Miracle-dz/UniFAR-FTUs huggingface dataset:
Adoptive T Cell Therapy with IL-12–Preconditioned Low-Avidity T Cells Prevents Exhaustion and Results in Enhanced T Cell Activation, Enhanced Tumor Clearance, and Decreased Risk for Autoimmunity

Key Points Low-avidity T cells provide poor tumor control and exhibit an exhausted phenotype. IL-12 cytokine priming corrects low-avidity T cell defects and prevents exhaustion. Low- and high-avidity T cells function equivalently with increased tumor Ag. Optimal ex vivo expansion protocols of tumor-specific T cells followed by adoptive cell therapy must yield T cells able to home to tumors and effectively kill them. Our previous study demonstrated ex vivo activation in the presence of IL-12–induced optimal CD8+ T cell expansion and melanoma regression; however, adverse side effects, including autoimmunity, can occur. This may be due to transfer of high-avidity self-specific T cells. In this study, we compared mouse low- and high-avidity T cells targeting the tumor Ag tyrosinase-related protein 2 (TRP2). Not surprisingly, high-avidity T cells provide superior tumor control, yet low-avidity T cells can promote tumor regression. The addition of IL-12 during in vitro expansion boosts low-avidity T cell responsiveness, tumor regression, and prevents T cell exhaustion. In this study, we demonstrate that IL-12–primed T cells are resistant to PD-1/PD-L1–mediated suppression and retain effector function. Importantly, IL-12 preconditioning prevented exhaustion as LAG-3, PD-1, and TOX were decreased while simultaneously increasing KLRG1. Using intravital imaging, we also determined that high-avidity T cells have sustained contacts with intratumoral dendritic cells and tumor targets compared with low-avidity T cells. However, with Ag overexpression, this defect is overcome, and low-avidity T cells control tumor growth. Taken together, these data illustrate that low-avidity T cells can be therapeutically beneficial if cocultured with IL-12 cytokine during in vitro expansion and highly effective in vivo if Ag is not limiting. Clinically, low-avidity T cells provide a safer alternative to high-avidity, TCR-engineered T cells, as IL-12–primed, low-avidity T cells cause less autoimmune vitiligo.
Current concepts underlying the pathophysiology of acute Charcot neuroarthropathy in the diabetic foot and ankle

ABSTRACT Introduction With a complex and often misunderstood etiology, acute Charcot neuroarthropathy (ACN) is a devastating complication of peripheral neuropathy. In patients with diabetes, timely diagnosis of ACN in the foot and ankle is essential to prevent loss of both limb and life. Areas covered Herein, the authors evaluate the growing body of evidence in identifying targeted pathways for future therapeutic interventions. A literature search was conducted through the PubMed research database. Searched terms included ‘Charcot,’ ‘foot and ankle,’ ‘neuroarthropathy,’ ‘pathophysiology,’ ‘arthropathy,’ ‘diabetic foot,’ and ‘Charcot foot. ’ Expert opinion The interplay between the acute inflammatory response, cytokine signaling, and bone metabolism equilibrium can now be better understood with the aid of several novel immunobiologic mechanisms. The more recently elucidated roles of advanced glycation end-products, neuropeptides, monocyte differentiation, and genomics combine with classical Charcot pathophysiology to aid researchers and clinicians alike in combatting this often puzzling consequence of peripheral neuropathy.
REDUNDANCY IN THE SEMIOCHEMICAL MESSAGE REQUIRED TO INDUCE ATTACK ON LODGEPOLE PINES BY THE MOUNTAIN PINE BEETLE, DENDROCTONUS PONDEROSAE HOPKINS (COLEOPTERA: SCOLYTIDAE)

