Needle-like structures discovered on positively charged lightning branches.

Lightning is a dangerous yet poorly understood natural phenomenon. Lightning forms a network of plasma channels propagating away from the initiation point with both positively and negatively charged ends-called positive and negative leaders1. Negative leaders propagate in discrete steps, emitting copious radio pulses in the 30-300-megahertz frequency band2-8 that can be remotely sensed and imaged with high spatial and temporal resolution9-11. Positive leaders propagate more continuously and thus emit very little high-frequency radiation12. Radio emission from positive leaders has nevertheless been mapped13-15, and exhibits a pattern that is different from that of negative leaders11-13,16,17. Furthermore, it has been inferred that positive leaders can become transiently disconnected from negative leaders9,12,16,18-20, which may lead to current pulses that both reconnect positive leaders to negative leaders11,16,17,20-22 and cause multiple cloud-to-ground lightning events1. The disconnection process is thought to be due to negative differential resistance18, but this does not explain why the disconnections form primarily on positive leaders22, or why the current in cloud-to-ground lightning never goes to zero23. Indeed, it is still not understood how positive leaders emit radio-frequency radiation or why they behave differently from negative leaders. Here we report three-dimensional radio interferometric observations of lightning over the Netherlands with unprecedented spatiotemporal resolution. We find small plasma structures-which we call 'needles'-that are the dominant source of radio emission from the positive leaders. These structures appear to drain charge from the leader, and are probably the reason why positive leaders disconnect from negative ones, and why cloud-to-ground lightning connects to the ground multiple times.

Search for Daily Modulation of MeV Dark Matter Signals with DAMIC-M.

Dark matter (DM) particles with sufficiently large cross sections may scatter as they travel through Earth's bulk. The corresponding changes in the DM flux give rise to a characteristic daily modulation signal in detectors sensitive to DM-electron interactions. Here, we report results obtained from the first underground operation of the DAMIC-M prototype detector searching for such a signal from DM with MeV-scale mass. A model-independent analysis finds no modulation in the rate of 1 e^{-} events with sidereal period, where a DM signal would appear. We then use these data to place exclusion limits on DM in the mass range [0.53,2.7] MeV/c^{2} interacting with electrons via a dark photon mediator. Taking advantage of the time-dependent signal we improve by ∼2 orders of magnitude on our previous limit obtained from the total rate of 1 e^{-} events, using the same dataset. This daily modulation search represents the current strongest limit on DM-electron scattering via ultralight mediators for DM masses around 1 MeV/c^{2}.

First Constraints from DAMIC-M on Sub-GeV Dark-Matter Particles Interacting with Electrons.

We report constraints on sub-GeV dark matter particles interacting with electrons from the first underground operation of DAMIC-M detectors. The search is performed with an integrated exposure of 85.23 g days, and exploits the subelectron charge resolution and low level of dark current of DAMIC-M charge-coupled devices (CCDs). Dark-matter-induced ionization signals above the detector dark current are searched for in CCD pixels with charge up to 7e^{-}. With this dataset we place limits on dark matter particles of mass between 0.53 and 1000 MeV/c^{2}, excluding unexplored regions of parameter space in the mass ranges [1.6,1000] MeV/c^{2} and [1.5,15.1] MeV/c^{2} for ultralight and heavy mediator interactions, respectively.

Recent advances in cutaneous lupus.

