The structure of a complex between a peptide inhibitor with the sequence N-acetyl-Thr-Ile-Nle-psi[CH2-NH]-Nle-Gln-Arg.amide (Nle, norleucine) with chemically synthesized HIV-1 (human immunodeficiency virus 1) protease was determined at 2.3 A resolution (R factor of 0.176). Despite the symmetric nature of the unliganded enzyme, the asymmetric inhibitor lies in a single orientation and makes extensive interactions at the interface between the two subunits of the homodimeric protein. Compared with the unliganded enzyme, the protein molecule underwent substantial changes, particularly in an extended region corresponding to the "flaps" (residues 35 to 57 in each chain), where backbone movements as large as 7 A are observed.

Increasing predictability of animal models of posttraumatic stress disorder (PTSD) has required active collaboration between clinical and preclinical scientists. Modeling PTSD is challenging, as it is a heterogeneous disorder with ≥20 symptoms. Clinical research increasingly utilizes objective biological measures (e.g., imaging, peripheral biomarkers) or nonverbal behaviors and/or physiological responses to complement verbally reported symptoms. This shift toward more-objectively measurable phenotypes enables refinement of current animal models of PTSD, and it supports the incorporation of homologous measures across species. We reviewed >600 articles to examine the ability of current rodent models to probe biological phenotypes of PTSD (e.g., sleep disturbances, hippocampal and fear-circuit dysfunction, inflammation, glucocorticoid receptor hypersensitivity) in addition to behavioral phenotypes. Most models reliably produced enduring generalized anxiety-like or depression-like behaviors, as well as hyperactive fear circuits, glucocorticoid receptor hypersensitivity, and response to long-term selective serotonin reuptake inhibitors. Although a few paradigms probed fear conditioning/extinction or utilized peripheral immune, sleep, and noninvasive imaging measures, we argue that these should be incorporated more to enhance translation. Data on female subjects, on subjects at different ages across the life span, or on temporal trajectories of phenotypes after stress that can inform model validity and treatment study design are needed. Overall, preclinical (and clinical) PTSD researchers are increasingly incorporating homologous biological measures to assess markers of risk, response, and treatment outcome. This shift is exciting, as we and many others hope it not only will support translation of drug efficacy from animal models to clinical trials but also will potentially improve predictability of stage II for stage III clinical trials.

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Nnve! flunrngenic substrates for human immunodeficiency viril pmteise hnve been dcvslopod based on the principle of fluorescence energy transfer. Starting from a p24/p 15 cleavage site-derived hexapeptide substrate, Ac-Thr-Ile-Nle-Nle-Gln-Arg-NH2, incorporation of 2-aminobenzoic acid in place of the acetyl group as the donor and p-NO,-Phe at the P1' position as acceptor gave the intramolecularly quenched fluorogenic substrate. Cleavage of the substrate by HIV protease released the fluorescent N-terminal tripeptide from its close apposition to the quenching nitrobenzyl group, resulting in enhanced fluorescence. An automated assay based on 96=wcll microtitcr plotcs and a fluoromctric platc reader have hccn devclopcd, which allow high throughput of compounds in the search for HIV protease inhibitors.

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Disturbed social relations during childhood (e.g., social neglect) often lead to aggression-related psychopathologies in adulthood. Social isolation also increased aggressiveness in laboratory animals. Here the authors show in rats, that social isolation from weaning not only increases the level of aggressiveness, but results in abnormal attack patterns and deficits in social communication. In socially deprived rats, the share of attacks aimed at vulnerable body parts of opponents (head, throat, and belly) dramatically increased and the attack/threat ratio was shifted toward attacks, suggesting a decrease in intention signaling. Moreover, a Multiple Regression Analysis showed that the nonassociation of attacks with offensive threats predicted the occurrence of vulnerable attacks with 81.1% accuracy. The authors suggest that the social deprivation-induced abnormal aggression models the aggression-related problems resulting from early social neglect in humans, and studies on its brain mechanisms may increase our understanding of the mechanisms underlying psychopathologies resulting from early social problems.

The goals of animal research in post-traumatic stress disorder (PTSD) include better understanding the neurophysiological etiology of PTSD, identifying potential targets for novel pharmacotherapies, and screening drugs for their potential use as PTSD treatment in humans. Diagnosis of PTSD relies on a patient interview and, as evidenced by changes to the diagnostic criteria in the DSM-5, an adequate description of this disorder in humans is a moving target. Therefore, it may seem insurmountable to model the construct of PTSD in animals such as rodents. Fortunately, the neural circuitry involved in fear and anxiety, thought to be essential to the etiology of PTSD in humans, is highly conserved throughout evolution. Furthermore, many symptoms can be modeled using behavioral tests that have face, construct, and predictive validity. Because PTSD is precipitated by a definite traumatic experience, animal models can simulate the induction of PTSD, and test causal factors with longitudinal designs. Accordingly, several animal models of physical and psychological trauma have been established. This review discusses the widely used animal models of PTSD in rodents, and overviews their strengths and weaknesses in terms of face, construct, and predictive validity.

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