Abstract Baited tree experiments confirmed the hypothesis that frontalin is a multifunctional pheromone that can induce the mountain pine beetle, Dendroctonus ponderosae Hopkins, to aggregate on and mass-attack lodgepole pine, Pinus conforta var. latifolia Engelmann. A re-examination was undertaken of the role of four known semiochemicals, myrcene, trans-verbenol, exo-brevicomin, and frontalin, tested as tree baits alone (with the exception of myrcene) and in all possible combinations. There was considerable redundancy evident in the semiochemical signal. For example, myrcene + frontalin and trans-verbenol + exo-brevicomin induced attack on baited trees at similar levels of intensity. The results suggest that beetles of either sex could initiate a mass attack. During the most attractive phase of host colonization, redundancy in the semiochemical signal could act as a fail-safe mechanism to ensure perception of and response to odors from an attacked tree. In addition the standard, commercial, tree bait containing myrcene, trans-verbenol, and exo-brevicomin might be modified by deleting myrcene, making a more acceptable and cost-effective operational bait. Résumé Des expériences avec des arbres amorcés ont fortifié des hypothèses que la frontaline est une phéromone de fonction multiple, qui peut influer le dendroctone du pin ponderosa, Dendroctonus ponderosae Hopkins, de se rassembler dessus et d’attaquer en masse le pin tordu, Pinus conforta var. latifolia Engelmann. Un nouvel examen du rôle de quatre substances sémiochimiques connues, la myrocène, le trans-verbénol, l’exo-brévicomine et la frontaline a été entrepris, en les essayant comme appâts dans les arbres seulement (sauf pour la myrocène) et dans toutes les combinaisons possibles. Une redondance considérable a été évidente au signal sémiochimique. Par exemple, myrocène + frontaline et trans-verbénol + exo-brévicomine ont induit des attaques de niveaux d’intensité semblables aux arbres amorcés. Les résultats ont suggéré que les dendroctones de n’importe quel sexe pourrait initier une attaque en masse. Pendant la phase la plus attrayante de la colonisation de l’hôte, la redondance du signal sémiochimique pouvait agir comme un mécanisme manqué-réussi pour assurer la perception et la réponse aux odeurs émanant d’un arbre attaqué. De plus, l’appât commercial normal pour les arbres contenant la myrocène, le trans-verbénol et l’exo-brévicomine pourrait être modifié par la suppression de myrocène, pour le faire plus acceptable et un appât opératif économique.
Inorganic nitrogen assimilation by picoplankton and whole plankton in a coastal ecosystem

NH4+ and NO3− seasonal uptake by the phytoplankton and <2−µm communities were investigated in the Menai Strait using 15N tracer techniques. Based on O2‐determined primary production and DIN metabolism measurements, five phases were defined: (1) prebloom (before April), (2) primary net autotrophic (April and May), (3) net heterotrophic (June), (4) secondary net autotrophic (July and August), and (5) regenerative (remainder of calendar year). The inorganic N nutrition of phytoplankton and <2–µm organisms was NO3−−based in spring and NH4+ ‐based in summer and autumn, reflecting varying ambient concentrations of these nutrients superimposed on a general preference for NH4+ by both communities. The percent contribution of picoplankton to the total NH4+ uptake was higher than to nitrate (seasonal averages of 50 ± 14% and 32 ± 24%, respectively). The contribution of the <2–µm size fraction was lowest during both net autotrophic phases (4–13%) and highest during the net heterotrophic, prebloom and regenerative phase (70–84%). A strong correlation between percent NH4+ and NO3− assimilation by the <2–µm size fraction and bacteria abundance between May and July suggests significant bacterial uptake at this time. Bacterial DIN utilization was estimated by correcting uptake rates by the <2−µm fraction, for picophytoplankton presence. During the primary net autotrophic phase, inferred bacterial uptake constituted 13 and 34% of total NO3− and NH4+ uptake, respectively. In the net heterotrophic phase, it amounted to ca. 70% of the total DIN uptake, with no differences between nutrients. Competition between bacteria and phytoplankton for depleted DIN could have contributed to the phytoplankton bloom termination.
Ocular dominance plasticity: Molecular mechanisms revisited

