GesturalOrigins : a bottom-up framework for establishing systematic gesture data across ape species

Funding: This research received funding from the European Union’s 8th Framework Programme, Horizon 2020, under grant agreement no 802719.Current methodologies present significant hurdles to understanding patterns in the gestural communication of individuals, populations, and species. To address this issue, we present a bottom-up data collection framework for the study of gesture: GesturalOrigins. By “bottom-up”, we mean that we minimise a priori structural choices, allowing researchers to define larger concepts (such as ‘gesture types’, ‘response latencies’, or ‘gesture sequences’) flexibly once coding is complete. Data can easily be re-organised to provide replication of, and comparison with, a wide range of datasets in published and planned analyses. We present packages, templates, and instructions for the complete data collection and coding process. We illustrate the flexibility that our methodological tool offers with worked examples of (great ape) gestural communication, demonstrating differences in the duration of action phases across distinct gesture action types and showing how species variation in the latency to respond to gestural requests may be revealed or masked by methodological choices. While GesturalOrigins is built from an ape-centred perspective, the basic framework can be adapted across a range of species and potentially to other communication systems. By making our gesture coding methods transparent and open access, we hope to enable a more direct comparison of findings across research groups, improve collaborations, and advance the field to tackle some of the long-standing questions in comparative gesture research.Publisher PDFPeer reviewe

Towards improved cover glasses for photovoltaic devices

For the solar energy industry to increase its competitiveness there is a global drive to lower the cost of solar generated electricity. Photovoltaic (PV) module assembly is material-demanding and the cover glass constitutes a significant proportion of the cost. Currently, 3 mm thick glass is the predominant cover material for PV modules, accounting for 10-25% of the total cost. Here we review the state-of-the-art of cover glasses for PV modules and present our recent results for improvement of the glass. These improvements were demonstrated in terms of mechanical, chemical and optical properties by optimizing the glass composition, including addition of novel dopants, to produce cover glasses that can provide: (i) enhanced UV protection of polymeric PV module components, potentially increasing module service lifetimes; (ii) re-emission of a proportion of the absorbed UV photon energy as visible photons capable of being absorbed by the solar cells, thereby increasing PV module efficiencies; (iii) Successful laboratory-scale demonstration of proof-of-concept, with increases of 1-6% in Isc and 1-8% Ipm. Improvements in both chemical and crack resistance of the cover glass were also achieved through modest chemical reformulation, highlighting what may be achievable within existing manufacturing technology constraints

STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway

Prostate cancer (PCa) is a common and fatal type of cancer in men. Metastatic PCa (mPCa) is a major factor contributing to its lethality, although the mechanisms remain poorly understood. PTEN is one of the most frequently deleted genes in mPCa. Here we show a frequent genomic co-deletion of PTEN and STAT3 in liquid biopsies of patients with mPCa. Loss of Stat3 in a Pten-null mouse prostate model leads to a reduction of LKB1/pAMPK with simultaneous activation of mTOR/CREB, resulting in metastatic disease. However, constitutive activation of Stat3 led to high LKB1/pAMPK levels and suppressed mTORC1/CREB pathway, preventing mPCa development. Metformin, one of the most widely prescribed therapeutics against type 2 diabetes, inhibits mTORC1 in liver and requires LKB1 to mediate glucose homeostasis. We find that metformin treatment of STAT3/AR-expressing PCa xenografts resulted in significantly reduced tumor growth accompanied by diminished mTORC1/CREB, AR and PSA levels. PCa xenografts with deletion of STAT3/AR nearly completely abrogated mTORC1/CREB inhibition mediated by metformin. Moreover, metformin treatment of PCa patients with high Gleason grade and type 2 diabetes resulted in undetectable mTORC1 levels and upregulated STAT3 expression. Furthermore, PCa patients with high CREB expression have worse clinical outcomes and a significantly increased risk of PCa relapse and metastatic recurrence. In summary, we have shown that STAT3 controls mPCa via LKB1/pAMPK/mTORC1/CREB signaling, which we have identified as a promising novel downstream target for the treatment of lethal mPCa

