A cortical circuit for gain control by behavioral state.

The brain's response to sensory input is strikingly modulated by behavioral state. Notably, the visual response of mouse primary visual cortex (V1) is enhanced by locomotion, a tractable and accessible example of a time-locked change in cortical state. The neural circuits that transmit behavioral state to sensory cortex to produce this modulation are unknown. In vivo calcium imaging of behaving animals revealed that locomotion activates vasoactive intestinal peptide (VIP)-positive neurons in mouse V1 independent of visual stimulation and largely through nicotinic inputs from basal forebrain. Optogenetic activation of VIP neurons increased V1 visual responses in stationary awake mice, artificially mimicking the effect of locomotion, and photolytic damage of VIP neurons abolished the enhancement of V1 responses by locomotion. These findings establish a cortical circuit for the enhancement of visual response by locomotion and provide a potential common circuit for the modulation of sensory processing by behavioral state.

Minimum in the pressure dependence of the interfacial free energy between ice Ih and water.

Despite the importance of ice nucleation, this process has been barely explored at negative pressures. Here, we study homogeneous ice nucleation in stretched water by means of molecular dynamics seeding simulations using the TIP4P/Ice model. We observe that the critical nucleus size, interfacial free energy, free energy barrier, and nucleation rate barely change between isobars from -2600 to 500 bars when they are represented as a function of supercooling. This allows us to identify universal empirical expressions for homogeneous ice nucleation in the pressure range from -2600 to 500 bars. We show that this universal behavior arises from the pressure dependence of the interfacial free energy, which we compute by means of the mold integration technique, finding a shallow minimum around -2000 bars. Likewise, we show that the change in the interfacial free energy with pressure is proportional to the excess entropy and the slope of the melting line, exhibiting in the latter a reentrant behavior also at the same negative pressure. Finally, we estimate the excess internal energy and the excess entropy of the ice Ih-water interface.

Segregation of four Agrobacterium tumefaciens replicons during polar growth: PopZ and PodJ control segregation of essential replicons.

Agrobacterium tumefaciens C58 contains four replicons, circular chromosome (CC), linear chromosome (LC), cryptic plasmid (pAt), and tumor-inducing plasmid (pTi), and grows by polar growth from a single growth pole (GP), while the old cell compartment and its old pole (OP) do not elongate. We monitored the replication and segregation of these four genetic elements during polar growth. The three largest replicons (CC, LC, pAt) reside in the OP compartment prior to replication; post replication one copy migrates to the GP prior to division. CC resides at a fixed location at the OP and replicates first. LC does not stay fixed at the OP once the cell cycle begins and replicates from varied locations 20 min later than CC. pAt localizes similarly to LC prior to replication, but replicates before the LC and after the CC. pTi does not have a fixed location, and post replication it segregates randomly throughout old and new cell compartments, while undergoing one to three rounds of replication during a single cell cycle. Segregation of the CC and LC is dependent on the GP and OP identity factors PopZ and PodJ, respectively. Without PopZ, replicated CC and LC do not efficiently partition, resulting in sibling cells without CC or LC. Without PodJ, the CC and LC exhibit abnormal localization to the GP at the beginning of the cell cycle and replicate from this position. These data reveal PodJ plays an essential role in CC and LC tethering to the OP during early stages of polar growth.

How the COVID-19 pandemic affects the moral reasoning of pediatric residents and the general population.