Ocular dominance plasticity (ODP) is a type of cortical plasticity operating in visual cortex of mammals that are endowed with binocular vision based on the competition‐driven disparity. Earlier, a molecular mechanism was proposed that catecholamines play an important role in the maintenance of ODP in kittens. Having survived the initial test, the hypothesis was further advanced to identify noradrenaline (NA) as a key factor that regulates ODP in the immature cortex. Later, the ODP‐promoting effect of NA is extended to the adult with age‐related limitations. Following the enhanced NA availability, the chain events downstream lead to the β‐adrenoreceptor‐induced cAMP accumulation, which in turn activates the protein kinase A. Eventually, the protein kinase translocates to the cell nucleus to activate cAMP responsive element binding protein (CREB). CREB is a cellular transcription factor that controls the transcription of various genes, underpinning neuronal plasticity and long‐term memory. In the advent of molecular genetics in that various types of new tools have become available with relative ease, ODP research has lightly adopted in the rodent model the original concepts and methodologies. Here, after briefly tracing the strategic maturation of our quest, the review moves to the later development of the field, with the emphasis placed around the following issues: (a) Are we testing ODP per se? (b) What does monocular deprivation deprive of the immature cortex? (c) The critical importance of binocular competition, (d) What is the adult plasticity? (e) Excitation–Inhibition balance in local circuits, and (f) Species differences in the animal models.
Estimation of inbreeding rates and extinction risk of forty one belgian chicken breeds in 2005 and 2010

In Belgium, as generally in Europe, the dominant position of the high producing commercial strains specialized in meat or eggs production threats of extinction the local traditional breeds. In this work, a follow up of the changes in populations size, and the rates of inbreeding of the Belgian poultry breeds, has been carried out in 2005 and 2010. About forty breeds were concerned. The Belgian hen breeds being overwhelmingly under threat of extinction, because of the low number of individuals by breed. For each of these breeds, various criteria were considered, risk status, breeding male to breeding female ratio, effective population size, effective population size to actual size ratio and rate of inbreeding.
Retention Forestry to Maintain Multifunctional Forests: A World Perspective

The majority of the world's forests are used for multiple purposes, which often include the potentially conflicting goals of timber production and biodiversity conservation. A scientifically validated management approach that can reduce such conflicts is retention forestry, an approach modeled on natural processes, which emerged in the last 25 years as an alternative to clearcutting. A portion of the original stand is left unlogged to maintain the continuity of structural and compositional diversity. We detail retention forestry's ecological role, review its current practices, and summarize the large research base on the subject. Retention forestry is applicable to all forest biomes, complements conservation in reserves, and represents bottom-up conservation through forest manager involvement. A research challenge is to identify thresholds for retention amounts to achieve desired outcomes. We define key issues for future development and link retention forestry with land-zoning allocation at various scales, expanding its uses to forest restoration and the management of uneven—age forests.
Framing Open Design through Theoretical Concepts and Practical Applications: A Systematic Literature Review

This study reports on the results of a systematic literature review on ‘open design’ in academic fields including and beyond design and HCI. The review investigates how studies are framed as open design and open-source design (including ‘open hardware’): how researchers contribute to conceptual theorizing about open design or study its practical operationalization, in do-it-yourself ‘making,’ manufacturing and practices in-between these domains. Most of the papers reviewed were empirical studies from diverse fields. Open design was analyzed not only as contributions and solutions, but also as open-to-participate processes, openly shared processes, and open, closed, and modular (open and closed) outcomes. Various research fields presented an open design framing as an alternative to the status quo: new ways to do business and/or to foster socio-environmental sustainability. On the manufacturing side, open design was sought especially to accelerate innovation cycles; on the making side, it was espoused to foster democratization. However, the studies reviewed indicated that companies do not appear to develop much beyond business-as-usual. From the research perspective, the conceptual potential of open design to promote sustainability saw little practical exploration. Additionally, issues around open design community governance and ownership, safety and reliability of open outcomes require further investigation.
Continuity and Change in Cuba at 50