International Journal of Cancer / Synergistic crosstalk of hedgehog and interleukin6 signaling drives growth of basal cell carcinoma

Persistent activation of hedgehog (HH)/GLI signaling accounts for the development of basal cell carcinoma (BCC), a very frequent nonmelanoma skin cancer with rising incidence. Targeting HH/GLI signaling by approved pathway inhibitors can provide significant therapeutic benefit to BCC patients. However, limited response rates, development of drug resistance, and severe side effects of HH pathway inhibitors call for improved treatment strategies such as rational combination therapies simultaneously inhibiting HH/GLI and cooperative signals promoting the oncogenic activity of HH/GLI. In this study, we identified the interleukin6 (IL6) pathway as a novel synergistic signal promoting oncogenic HH/GLI via STAT3 activation. Mechanistically, we provide evidence that signal integration of IL6 and HH/GLI occurs at the level of cisregulatory sequences by cobinding of GLI and STAT3 to common HHIL6 target gene promoters. Genetic inactivation of Il6 signaling in a mouse model of BCC significantly reduced in vivo tumor growth by interfering with HH/GLIdriven BCC proliferation. Our genetic and pharmacologic data suggest that combinatorial HHIL6 pathway blockade is a promising approach to efficiently arrest cancer growth in BCC patients.(VLID)301234

Efficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO): a randomised controlled trial

BACKGROUND: We aimed to assess the efficacy and safety of two neutralising monoclonal antibody therapies (sotrovimab [Vir Biotechnology and GlaxoSmithKline] and BRII-196 plus BRII-198 [Brii Biosciences]) for adults admitted to hospital for COVID-19 (hereafter referred to as hospitalised) with COVID-19. METHODS: In this multinational, double-blind, randomised, placebo-controlled, clinical trial (Therapeutics for Inpatients with COVID-19 [TICO]), adults (aged ≥18 years) hospitalised with COVID-19 at 43 hospitals in the USA, Denmark, Switzerland, and Poland were recruited. Patients were eligible if they had laboratory-confirmed SARS-CoV-2 infection and COVID-19 symptoms for up to 12 days. Using a web-based application, participants were randomly assigned (2:1:2:1), stratified by trial site pharmacy, to sotrovimab 500 mg, matching placebo for sotrovimab, BRII-196 1000 mg plus BRII-198 1000 mg, or matching placebo for BRII-196 plus BRII-198, in addition to standard of care. Each study product was administered as a single dose given intravenously over 60 min. The concurrent placebo groups were pooled for analyses. The primary outcome was time to sustained clinical recovery, defined as discharge from the hospital to home and remaining at home for 14 consecutive days, up to day 90 after randomisation. Interim futility analyses were based on two seven-category ordinal outcome scales on day 5 that measured pulmonary status and extrapulmonary complications of COVID-19. The safety outcome was a composite of death, serious adverse events, incident organ failure, and serious coinfection up to day 90 after randomisation. Efficacy and safety outcomes were assessed in the modified intention-to-treat population, defined as all patients randomly assigned to treatment who started the study infusion. This study is registered with ClinicalTrials.gov, NCT04501978. FINDINGS: Between Dec 16, 2020, and March 1, 2021, 546 patients were enrolled and randomly assigned to sotrovimab (n=184), BRII-196 plus BRII-198 (n=183), or placebo (n=179), of whom 536 received part or all of their assigned study drug (sotrovimab n=182, BRII-196 plus BRII-198 n=176, or placebo n=178; median age of 60 years [IQR 50-72], 228 [43%] patients were female and 308 [57%] were male). At this point, enrolment was halted on the basis of the interim futility analysis. At day 5, neither the sotrovimab group nor the BRII-196 plus BRII-198 group had significantly higher odds of more favourable outcomes than the placebo group on either the pulmonary scale (adjusted odds ratio sotrovimab 1·07 [95% CI 0·74-1·56]; BRII-196 plus BRII-198 0·98 [95% CI 0·67-1·43]) or the pulmonary-plus complications scale (sotrovimab 1·08 [0·74-1·58]; BRII-196 plus BRII-198 1·00 [0·68-1·46]). By day 90, sustained clinical recovery was seen in 151 (85%) patients in the placebo group compared with 160 (88%) in the sotrovimab group (adjusted rate ratio 1·12 [95% CI 0·91-1·37]) and 155 (88%) in the BRII-196 plus BRII-198 group (1·08 [0·88-1·32]). The composite safety outcome up to day 90 was met by 48 (27%) patients in the placebo group, 42 (23%) in the sotrovimab group, and 45 (26%) in the BRII-196 plus BRII-198 group. 13 (7%) patients in the placebo group, 14 (8%) in the sotrovimab group, and 15 (9%) in the BRII-196 plus BRII-198 group died up to day 90. INTERPRETATION: Neither sotrovimab nor BRII-196 plus BRII-198 showed efficacy for improving clinical outcomes among adults hospitalised with COVID-19. FUNDING: US National Institutes of Health and Operation Warp Speed

