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Pre-existing immunity to seasonal endemic coronaviruses could have profound consequences for antibody responses to SARS-CoV-2, induced from natural infection or vaccination. A first step to establish whether pre-existing responses can impact SARS-CoV-2 infection is to understand the nature and extent of cross-reactivity in humans to coronaviruses. Here we compare serum antibody and memory B cell responses to coronavirus spike proteins from pre-pandemic and SARS-CoV-2 convalescent donors using binding and functional assays. We show weak evidence of pre-existing SARS-CoV-2 cross-reactive serum antibodies in pre-pandemic donors. However, we find evidence of pre-existing cross-reactive memory B cells that are activated during SARS-CoV-2 infection. Monoclonal antibodies show varying degrees of cross-reactivity with betacoronaviruses, including SARS-CoV-1 and endemic coronaviruses. We identify one cross-reactive neutralizing antibody specific to the S2 subunit of the S protein. Our results suggest that pre-existing immunity to endemic coronaviruses should be considered in evaluating antibody responses to SARS-CoV-2. Pre-existing immune responses between antigenically related viruses can influence responses in viral infections or vaccinations. Here the authors assess and characterize the presence of antibody and memory B cell populations specific to SARS-CoV2 and endemic human coronaviruses.

Recent work attributing decadal regime changes in temperature to radiative forcing is extended to atmospheric moisture. Temperature, and specific and relative humidity (T, q, RH) from the HadISDH data set were analyzed for regime shifts using the bivariate test. Most shifts in q and T for global and northern hemisphere (NH), and tropical land occurred within a year of each other. Only one shift of q was recorded in the southern hemisphere (SH). RH increased in the NH in 1990–91 and decreased in a series of shifts from the late 1990s, while in the SH decreased from 2001. The tropics have remained neutral, shifting negative over land and positive over the ocean. The global decreases in 2001 and 2011 was −0.56%. Global RH from 32 climate models from the CMIP5 RCP4.5 archive all contained regime shifts but only 4 reached or exceeded the observed decreases by 2100, the earliest in 2056. Regime shifts in RH and fire danger over Australia are consistent with the SH decreases in RH, shifting within one year of global fire season length in 2002, showing that impacts are also being underestimated by current analyses. Methods for nonlinear attribution and the contributing processes for nonlinear change are discussed. These results show that developing a better understanding of nonlinear change in moisture-related climate risk is an urgent task.

The Forest Fire Danger Index (FFDI) is the main measure used in Australia for estimating fire risk. Recent work by the authors showed that the FFDI forms stable state regimes, nominated as fire climate regimes. These regimes shifted to greater intensity in southern and eastern Australia around the year 2000 and, a decade later, further north. Reductions in atmospheric moisture were the primary contributor. These changes have not been fully incorporated into future projections. This paper compares the recent regime shifts with the most recent national projections of FFDI, published in 2015. They show that for most states and regions, the 2030 upper limit is approached or exceeded by the recent shift, except for two states with large arid zones, South Australia and Western Australia. Methods for attributing past changes, constructing projections, and the inability of climate models to reproduce the recent decreases in atmospheric moisture, all contribute to these underestimates. To address these shortcomings, we make some suggestions to modify efforts aiming to develop seamless predictions and projections of future fire risk.

