A highly efficient synthesis of sitagliptin, a potent and selective DPP-4 inhibitor for the treatment of type 2 diabetes mellitus (T2DM), has been developed. The key dehydrositagliptin intermediate 9 is prepared in three steps in one pot and directly isolated in 82% yield and >99.6 wt % purity. Highly enantioselective hydrogenation of dehydrositagliptin 9, with as low as 0.15 mol % of Rh(I)/(t)Bu JOSIPHOS, affords sitagliptin, which is finally isolated as its phosphate salt with nearly perfect optical and chemical purity. This environmentally friendly, 'green' synthesis significantly reduces the total waste generated per kilogram of sitagliptin produced in comparison with the first-generation route and completely eliminates aqueous waste streams. The efficiency of this cost-effective process, which has been implemented on manufacturing scale, results in up to 65% overall isolated yield.

The ongoing development of HPLC has been focused on increasing the speed and efficiency of separations over the past decade. The advances in separation speed have been primarily related to the development of column technology and instrumentation. Relatively short columns packed with sub-2 microm particles provide high-speed separations while maintaining or increasing resolution. Ultrahigh pressure pump systems have been developed to overcome the high-pressure drop generated by such sub-2 microm packings. In this review, fundamental and practical aspects of ultrahigh pressure or ultrahigh performance liquid chromatography (U-HPLC) are discussed. Applications of fast U-HPLC separations are also presented.

Dynamic nuclear polarization (DNP) of amorphous and crystalline ortho-terphenyl (OTP) in the absence of glass forming agents is presented in order to gauge the feasibility of applying DNP to pharmaceutical solid-state nuclear magnetic resonance experiments and to study the effect of intermolecular structure, or lack thereof, on the DNP enhancement. By way of 1H–13C cross-polarization, we obtained a DNP enhancement (ε) of 58 for 95% deuterated OTP in the amorphous state using the biradical bis-TEMPO terephthalate (bTtereph) and ε of 36 in the crystalline state. Measurements of the 1H T1 and electron paramagnetic resonance experiments showed the crystallization process led to phase separation of the polarization agent, creating an inhomogeneous distribution of radicals within the sample. Consequently, the effective radical concentration was decreased in the bulk OTP phase, and long-range 1H–1H spin diffusion was the main polarization propagation mechanism. Preliminary DNP experiments with the glass-forming anti-inflammation drug, indomethacin, showed promising results, and further studies are underway to prepare DNP samples using pharmaceutical techniques.

Background Posttraumatic stress disorder (PTSD) is associated with reduced executive functioning and verbal memory performance, as well as abnormal task-specific activity in prefrontal (PFC) and anterior cingulate cortices (ACC). The current study examined how PTSD symptoms and neuropsychological performance in combat veterans relates to 1) medial PFC and ACC activity during cognitive inhibition, and 2) task-independent PFC functional connectivity. Methods Thirty-nine male combat veterans with varying levels of PTSD symptoms completed the multisource interference task during functional magnetic resonance imaging. Robust regression analyses were used to assess relationships between percent signal change (PSC: Incongruent-Congruent) and both PTSD severity and neuropsychological performance. Analyses were conducted voxel-wise and for PSC extracted from medial PFC and ACC regions of interest. Resting state scans were available for veterans with PTSD. Regions identified via task-based analyses were used as seeds for resting state connectivity analyses. Results Worse PTSD severity and neuropsychological performance related to less medial PFC and rostral ACC activity during interference processing, driven partly by increased activation to congruent trials. Worse PTSD severity related to reduced functional connectivity between these regions and bilateral, lateral PFC (Brodmann area 10). Worse neuropsychological performance related to reduced functional connectivity between these regions and the inferior frontal gyrus. Conclusions PTSD and associated neuropsychological deficits may result from difficulties regulating medial PFC regions associated with “default mode”, or self-referential processing. Further clarification of functional coupling deficits between default mode and executive control networks in PTSD may enhance understanding of neuropsychological and emotional symptoms and provide novel treatment targets.

