Hot-carrier mechanisms in advanced NMOS transistors

Ph.DDOCTOR OF PHILOSOPH

Internal-state-dependent control of feeding behavior via hippocampal ghrelin signaling

Hunger is an internal state that not only invigorates feeding but also acts as a contextual cue for higher-order control of anticipatory feeding-related behavior. The ventral hippocampus is crucial for differentiating optimal behavior across contexts, but how internal contexts such as hunger influence hippocampal circuitry is unknown. In this study, we investigated the role of the ventral hippocampus during feeding behavior across different states of hunger in mice. We found that activity of a unique subpopulation of neurons that project to the nucleus accumbens (vS-NAc neurons) increased when animals investigated food, and this activity inhibited the transition to begin eating. Increases in the level of the peripheral hunger hormone ghrelin reduced vS-NAc activity during this anticipatory phase of feeding via ghrelin-receptor-dependent increases in postsynaptic inhibition and promoted the initiation of eating. Together, these experiments define a ghrelin-sensitive hippocampal circuit that informs the decision to eat based on internal state

Clinical Outcomes for Metastatic Renal Cell Carcinoma (mRCC) Patients Ineligible for Front-line Clinical Trials

Clinical trials for immunotherapy-based regimens in metastatic renal cell carcinoma (mRCC) have extensive inclusion and exclusion criteria. We investigated the clinical outcomes in a real-world cohort of patients who would not have met the criteria for inclusion in front-line mRCC trials. Patients treated with ipilimumab/nivolumab and axitinib/pembrolizumab for front-line mRCC were identified and divided into clinical trial eligible (CTE) and clinical trial ineligible (CTI) cohorts based on key inclusion or exclusion criteria from their respective Phase-3 registration trials. Clinical outcomes were compared in CTE and CTI cohorts. A total of 62 patients treated with axitinib/pembrolizumab and 103 treated with ipilimumab/nivolumab were identified. The International Metastatic RCC Database Consortium (IMDC) criteria were similar across CTE and CTI patients in axitinib/pembrolizumab and ipilimumab/nivolumab cohorts. In the axitinib/pembrolizumab cohort (n = 62), 24 (39%) patients were CTI. The major reasons for the ineligibility were lab abnormalities (n = 11), histology (n = 9), and brain metastases (n = 3). There was no significant difference in response rates (P = 0.08). The median progression-free survival (PFS) was numerically longer in CTE patients (28 vs 12 months; P = 0.09). The overall survival (OS) was higher in the CTE patients (P = 0.02). In the ipilimumab/nivolumab cohort (n = 103), 59 (57%) were CTI. The most common reasons for ineligibility were brain metastases (n = 18), lab abnormalities (n = 16), and histology (n = 16). There was no significant difference in response rates (P = 0.22). However, PFS (P = 0.003) and OS (P < 0.0001) were higher in the CTE patients. In conclusion, many real-world patients are ineligible for RCC clinical trials and had worse outcomes when compared to trial-eligible patients. Additional treatment options are needed for these patients, as well as strategies to include them in prospective trials

New WMO certified megaflash lightning extremes for flash distance (768 km) and duration (17.01 seconds) recorded from space

