Thiopeptide antibiotics are a group of highly modified peptide metabolites. The defining scaffold for the thiopeptides is a macrocycle containing a dehydropiperidine or pyridine ring, dehydrated amino acids, and multiple thiazole or oxazole rings. Some members of the thiopeptides, such as thiostrepton, also contain either a quinaldic acid or indolic acid substituent derived from tryptophan. Although the amino acid precursors of these metabolites are well-established, the biogenesis of these complex peptides has remained elusive. Whole-genome scanning of Streptomyces laurentii permitted identification of a thiostrepton prepeptide, TsrA, and involvement of TsrA in thiostrepton biosynthesis was confirmed by mutagenesis. A gene cluster responsible for thiostrepton biosynthesis is reported, and the encoded gene products are discussed. The disruption of a gene encoding an amidotransferase, tsrT, led to the loss of thiostrepton production and the detection of a new metabolite, contributing further support to the identification of the tsr cluster. The tsr locus also appears to possess the gene products needed to convert tryptophan to the quinaldic acid moiety, and an aminotransferase was found to catalyze an early step in this pathway. This work establishes that the thiopeptides are a type of bacteriocin, a family of genetically encoded antimicrobial peptides, and are subjected to extensive posttranslational modification during maturation of the prepeptide.

The clinical assessment of suicidal risk would be significantly complemented by a biologically-based measure that assesses alterations in the neural representations of concepts related to death and life in people who engage in suicidal ideation. This study used machine-learning algorithms (Gaussian Naïve Bayes) to identify such individuals (17 suicidal ideators vs 17 controls) with high (91%) accuracy, based on their altered fMRI neural signatures of death and life-related concepts. The most discriminating concepts were death, cruelty, trouble, carefree, good, and praise. A similar classification accurately (94%) discriminated 9 suicidal ideators who had made a suicide attempt from 8 who had not. Moreover, a major facet of the concept alterations was the evoked emotion, whose neural signature served as an alternative basis for accurate (85%) group classification. The study establishes a biological, neurocognitive basis for altered concept representations in participants with suicidal ideation, which enables highly accurate group membership classification.

Elevated activity in attention control circuitry, and reduced anterior cingulate gyral–insula functional connectivity, to 50% intensity angry faces in ATT than other groups suggest that ATT may show inefficient recruitment of attentional control neural circuitry when regulating attention to mild intensity angry faces, which may represent a potential biological marker for suicide risk.

Objectives Impaired attentional control and behavioral control are implicated in adult suicidal behavior. Little is known about the functional integrity of neural circuitry supporting these processes in suicidal behavior in adolescence. Method We employed fMRI in 15 adolescent suicide attempters with history of major depressive disorder (MDD; ATT), 15 adolescents with history of MDD but not suicide attempt (NAT), and 14 healthy controls (HC), during performance of a well-validated GoNoGo response inhibition and motor control task that measures attentional and behavioral control, and has been shown to activate prefrontal, anterior cingulate and parietal cortical circuitry. Questionnaires assessed symptoms and standardized interviews characterized suicide attempt. Results A 3 group × 2 condition (“GoNoGo” response inhibition versus “Go” motor control blocks) block-design whole-brain analysis (p<0.05, corrected) revealed that NAT showed greater activity than ATT in right anterior cingulate gyrus (p=0.008), and that NAT, but not ATT, showed significantly greater activity than HC in the left insula (p=0.004) to GoNoGo response inhibition blocks. Conclusions While ATT did not show differential patterns of neural activity from HC during GoNoGo response inhibition blocks, ATT and NAT showed differential activation of the right anterior cingulate gyrus during response inhibition. Our findings indicate that suicide attempt during adolescence is not associated with abnormal activity in response inhibition neural circuitry. The differential patterns of activity in response inhibition neural circuitry in ATT and NAT, however, suggest different neural mechanisms for suicide attempt versus MDD in general in adolescence that should be a focus of further study.

Background The ‘default mode network’ (DMN), a collection of brain regions including the posterior cingulate cortex (PCC), shows reliable inter-regional functional connectivity at rest. It has been implicated in rumination and other negative affective states, but its role in suicidal ideation is not well understood. Methods We employed seed based functional connectivity methods to analyze resting state fMRI data in 34 suicidal ideators and 40 healthy control participants, as well as low frequency BOLD within the regions of interest. Structural imaging of the cingulum bundle was also conducted using diffusion tensor imaging (DTI). Results Whole-brain connectivity with dorsal PCC or ventral PCC was broadly intact between the two groups, but while the control participants showed greater coupling between the dorsal anterior cingulate cortex (dACC) and dorsal PCC, compared to the dACC and ventral PCC, this difference was reversed in the ideators (T(72)=2.78, p=0.007). Furthermore, ongoing low frequency BOLD signal in these three regions (dorsal, ventral PCC, dACC) was reduced in the ideators (F(1, 72)=5.58, p=0.021). The structural integrity of the cingulum bundle also explained variation in the functional connectivity measures but did not abolish the group differences. Limitations Lack of external stimulus or self-report prevents inferences about the contribution of cingulate connectivity to influence cognitive state. No associations with clinical variables reached corrected significance. Conclusion These findings provide evidence of abnormalities in the DMN underlying the tendency towards suicidal ideation, supporting the involvement of cingulate regions previously implicated using task-based paradigms.

Examination of metabolic disorders in treatment-refractory depression identified an unexpectedly large proportion of patients with potentially treatable abnormalities. The etiology of these abnormalities remains to be determined.

The extent to which observed differences in emotion processing and regulation neural circuitry in adolescents with a history of suicide attempt are paralleled by structural differences is unknown. We measured brain cortical thickness and grey- and white-matter volumes in 100 adolescents: 28 with a history of suicide attempt and major depressive disorder (MDD); 31 with a history of MDD but no suicide attempt; and a healthy control group (n = 41). The first group compared with controls showed reduction in grey-matter volume in the right superior temporal gyrus (BA38), a region important for social emotion processing.

More than 36,000 people in the United States die from suicide annually, and suicide is the third leading cause of death in adolescence. Adolescence is a time of high risk for suicidal behavior, as well as a time that intervention and treatment may have the greatest impact because of structural brain changes and significant psychosocial development during this period. Functional and structural neuroimaging studies in adults who have attempted suicide suggest distinct gray matter volume abnormalities in cortical regions, as well as prefrontal cortical and dorsal anterior cingulate gyrus neural circuitry differences compared with affective and healthy adult controls. Recent functional neuroimaging studies in adolescents with a history of suicide attempt suggest differences in the attention and salience networks compared with adolescents with depression and no history of suicide attempt and healthy controls when viewing angry faces. In contrast, no abnormalities are seen in these areas in the absence of emotional stimuli. These networks may represent promising targets for future neuroimaging studies to identify markers of risk for future suicide attempt in adolescents.