Cytotoxic T lymphocyte–induced killing in the absence of granzymes A and B is unique and distinct from both apoptosis and perforin-dependent lysis

Cytotoxic T lymphocyte (CTL)–induced death triggered by the granule exocytosis pathway involves the perforin-dependent delivery of granzymes to the target cell. Gene targeting has shown that perforin is essential for this process; however, CTL deficient in the key granzymes A and B maintain the ability to kill their targets by granule exocytosis. It is not clear how granzyme AB−/− CTLs kill their targets, although it has been proposed that this occurs through perforin-induced lysis. We found that purified granzyme B or CTLs from wild-type mice induced classic apoptotic cell death. Perforin-induced lysis was far more rapid and involved the formation of large plasma membrane protrusions. Cell death induced by granzyme AB−/− CTLs shared similar kinetics and morphological characteristics to apoptosis but followed a distinct series of molecular events. Therefore, CTLs from granzyme AB−/− mice induce target cell death by a unique mechanism that is distinct from both perforin lysis and apoptosis

Centrosome docking at the immunological synapse is controlled by Lck signaling.

Docking of the centrosome at the plasma membrane directs lytic granules to the immunological synapse. To identify signals controlling centrosome docking at the synapse, we have studied cytotoxic T lymphocytes (CTLs) in which expression of the T cell receptor-activated tyrosine kinase Lck is ablated. In the absence of Lck, the centrosome is able to translocate around the nucleus toward the immunological synapse but is unable to dock at the plasma membrane. Lytic granules fail to polarize and release their contents, and target cells are not killed. In CTLs deficient in both Lck and the related tyrosine kinase Fyn, centrosome translocation is impaired, and the centrosome remains on the distal side of the nucleus relative to the synapse. These results show that repositioning of the centrosome in CTLs involves at least two distinct steps, with Lck signaling required for the centrosome to dock at the plasma membrane

TESS Discovery of an ultra-short-period planet around the nearby M dwarf LHS 3844

Data from the newly-commissioned \textit{Transiting Exoplanet Survey Satellite} (TESS) has revealed a "hot Earth" around LHS 3844, an M dwarf located 15 pc away. The planet has a radius of $1.32\pm 0.02$ $R_\oplus$ and orbits the star every 11 hours. Although the existence of an atmosphere around such a strongly irradiated planet is questionable, the star is bright enough ($I=11.9$, $K=9.1$) for this possibility to be investigated with transit and occultation spectroscopy. The star's brightness and the planet's short period will also facilitate the measurement of the planet's mass through Doppler spectroscopy.Comment: 10 pages, 4 figures. Submitted to ApJ Letters. This letter makes use of the TESS Alert data, which is currently in a beta test phase, using data from the pipelines at the TESS Science Office and at the TESS Science Processing Operations Cente

Better Together: Expanding Rural Partnerships to Support Families

Chronic shortages of health, social service, and mental health professionals in rural areas necessitate creative partnerships in support of families. Cooperative extension professionals in Family and Consumer Sciences and community health nurses are introduced as trusted professionals in rural communities who can bring critical skills to human services teams. Multidisciplinary prevention programs offer particularly good contexts for county extension educators and community health nurses to work in collaboration with social workers. The case of grandparents raising grandchildren illustrates the critical roles that can be filled by professionals in these two fields to extend the reach of family support programs

Hot, rocky and warm, puffy super-Earths orbiting TOI-402 (HD 15337)

Context: The Transiting Exoplanet Survey Satellite (TESS) is revolutionising the search for planets orbiting bright and nearby stars. In sectors 3 and 4, TESS observed TOI-402 (TIC-120896927), a bright V = 9.1 K1 dwarf also known as HD 15337, and found two transiting signals with periods of 4.76 and 17.18 days and radii of 1.90 and 2.21 R⊕, respectively. This star was observed prior to the TESS detection as part of the radial-velocity (RV) search for planets using the HARPS spectrometer, and 85 precise RV measurements were obtained before the launch of TESS over a period of 14 yr. Aims: In this paper, we analyse the HARPS RV measurements in hand to confirm the planetary nature of these two signals. Methods: HD 15337 happens to present a stellar activity level similar to the Sun, with a magnetic cycle of similar amplitude and RV measurements that are affected by stellar activity. By modelling this stellar activity in the HARPS radial velocities using a linear dependence with the calcium activity index log(RHK′), we are able, with a periodogram approach, to confirm the periods and the planetary nature of TOI-402.01 and TOI-402.02. We then derive robust estimates from the HARPS RVs for the orbital parameters of these two planets by modelling stellar activity with a Gaussian process and using the marginalised posterior probability density functions obtained from our analysis of TESS photometry for the orbital period and time of transit. Results: By modelling TESS photometry and the stellar host characteristics, we find that TOI-402.01 and TOI-402.02 have periods of 4.75642 ± 0.00021 and 17.1784 ± 0.0016 days and radii of 1.70 ± 0.06 and 2.52 ± 0.11 R⊕ (precision 3.6 and 4.2%), respectively. By analysing the HARPS RV measurements, we find that those planets are both super-Earths with masses of 7.20 ± 0.81 and 8.79 ± 1.68 M⊕ (precision 11.3 and 19.1%), and small eccentricities compatible with zero at 2σ. Conclusions: Although having rather similar masses, the radii of these two planets are very different, putting them on different sides of the radius gap. By studying the temporal evolution under X-ray and UV (XUV) driven atmospheric escape of the TOI-402 planetary system, we confirm, under the given assumptions, that photo-evaporation is a plausible explanation for this radius difference. Those two planets, being in the same system and therefore being in the same irradiation environment are therefore extremely useful for comparative exoplanetology across the evaporation valley and thus bring constraints on the mechanisms responsible for the radius gap

TESS Discovery of an Ultra-short-period Planet around the Nearby M Dwarf LHS 3844

Data from the newly commissioned Transiting Exoplanet Survey Satellite has revealed a 'hot Earth' around LHS 3844, an M dwarf located 15 pc away. The planet has a radius of R ⊕ and orbits the star every 11 hr. Although the existence of an atmosphere around such a strongly irradiated planet is questionable, the star is bright enough (I = 11.9, K = 9.1) for this possibility to be investigated with transit and occultation spectroscopy. The star's brightness and the planet's short period will also facilitate the measurement of the planet's mass through Doppler spectroscopy

Synthetic biology, genetic circuits and machine learning: a new age of cancer therapy

Synthetic biology has made it possible to rewire natural cellular responses to treat disease, notably demonstrated by chimeric antigen receptor (CAR) T cells as cancer immunotherapy. Building on the success of T‐cell activation using synthetic receptors, the field is now investigating how induction of noncanonical signalling pathways and sophisticated synthetic gene circuitry can enhance the antitumour phenotype of engineered T cells. This commentary explores two recently published studies that provide proof of concept for how new technologies achieve this. The first demonstrated that non‐naturally occurring combinations of signalling motifs derived from various immune receptors and arranged as a CAR drove unique signal transduction pathways in T cells and improved their tumour killing ability. Here, machine learning complemented the screening process and successfully predicted CAR T‐cell phenotype dependent on signalling motif choice. The second explored how synthetic zinc fingers can be engineered into controllable transcriptional regulators, where their activity was dependent on the presence or absence of FDA‐approved small‐molecule drugs. These studies are pivotal in expanding the design choices available for gene circuits of the future and highlight how a single cellular therapy could respond to multiple environmental cues including target cell antigen expression, the tumour microenvironment composition and small molecule drugs