Initial global extremes in lightning duration and horizontal distance were established in 2017 (Lang et al. 2017) by an international panel of atmospheric lightning scientists and engineers assembled by the WMO. The subsequent launch of NOAA’s latest GOES-16/17 satellites with their Geostationary Lightning Mappers (GLMs) enabled extreme lightning to be monitored continuously over the western hemisphere up to 55° latitude for the first time. As a result, the former lightning extremes were more than doubled in 2019 to 709 km for distance and 16.730 s for duration (Peterson et al. 2020). Continued detection and analysis of lightning “megaflashes” (Sequin, 2021) has now revealed two flashes that even exceed those 2019 records. As part of the ongoing work of the WMO in detection and documentation of global weather extremes (e.g., El Fadli et al. 2013; Merlone et al. 2010), an international WMO evaluation committee was created to critically adjudicate these two GLM megaflash cases as new records for extreme lightning.We thank S. A. Rutledge and two other reviewers for their valuable comments. M. J. Peterson was supported by the U.S. Department of Energy through the Los Alamos National Laboratory (LANL) Laboratory Directed Research and Development (LDRD) program under project number 20200529ECR. Los Alamos National Laboratory is operated by Triad National Security, LLC, for the National Nuclear Security Administration of U.S. Department of Energy (Contract 89233218CNA000001). T. Logan supported by a NOAA Grant NA16OAR4320115 “Lightning Mapper Array Operation in Oklahoma and the Texas Gulf Coast Region to Aid Preparation for the GOES-R GLM.” I. Kolmasova was supported by GACR Grant 20-09671. S. D. Zhang was supported by a NOAA Grant NNH19ZDA001N-ESROGSS. The participation of J. Montanya in this work is supported by research Grant ESP2017-86263-C4-2-R funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe,” by the “European Union”; and Grants PID2019-109269RB-C42 funded by MCIN/AEI/10.13039/501100011033.Peer ReviewedPostprint (author's final draft

Healthcare Worker Seroconversion in SARS Outbreak

Serum samples were obtained from healthcare workers 5 weeks after exposure to an outbreak of severe acute respiratory syndrome (SARS). A sensitive dot blot enzyme-linked immunosorbent assay, complemented by a specific neutralization test, shows that only persons in whom probable SARS was diagnosed had specific antibodies and suggests that subclinical SARS is not an important feature of the disease

Homologous recombination suppresses transgenerational DNA end resection and chromosomal instability in fission yeast

Chromosomal instability (CIN) drives cell-to-cell heterogeneity, and the development of genetic diseases, including cancer. Impaired homologous recombination (HR) has been implicated as a major driver of CIN, however, the underlying mechanism remains unclear. Using a fission yeast model system, we establish a common role for HR genes in suppressing DNA double-strand break (DSB)-induced CIN. Further, we show that an unrepaired single-ended DSB arising from failed HR repair or telomere loss is a potent driver of widespread CIN. Inherited chromosomes carrying a single-ended DSB are subject to cycles of DNA replication and extensive end-processing across successive cell divisions. These cycles are enabled by Cullin 3-mediated Chk1 loss and checkpoint adaptation. Subsequent propagation of unstable chromosomes carrying a single-ended DSB continues until transgenerational end-resection leads to fold-back inversion of single-stranded centromeric repeats and to stable chromosomal rearrangements, typically isochromosomes, or to chromosomal loss. These findings reveal a mechanism by which HR genes suppress CIN and how DNA breaks that persist through mitotic divisions propagate cell-to-cell heterogeneity in the resultant progeny

Homologous recombination repair intermediates promote efficient de novo telomere addition at DNA double-strand breaks

The healing of broken chromosomes by de novo telomere addition, while a normal developmental process in some organisms, has the potential to cause extensive loss of heterozygosity, genetic disease, or cell death. However, it is unclear how de novo telomere addition (dnTA) is regulated at DNA double-strand breaks (DSBs). Here, using a non-essential minichromosome in fission yeast, we identify roles for the HR factors Rqh1 helicase, in concert with Rad55, in suppressing dnTA at or near a DSB. We find the frequency of dnTA in rqh1Δ rad55Δ cells is reduced following loss of Exo1, Swi5 or Rad51. Strikingly, in the absence of the distal homologous chromosome arm dnTA is further increased, with nearly half of the breaks being healed in rqh1Δ rad55Δ or rqh1Δ exo1Δ cells. These findings provide new insights into the genetic context of highly efficient dnTA within HR intermediates, and how such events are normally suppressed to maintain genome stabilit

Legionella pneumophila strain 130b possesses a unique combination of type IV secretion systems and novel Dot/Icm secretion system effector proteins

