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9 years (range 9-16) and the average age of the patient at time of presentation was 60.1. The average body mass index at the time of the HH repair was 34 kg/m2. The most common presenting symptom was gastroesophageal reflux. Both computed tomography and upper gastrointestinal series were used for diagnosis with a common finding of HH and pouch migration into the mediastinum. HH repair with bioabsorbable mesh was performed in all patients, with an average operative time of 105 minutes. CONCLUSION HH can present late after gastric bypass become symptomatic. When symptomatic, it needs to be addressed surgically and can usually be done through a minimally invasive approach. Compensatory endocytosis of released synaptic vesicles (SVs) relies on coordinated signaling at the lipid-protein interface. Here, we address the synaptic function of C-terminal binding protein 1 (CtBP1), a ubiquitous regulator of gene expression and membrane trafficking in cultured hippocampal neurons. In the absence of CtBP1, synapses form in greater density and show changes in SV distribution and size. The increased basal neurotransmission and enhanced synaptic depression could be attributed to a higher vesicular release probability and a smaller fraction of release-competent SVs, respectively. buy compound W13 Rescue experiments with specifically targeted constructs indicate that, while synaptogenesis and release probability are controlled by nuclear CtBP1, the efficient recycling of SVs relies on its synaptic expression. The ability of presynaptic CtBP1 to facilitate compensatory endocytosis depends on its membrane-fission activity and the activation of the lipid-metabolizing enzyme PLD1. Thus, CtBP1 regulates SV recycling by promoting a permissive lipid environment for compensatory endocytosis. Cells have developed protein quality-control strategies to manage the accumulation of misfolded substrates during heat stress. Using a soluble reporter of misfolding in fission yeast, Rho1.C17R-GFP, we demonstrate that upon mild heat shock, the reporter collapses in protein aggregate centers (PACs). They contain and/or require several chaperones, such as Hsp104, Hsp16, and the Hsp40/70 couple Mas5/Ssa2. Stress granules do not assemble at mild temperatures and, therefore, are not required for PAC formation; on the contrary, PACs may serve as nucleation centers for the assembly of stress granules. In contrast to the general belief, the dominant fate of these PACs is not degradation, and the aggregated reporter can be disassembled by chaperones and recovers native structure and activity. Using mass spectrometry, we show that thermo-unstable endogenous proteins form PACs as well. In conclusion, formation of PACs during heat shock is a chaperone-mediated adaptation strategy. Cells deficient in ataxia telangiectasia mutated (ATM) are hypersensitive to ionizing radiation and other anti-cancer agents that induce double-strand DNA breaks. ATM inhibitors may therefore sensitize cancer cells to these agents. Some cancers may also have underlying genetic defects predisposing them to an ATM inhibitor monotherapy response. We have conducted a genome-wide CRISPR screen to identify genetic vulnerabilities that sensitize lung cancer cells to ATM inhibitors. Knockout of genes in the Fanconi anemia (FA)/BRCA pathway results in hypersensitivity to the ATM inhibitor M3541. Knockdown of either an FA gene or of ATM results in reduced double-strand break end resection, enhanced non-homologous end joining (NHEJ) repair, and decreased homologous recombination repair. Knockout of both the FA/BRCA pathway and ATM strongly inhibits end resection and generates toxic levels of NHEJ, thereby elucidating a mechanism of cellular death by synthetic lethality. ATM inhibitors may therefore be useful for the treatment of tumors with a defective FA/BRCA pathway. Degradation of transcripts in human nuclei is primarily facilitated by the RNA exosome. To obtain substrate specificity, the exosome is aided by adaptors; in the nucleoplasm, those adaptors are the nuclear exosome-targeting (NEXT) complex and the poly(A) (pA) exosome-targeting (PAXT) connection. How these adaptors guide exosome targeting remains enigmatic. Employing high-resolution 3' end sequencing, we demonstrate that NEXT substrates arise from heterogenous and predominantly pA- 3' ends often covering kilobase-wide genomic regions. In contrast, PAXT targets harbor well-defined pA+ 3' ends defined by canonical pA site use. Irrespective of this clear division, NEXT and PAXT act redundantly in two ways (1) regional redundancy, where the majority of exosome-targeted transcription units produce NEXT- and PAXT-sensitive RNA isoforms, and (2) isoform redundancy, where the PAXT connection ensures fail-safe decay of post-transcriptionally polyadenylated NEXT targets. In conjunction, this provides a two-layered targeting mechanism for efficient nuclear sorting of the human transcriptome. The neurodevelopmental origin of hyperactivity disorder has been suggested to involve the dopaminergic system, but the underlying mechanisms are still unknown. Here, transcription factors Lmx1a and Lmx1b are shown to be essential for midbrain dopaminergic (mDA) neuron excitatory synaptic inputs and dendritic development. Strikingly, conditional knockout (cKO) of Lmx1a/b in postmitotic mDA neurons results in marked hyperactivity. In seeking Lmx1a/b target genes, we identify positively regulated Slitrk2 and negatively regulated Slitrk5. These two synaptic adhesion proteins promote excitatory and inhibitory synapses on mDA neurons, respectively. Knocking down Slitrk2 reproduces some of the Lmx1a/b cKO cellular and behavioral phenotypes, whereas Slitrk5 knockdown has opposite effects. The hyperactivity caused by this imbalance in excitatory/inhibitory synaptic inputs on dopamine neurons is reproduced by chronically inhibiting the ventral tegmental area during development using pharmacogenetics. Our study shows that alterations in developing dopaminergic circuits strongly impact locomotor activity, shedding light on mechanisms causing hyperactivity behaviors. Considerable work emphasizes a role for hippocampal circuits in governing contextual fear discrimination. However, the intra- and extrahippocampal pathways that route contextual information to cortical and subcortical circuits to guide adaptive behavioral responses are poorly understood. Using terminal-specific optogenetic silencing in a contextual fear discrimination learning paradigm, we identify opposing roles for dorsal CA3-CA1 (dCA3-dCA1) projections and dorsal CA3-dorsolateral septum (dCA3-DLS) projections in calibrating fear responses to certain and ambiguous contextual threats, respectively. Ventral CA3-DLS (vCA3-DLS) projections suppress fear responses in both certain and ambiguous contexts, whereas ventral CA3-CA1 (vCA3-vCA1) projections promote fear responses in both these contexts. Lastly, using retrograde monosynaptic tracing, ex vivo electrophysiological recordings, and optogenetics, we identify a sparse population of DLS parvalbumin (PV) neurons as putative relays of dCA3-DLS projections to diverse subcortical circuits.