Millisecond pulsars (MSPs) are old neutron stars that spin hundreds of times per second and appear to pulsate as their emission beams cross our line of sight. To date, radio pulsations have been ...detected from all rotation-powered MSPs. In an attempt to discover radio-quiet gamma-ray MSPs, we used the aggregated power from the computers of tens of thousands of volunteers participating in the Einstein@Home distributed computing project to search for pulsations from unidentified gamma-ray sources in Fermi Large Area Telescope data. This survey discovered two isolated MSPs, one of which is the only known rotation-powered MSP to remain undetected in radio observations. These gamma-ray MSPs were discovered in completely blind searches without prior constraints from other observations, raising hopes for detecting MSPs from a predicted Galactic bulge population.
The objective of this study was to examine FoxO expression and FoxO function in meniscus. In menisci from human knee joints with osteoarthritis (OA), FoxO1 and 3 expression were significantly reduced ...compared with normal menisci from young and old normal donors. The expression of FoxO1 and 3 was also significantly reduced in mouse menisci during aging and OA induced by surgical meniscus destabilization or mechanical overuse. Deletion of FoxO1 and combined FoxO1, 3, and 4 deletions induced abnormal postnatal meniscus development in mice and these mutant mice spontaneously displayed meniscus pathology at 6 mo. Mice with Col2Cre-mediated deletion of FoxO3 or FoxO4 had normal meniscus development but had more severe aging-related damage. In mature AcanCreERT2 mice, the deletion of FoxO1, 3, and 4 aggravated meniscus lesions in all experimental OA models. FoxO deletion suppressed autophagy and antioxidant defense genes and altered several meniscus-specific genes. Expression of these genes was modulated by adenoviral FoxO1 in cultured human meniscus cells. These results suggest that FoxO1 plays a key role in meniscus development and maturation, and both FoxO1 and 3 support homeostasis and protect against meniscus damage in response to mechanical overuse and during aging and OA.
Body condition indices, measures of body ‘plumpness’ or mass relative to frame size, are often used as a proxy for lipid reserves or fitness‐related traits of animals and assumed to be positively ...related to fitness. The quantification and analysis of body condition indices has been the subject of debate for decades. Here, we summarize three additional concerns with the use of body condition indices. First, body condition index is often poorly correlated with lipid content in animals. Second, even if body condition index and lipid content are correlated, lipid content of an animal may not be the most important aspect of body composition influencing fitness. Finally, neither body condition index nor lipid reserves are likely to be directly positively related to fitness in animals, as many animals homeostatically regulate intermediate levels of condition index or lipid reserves, with both higher and lower values incurring fitness costs. A wide range of analytical methods, including some relatively inexpensive and simple measures, are available for more detailed measures of animal body composition or fitness‐related traits. Replacing body condition indices with more direct measures of body composition – even relatively simple measures – can inform understanding of the physiological mechanisms underlying animal responses in a wide range of behavioural, ecological and evolutionary studies.
Summary
Renewed interests in the development of bioenergy, biochemicals, and biomaterials have elicited new strategies for engineering the lignin of biomass feedstock plants. This study shows, for ...the first time, that 3,4‐dihydroxybenzoate (DHB) is compatible with the radical coupling reactions that assemble polymeric lignin in plants.
We introduced a bacterial 3‐dehydroshikimate dehydratase into hybrid poplar (Populus alba × grandidentata) to divert carbon flux away from the shikimate pathway, which lies upstream of lignin biosynthesis.
Transgenic poplar wood had up to 33% less lignin with p‐hydroxyphenyl units comprising as much as 10% of the lignin. Mild alkaline hydrolysis of transgenic wood released fewer ester‐linked p‐hydroxybenzoate groups than control trees, and revealed the novel incorporation of cell‐wall‐bound DHB, as well as glycosides of 3,4‐dihydroxybenzoic acid (DHBA). Two‐dimensional nuclear magnetic resonance (2D‐NMR) analysis uncovered DHBA‐derived benzodioxane structures suggesting that DHB moieties were integrated into the lignin polymer backbone. In addition, up to 40% more glucose was released from transgenic wood following ionic liquid pretreatment and enzymatic hydrolysis.
This work highlights the potential of diverting carbon flux from the shikimate pathway for lignin engineering and describes a new type of ‘zip‐lignin’ derived from the incorporation of DHB into poplar lignin.
•Forensic analysis of Android and iOS Happn dating apps.•iTunes backup artifacts from Happn mobile app forensics.•Physical image and network traffic artifacts from Happn forensics.