Cutaneous lupus erythematosus (CLE) is an inflammatory and autoimmune skin condition that affects patients with systemic lupus erythematosus (SLE) and exists as an isolated entity without associated SLE. Flares of CLE, often triggered by exposure to ultraviolet (UV) light result in lost productivity and poor quality of life for patients and can be associated with trigger of systemic inflammation. In the past 10 years, the knowledge of CLE etiopathogenesis has grown, leading to promising targets for better therapies. Development of lesions likely begins in a pro-inflammatory epidermis, conditioned by excess type I interferon (IFN) production to undergo increased cell death and inflammatory cytokine production after UV light exposure. The reasons for this inflammatory predisposition are not well-understood, but may be an early event, as ANA + patients without criteria for autoimmune disease exhibit similar (although less robust) findings. Non-lesional skin of SLE patients also exhibits increased innate immune cell infiltration, conditioned by excess IFNs to release pro-inflammatory cytokines, and potentially increase activation of the adaptive immune system. Plasmacytoid dendritic cells are also found in non-lesional skin and may contribute to type I IFN production, although this finding is now being questioned by new data. Once the inflammatory cycle begins, lesional infiltration by numerous other cell populations ensues, including IFN-educated T cells. The heterogeneity amongst lesional CLE subtypes isn't fully understood, but B cells appear to discriminate discoid lupus erythematosus from other subtypes. Continued discovery will provide novel targets for additional therapeutic pursuits. This review will comprehensively discuss the contributions of tissue-specific and immune cell populations to the initiation and propagation of disease.

Cutaneous and systemic connections in lupus.

PURPOSE OF REVIEW: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with multiple manifestations, with a majority of SLE patients having cutaneous involvement. Despite ongoing research, the relationship between SLE and cutaneous lupus erythematosus (CLE) pathogeneses remains unknown. This review will compare advances in understanding the cause and pathogenesis of SLE and CLE. RECENT FINDINGS: Recently, mechanisms by which immune cell populations contribute to the pathogenesis of SLE and CLE have been queried. Studies have pointed to transitional B cells and B-cell activating factor (BAFF) signaling as potential drivers of SLE and CLE, with belimumab clinical data supporting these hypotheses. Ustekinumab trials and an exciting regulatory T cell (Treg) adoptive transfer in an SLE patient with cutaneous disease have suggested a role for T-cell-targeted therapies. The theory that neutrophil extracellular traps may be a source of autoantigens in SLE remains controversial, while neutrophils have been suggested as early drivers of cutaneous disease. Finally, plasmacytoid dendritic cells (pDCs) have been studied as a potential therapeutic target in SLE, and anti-blood DC antigen (anti-BDCA) antibody clinical trials have shown promise in treating cutaneous disease. SUMMARY: Although recent findings have contributed to understanding SLE and CLE pathogenesis, the mechanistic link between these diseases remains an area requiring further research.

Radio Emission Reveals Inner Meter-Scale Structure of Negative Lightning Leader Steps.

We use the Low Frequency Array (LOFAR) to probe the dynamics of the stepping process of negatively charged plasma channels (negative leaders) in a lightning discharge. We observe that at each step of a leader, multiple pulses of vhf (30-80 MHz) radiation are emitted in short-duration bursts (<10 µs). This is evidence for streamer formation during corona flashes that occur with each leader step, which has not been observed before in natural lightning and it could help explain x-ray emission from lightning leaders, as x rays from laboratory leaders tend to be associated with corona flashes. Surprisingly, we find that the stepping length is very similar to what was observed near the ground, however with a stepping time that is considerably larger, which as yet is not understood. These results will help to improve lightning propagation models, and eventually lightning protection models.

Results on Low-Mass Weakly Interacting Massive Particles from an 11 kg d Target Exposure of DAMIC at SNOLAB.

We present constraints on the existence of weakly interacting massive particles (WIMPs) from an 11 kg d target exposure of the DAMIC experiment at the SNOLAB underground laboratory. The observed energy spectrum and spatial distribution of ionization events with electron-equivalent energies >200 eV_{ee} in the DAMIC CCDs are consistent with backgrounds from natural radioactivity. An excess of ionization events is observed above the analysis threshold of 50 eV_{ee}. While the origin of this low-energy excess requires further investigation, our data exclude spin-independent WIMP-nucleon scattering cross sections σ_{χ-n} as low as 3×10^{-41} cm^{2} for WIMPs with masses m_{χ} from 7 to 10 GeV c^{-2}. These results are the strongest constraints from a silicon target on the existence of WIMPs with m_{χ}<9 GeV c^{-2} and are directly relevant to any dark matter interpretation of the excess of nuclear-recoil events observed by the CDMS silicon experiment in 2013.