Earth’s energy imbalance (EEI) is a major indicator of climate change. Its metrics are top of the atmosphere radiation imbalance (EEI TOA) and net internal heat uptake. Both EEI and temperature are expected to respond gradually to forcing on annual timescales. This expectation was tested by analyzing regime changes in the inputs to EEI TOA along with increasing ocean heat content (OHC). Outward longwave radiation (OLR) displayed rapid shifts in three observational and two reanalysis records. The reanalysis records also contained shifts in surface fluxes and temperature. OLR, outward shortwave radiation (OSR) and TOA net radiation (Net) from the CERES Energy Balanced and Filled Ed-4.2.1 (2001–2023) record and from 27 CMIP5 historical and RCP4.5 forced simulations 1861–2100, were also analyzed. All variables from CERES contained shifts but the record was too short to confirm regime changes. Contributions of OLR and OSR to net showed high complementarity over space and time. EEI TOA was −0.47 ± 0.11 W m−2 in 2001–2011 and −1.09 ± 0.11 W m−2 in 2012–2023. Reduced OSR due to cloud feedback was a major contributor, coinciding with rapid increases in sea surface temperatures in 2014. Despite widely varying OLR and OSR, 26/27 climate models produced stable regimes for net radiation. EEI TOA was neutral from 1861, shifting downward in the 26 reliable records between 1963 and 1995, with 25 records showing it stabilizing by 2039. To investigate heat uptake, temperature and OHC 1955/57–2023 was analyzed for regime change in the 100 m, 700 m and 2000 m layers. The 100 m layer, about one third of total heat content, was dominated by regimes. Increases became more gradual with depth. Annual changes between the 700 m layer and 1300 m beneath were negatively correlated (−0.67), with delayed oscillations during lag years 2–9. Heat uptake at depth is dynamic. These changes reveal a complex thermodynamic response to gradual forcing. We outline a complex arrangement of naturally evolved heat engines, dominated by a dissipative heat engine nested within a radiative engine. EEI is a property of the dissipative heat engine. This far-from-equilibrium natural engine has evolved to take the path of least resistance while being constrained by its maximum power limit (~2 W m−2). It is open to the radiative engine, receiving solar radiation and emitting scattered shortwave and longwave radiation. Steady states maximize entropy within the dissipative engine by regulating spatial patterns in surface variables that influence outgoing OLR and OSR. Regime shifts to warmer climates balance the cost of greater irreversibility with increased energy rate density. The result is the regulation of EEI TOA through a form of thermodynamic metabolism.

This paper introduces and analyzes fire climate regimes, steady-state conditions that govern the behavior of fire weather. A simple model representing fire climate was constructed by regressing high-quality regional climate averages against the station-averaged annual Forest Fire Danger Index (FFDI) for Victoria, Australia. Four FFD indices for fire years 1957–2021 were produced for 10 regions. Regions with even coverage of station-averaged total annual FFDI (ΣFFDI) from 1971–2016 exceeded Nash–Sutcliffe efficiencies of 0.84, validating its widespread application. Data were analyzed for shifts in mean, revealing regime shifts that occurred between 1996 and 2003 in the southern states and 2012–2013 in Queensland. ΣFFDI shifted up by ~25% in SE Australia to 8% in the west; by approximately one-third in the SE to 7% in the west for days above high fire danger; by approximately half in the SE to 11% in the west for days above very high, with a greater increase in Tasmania; and by approximately three-quarters in the SE to 9% in the west for days above severe FFDI. Attribution of the causes identified regime shifts in the fire season maximum temperature and a 3 p.m. relative humidity, with changing drought factor and rainfall patterns shaping the results. The 1:10 fire season between Regimes 1 and 2 saw a three to seven times increase with an average of five. For the 1:20 fire season, there was an increase of 2 to 14 times with an average of 8. Similar timing between shifts in the Australian FFDI and the global fire season length suggests that these changes may be global in extent. A trend analysis will substantially underestimate these changes in risk.

Interactions between externally forced and internally generated climate variations on decadal timescales is a major determinant of changing climate risk. Severe testing is applied to observed global and regional surface and satellite temperatures and modelled surface temperatures to determine whether these interactions are independent, as in the traditional signal-to-noise model, or whether they interact, resulting in step-like warming. The multistep bivariate test is used to detect step changes in temperature data. The resulting data are then subject to six tests designed to distinguish between the two statistical hypotheses, hstep and htrend. Test 1: since the mid-20th century, most observed warming has taken place in four events: in 1979/80 and 1997/98 at the global scale, 1988/89 in the Northern Hemisphere and 1968–70 in the Southern Hemisphere. Temperature is more step-like than trend-like on a regional basis. Satellite temperature is more step-like than surface temperature. Warming from internal trends is less than 40 % of the total for four of five global records tested (1880–2013/14). Test 2: correlations between step-change frequency in observations and models (1880–2005) are 0.32 (CMIP3) and 0.34 (CMIP5). For the period 1950–2005, grouping selected events (1963/64, 1968–70, 1976/77, 1979/80, 1987/88 and 1996–98), the correlation increases to 0.78. Test 3: steps and shifts (steps minus internal trends) from a 107-member climate model ensemble (2006–2095) explain total warming and equilibrium climate sensitivity better than internal trends. Test 4: in three regions tested, the change between stationary and non-stationary temperatures is step-like and attributable to external forcing. Test 5: step-like changes are also present in tide gauge observations, rainfall, ocean heat content and related variables. Test 6: across a selection of tests, a simple stepladder model better represents the internal structures of warming than a simple trend, providing strong evidence that the climate system is exhibiting complex system behaviour on decadal timescales. This model indicates that in situ warming of the atmosphere does not occur; instead, a store-and-release mechanism from the ocean to the atmosphere is proposed. It is physically plausible and theoretically sound. The presence of step-like – rather than gradual – warming is important information for characterising and managing future climate risk.