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...With today’s world revolving around online interaction, dating applications (apps) are a prime example of how people are able to discover and converse with others that may share similar interests or lifestyles, including during the recent COVID-19 lockdowns. To connect the users, geolocation is often utilized. However, with each new app comes the possibility of criminal exploitation. For example, while apps with geolocation feature are intended for users to provide personal information that drive their search to meet someone, that same information can be used by hackers or forensic analysts to gain access to personal data, albeit for different purposes. This paper examines the Happn dating app (versions 9.6.2, 9.7, and 9.8 for iOS devices, and versions 3.0.22 and 24.18.0 for Android devices), which geographically works differently compared to most notable dating apps by providing users with profiles of other users that might have passed by them or in the general radius of their location. Encompassing both iOS and Android devices along with eight varying user profiles with diverse backgrounds, this study aims to explore the potential for a malicious actor to uncover the personal information of another user by identifying artifacts that may pertain to sensitive user data.
Leucine-rich repeat kinase 2 (LRRK2) has been implicated in both familial and sporadic Parkinson’s disease (PD), yet its pathogenic role remains unclear. A previous screen in Drosophila identified ...Scar/WAVE (Wiskott-Aldrich syndrome protein-family verproline) proteins as potential genetic interactors of LRRK2. Here, we provide evidence that LRRK2 modulates the phagocytic response of myeloid cells via specific modulation of the actin-cytoskeletal regulator, WAVE2. We demonstrate that macrophages and microglia from LRRK2–G2019S PD patients and mice display a WAVE2-mediated increase in phagocytic response, respectively. Lrrk2 loss results in the opposite effect. LRRK2 binds and phosphorylates Wave2 at Thr470, stabilizing and preventing its proteasomal degradation. Finally, we show that Wave2 also mediates Lrrk2–G2019S-induced dopaminergic neuronal death in both macrophage-midbrain cocultures and in vivo. Taken together, a LRRK2–WAVE2 pathway, which modulates the phagocytic response in mice and human leukocytes, may define an important role for altered immune function in PD.
Delayed healing of diabetic foot ulcers (DFUs) is known to be caused by dysregulated M1/M2-type macrophages, and restoring the balance between these macrophage types plays a critical role in healing. ...However, drugs used to regulate M1/M2 macrophages have not yet been studied in large randomized clinical trials.
To compare the topical application of ON101 cream with use of an absorbent dressing (Hydrofiber; ConvaTec Ltd) when treating DFUs.
This multicenter, evaluator-blinded, phase 3 randomized clinical trial was performed in 21 clinical and medical centers across the US, China, and Taiwan from November 23, 2012, to May 11, 2020. Eligible patients with debrided DFUs of 1 to 25 cm2 present for at least 4 weeks and with Wagner grade 1 or 2 were randomized 1:1 to receive ON101 or control absorbent dressings.
Twice-daily applications of ON101 or a absorbent dressing changed once daily or 2 to 3 times a week for 16 weeks, with a 12-week follow-up.
The primary outcome was the incidence of complete healing, defined as complete re-epithelialization at 2 consecutive visits during the treatment period assessed on the full-analysis set (FAS) of all participants with postrandomization data collected. Safety outcomes included assessment of the incidences of adverse events, clinical laboratory values, and vital signs.
In the FAS, 236 eligible patients (175 men 74.2%; mean SD age, 57.0 10.9 years; mean SD glycated hemoglobin level, 8.1% 1.6%) with DFUs classified as Wagner grade 1 or 2 (mean SD ulcer area, 4.8 4.4 cm2) were randomized to receive either the ON101 cream (n = 122) or the absorbent dressing (n = 114) for as long as 16 weeks. The incidence of complete healing in the FAS included 74 patients (60.7%) in the ON101 group and 40 (35.1%) in the comparator group during the 16-week treatment period (difference, 25.6 percentage points; odds ratio, 2.84; 95% CI, 1.66-4.84; P < .001). A total of 7 (5.7%) treatment-emergent adverse events occurred in the ON101 group vs 5 (4.4%) in the comparator group. No treatment-related serious adverse events occurred in the ON101 group vs 1 (0.9%) in the comparator group.
In this multicenter randomized clinical trial, ON101 exhibited better healing efficacy than absorbent dressing alone in the treatment of DFUs and showed consistent efficacy among all patients, including those with DFU-related risk factors (glycated hemoglobin level, ≥9%; ulcer area, >5 cm2; and DFU duration, ≥6 months).
ClinicalTrials.gov Identifier: NCT01898923.
We used a novel method (omega score) to analyse the effects of short-term androgen deprivation therapy (ADT) for prostate cancer according to the relative risk of competing events. Among patients ...with low-risk or favourable intermediate-risk disease, those with higher omega scores selectively benefitted from ADT.
Previous studies indicate that the benefit of short-term androgen deprivation therapy (ADT) with radiotherapy (RT) for prostate cancer depends on competing risks.
To determine whether a quantitative method to stratify patients by risk for competing events (omega score) could identify subgroups that selectively benefit from ADT.
An ancillary analysis of NRG/RTOG 9408 phase 3 trial (NCT00002597) involving 1945 prostate cancer patients was conducted.
Short-term ADT.