Constraints on Light Dark Matter Particles Interacting with Electrons from DAMIC at SNOLAB.

We report direct-detection constraints on light dark matter particles interacting with electrons. The results are based on a method that exploits the extremely low levels of leakage current of the DAMIC detector at SNOLAB of 2-6×10^{-22} A cm^{-2}. We evaluate the charge distribution of pixels that collect <10e^{-} for contributions beyond the leakage current that may be attributed to dark matter interactions. Constraints are placed on so-far unexplored parameter space for dark matter masses between 0.6 and 100 MeV c^{-2}. We also present new constraints on hidden-photon dark matter with masses in the range 1.2-30 eV c^{-2}.

Dark Matter Search Results from the PICO-60 C_{3}F_{8} Bubble Chamber.

New results are reported from the operation of the PICO-60 dark matter detector, a bubble chamber filled with 52 kg of C_{3}F_{8} located in the SNOLAB underground laboratory. As in previous PICO bubble chambers, PICO-60 C_{3}F_{8} exhibits excellent electron recoil and alpha decay rejection, and the observed multiple-scattering neutron rate indicates a single-scatter neutron background of less than one event per month. A blind analysis of an efficiency-corrected 1167-kg day exposure at a 3.3-keV thermodynamic threshold reveals no single-scattering nuclear recoil candidates, consistent with the predicted background. These results set the most stringent direct-detection constraint to date on the weakly interacting massive particle (WIMP)-proton spin-dependent cross section at 3.4×10^{-41} cm^{2} for a 30-GeV c^{-2} WIMP, more than 1 order of magnitude improvement from previous PICO results.

Dark Matter Search Results from the PICO-2L C3F8 Bubble Chamber.

New data are reported from the operation of a 2 liter C3F8 bubble chamber in the SNOLAB underground laboratory, with a total exposure of 211.5 kg days at four different energy thresholds below 10 keV. These data show that C3F8 provides excellent electron-recoil and alpha rejection capabilities at very low thresholds. The chamber exhibits an electron-recoil sensitivity of <3.5×10(-10) and an alpha rejection factor of >98.2%. These data also include the first observation of a dependence of acoustic signal on alpha energy. Twelve single nuclear recoil event candidates were observed during the run. The candidate events exhibit timing characteristics that are not consistent with the hypothesis of a uniform time distribution, and no evidence for a dark matter signal is claimed. These data provide the most sensitive direct detection constraints on WIMP-proton spin-dependent scattering to date, with significant sensitivity at low WIMP masses for spin-independent WIMP-nucleon scattering.

Germinal center B cells that acquire nuclear proteins are specifically suppressed by follicular regulatory T cells.

Follicular regulatory T cells (Tfr) restrict development of autoantibodies and autoimmunity while supporting high-affinity foreign antigen-specific humoral response. However, whether Tfr can directly repress germinal center (GC) B cells that acquire autoantigens is unclear. Moreover, TCR specificity of Tfr to self-antigens is not known. Our study suggests that nuclear proteins contain antigens specific to Tfr. Targeting of these proteins to antigen-specific B cells in mice triggers rapid accumulation of Tfr with immunosuppressive characteristics. Tfr then exert negative regulation of GC B cells with predominant inhibition of the nuclear protein-acquiring GC B cells, suggesting an important role of direct cognate Tfr-GC B cells interactions for the control of effector B cell response.

Regulation of Photosensitivity by the Hippo Pathway in Lupus Skin.

