odels of type 1 diabetes mimic many of the pathogenic processes involved in disease progression in humans, they remain an essential step for the proof of concept for all the novel therapies. Better preclinical testing will deliver benefits to researchers studying disease process, drug developers testing candidate treatments, and regulators/funders seeking to establish potential efficacy in rodent models, all with the goal to improve the efficiency, safety, and outcomes of clinical trials in type 1 diabetes. Acknowledgements PharmaIN Corp. highly appreciated the opportunity to asses PGCGLP-1 for reversal of T1D and very much grateful to NIDDK for the study. The NIDDK and BRM, Inc. 
gratefully acknowledge the participation of Yousef Al-Abed, Elijah Bolotin, Thomas R. Coleman, Leslie Cousens, Maria Koulmanda, Vipin Kumar, Mary Ann Nadler, Jerry L. Nadler, Sandra Reichstetter, and Terry Strom, who provided information and/or test articles, helped in designing and interpreting experiments, and for comments on the paper, and to Shalesh Kaushal, who provided preliminary data and suggested that celastrol be tested in the program. MRT-67307 site Bortezomib is the first proteasome inhibitor with significant antineoplastic activity for the treatment of relapsed/refractory multiple myeloma as well as a variety of other hematological and solid neoplasms. It acts through highaffinity and specific binding of its boron atom to the catalytic site of the 26S proteasome. A variety of mechanisms are involved in the anti-proliferative effect of bortezomib, 18339876 including reversible inhibition of 11881984 the proteasome and NF-B signaling pathway, which inhibits anti-apoptotic factors and permits the activation of programmed death in cancer cells. Peripheral neurological complications are among the major side effects associated with bortezomib therapy particularly if given intravenously and they severely affect normal activities of daily living in MM patients. Bortezomib-induced peripheral neuropathy is characterized by paresthesias, burning sensations, dysesthesias, numbness, sensory loss, reduced proprioception and vibratory sensation that presents in a stocking-and-glove distribution. Deep tendon reflexes are also reduced, while motor impairment is generally only subclinical above all when patients had a pre-existing neuropathy. Reduced autonomic innervation in the skin of bortezomib-treated patients has also been reported. The most clinically relevant bortezomib-induced adverse effect is neuropathic pain, evident as abnormal touch detection and reduced thermal thresholds that usually do not subside between courses of therapy. Although bortezomib-induced painful PN is easy to diagnose, its pathophysiology remains unclear. Peripheral neuropathic pain is attributed to plastic changes that affect either the primary afferent fibers or their synapses in the central nervous system. These changes include peripheral/central sensitization and alterations in the function of CNS centers involved in the processing of nociceptive information. If and how bortezomib, which does not cross the blood brain barrier, causes alterations in the central part of sensory pathways remains to be elucidated. In studies of rat and mouse models, chronic treatment with bortezomib induces a significant and dose-dependent reduction of nerve conduction velocity, resulting from mild to moderate pathological changes that involve both myelinated and unmyelinated peripheral nerve fibers. Moreover, intracytoplasmic vacuo
