FOXI3 haploinsufficiency contributes to low T-cell receptor excision circles and T-cell lymphopenia.

BACKGROUND: Newborn screening can identify neonatal T-cell lymphopenia through detection of a low number of copies of T-cell receptor excision circles in dried blood spots collected at birth. After a positive screening result, further diagnostic testing is required to determine whether the subject has severe combined immunodeficiency or other causes of T-cell lymphopenia. Even after thorough evaluation, approximately 15% of children with a positive result of newborn screening for T-cell receptor excision circles remain genetically undiagnosed. Identifying the underlying genetic etiology is necessary to guide subsequent clinical management and family planning. OBJECTIVE: We sought to elucidate the genetic basis of patients with T-cell lymphopenia without an apparent genetic diagnosis. METHODS: We used clinical genomic testing as well as functional and immunologic assays to identify and elucidate the genetic and mechanistic basis of T-cell lymphopenia. RESULTS: We report 2 unrelated individuals with nonsevere T-cell lymphopenia and abnormal T-cell receptor excision circles who harbor heterozygous loss-of-function variants in forkhead box I3 transcription factor (FOXI3). CONCLUSION: Our findings support the notion that haploinsufficiency of FOXI3 results in T-cell lymphopenia with variable expressivity and that FOXI3 may be a key modulator of thymus development.

Childhood Threat Is Associated With Lower Resting-State Connectivity Within a Central Visceral Network.

Childhood adversity is associated with altered or dysregulated stress reactivity; these altered patterns of physiological functioning persist into adulthood. Evidence from both preclinical animal models and human neuroimaging studies indicates that early life experience differentially influences stressor-evoked activity within central visceral neural circuits proximally involved in the control of stress responses, including the subgenual anterior cingulate cortex (sgACC), paraventricular nucleus of the hypothalamus (PVN), bed nucleus of the stria terminalis (BNST) and amygdala. However, the relationship between childhood adversity and the resting-state connectivity of this central visceral network remains unclear. To this end, we examined relationships between childhood threat and childhood socioeconomic deprivation, the resting-state connectivity between our regions of interest (ROIs), and affective symptom severity and diagnoses. We recruited a transdiagnostic sample of young adult males and females (n = 100; mean age = 27.28, SD = 3.99; 59 females) with a full distribution of maltreatment history and symptom severity across multiple affective disorders. Resting-state data were acquired using a 7.2-min functional magnetic resonance imaging (fMRI) sequence; noted ROIs were applied as masks to determine ROI-to-ROI connectivity. Threat was determined by measures of childhood traumatic events and abuse. Socioeconomic deprivation (SED) was determined by a measure of childhood socioeconomic status (parental education level). Covarying for age, race and sex, greater childhood threat was significantly associated with lower BNST-PVN, amygdala-sgACC and PVN-sgACC connectivity. No significant relationships were found between SED and resting-state connectivity. BNST-PVN connectivity was associated with the number of lifetime affective diagnoses. Exposure to threat during early development may entrain altered patterns of resting-state connectivity between these stress-related ROIs in ways that contribute to dysregulated neural and physiological responses to stress and subsequent affective psychopathology.

Opposing relationships of childhood threat and deprivation with stria terminalis white matter.

While stress may be a potential mechanism by which childhood threat and deprivation influence mental health, few studies have considered specific stress-related white matter pathways, such as the stria terminalis (ST) and medial forebrain bundle (MFB). Our goal was to examine the relationships between childhood adversity and ST and MFB structural integrity and whether these pathways may provide a link between childhood adversity and affective symptoms and disorders. Participants were young adults (n = 100) with a full distribution of maltreatment history and affective symptom severity. Threat was determined by measures of childhood abuse and repeated traumatic events. Socioeconomic deprivation (SED) was determined by a measure of childhood socioeconomic status (parental education). Participants underwent diffusion spectrum imaging. Human Connectome Project data was used to perform ST and MFB tractography; these tracts were used as ROIs to extract generalized fractional anisotropy (gFA) from each participant. Childhood threat was associated with ST gFA, such that greater threat was associated with less ST gFA. SED was also associated with ST gFA, however, conversely to threat, greater SED was associated with greater ST gFA. Additionally, threat was negatively associated with MFB gFA, and MFB gFA was negatively associated with post-traumatic stress symptoms. Our results suggest that childhood threat and deprivation have opposing influences on ST structural integrity, providing new evidence that the context of childhood adversity may have an important influence on its neurobiological effects, even on the same structure. Further, the MFB may provide a novel link between childhood threat and affective symptoms.