Background One in three college students experience significant depression or anxiety interfering with daily functioning. Resilience programs that can be administered to all students offer an opportunity for addressing this public health problem. The current study objective was to assess the benefit of a brief, universal resilience program for first‐year college students. Method First‐year students at a private, midwestern university participated. This trial used a pragmatic design, delivering the intervention within university‐identified orientation courses and was not randomized. The four‐session resilience program included goal‐building, mindfulness, and resilience skills. The comparison was orientation‐as‐usual. Primary outcomes included PROMIS® Depression and Anxiety and Connor‐Davidson Resilience Scale. Secondary and exploratory outcomes included the Perceived Stress Scale, Emotion Regulation, and Cognitive Behavioral Therapy (CBT) Skills Questionnaires, and Freiburg Mindfulness Inventory. Time by treatment interactions at post‐training and semester‐end were examined using linear mixed models. Results Analysis included 252 students, 126 who completed resilience programming and a matched comparison sample. Resilience programming did not relate to improvements in depression at post‐training (CI: −2.53 to 1.02; p = .404, d =−0.08), but did at semester‐end (95% CI: −4.27 to −0.72; p = .006, d = −0.25) and improvements in perceived stress were observed at post‐training (CI: −3.31 to −0.44; p = .011, d = −0.24) and semester‐end (CI: −3.30 to −0.41; p = .013, d = −0.24). Emotion regulation, mindfulness, and CBT skills increased, with CBT skills mediating clinical improvements. Conclusions Universal implementation of a brief, resilience intervention may be effective for improving college student mental health.

Resilience is a neurobiological entity that shapes an individual's response to trauma. Resilience has been implicated as the principal mediator in the development of mental illness following exposure to trauma. Although animal models have traditionally defined resilience as molecular and behavioral changes in stress responsive circuits following trauma, this concept needs to be further clarified for both research and clinical use. Here, we analyze the construct of resilience from a translational perspective and review optimal measurement methods and models. We also seek to distinguish between resilience, stress vulnerability, and posttraumatic growth. We propose that resilience can be quantified as a multifactorial determinant of physiological parameters, epigenetic modulators, and neurobiological candidate markers. This multifactorial definition can determine PTSD risk before and after trauma exposure. From this perspective, we propose the use of an 'R Factor' analogous to Spearman's g factor for intelligence to denote these multifactorial determinants. In addition, we also propose a novel concept called 'resilience reserve', analogous to Stern's cognitive reserve, to summarize the sum total of physiological processes that protect and compensate for the effect of trauma. We propose the development and application of challenge tasks to measure 'resilience reserve' and guide the assessment and monitoring of 'R Factor' as a biomarker for PTSD. Rakesh et al.

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Zirconium dioxide (zirconia) has a great affinity for inorganic and organic phosphate. Previous work from this laboratory demonstrated the utility of phosphate-modified microparticulate zirconia as a support for protein separations. We have extended this investigation to include the study of ethylenediamine-N,N'-tetramethylphosphonic acid (EDTPA), a phosphonate analog of EDTA, as a surface modifier for zirconia. Our work explores the use of EDTPA-modified zirconia (PEZ) for its potential use as a high-performance inorganic cation-exchange support for the separation of proteins. The phosphate groups in EDTPA very effectively block the sites responsible for strong interactions of hard Lewis bases with zirconia's surface. Modification of zirconia with EDTPA provides a "biocompatible" stationary phase, resulting in high mass recoveries of proteins. We compare PEZ with inorganic phosphate-modified zirconia to show increased efficiency, as well as unique selectivities for chromatography of proteins on the chelator-modified surface. Finally, the selectivity, efficiency, and separation mechanism are reported. The studies show that PEZ is a useful high-performance ion-exchange support for the separation of cationic proteins and for modulating the sites responsible for the high affinity of zirconia toward certain classes of anions.