Legionella pneumophila is a ubiquitous inhabitant of environmental water reservoirs. The bacteria infect a wide variety of protozoa and, after accidental inhalation, human alveolar macrophages, which can lead to severe pneumonia. The capability to thrive in phagocytic hosts is dependent on the Dot/Icm type IV secretion system (T4SS), which translocates multiple effector proteins into the host cell. In this study, we determined the draft genome sequence of L. pneumophila strain 130b (Wadsworth). We found that the 130b genome encodes a unique set of T4SSs, namely, the Dot/Icm T4SS, a Trb-1-like T4SS, and two Lvh T4SS gene clusters. Sequence analysis substantiated that a core set of 107 Dot/Icm T4SS effectors was conserved among the sequenced L. pneumophila strains Philadelphia-1, Lens, Paris, Corby, Alcoy, and 130b. We also identified new effector candidates and validated the translocation of 10 novel Dot/Icm T4SS effectors that are not present in L. pneumophila strain Philadelphia-1. We examined the prevalence of the new effector genes among 87 environmental and clinical L. pneumophila isolates. Five of the new effectors were identified in 34 to 62% of the isolates, while less than 15% of the strains tested positive for the other five genes. Collectively, our data show that the core set of conserved Dot/Icm T4SS effector proteins is supplemented by a variable repertoire of accessory effectors that may partly account for differences in the virulences and prevalences of particular L. pneumophila strains. Copyright © 2010, American Society for Microbiology. All Rights Reserved

Bovine Staphylococcus aureus superantigens stimulate the entire T 2 cell repertoire of cattle.

Superantigens (SAgs) represent a diverse family of bacterial toxins that induce Vβ-specific T cell proliferation associated with an array of important diseases in humans and animals, including mastitis of dairy cows. However, an understanding of the diversity and distribution of SAg genes among bovine Staphylococcus aureus and their role in the pathogenesis of mastitis is lacking. Population genomic analysis of 195 bovine S. aureus isolates representing 57 unique sequence types revealed that strains encode 2 to 12 distinct SAgs and that the majority of isolates contain 5 or more SAg genes. A genome-scale analysis of bovine reference strain RF122 revealed a complement of 11 predicted SAg genes, which were all expressed in vitro. Detection of specific antibodies in convalescent cows suggests expression of 7 of 11 SAgs during natural S. aureus infection. We determined the Vβ T cell activation profile for all functional SAgs encoded by RF122 revealing evidence for bovine host-specific activity among recently identified RF122-encoded SAgs SElY and SElZ. Remarkably, we discovered that some strains have evolved the capacity to stimulate the entire T-cell repertoire of cattle through an array of diverse SAgs suggesting a key role in bovine immune evasion

Short-term comparative outcomes between reverse shoulder arthroplasty for shoulder trauma and shoulder arthritis: a Southeast Asian experience

Background Reverse shoulder arthroplasty (RSA), first introduced as a management option for cuff tear arthropathy, is now an accepted treatment for complex proximal humeral fractures. Few studies have identified whether the outcomes of RSA for shoulder trauma are comparable to those of RSA for shoulder arthritis. Methods This is a retrospective, single-institution cohort study of all patients who underwent RSA at our institution between January 2013 and December 2019. In total, 49 patients met the inclusion criteria. As outcomes, we evaluated the 1-year American Shoulder and Elbow Surgeons (ASES) and Constant shoulder scores, postoperative shoulder range of motion, intra- and postoperative complications, and cumulative revision rate. The patients were grouped based on preoperative diagnosis to compare postoperative outcomes across two broad groups. Results The median follow-up period was 32.8 months (interquartile range, 12.6–66.6 months). The 1-year visual analog scale, range of motion, and Constant and ASES functional scores were comparable between RSAs performed to treat shoulder trauma and that performed for arthritis. The overall complication rate was 20.4%, with patients with a preoperative diagnosis of arthritis having significantly more complications than those with a preoperative diagnosis of trauma (34.8% vs. 7.7%). Conclusions Patients who underwent RSA due to a proximal humeral fracture or dislocation did not fare worse than those who underwent RSA for arthritis at 1 year, in terms of both functional and radiological outcomes