Biology and postnatal development of organ systems of cynomolgus monkeys (Macaca fascicularis).

BACKGROUND: The cynomolgus macaque has become the most used non-human primate species in nonclinical safety assessment during the past decades. METHODS: This review summarizes the biological data and organ system development milestones of the cynomolgus macaque available in the literature. RESULTS: The cynomolgus macaque is born precocious relative to humans in some organ systems (e.g., nervous, skeletal, respiratory, and gastrointestinal). Organ systems develop, refine, and expand at different rates after birth. In general, the respiratory, gastrointestinal, renal, and hematopoietic systems mature at approximately 3 years of age. The female reproductive, cardiovascular and hepatobiliary systems mature at approximately 4 years of age. The central nervous, skeletal, immune, male reproductive, and endocrine systems complete their development at approximately 5 to 9 years of age. CONCLUSIONS: The cynomolgus macaque has no meaningful developmental differences in critical organ systems between 2 and 3 years of age for use in nonclinical safety assessment.

Accelerating Global Deletion of the Abnormal Toxicity Test for vaccines and biologicals. Planning common next steps. A workshop Report.

This online workshop Accelerating Global Deletion of the Abnormal Toxicity Test for vaccines and biologicals. Planning common next steps was organized on October 14th, 2021, by the Animal Free Safety Assessment Collaboration (AFSA), the Humane Society International (HSI), the European Federation of Pharmaceutical Industries and Associations (EFPIA), in collaboration with the International Alliance of Biological Standardization (IABS). The workshop saw a participation of over a hundred representatives from international organizations, pharmaceutical industries and associations, and regulatory authorities of 28 countries. Participants reported on country- and region-specific regulatory requirements and, where present, on the perspectives on the waiving and elimination of the Abnormal Toxicity Test. With AFSA, HSI, EFPIA and IABS representatives as facilitators, the participants also discussed specific country/global actions to further secure the deletion of ATT from all regulatory requirements worldwide.

Age- and sex-related changes in body weights and clinical pathology analytes in cynomolgus monkeys (Macaca Fascicularis) of Mauritius origin.

BACKGROUND: Clinical pathology and body weight information for the cynomolgus monkey in the literature is primarily derived from a small number of animals with limited age ranges, varying geographic origins, and mixed genders. OBJECTIVES: This study aimed to summarize the age- and sex-related changes in clinical pathology analytes and body weights in cynomolgus monkeys of Mauritian origin. METHODS: Pre-study age and body weight data were reviewed in 1819 animals, and pre-study hematologic, coagulation, and serum biochemical analytes were reviewed in 1664 animals. RESULTS: Body weights were statistically higher (P < 0.01) in males than females in all age groups (2-10 years). These measurements became prominent after 4 years of age and peaked at 7 to 8 years of age in both sexes. Sex-related differences were noted in reticulocyte (RETIC) counts, creatinine, cholesterol, and triglyceride concentrations, and alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) activities. Age-related differences were noted in RETIC and lymphocyte counts, creatinine, triglyceride, phosphorus, and globulin concentrations, and ALP and GGT activities. The youngest (2 to <3 year) age group had the fewest number of clinical pathologic analyte differences including ALP and GGT activity differences which occurred in all age groups from 2 to 10 years; they also had age-related lower globulin concentrations. There were no age- or sex-related differences in coagulation measurands. CONCLUSIONS: Sexual dimorphism in body weight was apparent for all ages from 2 to 10 years of age. The only difference in clinical pathology analytes unique to the 2 to <3 years of age group were age-related lower globulin levels.

Combining Three Mapping Strategies to Reveal Quantitative Trait Loci and Candidate Genes for Maize Ear Length.

Ear length (EL) is an important trait in maize ( L.) because it is positively correlated with grain yield. To understand the genetic basis of natural EL variation, a F, a four-way cross and a genome-wide association study (GWAS) population were used to identify the quantitative trait loci (QTLs) and candidate EL genes. Linkage mapping identified 14 QTLs in two types of populations from multiple environments. Six of them were located in three common genomic regions considered "stable QTLs". Candidate genes for the three stable QTLs were identified by the GWAS results. These were related to auxin transport, cell proliferation, and developmental regulation. These results confirm that maize EL is under strong genetic control by many small-effect genes. They also improve our understanding of the genetic basis of maize EL.