The ongoing pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), necessitates strategies to identify prophylactic and therapeutic drug candidates for rapid clinical deployment. Here, we describe a screening pipeline for the discovery of efficacious SARS-CoV-2 inhibitors. We screen a best-in-class drug repurposing library, ReFRAME, against two high-throughput, high-content imaging infection assays: one using HeLa cells expressing SARS-CoV-2 receptor ACE2 and the other using lung epithelial Calu-3 cells. From nearly 12,000 compounds, we identify 49 (in HeLa-ACE2) and 41 (in Calu-3) compounds capable of selectively inhibiting SARS-CoV-2 replication. Notably, most screen hits are cell-line specific, likely due to different virus entry mechanisms or host cell-specific sensitivities to modulators. Among these promising hits, the antivirals nelfinavir and the parent of prodrug MK-4482 possess desirable in vitro activity, pharmacokinetic and human safety profiles, and both reduce SARS-CoV-2 replication in an orthogonal human differentiated primary cell model. Furthermore, MK-4482 effectively blocks SARS-CoV-2 infection in a hamster model. Overall, we identify direct-acting antivirals as the most promising compounds for drug repurposing, additional compounds that may have value in combination therapies, and tool compounds for identification of viral host cell targets. Here, the authors perform repurposing screens of the ReFRAME drug library in two cell lines and identify inhibitors of SARS-CoV-2 infection. Antiviral activity of prodrug MK-4482 is confirmed in hamsters.

ObjectiveThe Frontotemporal Dementias (FTDs) comprise a clinically and pathologically heterogeneous group of disorders which usually have in common selective degeneration of the frontal and temporal lobes. They account for 10–20% of cases of dementia occurring before the age of 65. On review, it was observed that subtle but relevant changes on initial brain imaging were often not mentioned in the initial radiological report and only came to light during the neuroradiology review meeting.MethodWe audited a series of 39 consecutive patients seen by a single cognitive neurologist (AZ) in whom the initial diagnosis was of a form of FTD.Results38 sets of notes were available for review. Two patients progressed in a manner suggestive of Alzheimer's Disease and were excluded. 22 of the remaining 36 patients satisfied formal diagnostic criteria for forms of FTD (6 behavioural variant FTD (BvFTD), 5 semantic dementia (SD), 3 non-fluent primary progressive aphasia (PNFA), 4 progressive supra-nuclear palsy (PSP), 4 corticobasal syndrome (CBS). We compared the initial non-specialist radiological reports of the MRI scans performed in these 22 patients with the reports of a radiologist who specifically examined the scans with the possibility of an atypical dementia in mind. We found that 6/22 of the original reports provided a full and accurate description of the radiological findings, while 2/22 provided a fully accurate interpretation.ConclusionWe conclude that in this group of patients, with early-onset dementia, valuable diagnostic information may be missed unless clinicians and radiologists jointly review and discuss the brain imaging. We review the diagnostic criteria for this family of disorders and provide illustrative examples of the typical brain imaging findings. It may be advisable to apply standardised scales to facilitate the radiological reporting of scans performed to investigate cognitive disorder.

Function of a renal allograft relies on the integrity of its vascular anatomy. Renal biochemistry, ultrasound and percutaneous biopsy are used in combination to determine allograft function. Biopsy is not without risk, and in this case study we demonstrate a rare but a potentially life-threatening complication of renal allograft biopsy.