Both depression and substance use disorders represent major global public health concerns and are often co-occurring. Although there are ongoing discoveries regarding the pathophysiology and treatment of each condition, common mechanisms and effective treatments for co-occurring depression and substance abuse remain elusive. Mindfulness training has recently been shown to benefit both depression and substance use disorders, suggesting that this approach may target common behavioral and neurobiological processes. However, it remains unclear whether these pathways constitute specific shared neurobiological mechanisms or more extensive components universal to the broader human experience of psychological distress or suffering. We offer a theoretical, clinical and neurobiological perspective of the overlaps between these disorders, highlight common neural pathways that play a role in depression and substance use disorders, and discuss how these commonalities may frame our conceptualization and treatment of co-occurring disorders. Finally, we discuss how advances in our understanding of potential mechanisms of mindfulness training may offer not only unique effects on depression and substance use, but also offer promise for treatment of co-occurring disorders. KeywordsMindfulness; Addiction; Depression; Substance Use Treatment; Functional Magnetic Resonance Imaging (fMRI); co-occurring disorders; dual diagnosis Mindfulness training (MT) may target common underlying mechanisms of major depressive disorder (MDD) and substance use disorders (SUDs), providing an effective treatment for co-occurrence of these maladies where few currently exist. We will use "co-occurring disorder" and "dual diagnosis" to refer to the co-occurrence of MDD and an SUD in which "diagnoses of these disorders must occur simultaneously or within a one year time frame of each other" (1). As first-line treatment for substance-induced mood disorders is to treat the underlying SUD (2), substance-induced mood disorders will not be included in this discussion. Additionally, although co-occurring psychotic and anxiety disorders are common

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bTrypanosoma brucei, a parasitic protozoan that causes African trypanosomiasis, possesses a single member of the presequence and amino acid transporter (PRAT) protein family, which is referred to as TbTim17. In contrast, three homologous proteins, ScTim23, ScTim17, and ScTim22, are found in Saccharomyces cerevisiae and higher eukaryotes. Here, we show that TbTim17 cannot rescue Tim17, Tim23, or Tim22 mutants of S. cerevisiae. We expressed S. cerevisiae Tim23, Tim17, and Tim22 in T. brucei. These heterologous proteins were properly imported into mitochondria in the parasite. Further analysis revealed that although ScTim23 and ScTim17 were integrated into the mitochondrial inner membrane and assembled into a protein complex similar in size to TbTim17, only ScTim17 was stably associated with TbTim17. In contrast, ScTim22 existed as a protease-sensitive soluble protein in the T. brucei mitochondrion. In addition, the growth defect caused by TbTim17 knockdown in T. brucei was partially restored by the expression of ScTim17 but not by the expression of either ScTim23 or ScTim22, whereas the expression of TbTim17 fully complemented the growth defect caused by TbTim17 knockdown, as anticipated. Similar to the findings for cell growth, the defect in the import of mitochondrial proteins due to depletion of TbTim17 was in part restored by the expression of ScTim17 but was not complemented by the expression of either ScTim23 or ScTim22. Together, these results suggest that TbTim17 is divergent compared to ScTim23 but that its function is closer to that of ScTim17. In addition, ScTim22 could not be sorted properly in the T. brucei mitochondrion and thus failed to complement the function of TbTim17.A majority of proteins in the mitochondria are encoded by nuclear DNA. These proteins are imported by the translocase of the mitochondrial outer membrane (TOM) and the translocase of the mitochondrial inner membrane (TIM) (1, 2). The TOMs and TIMs are multiprotein complexes whose structure and function have been extensively characterized in fungi and recently in humans and plants. The TOM complex serves as the entry gate for virtually all mitochondrial proteins (3). There are two TIM complexes, TIM23 and TIM22, in the majority of eukaryotes analyzed so far. Unlike TOM, the TIM complexes have substrate specificities. The TIM23 complex imports proteins that contain an N-terminal targeting signal (MTS) into the mitochondrial matrix and, if they contain an additional sorting signal, into the inner membrane (4, 5). Tim23 and Tim17, together with the receptor Tim50, form the core of the TIM23 complex. This core complex seems to be sufficient for transport of proteins into the mitochondrial inner membrane by a stop-transfer pathway. For translocation of proteins to the mitochondrial matrix, the ATP-dependent action of the import motor of the TIM23 complex is additionally required (4-6). The TIM22 complex, on the other hand, is involved in the translocation and insertion of a special class of mitochondrial inner membrane proteins. These pr...

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This paper presents a new concept combining flexible organic light emitting diode (OLED) display technology with fluorescent biorecognition microarray technology to fabricate point-of-care immunobiosensors. Our approach is designed to leverage commercial OLED display technology to reduce pre-functionalized biosensor substrate costs to pennies per cm 2 combined with leveraging the display industries ability to manufacture an immense number of low-cost consumer electronic products annually. For this work, we demonstrate that our new approach using high brightness flexible OLED display technology combined with a charge integrating readout circuit and optical filters can offer point-of-care diagnostic sensitivity at or below 10 pg/mL, which approaches the lower limit of detection (LLOD) of typical clinical laboratory instrumentation.

Trypanosoma brucei is the causative agent of African sleeping sickness. The parasite’s mitochondrion represents a useful source for potential chemotherapeutic targets. Similarly to yeast and humans, mitochondrial functions depend on the import of proteins that are encoded in the nucleus and made in the cytosol. Even though the machinery involved in this mitochondrial protein import process is becoming clearer in T. brucei, a comprehensive picture of protein complex composition and function is still lacking. In this study, we characterized three T. brucei small Tim proteins, TbTim9, TbTim10, and TbTim8/13. Although the parasite does not have the classical TIM22 complex that imports mitochondrial inner membrane proteins containing internal targeting signals in yeast or humans, we found that these small TbTims associate with TbTim17, the major subunit of the TbTIM complex in T. brucei, and play an essential role in the stability of the TbTim17 complexes. Therefore, these divergent proteins are critical for mitochondrial protein biogenesis in T. brucei.

Recognition of mitochondrial targeting signals (MTS) by receptor translocases of outer and inner membranes of mitochondria is one of the prerequisites for import of nucleus-encoded proteins into this organelle. The MTS for a majority of trypanosomatid mitochondrial proteins have not been well defined. Here we analyzed the targeting signal for trypanosome alternative oxidase (TAO), which functions as the sole terminal oxidase in the infective form of Trypanosoma brucei. Deleting the first 10 of 24 amino acids predicted to be the classical N-terminal MTS of TAO did not affect its import into mitochondria in vitro. Furthermore, ectopically expressed TAO was targeted to mitochondria in both forms of the parasite even after deletion of first 40 amino acid residues. However, deletion of more than 20 amino acid residues from the N terminus reduced the efficiency of import. These data suggest that besides an N-terminal MTS, TAO possesses an internal mitochondrial targeting signal. In addition, both the N-terminal MTS and the mature TAO protein were able to target a cytosolic protein, dihydrofolate reductase (DHFR), to a T. brucei mitochondrion. Further analysis identified a cryptic internal MTS of TAO, located within amino acid residues 115 to 146, which was fully capable of targeting DHFR to mitochondria. The internal signal was more efficient than the N-terminal MTS for import of this heterologous protein. Together, these results show that TAO possesses a cleavable N-terminal MTS as well as an internal MTS and that these signals act together for efficient import of TAO into mitochondria.