Although the BCL-2 family constitutes a crucial checkpoint in apoptosis, the intricate interplay between these family members remains elusive. Here, we demonstrate that BIM and PUMA, similar to truncated BID (tBID), directly activate BAX-BAK to release cytochrome c. Conversely, anti-apoptotic BCL-2-BCL-X(L)-MCL-1 sequesters these 'activator' BH3-only molecules into stable complexes, thus preventing the activation of BAX-BAK. Extensive mutagenesis of BAX-BAK indicates that their activity is not kept in check by BCL-2-BCL-X(L)-MCL-1. Anti-apoptotic BCL-2 members are differentially inactivated by the remaining 'inactivator' BH3-only molecules including BAD, NOXA, BMF, BIK/BLK and HRK/DP5. BAD displaces tBID, BIM or PUMA from BCL-2-BCL-X(L) to activate BAX-BAK, whereas NOXA specifically antagonizes MCL-1. Coexpression of BAD and NOXA killed wild-type but not Bax, Bak doubly deficient cells or Puma deficient cells with Bim knockdown, indicating that activator BH3-only molecules function downstream of inactivator BH3-only molecules to activate BAX-BAK. Our data establish a hierarchical regulation of mitochondrion-dependent apoptosis by various BCL-2 subfamilies.

statement: Chest computed tomography scans for the primary screening or diagnosis of coronavirus disease 2019 would not be beneficial in a low-prevalence region due to the substantial rate of false-positives.This copy is for personal use only. To order printed copies, contact reprints@rsna.org I n P r e s s Key Results• The pooled sensitivity and specificity were 94% (95% CI: 91%, 96%) and 37% (95% CI: 26%, 50%), respectively, for chest CT. The pooled sensitivity of reverse transcriptasepolymerase chain reaction (RT-PCR) was 89% (95% CI: 81%, 94%).• In low-prevalence (<10%) countries, the positive predictive value of RT-PCR (range: 47.3%, 84.3%) was more than ten times higher than that of CT scans (range: 1.5%, 8.3%).The negative predictive value of both methods ranged from 99.0% to 99.9%. AbbreviationsCI = confidence interval, COVID-19 = coronavirus disease 2019, NPV = negative predictive value, ORF = open reading frame, PPV = positive predictive value, PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-analyses, QUADAS-2 = Quality Assessment of Diagnostic Accuracy Studies-2, RT-PCR = reverse transcriptase-polymerase chain reaction, SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2, WHO = World Health Organization I n P r e s s Abstract Background: Recent studies have suggested that chest computed tomography (CT) scans could be used as a primary screening or diagnostic tool for coronavirus disease 2019 (COVID-19) in epidemic areas.Purpose: To perform a meta-analysis to evaluate diagnostic performance measures, including predictive values, of chest CT and initial reverse transcriptase-polymerase chain reaction (RT-PCR). studies on COVID-19 that reported the sensitivity and/or specificity of CT scans and/or RT-PCR assays. The pooled sensitivity and specificity were estimated by using random-effects models. The actual prevalence (i.e., the proportion of confirmed patients among those tested) in eight countries was obtained from web sources, and the predictive values were calculated. Meta-regression was performed to reveal the effect of potential explanatory factors on the diagnostic performance measures. Results:The pooled sensitivity was 94% (95% CI: 91%, 96%; I 2 =95%) for chest CT and 89% (95% CI: 81%, 94%; I 2 =90%) for RT-PCR. The pooled specificity was 37% (95% CI: 26%, 50%; I 2 =83%) for chest CT. The prevalence of COVID-19 outside China ranged from 1.0% to 22.9%. For chest CT scans, the positive predictive value (PPV) ranged from 1.5% to 30.7%, and the negative predictive value (NPV) ranged from 95.4% to 99.8%. For RT-PCR, the PPV ranged from 47.3% to 96.4%, while the NPV ranged from 96.8% to 99.9%. The sensitivity of CT was affected by the distribution of disease severity, the proportion of patients with comorbidities, and the proportion of asymptomatic patients (all p < 0.05). The sensitivity of RT-PCR was negatively associated with the proportion of elderly patients (p = 0.01). Conclusion:Outside of China where there is a low-prevalence of COVID-19 (1-22.9%), chest CT screening...

SUMMARY While activation of BAX/BAK by BH3-only molecules (BH3s) is essential for mitochondrial apoptosis, the underlying mechanisms remain unsettled. Here, we demonstrate that BAX undergoes stepwise structural reorganization leading to mitochondrial targeting and homo-oligomerization. The α1 helix of BAX keeps the α9 helix engaged in the dimerization pocket, rendering BAX as a monomer in cytosol. The activator BH3s, tBID/BIM/PUMA, attack and expose the α1 helix of BAX, resulting in secondary disengagement of the α9 helix and thereby mitochondrial insertion. Activator BH3s remain associated with the N-terminally exposed BAX through the BH1 domain to drive homo-oligomerization. BAK, an integral mitochondrial membrane protein, has bypassed the first activation step, explaining its faster killing kinetics than BAX. Furthermore, death signals initiated at ER induce BIM and PUMA to activate mitochondrial apoptosis. Accordingly, deficiency of Bim/Puma impedes ER stress-induced BAX/BAK activation and apoptosis. Our study provides mechanistic insights regarding the spatiotemporal execution of BAX/BAK-governed cell death.