Hyperimmune immunoglobulin for hospitalised patients with COVID-19 (ITAC): a double-blind, placebo-controlled, phase 3, randomised trial

BACKGROUND: Passive immunotherapy using hyperimmune intravenous immunoglobulin (hIVIG) to SARS-CoV-2, derived from recovered donors, is a potential rapidly available, specific therapy for an outbreak infection such as SARS-CoV-2. Findings from randomised clinical trials of hIVIG for the treatment of COVID-19 are limited. METHODS: In this international randomised, double-blind, placebo-controlled trial, hospitalised patients with COVID-19 who had been symptomatic for up to 12 days and did not have acute end-organ failure were randomly assigned (1:1) to receive either hIVIG or an equivalent volume of saline as placebo, in addition to remdesivir, when not contraindicated, and other standard clinical care. Randomisation was stratified by site pharmacy; schedules were prepared using a mass-weighted urn design. Infusions were prepared and masked by trial pharmacists; all other investigators, research staff, and trial participants were masked to group allocation. Follow-up was for 28 days. The primary outcome was measured at day 7 by a seven-category ordinal endpoint that considered pulmonary status and extrapulmonary complications and ranged from no limiting symptoms to death. Deaths and adverse events, including organ failure and serious infections, were used to define composite safety outcomes at days 7 and 28. Prespecified subgroup analyses were carried out for efficacy and safety outcomes by duration of symptoms, the presence of anti-spike neutralising antibodies, and other baseline factors. Analyses were done on a modified intention-to-treat (mITT) population, which included all randomly assigned participants who met eligibility criteria and received all or part of the assigned study product infusion. This study is registered with ClinicalTrials.gov, NCT04546581. FINDINGS: From Oct 8, 2020, to Feb 10, 2021, 593 participants (n=301 hIVIG, n=292 placebo) were enrolled at 63 sites in 11 countries; 579 patients were included in the mITT analysis. Compared with placebo, the hIVIG group did not have significantly greater odds of a more favourable outcome at day 7; the adjusted OR was 1·06 (95% CI 0·77–1·45; p=0·72). Infusions were well tolerated, although infusion reactions were more common in the hIVIG group (18·6% vs 9·5% for placebo; p=0·002). The percentage with the composite safety outcome at day 7 was similar for the hIVIG (24%) and placebo groups (25%; OR 0·98, 95% CI 0·66–1·46; p=0·91). The ORs for the day 7 ordinal outcome did not vary for subgroups considered, but there was evidence of heterogeneity of the treatment effect for the day 7 composite safety outcome: risk was greater for hIVIG compared with placebo for patients who were antibody positive (OR 2·21, 95% CI 1·14–4·29); for patients who were antibody negative, the OR was 0·51 (0·29–0·90; pinteraction=0·001). INTERPRETATION: When administered with standard of care including remdesivir, SARS-CoV-2 hIVIG did not demonstrate efficacy among patients hospitalised with COVID-19 without end-organ failure. The safety of hIVIG might vary by the presence of endogenous neutralising antibodies at entry. FUNDING: US National Institutes of Health