The Genetic Basis of Natural Variation in Kernel Size and Related Traits Using a Four-Way Cross Population in Maize.

Kernel size is an important component of grain yield in maize breeding programs. To extend the understanding on the genetic basis of kernel size traits (i.e., kernel length, kernel width and kernel thickness), we developed a set of four-way cross mapping population derived from four maize inbred lines with varied kernel sizes. In the present study, we investigated the genetic basis of natural variation in seed size and other components of maize yield (e.g., hundred kernel weight, number of rows per ear, number of kernels per row). In total, ten QTL affecting kernel size were identified, three of which (two for kernel length and one for kernel width) had stable expression in other components of maize yield. The possible genetic mechanism behind the trade-off of kernel size and yield components was discussed.

Genomic Dissection of Leaf Angle in Maize (Zea mays L.) Using a Four-Way Cross Mapping Population.

Increasing grain yield by the selection for optimal plant architecture has been the key focus in modern maize breeding. As a result, leaf angle, an important determinant of plant architecture, has been significantly improved to adapt to the ever-increasing plant density in maize production over the past several decades. To extend our understanding on the genetic mechanisms of leaf angle in maize, we developed the first four-way cross mapping population, consisting of 277 lines derived from four maize inbred lines with varied leaf angles. The four-way cross mapping population together with the four parental lines were evaluated for leaf angle in two environments. In this study, we reported linkage maps built in the population and quantitative trait loci (QTL) on leaf angle detected by inclusive composite interval mapping (ICIM). ICIM applies a two-step strategy to effectively separate the cofactor selection from the interval mapping, which controls the background additive and dominant effects at the same time. A total of 14 leaf angle QTL were identified, four of which were further validated in near-isogenic lines (NILs). Seven of the 14 leaf angle QTL were found to overlap with the published leaf angle QTL or genes, and the remaining QTL were unique to the four-way population. This study represents the first example of QTL mapping using a four-way cross population in maize, and demonstrates that the use of specially designed four-way cross is effective in uncovering the basis of complex and polygenetic trait like leaf angle in maize.

Morphogenesis of postmortem hepatocyte vacuolation and liver weight increases in Sprague-Dawley rats.

Accurate interpretation of microscopic changes in tissues is critical in hazard identification and risk assessment. To address a possible confounder, the effects of postmortem interval on hepatocyte vacuolation and liver weight were studied in fasted and nonfasted Sprague-Dawley rats. Male and female rats (5/sex/interval) were euthanized with CO2, weighed, and necropsied either immediately or after remaining in the closed CO2 chamber for 5, 10, or 25 minutes after respirations ceased. The liver was removed, weighed, and fixed for light microscopy, immunohistochemistry, and electron microscopy. The liver weight and liver to body weight ratio increased significantly in both male and female rats. Postmortem hepatocellular vacuolation was more prominent in males than in females. Both fasted and nonfasted males were similarly affected, however, fasted females were affected more than nonfasted females at the 25-minute interval. Ultrastructurally, intracytoplasmic vacuoles in hepatocytes and/or endothelial cells contained electron-lucent material that was morphologically similar to plasma in sinusoidal spaces. Results of our study suggest that hepatocyte vacuoles were formed in a postmortem time-dependent manner as a result of plasma influx into the cytoplasm. This change was associated with hepatic sinusoidal congestion and increases in liver weight. Males were more sensitive than females to postmortem hepatocyte vacuolation.

Epidermotropic Lymphoma (Mycosis Fungoides) in an ICR Mouse.

