four hours. The results demonstrated that the dressings did not cause unfavorable reactions, such as inflammation, erythema, or edema, on the unbroken skin of rabbits. As a result, MABGmscg dressing material was considered practically non-irritating based on its rating of primary irritation index. In the case of the Buehler test, three different doses of the MABG (mscg dressing) were used to initially sensitize the guinea pigs. They were later challenged at different sites with patches applied for 24 hours. The MABG dressing patches did not trigger any skin reactions when tested with various doses of the MABG (mscg dressing). These findings collectively indicate that the MABGmscg dressing did not induce any skin irritation or sensitization upon direct skin application in laboratory animals.

Remdesivir (RDV) is the first drug approved by the FDA for clinical treatment of hospitalized patients infected with COVID-19 because it has been shown to have good antiviral activity against a variety of viruses, including Arenaviridae and Coronaviridae viral families. However, it has been reported that its clinical treatment leads to the symptoms of sick sinus syndrome such as sinus bradycardia, conduction block, and sinus arrest, but the electrophysiological mechanism of its specific cardiac adverse events is still unclear. We report complementary, experimental, studies of its electrophysiological effects. In wireless cardiac telemetry experiments in vivo and electrocardiographic studies in ex vivo cardiac preparations, RDV significantly caused sinus bradycardia, sinus atrial block, and prolongation of the QT interval in guinea pigs. Dose-dependent effects of RDV on the electrical activities of sinoatrial node (SA node) preparations of guinea pigs were characterised by multielectrode, optical RH237 voltage mapping. These revealed reversibly reduced sinoatrial conduction time (SACT), increased AP durations (APDs), and decreased the pacemaking rate of the SA node. Patch-clamp experiments showed that RDV significantly inhibited the If current of HCN4 channels, resulting in a significant decrease in the spontaneous firing rate of SA node cells, which may underlie the development of sick sinus node syndrome. In addition, RDV significantly inhibits IKr currents in hERG channels, leading to prolongation of the QT interval and playing a role in bradycardia. Therefore, these findings provide insights into the understanding the bradycardia effect of RDV, which may be used as basic theoretical guidance for the intervention of its adverse events, and prompt safety investigations of RDV's cardiac safety in the future. [ABSTRACT FROM AUTHOR]

Rodent models of tinnitus are commonly used to study its mechanisms and potential treatments. Tinnitus can be identified by changes in the gap-induced prepulse inhibition of the acoustic startle (GPIAS), most commonly by using pressure detectors to measure the whole-body startle (WBS). Unfortunately, the WBS habituates quickly, the measuring system can introduce mechanical oscillations and the response shows considerable variability. We have instead used a motion tracking system to measure the localized motion of small reflective markers in response to an acoustic startle reflex in guinea pigs and mice. For guinea pigs, the pinna had the largest responses both in terms of displacement between pairs of markers and in terms of the speed of the reflex movement. Smaller, but still reliable responses were observed with markers on the thorax, abdomen and back. The peak speed of the pinna reflex was the most sensitive measure for calculating GPIAS in the guinea pig. Recording the pinna reflex in mice proved impractical due to removal of the markers during grooming. However, recordings from their back and tail allowed us to measure the peak speed and the twitch amplitude (area under curve) of reflex responses and both analysis methods showed robust GPIAS. When mice were administered high doses of sodium salicylate, which induces tinnitus in humans, there was a significant reduction in GPIAS, consistent with the presence of tinnitus. Thus, measurement of the peak speed or twitch amplitude of pinna, back and tail markers provides a reliable assessment of tinnitus in rodents. [ABSTRACT FROM AUTHOR]

The aim of this study is to evaluate the cell responses, potential skin reactions during the treatment process and burn wound healing efficacy of electrospun polycaprolactone/polyethylene oxide (PCL/PEO) nanofibers (NFs) containing Centella asiatica mediated synthesized silver nanoparticles (CA‐AgNPs) by in vitro and in vivo studies. Apoptosis‐necrosis, genotoxicity, hemolysis, and cell attachment studies are carried out within the scope of in vitro tests, and irritation, sensitivity, and burn wound studies are carried out within the scope of in vivo tests. The apoptotic index value of CA‐AgNPs‐[PCL/PEO] NFs material on L929 fibroblast cells is determined as 5.0 ± 1.0% at the highest concentration and the necrotic index value is 5.0 ± 0.3%. Micronucleus rates (%) of NFs treated with CHO (Chinese Hamster Ovary) cells are not at genotoxic level. The hemolytic index value of NFs dressing is determined as 0.23 ± 0.03%, The primary irritation index (PII) value of NFs wound dressing is calculated as 0.36 by irritation tests. In addition, the potential sensitization reaction of NFs extract on guinea pigs is evaluated and the sensitization score is determined as 0.9. The healing efficacy of NFs material on second‐degree burn wounds compared to a commercial product is supported by pathomorphological findings. [ABSTRACT FROM AUTHOR]