OBJECTIVE: Photosensitivity is one of the most common manifestations of systemic lupus erythematosus (SLE), yet its pathogenesis is not well understood. The normal-appearing epidermis of patients with SLE exhibits increased ultraviolet B (UVB)-driven cell death that persists in cell culture. Here, we investigated the role of epigenetic modification and Hippo signaling in enhanced UVB-induced apoptosis seen in SLE keratinocytes. METHODS: We analyzed DNA methylation in cultured keratinocytes from SLE patients compared to keratinocytes from healthy controls (n = 6/group). Protein expression was validated in cultured keratinocytes using immunoblotting and immunofluorescence. An immortalized keratinocyte line overexpressing WWC1 was generated via lentiviral vector. WWC1-driven changes were inhibited using a large tumor suppressor kinase 1/2 (LATS1/2) inhibitor (TRULI) and small interfering RNA (siRNA). The interaction between the Yes-associated protein (YAP) and the transcriptional enhancer associate domain (TEAD) was inhibited by overexpression of an N/TERT cell line expressing a tetracycline-inducible green fluorescent protein-tagged protein that inhibits YAP-TEAD binding (TEADi). Apoptosis was assessed using cleaved caspase 3/7 and TUNEL staining. RESULTS: Hippo signaling was the top differentially methylated pathway in SLE versus control keratinocytes. SLE keratinocytes (n = 6) showed significant hypomethylation (Δß = -0.153) and thus overexpression of the Hippo regulator WWC1 (P = 0.002). WWC1 overexpression increased LATS1/2 kinase activation, leading to YAP cytoplasmic retention and altered proapoptotic transcription in SLE keratinocytes. Accordingly, UVB-mediated apoptosis in keratinocytes could be enhanced by WWC1 overexpression or YAP-TEAD inhibition, mimicking SLE keratinocytes. Importantly, inhibition of LATS1/2 with either the chemical inhibitor TRULI or siRNA effectively eliminated enhanced UVB-apoptosis in SLE keratinocytes. CONCLUSION: Our work unravels a novel driver of photosensitivity in SLE: overactive Hippo signaling in SLE keratinocytes restricts YAP transcriptional activity, leading to shifts that promote UVB apoptosis.

Mechanisms of Photosensitivity in Autoimmunity.

Aberrant responses to UV light frequently lead to the formation of skin lesions and the activation of systemic inflammation in some autoimmune diseases, especially systemic lupus erythematosus. Whereas the effects of UV light on the skin have been studied for decades, only recently have some of the mechanisms that contribute to abnormal responses to UV light in patients with autoimmune diseases been uncovered. This review will discuss the biology of UV in the epidermis and discuss the abnormal epidermal and inflammatory mechanisms that contribute to photosensitivity. Further research is required to fully understand how to normalize UV-mediated inflammation in patients with autoimmune diseases.

The Relationship of Lightning Radio Pulse Amplitudes and Source Altitudes as Observed by LOFAR.

When a lightning flash is propagating in the atmosphere it is known that especially the negative leaders emit a large number of very high frequency (VHF) radio pulses. It is thought that this is due to streamer activity at the tip of the growing negative leader. In this work, we have investigated the dependence of the strength of this VHF emission on the altitude of such emission for two lightning flashes as observed by the Low Frequency ARray (LOFAR) radio telescope. We find for these two flashes that the extracted amplitude distributions are consistent with a power-law, and that the amplitude of the radio emissions decreases very strongly with source altitude, by more than a factor of 2 from 1 km altitude up to 5 km altitude. In addition, we do not find any dependence on the extracted power-law with altitude, and that the extracted power-law slope has an average around 3, for both flashes.

Single-cell transcriptomics reveals distinct effector profiles of infiltrating T cells in lupus skin and kidney.