After Fidel Castro's retirement from his main governmental positions, Cuba finds itself at a crossroads. Two main challenges emerge, one economic and one political. The economic one arises from the need to design a productive system that resolves the imbalance between workers' salaries and the actual distribution of basic goods and the imbalance between different sectors of society without destroying the revolution's social achievements. The political one must deal with the creation of a new form of governance and consensus building in the absence of the revolution's founder and leader. The changes to be introduced require the broadening of democracy. These challenges entail a national deliberation process during the Sixth Congress of the Cuban Communist Party that will identify several fundamental issues.
Diabetes Management in Resource Poor Countries

The aim of this study was to evaluate the diabetes status and health beliefs of individuals living in villages in Northeast Guatemala. Our study explored current understanding of diabetes in the Peten region of Guatemala concerning the cause, treatment, and effect of type two diabetes by engaging and interviewing 21 diabetic patients in a qualitative study. Interview results showed that among study participants, the cause of diabetes was often “unknown”. With an average of 3.5 years of education among survey participants and many reporting being mostly or fully illiterate, it is likely that health education status plays a major role in their concept of diabetes. The majority of responses claimed some form of “asusto”—defined as a negative emotional event causing physical maladies—to have caused their diabetes. Patient surveys revealed that Gods and prayer ranked the highest among factors controlling their diabetes, with medications being seen as a tertiary control factor, as seen in Figure 1. Only two study participants (2/21) ranked diet/exercise as more impactful on their diabetes than gods/prayer. Survey responses also show that most individuals agree that taking their medications is important, with the most common reported barriers to control of their blood sugar being cost of medications and lifestyle barriers. Altogether, lack of education and resource availability appears to be the most heavily implicated reasons why uncontrolled diabetes is on the rise in Guatemala—it is clear that health education needs to be a major part of therapeutic efforts in this region.
Lateral release in the repair of large ventral hernia

Lateral release or component separation technique for the repair of large midline ventral hernias show encouraging results. Successive modifications to the initial technique have incrementally improved outcome. Modifications include minimizing subcutaneous dissection, mesh reinforcement, perforator sparing dissection, variations of released muscle, and application of minimally invasive surgery techniques. Pre-operative assessment may provide valuable cues on the feasibility of or predict successful abdominal wall reconstruction with the lateral release technique. In cases with loss of domain, the application of adjunct preoperative tissue lengthening techniques may allow successful abdominal wall reconstruction with component
Measuring performance and impact of rural community-led library initiatives in Thailand

Reports the results of performance and impact evaluation of three community-led library initiatives in Central Thailand. The methodology included both quantitative and qualitative approaches. Point of exit interviews with library users were undertaken to gather their opinions on library collections, performance and impact. The constraints faced by community dwellers in using the libraries were also identified. Interviews with community leaders were conducted to gain their perspectives on the problems and how library services could be improved. The results showed that small-scale community-run library services have the potential to make a positive impact on community development. The results also yielded several implications for community-based libraries in Thailand, including how their services could be improved to have even greater impact on the communities they serve. A model for community libraries is provided which can be replicated to speed up rural development in Thailand and beyond.
Global patterns of soil microbial nitrogen and phosphorus stoichiometry in forest ecosystems

