Biallelic loss-of-function (LOF) mutations of the NCF4 gene, encoding the p40^phox subunit of the phagocyte NADPH oxidase, have been described in only 1 patient. We report on 24 p40^phox-deficient patients from 12 additional families in 8 countries. These patients display 8 different in-frame or out-of-frame mutations of NCF4 that are homozygous in 11 of the families and compound heterozygous in another. When overexpressed in NB4 neutrophil-like cells and EBV-transformed B cells in vitro, the mutant alleles were found to be LOF, with the exception of the p.R58C and c.120_134del alleles, which were hypomorphic. Particle-induced NADPH oxidase activity was severely impaired in the patients’ neutrophils, whereas PMA-induced dihydrorhodamine-1,2,3 (DHR) oxidation, which is widely used as a diagnostic test for chronic granulomatous disease (CGD), was normal or mildly impaired in the patients. Moreover, the NADPH oxidase activity of EBV-transformed B cells was also severely impaired, whereas that of mononuclear phagocytes was normal. Finally, the killing of Candida albicans and Aspergillus fumigatus hyphae by neutrophils was conserved in these patients, unlike in patients with CGD. The patients suffer from hyperinflammation and peripheral infections, but they do not have any of the invasive bacterial or fungal infections seen in CGD. Inherited p40^phox deficiency underlies a distinctive condition, resembling a mild, atypical form of CGD.

We present \emph{Task Super scalar}, an abstraction of instruction-level out-of-order pipeline that operates at the task-level. Like ILP pipelines, which uncover parallelism in a sequential instruction stream, task super scalar uncovers task-level parallelism among tasks generated by a sequential thread. Utilizing intuitive programmer annotations of task inputs and outputs, the task super scalar pipeline dynamically detects inter-task data dependencies, identifies task-level parallelism, and executes tasks out-of-order. Furthermore, we propose a design for a distributed task super scalar pipeline front end, that can be embedded into any many core fabric, and manages cores as functional units. We show that our proposed mechanism is capable of driving hundreds of cores simultaneously with non-speculative tasks, which allows our pipeline to sustain work windows consisting of tens of thousands of tasks. We further show that our pipeline can maintain a decode rate faster than 60ns per task and dynamically uncover data dependencies among as many as ~50,000 in-flight tasks, using 7MB of on-chip eDRAM storage. This configuration achieves speedups of 95-255x (average 183x) over sequential execution for nine scientific benchmarks, running on a simulated CMP with 256 cores. Task super scalar thus enables programmers to exploit many core systems effectively, while simultaneously simplifying their programming model.

Severe defects in human IFNγ immunity predispose individuals to both Bacillus Calmette–Guérin disease and tuberculosis, whereas milder defects predispose only to tuberculosis¹. Here we report two adults with recurrent pulmonary tuberculosis who are homozygous for a private loss-of-function TNF variant. Neither has any other clinical phenotype and both mount normal clinical and biological inflammatory responses. Their leukocytes, including monocytes and monocyte-derived macrophages (MDMs) do not produce TNF, even after stimulation with IFNγ. Blood leukocyte subset development is normal in these patients. However, an impairment in the respiratory burst was observed in granulocyte–macrophage colony-stimulating factor (GM-CSF)-matured MDMs and alveolar macrophage-like (AML) cells² from both patients with TNF deficiency, TNF- or TNFR1-deficient induced pluripotent stem (iPS)-cell-derived GM-CSF-matured macrophages, and healthy control MDMs and AML cells differentiated with TNF blockers in vitro, and in lung macrophages treated with TNF blockers ex vivo. The stimulation of TNF-deficient iPS-cell-derived macrophages with TNF rescued the respiratory burst. These findings contrast with those for patients with inherited complete deficiency of the respiratory burst across all phagocytes, who are prone to multiple infections, including both Bacillus Calmette–Guérin disease and tuberculosis³. Human TNF is required for respiratory-burst-dependent immunity to Mycobacterium tuberculosis in macrophages but is surprisingly redundant otherwise, including for inflammation and immunity to weakly virulent mycobacteria and many other infectious agents.

Over the past few years, computer architecture research has moved towards execution-driven simulation, due to the inability of traces to capture timing-dependent thread execution interleaving. However, trace-driven simulation has many advantages over execution-driven that are being missed in multithreaded application simulations. We present a methodology to properly simulate multithreaded applications using trace-driven environments. We distinguish the intrinsic application behavior from the computation for managing parallelism. Application traces capture the intrinsic behavior in the sections of code that are independent from the dynamic multithreaded nature, and the points where parallelism-management computation occurs. The simulation framework is composed of a trace-driven simulation engine and a dynamic-behavior component that implements the parallelism-management operations for the application. Then, at simulation time, these operations are reproduced by invoking their implementation in the dynamic-behavior component. The decisions made by these operations are based on the simulated architecture, allowing to dynamically reschedule sections of code taken from the trace to the target simulated components. As the captured sections of code are independent from the parallel state of the application, they can be simulated on the trace-driven engine, while the parallelism-management operations, that require to be re-executed, are carried out by the execution-driven component, thus achieving the best of both trace- and execution-driven worlds. This simulation methodology creates several new research opportunities, including research on scheduling and other parallelism-management techniques for future architectures, and hardware support for programming models.