Cutaneous lupus is commonly present in patients with systemic lupus erythematosus (SLE). T cells have been strongly suspected to contribute to the pathology of cutaneous lupus; however, our understanding of the relevant T cell phenotypes and functions remains incomplete. Here, we present a detailed single-cell RNA-Seq profile of T and NK cell populations present within lesional and nonlesional skin biopsies of patients with cutaneous lupus. T cells across clusters from lesional and nonlesional skin biopsies expressed elevated levels of IFN-simulated genes (ISGs). Compared with T cells from control skin, however, T cells from cutaneous lupus lesions did not show elevated expression profiles of activation, cytotoxicity, or exhaustion. Integrated analyses indicated that skin lymphocytes appeared less activated and lacked the expanded cytotoxic populations prominent in lupus nephritis kidney T/NK cells. Comparison of skin T cells from lupus and systemic sclerosis skin biopsies further revealed an elevated ISG signature specific to cells from lupus biopsies. Overall, these data represent the first detailed transcriptomic analysis to our knowledge of the T and NK cells in cutaneous lupus at the single-cell level and have enabled a cross-tissue comparison that highlights stark differences in composition and activation of T/NK cells in distinct tissues in lupus.

Nonlesional lupus skin contributes to inflammatory education of myeloid cells and primes for cutaneous inflammation.

Cutaneous lupus erythematosus (CLE) is a disfiguring and poorly understood condition frequently associated with systemic lupus. Previous studies suggest that nonlesional keratinocytes play a role in disease predisposition, but this has not been investigated in a comprehensive manner or in the context of other cell populations. To investigate CLE immunopathogenesis, normal-appearing skin, lesional skin, and circulating immune cells from lupus patients were analyzed via integrated single-cell RNA sequencing and spatial RNA sequencing. We demonstrate that normal-appearing skin of patients with lupus represents a type I interferon-rich, prelesional environment that skews gene transcription in all major skin cell types and markedly distorts predicted cell-cell communication networks. We also show that lupus-enriched CD16+ dendritic cells undergo robust interferon education in the skin, thereby gaining proinflammatory phenotypes. Together, our data provide a comprehensive characterization of lesional and nonlesional skin in lupus and suggest a role for skin education of CD16+ dendritic cells in CLE pathogenesis.

Hypoxia-induced inflammatory cytokine secretion in human adipose tissue stromovascular cells.

AIMS: Hypoxia has been implicated as a cause of adipose tissue inflammation in obesity, although the inflammatory response of human adipose tissue to hypoxia is not well understood. The goal of this study was to define in vitro inflammatory responses of human adipose tissue to hypoxia and identify molecular mechanisms of hypoxia-induced inflammation. METHODS: The inflammatory milieu and responses of visceral (VAT) and subcutaneous (SAT) adipose tissue explants and purified stromovascular cells (SVFs) from obese and lean humans were studied in an in vitro hypoxic culture system using quantitative real-time PCR, ELISA, western blotting, immunofluorescence microscopy, flow cytometry and immunohistochemistry. RESULTS: Human adipose tissue in obesity demonstrates an increased leucocyte infiltrate that is greater in VAT than SAT and involves macrophages, T cells and natural killer (NK) cells. Hypoxic culture regulates inflammatory cytokine secretion and transcription of metabolic stress response genes in human adipose tissue SVF. Adipocyte diameter is increased and adipose tissue capillary density is decreased in obese participants. Inhibition of c-Jun terminal kinase (JNK) or p38 significantly attenuates hypoxia-induced SVF inflammatory responses. Hypoxia induces phosphorylation of p38 in adipose tissue. CONCLUSIONS: Human adipose tissue in obesity is characterised by a depot-specific inflammatory cell infiltrate that involves not only macrophages, but also T cells and NK cells. Hypoxia induces inflammatory cytokine secretion by human adipose tissue SVF, the primary source of which is adipose tissue macrophages. These data implicate p38 in the regulation of hypoxia-induced inflammation and suggest that alterations in adipocyte diameter and adipose tissue capillary density may be potential underlying causes of adipose tissue hypoxia.

A distinct negative leader propagation mode.