Aim To investigate broad-scale patterns of soil microbial nitrogen (N) and phosphorus (P) stoichiometry and their environmental drivers. Location Global forests. Methods By synthesizing 652 observations of soil microbial biomass N and P derived from the published literature, we investigated global patterns of soil microbial N, P and N:P ratios and their relationships with climate, soil and vegetation types. Results Microbial N and P concentrations varied widely among forest types, with relatively low N and P concentrations but high N:P ratios in tropical forests. The N and P concentrations increased and the N:P ratio decreased with increasing latitude (or decreasing temperature). The N:P ratio showed a similar pattern along the precipitation gradient to that along the temperature gradient, whereas microbial N and P displayed weak trends along the precipitation gradient. Edaphic variables also regulated the patterns of microbial N and P stoichiometry: microbial N and P concentrations increased with soil N and P concentrations as well as with soil pH. Mixed-effects models revealed that edaphic factors explained the largest part of the variation in microbial N, P and the N:P ratio, suggesting their dominant role. Main conclusions Our findings highlight that there are broad-scale patterns in microbial N, P and the N:P ratio along the gradients of latitude, temperature and precipitation, which are similar to those reported in plants and soils. The consistency of these patterns in plant–soil–microbe ecosystems supports the hypothesis that P is more often the major limiting element at low latitudes than at high latitudes.
Effects of age and liveweight of dairy heifers at first calving on multiple lactation production

This paper reports on both the individual and combined effects of age and liveweight at first calving (AFC and LWFC, respectively) for Australian Holstein–Friesian heifers on multiple lactation production. One hundred and thirty-five heifers were allocated to 1 of 3 AFC treatments. Within each AFC treatment, heifers were randomly assigned to 1 of 3 LWFC treatments. From 16 weeks of age until first calving, heifers in all groups grazed pasture and were provided with supplementary feed when the quantity and quality of pasture was inadequate to meet growth requirements. Mean AFC and LWFC achieved were 25.1 ± 0.121, 29.9 ± 0.11 and 33.9 ± 0.09 months and 498 ± 4.09, 549 ± 5.40 and 595 ± 5.09 kg, respectively. As AFC increased, total production over the first 3 lactations increased. For each month's delay in AFC an extra 56.7 L milk, 1.78 kg milk fat, 1.45 kg milk protein and 3.23 kg fat + protein over the first 3 lactations was produced but by the third lactation the response was minimal. By end of third lactation the remaining heifers that calved at 25.1 months AFC were producing similar amounts to those that calved at the older AFC. As LWFC increased from 498 to 595 kg, production over the first 3 lactations increased. The response to an extra kilogram increase in LWFC was 4.82 L milk, 0.20 kg milk fat, 0.18 kg milk protein and 0.38 kg fat + protein over the first 3 lactations. The greatest benefit was when LWFC increased from 498 to 549 kg. Increasing LWFC from 549 to 595 kg did not significantly increase milk, milk fat and milk protein yields from the second to third lactation. The combined effects of AFC and LWFC indicated that to reduce the negative effects on production due to decreasing AFC, LWFC would have to increase by 7.2, 2.9 and 2.2 kg for each month decrease in AFC (for milk, fat and protein production, respectively). By the end of the third lactation, only 58 heifers remained in the herd. The number of heifers remaining within the 9 groups ranged from 4 to 10. Increasing LWFC while decreasing AFC reduced the chances of a heifer remaining in the herd but this may have been biased by the feeding regime imposed during lactation. Responses to increasing AFC decreased as the number of lactations increased, indicating that heifers calving at younger AFC produce similar amounts to their older herd-mates by the end of third lactation. Increasing LWFC from 498 to 549 kg had the greatest benefits for yield, indicating a possible maximum LWFC of 549 kg for our study. Therefore, the negative effects due to decreasing AFC can be offset in part, by increasing LWFC. However, on-farm resources and ultimately milk price will determine the choice of combination of AFC and LWFC.
Genetically encoded phenyl azide photochemistry drives positive and negative functional modulation of a red fluorescent protein

The photochemical properties of phenyl azide have been exploited to modulate the function of a red autofluorescent protein, mCherry. Using genetic code reprogramming, phenyl azide chemistry has been introduced at functionally strategic positions in mCherry leading to deactivation, activation or enhancement upon UV irradiation.