BACKGROUND: Kohlberg's theory of moral development asserts that people progress through different stages of moral reasoning as their cognitive abilities and social interactions mature. Individuals at the lowest stage of moral reasoning (preconventional stage) judge moral issues based on self-interest, those with a medium stage (conventional stage) judge them based on compliance with rules and norms, and those at the highest stage (postconventional stage) judge moral issues based on universal principles and shared ideals. Upon attaining adulthood, it can be considered that there is stability in the stage of individuals' moral development; however, the effect of a global population crisis such as the one experienced in March 2020, when the World Health Organization (WHO) declared the COVID-19 pandemic, is unknown. The purpose of this study was to evaluate the changes in the moral reasoning of pediatric residents before and after one year of the COVID-19 pandemic and compare them with a general population group. METHODS: This is a naturalistic quasi-experimental study conducted with two groups, one comprised 47 pediatric residents of a tertiary hospital converted into a COVID hospital during the pandemic and another group comprised 47 beneficiaries of a family clinic who were not health workers. The defining issues test (DIT) was applied to the 94 participants during March 2020, before the pandemic initiated in Mexico, and later during March 2021. To assess intragroup changes, the McNemar-Bowker and Wilcoxon tests were used. RESULTS: Pediatric residents showed higher baseline stages of moral reasoning: 53% in the postconventional group compared to the general population group (7%). In the preconventional group, 23% were residents and 64% belonged to the general population. In the second measurement, one year after the start of the pandemic, the group of residents had a significant decrease of 13 points in the P index, unlike the general population group in which a decrease of 3 points was observed. This decrease however, did not equalize baseline stages. Pediatric residents remained 10 points higher than the general population group. Moral reasoning stages were associated with age and educational stage. CONCLUSIONS: After a year of the COVID-19 pandemic, we found a decrease in the stage of moral reasoning development in pediatric residents of a hospital converted for the care of patients with COVID-19, while it remained stable in the general population group. Physicians showed higher stages of moral reasoning at baseline than the general population.

Experience-dependent structural plasticity at pre- and postsynaptic sites of layer 2/3 cells in developing visual cortex.

The developing brain can respond quickly to altered sensory experience by circuit reorganization. During a critical period in early life, neurons in the primary visual cortex rapidly lose responsiveness to an occluded eye and come to respond better to the open eye. While physiological and some of the molecular mechanisms of this process have been characterized, its structural basis, except for the well-known changes in the thalamocortical projection, remains obscure. To elucidate the relationship between synaptic remodeling and functional changes during this experience-dependent process, we used 2-photon microscopy to image synaptic structures of sparsely labeled layer 2/3 neurons in the binocular zone of mouse primary visual cortex. Anatomical changes at presynaptic and postsynaptic sites in mice undergoing monocular visual deprivation (MD) were compared to those in control mice with normal visual experience. We found that postsynaptic spines remodeled quickly in response to MD, with neurons more strongly dominated by the deprived eye losing more spines. These postsynaptic changes parallel changes in visual responses during MD and their recovery after restoration of binocular vision. In control animals with normal visual experience, the formation of presynaptic boutons increased during the critical period and then declined. MD affected bouton formation, but with a delay, blocking it after 3 d. These findings reveal intracortical anatomical changes in cellular layers of the cortex that can account for rapid activity-dependent plasticity.

GROWTH POLE RING protein forms a 200-nm-diameter ring structure essential for polar growth and rod shape in Agrobacterium tumefaciens.

Polar growth in Agrobacterium pirates and repurposes well-known bacterial cell cycle proteins, such as FtsZ, FtsA, PopZ, and PodJ. Here we identify a heretofore unknown protein that we name GROWTH POLE RING (GPR) due to its striking localization as a hexameric ring at the growth pole during polar growth. GPR also localizes at the midcell late in the cell cycle just before division, where it is then poised to be precisely localized at new growth poles in sibling cells. GPR is 2,115 aa long, with two N-terminal transmembrane domains placing the bulk of the protein in the cytoplasm, N- and C-terminal proline-rich disordered regions, and a large 1,700-aa central region of continuous α-helical domains. This latter region contains 12 predicted adjacent or overlapping apolipoprotein domains that may function to sequester lipids during polar growth. Stable genetic deletion or riboswitch-controlled depletion results in spherical cells that grow poorly; thus, GPR is essential for wild-type growth and morphology. As GPR has no predicted enzymatic domains and it forms a distinct 200-nm-diameter ring, we propose that GPR is a structural component of an organizing center for peptidoglycan and membrane syntheses critical for cell envelope formation during polar growth. GPR homologs are found in numerous Rhizobiales; thus, our results and proposed model are fundamental to understanding polar growth strategy in a variety of bacterial species.

Differences in moral reasoning among medical graduates, graduates with other degrees, and nonprofessional adults.