The maintenance of genome stability is critical for survival, and its failure is often associated with tumorigenesis. The Fanconi anemia (FA) pathway is essential for the repair of DNA interstrand cross-links (ICLs), and a germline defect in the pathway results in FA, a cancer predisposition syndrome driven by genome instability. Central to this pathway is the monoubiquitination of FANCD2, which coordinates multiple DNA repair activities required for the resolution of ICLs. Recent studies have demonstrated how the FA pathway coordinates three critical DNA repair processes, including nucleolytic incision, translesion DNA synthesis (TLS), and homologous recombination (HR). Here, we review recent advances in our understanding of the downstream ICL repair steps initiated by ubiquitin-mediated FA pathway activation.

Defects in conventional semiconductors substantially lower the photoluminescence (PL)quantum yield (QY), a key metric of optoelectronic performance that directly dictates the maximum device efficiency. Two-dimensional (2D) transition metal dichalcogenides (TMDCs), such as monolayer MoS2, often exhibit low PL QY for as-processed samples, which has typically been attributed to a large native defect density. We show that the PL QY of as-processed MoS2 and WS2 monolayers reaches near-unity when they are made intrinsic by electrostatic doping, without any chemical passivation. Surprisingly, neutral exciton recombination is entirely radiative even in the presence of a high native defect density. This finding enables TMDC monolayers for optoelectronic device applications as the stringent requirement of low defect density is eased.Multiparticle Coulomb interactions are particularly pronounced in transition metal dichalcogenide (TMDC) monolayers, leading to a multitude of recombination pathways, each associated with the different quasiparticles produced by these interactions (1). The recombination rate of excitons formed by photogenerated carriers (2, 3), depends nonlinearly on the concentration. Because excitons interact with background charge to form trions (4-8), the Fermi level also controls the dominant recombination pathway. Thus, both the background carrier concentration and the generation rate must be tuned to investigate the complete effect of multiparticle interactions on TMDC photoluminescence (PL) quantum yield (QY).In this work, we simultaneously altered the photocarrier generation rate (G) by varying the incident pump power, and the total charge concentration (electron and hole population densities; N and P) by varying the back-gate voltage (Vg) in a capacitor structure (Fig. 1A). Surprisingly, we found that all neutral excitons recombine radiatively in as-processed monolayers of MoS2, resulting in near-unity QY at low generation rates. This high QY occurred despite a reported high

Two-dimensional (2D) materials, particularly black phosphorus (bP), have demonstrated themselves to be excellent candidates for high-performance infrared photodetectors and transistors. However, high-quality bP can be obtained only via mechanical exfoliation from high-temperature- and high-pressure-grown bulk crystals and degrades rapidly when exposed to ambient conditions. Here, we report solution-synthesized and air-stable quasi-2D tellurium (Te) nanoflakes for short-wave infrared (SWIR) photodetectors. We perform comprehensive optical characterization via polarization-resolved transmission and reflection measurements and report the absorbance and complex refractive index of Te crystals. It is found that this material is an indirect semiconductor with a band gap of 0.31 eV. From temperature-dependent electrical measurements, we confirm this band-gap value and find that 12 nm thick Te nanoflakes show high hole mobilities of 450 and 1430 cm V s at 300 and 77 K, respectively. Finally, we demonstrate that despite its indirect band gap, Te can be utilized for high-performance SWIR photodetectors by employing optical cavity substrates consisting of Au/AlO to dramatically increase the absorption in the semiconductor. By changing the thickness of the AlO cavity, the peak responsivity of Te photoconductors can be tuned from 1.4 μm (13 A/W) to 2.4 μm (8 A/W) with a cutoff wavelength of 3.4 μm, fully capturing the SWIR band. An optimized room-temperature specific detectivity ( D*) of 2 × 10 cm Hz W is obtained at a wavelength of 1.7 μm.

Although the proteins BAX and BAK are required for initiation of apoptosis at the mitochondria, how BAX and BAK are activated remains unsettled. We provide in vivo evidence demonstrating an essential role of the proteins BID, BIM, and PUMA in activating BAX and BAK. Bid, Bim, and Puma triple-knockout mice showed the same developmental defects that are associated with deficiency of Bax and Bak, including persistent interdigital webs and imperforate vaginas. Genetic deletion of Bid, Bim, and Puma prevented the homo-oligomerization of BAX and BAK, and thereby cytochrome c-mediated activation of caspases in response to diverse death signals in neurons and T lymphocytes, despite the presence of other BH3-only molecules. Thus, many forms of apoptosis require direct activation of BAX and BAK at the mitochondria by a member of the BID, BIM, or PUMA family of proteins.

Prediction of monsoon changes in the coming decades is important for infrastructure planning and sustainable economic development. The decadal prediction involves both natural decadal variability and anthropogenic forcing. Hitherto, the causes of the decadal variability of Northern Hemisphere summer monsoon (NHSM) are largely unknown because the monsoons over Asia, West Africa, and North America have been studied primarily on a regional basis, which is unable to identify coherent decadal changes and the overriding controls on planetary scales. Here, we show that, during the recent global warming of about 0.4°C since the late 1970s, a coherent decadal change of precipitation and circulation emerges in the entirety of the NHSM system. Surprisingly, the NHSM as well as the Hadley and Walker circulations have all shown substantial intensification, with a striking increase of NHSM rainfall by 9.5% per degree of global warming. This is unexpected from recent theoretical prediction and model projections of the 21st century. The intensification is primarily attributed to a mega-El Niño/Southern Oscillation (a leading mode of interannual-to-interdecadal variation of global sea surface temperature) and the Atlantic Multidecadal Oscillation, and further influenced by hemispherical asymmetric global warming. These factors driving the present changes of the NHSM system are instrumental for understanding and predicting future decadal changes and determining the proportions of climate change that are attributable to anthropogenic effects and long-term internal variability in the complex climate system.