Tyler D. Ames

The first objective of this study was to describe the effect of on-farm heat treatment of colostrum on colostral bacteria counts and IgG concentrations. The second objective was to describe the effect of feeding heat-treated (vs. raw) colostrum on passive transfer of colostral immune and nutritional parameters in neonatal calves. Pooled batches of colostrum were mixed and divided equally: one half was fed raw whereas the other half was fed after heat treatment at 60 degrees C for 60 min using a commercial on-farm batch pasteurizer. Colostrum samples were cultured for total bacteria count and total coliform count and analyzed for total IgG concentration. Forty-nine Holstein calves were fed either raw colostrum (n = 24) or heat-treated colostrums (n = 25) within 1 to 2 h after birth. Serum samples collected from calves at 0 h (precolostrum) and 24 h (postcolostrum) were assayed for serum total protein; IgG, IgA, and IgM concentrations; peripheral total leukocyte counts; neutrophil counts; lymphocyte counts; lymphocyte phenotypes; vitamin A, vitamin E, cholesterol, and beta-carotene concentrations. Serum samples collected from 2- to 5-d-old calves were tested for immunoglobulin function via a bovine viral diarrhea virus type I serum neutralization titer and for neutrophil bacterial opsonization activity. On-farm batch heat treatment of colostrum at 60 degrees C for 60 min resulted in lower colostrum bacteria concentrations while maintaining colostral IgG concentration. Calves fed heat-treated colostrum had significantly greater serum total protein and IgG concentrations at 24 h, plus greater apparent efficiency of IgG absorption (total protein = 6.3 mg/dL; IgG = 22.3 mg/mL; apparent efficiency of absorption = 35.6%) compared with calves fed raw colostrum (TP = 5.9 mg/dL; IgG = 18.1 mg/mL; apparent efficiency of absorption = 26.1%). There was no effect of treatment on serum concentrations of IgA, IgM, vitamin A, vitamin E, cholesterol, beta-carotene or vitamin E:cholesterol ratio, or on serum bovine viral diarrhea virus type I serum neutralization titers. There was no difference between treatment groups when examining calf plasma total leukocyte counts, neutrophil counts, lymphocyte counts, or neutrophil opsonization activity. However, the latter results were considered inconclusive.

The discovery of structured non-coding RNAs (ncRNAs) in bacteria can reveal new facets of biology and biochemistry. Comparative genomics analyses executed by powerful computer algorithms have successfully been used to uncover many novel bacterial ncRNA classes in recent years. However, this general search strategy favors the discovery of more common ncRNA classes, whereas progressively rarer classes are correspondingly more difficult to identify. In the current study, we confront this problem by devising several methods to select subsets of intergenic regions that can concentrate these rare RNA classes, thereby increasing the probability that comparative sequence analysis approaches will reveal their existence. By implementing these methods, we discovered 224 novel ncRNA classes, which include ROOL RNA, an RNA class averaging 581 nt and present in multiple phyla, several highly conserved and widespread ncRNA classes with properties that suggest sophisticated biochemical functions and a multitude of putative cis-regulatory RNA classes involved in a variety of biological processes. We expect that further research on these newly found RNA classes will reveal additional aspects of novel biology, and allow for greater insights into the biochemistry performed by ncRNAs.

PT-112 is a novel platinum-pyrophosphate conjugate under clinical development for cancer therapy. PT-112 mediates cytostatic and cytotoxic effects against a variety of human and mouse cancer cell lines in vitro. The cytotoxic response to PT-112 is associated with the emission of danger signals underpinning the initiation of anticancer immunity, including calreticulin exposure on the surface of dying cells, as well as ATP and HMGB1 secretion. Consistently, mouse cancer cells succumbing to PT-112 in vitro can be used to provide syngeneic, immunocompetent mice with immunological protection against a subsequent challenge with living tumor cells of the same type. Moreover, PT-112 administration synergizes with PD-1 or PD-L1 blockade in the control of mouse cancers in immunologically competent settings, as it simultaneously recruits immune effector cells and depletes immunosuppressive cells in the tumor microenvironment. Finally, PT-112 employed intratumorally in the context of immune checkpoint inhibition initiates a robust immune response that has systemic outreach and limits the growth of untreated, distant lesions. Thus, PT-112 induces the immunogenic demise of cancer cells, and hence stands out as a promising combinatorial partner of immune checkpoint blockers, especially for the treatment of otherwise immunologically cold tumors.