Interactions between childhood maltreatment and combat exposure trauma on stress-related activity within the cingulate cortex: a pilot study.

Childhood trauma may sensitize the brain, increasing vulnerability to maladaptive stress responses following adulthood trauma exposure. Previous work has identified the cingulum as a white matter pathway that may be sensitized to adulthood trauma by childhood maltreatment. In this pilot study of young adult male military veterans (N = 28), we examined a priori regions of interest (ROIs) connected by the cingulum, including regions involved in cognitive processes and stress responses. Our goal was to examine the interaction between childhood maltreatment and combat exposure on stress-related activity within cingulum-associated ROIs. As such we utilized a mild cognitive stress task, a performance-titrated multi-source interference task (MSIT). We found that childhood maltreatment moderated the effect of combat exposure on stress-related, interference-evoked activity within the dorsal anterior cingulate cortex (dACC, activation), subgenual ACC (sgACC, deactivation) and posterior midcingulate cortex (pMCC, deactivation). Greater combat exposure was associated with greater interference-evoked activation within the dACC, and less sgACC and pMCC deactivation among individuals with more severe childhood maltreatment. Our findings suggest that child maltreatment sensitizes these anterior and mid-cingulate regions to later life trauma. These findings may have implications for cognitive control, autonomic regulation/stress reactivity, and responses to noxious/aversive stimuli, which may contribute to increased psychiatric vulnerability.

Structure of female genitalia of glassy-winged sharpshooter, Homalodisca coagulata (Say) (Hemiptera: Cicadellidae).

The functional reproductive morphology of the female glassy-winged sharpshooter, Homalodisca coagulata (Say), is described at both light microscopy and scanning electron microscopy levels. The female has nine abdominal segments; the seventh to the ninth abdominal segments are modified for reproduction; the eighth tergite is reduced to two segments, with the ovipositor partially exposed from the modified ninth segment-the pygofer. The pygofer, covered with trichoid and coeloconic sensilla, almost completely encloses the ovipositor, which consists of three pairs of valvulae and two pairs of valvifers. The first and second valvulae function together for oviposition. The first valvulae are located exterior to the second valvulae, both of which bear many trichoid, campaniform, and coeloconic sensilla. The third valvulae, possessing many coeloconic sensilla, envelope the first and second valvulae. Seven major muscles are found to be associated with the ovipositor and the pygofer. The oviposition process is described with respect to the activity of the valvulae and their associated musculature. The female morphology follows the general pattern of cicadellids as a group.

Virulence and site of infection of the fungus, Hirsutella thompsonii, to the honey bee ectoparasitic mite, Varroa destructor.

The Varroa mite, Varroa destructor, is recognized as the most serious pest of both managed and feral Western honey bee (Apis mellifera) in the world. The mite has developed resistance to fluvalinate, an acaricide used to control it in beehives, and fluvalinate residues have been found in the beeswax, necessitating an urgent need to find alternative control measures to suppress this pest. Accordingly, we investigated the possibility of using the fungus, Hirsutella thompsonii, as a biocontrol agent of the Varroa mite. Among the 9 isolates of H. thompsonii obtained from the University of Florida and the USDA, only the 3 USDA isolates (ARSEF 257, 1947 and 3323) were infectious to the Varroa mite in laboratory tests. The mite became infected when it was allowed to walk on a sporulating H. thompsonii culture for 5 min. Scanning electron micrographs revealed that the membranous arolium of the mite leg sucker is the focus of infection where the fungal conidia adhered and germinated. The infected mites died from mycosis, with the lethal times to kill 50% (LT(50)s) dependent on the fungal isolates. Thus, the LT(50)s were 52.7, 77.2, and 96.7h for isolates 3323, 257, and 1947, respectively. Passage of H. thompsonii through Varroa mite three times significantly reduced the LT(50)s of isolates 257 and 1947 (P<0.05) but not the LT(50) of isolate 3323. The fungus did not infect the honey bee in larval, prepupal, pupal, and adult stages under our laboratory rearing conditions. Our encouraging results suggest that some isolates of H. thompsonii have the potential to be developed as a biocontrol agent for V. destructor. However, fungal infectivity against the mites under beehive conditions needs to be studied before any conclusion can be made.