A case of epidermotropic lymphoma with systemic spread into lymph nodes and visceral organs was observed in a 7- to 8-month-old, female ICR mouse. The mouse developed progressive and generalized alopecia and lymphadenopathy of several weeks' duration. The affected skin was markedly and diffusely thickened, with multiple serous to hemorrhagic crusts, ulcerated plaques, and raised nodules. Microscopically, random and/or perivascular infiltration of pleomorphic lymphoid cells was present in the skin, lymph nodes, thymus, spleen, lungs, and liver. On cytologic examination, the lymphoid cells were similar in all affected tissues, and had hyperchromatic and irregularly oval, cleaved, and occasionally convoluted nuclei, approximately 6 to 9 mm in diameter. On immunohistochemical examination, most infiltrating cells were labeled with anti-CD3 (panT cell) antibody. A smaller proportion of the cells (, 5%) were labeled with anti-CD79a (panB cell) antibody.

Oropharyngeal Necrobacillosis with Septic Thrombophlebitis and Pulmonary Embolic Abscesses: Lemierre's Syndrome in a New Zealand White Rabbit.

Lemierre's syndrome, oropharyngeal infections induced by anaerobic bacteria, leading to fatal septic thrombophlebitis of the internal jugular vein and pulmonary embolic abscesses in humans, was diagnosed in a 6-month-old, male, New Zealand White rabbit. After acute onset of anorexia, lethargy, and depression, the rabbit died suddenly despite emergency clinical care. Necropsy revealed swelling, necrosis, and abscess in the soft tissues around the left caudal mandibular ramus, oral mucosa, and molar teeth, with systemic embolic abscesses and necrosis, especially in the jugular vein, lungs, and brain. Histologic examination revealed necrosis and embolic abscesses with filamentous bacteria in the mandibular soft tissues, salivary gland, jugular veins, alveolar bone and marrow, periodontal tissues and dental pulp, oral and pharyngeal mucosa, lungs, brain, liver, myocardium, meninges, and small intestine. Bacterial culture of the mandibular abscess and heart blood yielded Fusobacterium necrophorum.

Bulbourethral Gland Cysts in Three Mice.

Diseases of bulbourethral glands have rarely been reported in mice. The present report describes bulbourethral gland cysts in three male mice: a.1yearold DBA/2J mouse (case 1), a 10monthold nude mouse (case 2), and a 4.5monthold chimeric mouse (case 3). Round to oval fluctuant nodules were observed on their dorsal perineum. The nodules in cases 1 and 2 were pale, pink to tan, soft, and glistening; in case 3, the mass was purple-red and soft. All nodules were located subcutaneously between the bulbospongiosus and ischiocavernous muscles, with a deep connection to the urethra. The nodules were 13 mm (case 1), 6 mm (case 2), and 8 mm (case 3) in diameter. The cut surface of the nodules was cystic; the lumina were filled with clear gelatinous or viscous (cases 1 and 2) or thin blood-tinged fluid (case 3). The nodules comprised irregular cysts and acini that were lined by a single layer of cuboidal, pyramidal to tall columnar epithelial cells with little stroma. Bulbourethral gland cysts should be included as differential diagnoses for perineal nodules or swellings in mice.

Renal Cell Carcinoma in Two Siberian Hamsters (Phodopus sungorus).

Renal cell carcinoma was diagnosed in 2 Siberian hamsters (Phodopus sungorus). One hamster had a unilateral solitary papillary-tubular carcinoma. The other hamster had a clear-cell, a papillary-tubular, and mixed types of carcinomas in the left kidney and a cystic-papillary-tubular type of carcinoma in the right kidney. In the papillary-tubular carcinoma. there were cuboidal to columnar cells arranged in tubular or papillary patterns supported by delicate fibrous stroma. Nuclei were located basally, often perpendicular to the subjacent basement membrane. Cytoplasm was pale to eosinophilic and variably abundant. Pleomorphic oval to polygonal cells found in the clear-cell carcinoma were arranged in broad trabeculae, lobules, or nests, with congested capillary stroma and multifocal necrosis. Cytoplasm varied from eosinophilic and granular to pale and clear or vacuolated. In the cystic-papillary-tubular carcinoma, cuboidal to columnar cells were arranged in cystic, papillary, or tubular patterns. Cysts varied in size and shape and contained secretory material and erythrocytes.