The common phenomenon of lightning still harbors many secrets such as what are the conditions for lightning initiation and what is driving the discharge to propagate over several tens of kilometers through the atmosphere forming conducting ionized channels called leaders. Since lightning is an electric discharge phenomenon, there are positively and negatively charged leaders. In this work we report on measurements made with the LOFAR radio telescope, an instrument primarily build for radio-astronomy observations. It is observed that a negative leader rather suddenly changes, for a few milliseconds, into a mode where it radiates 100 times more VHF power than typical negative leaders after which it spawns a large number of more typical negative leaders. This mode occurs during the initial stage, soon after initiation, of all lightning flashes we have mapped (about 25). For some flashes this mode occurs also well after initiation and we show one case where it is triggered twice, some 100 ms apart. We postulate that this is indicative of a small (order of 5 km[Formula: see text]) high charge pocket. Lightning thus appears to be initiated exclusively in the vicinity of such a small but dense charge pocket.

Timing Calibration and Windowing Technique Comparison for Lightning Mapping Arrays.

Since their introduction 22 years ago, lightning mapping arrays (LMA) have played a central role in the investigation of lightning physics. Even in recent years with the proliferation of digital interferometers and the introduction of the LOw Frequency ARray (LOFAR) radio telescope, LMAs still play an important role in lightning science. LMA networks use a simple windowing technique that records the highest pulse in either 80 µs or 10 µs fixed windows in order to apply a time-of-arrival location technique. In this work, we develop an LMA-emulator that uses lightning data recorded by LOFAR to simulate an LMA, and we use it to test three new styles of pulse windowing. We show that they produce very similar results as the more traditional LMA windowing, implying that LMA lightning mapping results are relatively independent of windowing technique. In addition, each LMA station has its GPS-conditioned clock. While the timing accuracy of GPS receivers has improved significantly over the years, they still significantly limit the timing measurements of the LMA. Recently, new time-of-arrival techniques have been introduced that can be used to self-calibrate systematic offsets between different receiving stations. Applying this calibration technique to a set of data with 32 ns uncertainty, observed by the Colorado LMA, improves the timing uncertainty to 19 ns. This technique is not limited to LMAs and could be used to help calibrate future multi-station lightning interferometers.

Impact of T-cell costimulation modulation in patients with undifferentiated inflammatory arthritis or very early rheumatoid arthritis: a clinical and imaging study of abatacept (the ADJUST trial).

BACKGROUND: Several agents provide treatment for established rheumatoid arthritis (RA), but a crucial therapeutic goal is to delay/prevent progression of undifferentiated arthritis (UA) or very early RA. OBJECTIVE: To determine the impact of T-cell costimulation modulation in patients with UA or very early RA. METHODS: In this double-blind, phase II, placebocontrolled, 2-year study, anti-cyclic citrullinated peptide (CCP)2-positive patients with UA (not fulfilling the ACR criteria for RA) and clinical synovitis of two or more joints were randomised to abatacept ( approximately 10 mg/kg) or placebo for 6 months; the study drug was then terminated. The primary end point was development of RA (by ACR criteria) at year 1. Patients were monitored by radiography, MRI, CCP2, rheumatoid factor and 28 joint count Disease Activity Score (DAS28) over 2 years. RESULTS: At year 1, 12/26 (46%) abatacept-treated versus 16/24 (67%) placebo-treated patients developed RA (difference (95% CI) -20.5% (-47.4% to 7.8%)). Adjusted mean changes from baseline to year 1 in Genant-modified Sharp radiographic scores for abatacepttreated versus placebo-treated patients, respectively, were 0 versus 1.1 for total score, and 0 versus 0.9 for erosion score. Mean changes from baseline to year 1 in MRI erosion, osteitis and synovitis scores were 0, 0.2 and 0.2, respectively, versus 5.0, 6.7 and 2.3 in the abatacept versus placebo groups. Safety was comparable between groups; serious adverse events occurred in one patient (3.6%) in each group. CONCLUSION: Abatacept delayed progression of UA/very early RA in some patients. An impact on radiographic and MRI inhibition was seen, which was maintained for 6 months after treatment stopped. This suggests that it is possible to alter the progression of RA by modulating T-cell responses at a very early stage of disease. Trial registration number NCT00124449.