BACKGROUND: Reasoning and moral action are necessary to resolve day-to-day moral conflicts, and there are certain professions where a greater moral character is expected, e.g., medicine. Thus, it is desirable that medical students develop skills in this field. Some studies have evaluated the level of moral reasoning among medical students; however, there are no comparative studies involving other types of populations. Therefore, the objective of this study was to compare the moral reasoning among medical graduates with that of a group of young graduates with other degrees and of a group of nonprofessional adults. METHODS: An exploratory cross-sectional study was conducted. Pediatric residents and pediatric subspecialty residents at a pediatric hospital were invited to participate, forming the group of "medical graduates". A group of young people from a social program and students with a master's degree in a science from the same pediatric hospital were also invited to participate, comprising the group of "graduates with other degrees". Finally, a group of beneficiaries of a family clinic was invited to participate, which we categorized as "nonprofessionals". To evaluate the differences in moral reasoning between these 3 groups, we applied the Defining Issues Test (DIT), a moral reasoning questionnaire designed by James Rest using Kohlberg's theory of moral development. RESULTS: The moral reasoning of 237 subjects-88 from the "medical graduates" group, 82 from the "graduates with other degrees" group and 67 from the "nonprofessionals" group- was evaluated. We found differences in the profiles of moral development of the groups. The profile of the "nonprofessionals" showed a very high predominance of subjects at the preconventional level, 70%, but only 4.5% at the postconventional level. Among the "medical graduates", we observed 37.5% at the preconventional level and 34% at the postconventional level (X2 p < 0.001); this group had the highest percentage in this category. This large difference could be because the differences in the ages and socioeducational levels of nonprofessionals are much wider than those among medical graduates. However, significant differences were also found when the profiles of medical graduates were compared with those of graduates with other degrees, since the latter demonstrated 56% at the preconventional level and 18% at the postconventional level (X2 test, p = 0.02). CONCLUSIONS: Significant differences were found in moral reasoning among the groups that we evaluated. Among the group of medical graduates, there was a higher percentage of subjects at the postconventional level than among the group of graduates with other degrees and a much higher percentage than among the group of nonprofessionals. Our conclusions give the first evidence that studying medicine seems to influence the development of moral reasoning in its students. Therefore, we consider it relevant to develop educational strategies where the student is involved in simulated but realistic decision-making situations, where there are moral dilemmas to resolve from their early years of training.

Homogeneous nucleation of NaCl in supersaturated solutions.

The seeding method is an approximate approach to investigate nucleation that combines molecular dynamics simulations with classical nucleation theory. Recently, this technique has been successfully implemented in a broad range of nucleation studies. However, its accuracy is subject to the arbitrary choice of the order parameter threshold used to distinguish liquid-like from solid-like molecules. We revisit here the crystallization of NaCl from a supersaturated brine solution and show that consistency between seeding and rigorous methods, like Forward Flux Sampling (from previous work) or spontaneous crystallization (from this work), is achieved by following a mislabelling criterion to select such threshold (i.e. equaling the fraction of the mislabelled particles in the bulk parent and nucleating phases). This work supports the use of seeding to obtain fast and reasonably accurate nucleation rate estimates and the mislabelling criterion as one giving the relevant cluster size for classical nucleation theory in crystallization studies.

[Initial findings in chest X-rays as predictors of worsening lung infection in patients with COVID-19: correlation in 265 patients]. / Hallazgos iniciales en la radiografía de tórax como predictores de empeoramiento en la infección pulmonar por SARS-CoV-2. Correlación en 265 pacientes.

Background and aims: We aimed to analyze the relationship between the initial chest X-ray findings in patients with severe acute respiratory syndrome due to infection with SARS-CoV-2 and eventual clinical worsening and to compare three systems of quantifying these findings. Material and methods: This retrospective study reviewed the clinical and radiological evolution of 265 adult patients with COVID-19 attended at our center between March 2020 and April 2020. We recorded data related to patients' comorbidities, hospital stay, and clinical worsening (admission to the ICU, intubation, and death). We used three scoring systems taking into consideration 6 or 8 lung fields (designated 6 A, 6 B, and 8) to quantify lung involvement in each patient's initial abnormal chest X-ray and to classify its severity as mild, moderate, or severe, and we compared these three systems. We also recorded the presence of alveolar opacities and linear opacities (fundamentally linear atelectasis) in the first chest X-ray with pathologic findings. Results: In the χ2 analysis, moderate or severe involvement in the three classification systems correlated with hospital admission (p = 0.009 in 6 A, p = 0.001 in 6 B, and p = 0.001 in 8) and with death (p = 0.02 in 6 A, p = 0.01 in 6 B, and p = 0.006 in 8). In the regression analysis, the most significant associations were 6 B with alveolar involvement (OR 2.3; 95%CI 1.1.-4.7; p = 0.025;) and 8 with alveolar involvement (OR 2.07; 95% CI 1.01.-4.25; p = 0.046). No differences were observed in the ability of the three systems to predict clinical worsening by classifications of involvement in chest X-rays as moderate or severe. Conclusion: Moderate/severe extension in the three chest X-ray scoring systems evaluating the extent of involvement over 6 or 8 lung fields and the finding of alveolar opacities in the first abnormal X-ray correlated with mortality and the rate of hospitalization in the patients studied. No significant difference was found in the predictive ability of the three classification systems proposed.