We applied generalised competing event regression models incorporating age, performance status, comorbidity, T category, Gleason score (GS), and prostate-specific antigen (PSA), to stratify patients according to relative hazards for primary cancer-related events (distant metastasis or prostate cancer death) versus competing noncancer mortality. We tested interactions between ADT and subgroups defined by standard risk criteria versus relative risk (RR) using the omega score.
T2b, higher GS, and higher PSA were associated with an increased RR for cancer-related versus competing mortality events (a higher omega score); increased age and comorbidity were associated with a decreased omega score. Of 996 patients with low-risk/favourable intermediate-risk (FIR) disease, 286 (28.7%) had a high omega score (≥0.314). Of 768 patients with unfavourable intermediate-risk disease, 175 (22.8%) had a low omega score. The overall discordance in risk classification was 26.1%. Both standard criteria and omega score identified significant interactions for the effect of ADT on cancer-related events and late mortality in low- versus high-risk subgroups. Within the low-risk/FIR subgroup, a higher omega score identified patients in whom ADT significantly reduced cancer events and improved event-free survival. Limitations are the need for external/prospective validation and lower RT doses than contemporary standards.
Stratification based on competing event risk is useful for identifying prostate cancer patients who selectively benefit from ADT.
We analysed the effectiveness of androgen deprivation therapy (ADT) for localised prostate cancer among patients, defined by the relative risk (RR) for cancer versus noncancer events. Among patients with traditional low-risk/favourable intermediate-risk disease, those with a higher RR benefitted from short-term ADT.
A previous study by our group showed that a 44-amino-acid fragment of pigment epithelium-derived factor (PEDF) facilitated corneal epithelial wound healing. In the present study this fragment was ...shortened to obtain peptides of 18, 20 and 29 amino acids in length, and their promoting effects on the healing of full-thickness skin wounds were assessed. Peptides were delivered periodically by topical application to punch wounds of mice. The wound healing speed was evaluated by measuring the reduction of wound areas at 4 and 7 days after injury. Histological analysis with Masson's trichrome staining was used to confirm epithelialization and dermal collagen deposition. Proliferation of epithelial basal cells was documented by 5-bromo-2′-deoxyuridine incorporation. Hair follicle stem cells were identified by immunostaining for leucine-rich repeat-containing G protein-coupled receptor 6. The results indicated that the 20- and 29-amino-acid short peptides significantly reduced the time required for wound healing compared to the vehicle. Histological analysis confirmed faster epithelial cell coverage of open wounds. Treatment with the PEDF peptide fragments also contributed to granulation, tissue formation by increasing the fibroblast population and enhancing collagen deposition in the dermis. Wounds treated with PEDF peptide fragments contained more basal cells proliferated in the epithelium. Moreover, hair follicle stem cells were also stimulated to proliferate by peptide exposure. In conclusion, the present study reported the identification of two short peptides that can enhance the healing of full-thickness skin wounds following topical application. The underlying mechanisms may involve activation of basal cell proliferation and mobilization of hair follicle stem cells.
Early life stress presents an important risk factor for drug addiction and comorbid depression and anxiety through persistent effects on the mesolimbic dopamine pathways. Using an early life stress ...model for child neglect (a single 24 h episode of maternal deprivation, MD) in rats, recent published works from our lab show that MD induces dysfunction in the ventral tegmental area and its negative controller, the lateral habenula (LHb). MD‐induced potentiation of glutamatergic synaptic transmission onto LHb neurons shifts the coordination of excitation/inhibition (E/I) balance towards excitation, resulting in an increase in the overall spontaneous neuronal activity with elevation in bursting and tonic firing, and in the intrinsic excitability of LHb neurons in early adolescent male rats. Here, we explored how MD affects intravenous morphine self‐administration (MSA) acquisition and sucrose preference as well as glutamatergic synaptic function in LHb neurons of adult male rats self‐administering morphine. We found that MD‐induced increases in LHb neuronal and glutamatergic synaptic activity and E/I ratio persisted into adulthood. Moreover, MD significantly reduced morphine intake, triggered anhedonia‐like behaviour in the sucrose preference test and was associated with persistent glutamatergic potentiation 24 h after the last MSA session. MSA also altered the decay time kinetics of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor (AMPAR) currents in LHb neurons of control rats during this time period. Our data highlight that early life stress‐induced glutamatergic plasticity in LHb may dampen the positive reinforcing and motivational properties of both natural rewards and opioids, and may contribute to the development of anhedonia and dysphoric states associated with opioids.
In this study, we demonstrate that early maternal deprivation (MD) in rats alters morphine self‐ administration acquisition, and decreases sucrose preference, and is associated with persistent MD‐induced LHb glutamatergic synaptic plasticity that supports LHb hyperactivity. This persistent MD‐induced glutamatergic potentiation in LHb neurons may contribute to anhedonia to natural rewarding stimuli as well as alter the reinforcing and motivational properties of opioids, potentially facilitating opioid‐related behaviors in adult male rats.
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