The gestural communication of mountain gorillas (Gorilla beringei beringei)

Gestures are communicative tools with which great apes navigate close-range social interaction. Sharing key commonalities with human linguistic behaviour, the ape gestural system has long been discussed as a potential precursor to language. While gesture studies have increasingly included data on natural wild-type ape behaviour, the role gestures play in wild gorilla sociality remains largely unexplored. I studied four social units of mountain gorillas living in the Bwindi Impenetrable National Park, Uganda, and collected ad libitum video data on daily social interactions across age classes (157 observation days, 53 individuals). Using a novel ELAN-based bottom-up framework for the systematic study of ape gesture (GesturalOrigins), I coded 3330 intentionally produced gesture instances. Mountain gorillas employed 63 gesture actions, ~75% of which were shared with other ape species. Applying latent class analysis, these were split into 126 finer-grained units (‘morphs’). Mountain gorillas requested 11 basic goals, and gesture actions showed high overlap in function with the use of gesture by Pan. Gorilla-specific units were primarily used in requests for sexual and (to an extent) affiliative interaction, and sexual solicitations were associated with the highest gesturing effort and the greatest diversity of synonymous gesture units (followed by play initiations). Play was mostly requested through audible gestures, while gesturing for sex and grooming was biased towards visual forms. In comparison to East African chimpanzees, mountain gorillas gestured more frequently from the ground, from closer proximity, and employed more contact and fewer audible gestures. Despite mountain gorillas’ smaller sized groups and less cooperative nature compared to Pan, they gesture as frequently, with a repertoire of similar size, and employ gestures for similar goals. Investigating wild gorilla gesture use contributes not only a better understanding of gorilla communication but crucial context for theories on the ancestral state of human communicative behaviour and the evolution of language

Complementary Medicine Down-regulates Side-effects of Hormone Therapy in Prostate Cancer Patients

Aim: The present clinical investigation was performed to evaluate the benefits of complementary medicine in prostate cancer patients undergoing hormone therapy (HT). Patients and Methods: Patients (N=93) were treated according to international guidelines. All patients suffered from side-effects induced by the HT. To reduce the side-effects, the patients were complementarily treated with a combination of sodium selenite, proteolytic plant enzymes and Lens culinaris (Lc) lectin. On case report formulas (CRFs), self assessment of defined side-effects of HT (arthralgia, mucosal dryness, bone pain and hot flushes) were documented before (T-0) and on days 25 (T-1) and 50 (T-2) after complementary treatment. Validation was carriedout by scoring from 1 (no side-effects/optimal tolerability) to 6 (extreme side-effects/extremely bad tolerability), however, only patients suffering from severe side-effects (symptom scores >3) were enrolled in this investigation. Results: The severity of side-effects of HT was reduced by complementary treatment with sodium selenite, proteolytic plant enzymes and Lc-lectin. The mean scores of side-effects declined for arthralgia from 4.72 (T-0) to 3.66 (T-1) to 2.76 (T-2), for mucosal dryness from 4.45 (T-0) to 3.65 (T-1) to 2.90 (T-2), for bone pain from 4.74 (T-0) to 3.44 (T-1) to 2.82 (T-2), for hot flushes from 4.97 (T-0) to 3.70 (T-1) to 3.15 (T-2). The reduced severity of the side-effects was statistically significant (p<0.001) for T-1 and T-2, compared to T-0. Conclusion: This investigation demonstrates benefits of indication-based complementary treatment with the combination of sodium selenite, proteolytic plant enzymes and Lc-lectin in prostate cancer patients, e.g. reduction of side-effects of HT