Medial opening wedge high tibial osteotomy: more than ten years of experience with Puddu plate technique supports its indication.

PURPOSE: To describe the short-term and long-term results of patients who underwent a medial opening wedge high tibial osteotomy (MOW-HTO) for unicompartmental medial knee joint osteoarthritis. METHODS: A retrospective review was conducted of patients with MOW-HTO using a Puddu plate®, with more than ten year follow-up. The degree of correction, initial chondral damage, number of meniscal lesions, preoperative and 1-year postoperative functional scale scores (IKDC and Lysholm), and arthroplasty conversion rates at the ten year follow-up were registered. We assumed early indication when patients underwent the operation before they were 40 years old and delayed ≥ 40. Functional outcomes were analyzed by adjusting for pre-operative values. Fisher's exact test was used to study the association between the arthroplasty conversion rates and the timing of indication. RESULTS: Fifty-five patients were included, 37 of whom were male (67%). Twenty-nine patients had early indications for surgery (53%). All patients completed ten year follow-up. All patients improved IKDC (p < 0.01) and Lysholm (p < 0.01) scores compared to their presurgical scores at the one year post-operative evaluation. We had six minor complications, none requiring revision surgery. We had three conversions to arthroplasty, all in the late indication group, not statistically significant different. Linear regression showed that early indication was associated with a higher IKDC score when adjusting for the Outerbridge chondral damage score, the number of meniscal lesions, and sex (p < 0.01). CONCLUSION: All patients improved functional scores one year after surgery. Early indication (i.e., younger than 40 years of age) was independently associated with better functional outcomes than late indication at one year follow-up.

Testing behavioral interventions to optimize participation in a population-based colorectal cancer screening program in Catalonia, Spain.

The aim of the study was to measure the effect of three cost-neutral behavioral interventions on participation compared to the standard invitation letter in a population-based colorectal cancer screening program in 2014. For that purpose, a four-arm randomized field trial was conducted among 5077 individuals aged 50 to 69 years. Over an 8-week period, each week was randomly allocated to the intervention or the control conditions. Individuals assigned to the intervention conditions additionally received a prompt to write down the date to pick up the screening test in a pharmacy. Two of the three intervention groups also included an additional paragraph in the invitation letter on either: 1) the high proportion of individuals participating regularly (social norms condition) or 2) the importance of regular participation (benefit condition). We measured screening participation before and after receiving a reminder letter six weeks after the screening invitation. An overall 8.0 percentage point increase in CRC screening was achieved as a direct result of receiving a reminder letter; however none of the intervention strategies influenced participation. The only significant difference was found for newly invited individuals. There, participation rates decreased from 34.9% to 24.2% when the invitation mailing mentioned the importance of regular participation (OR: 0.60; 95% CI: 0.38-0.95). While none of the intervention strategies improved participation rates we found that praising the benefit of regular screening may discourage individuals who have never been invited before as the continuous behavior may be perceived as a large request. Nevertheless, the reminder letter boosted participation rates independently of the intervention assigned.

Application of embryo biopsy and sex determination via polymerase chain reaction in a commercial equine embryo transfer program in Argentina.

Embryo biopsy for fetal sexing has clinical application, but few reports are available of its use within an active embryo transfer program. We evaluated results on biopsy of 459 embryos over one breeding season. There were no significant differences in pregnancy rate between biopsied and non-biopsied embryos (72% vs 73%) or for biopsied embryos recovered at the centre (73%) compared with those shipped overnight (72%). However, the pregnancy rate decreased significantly in shipped embryos biopsied ≥20h after collection. Overall, 86% of biopsies provided a sex diagnosis. The likelihood of a positive genomic (g) DNA result was significantly higher for biopsies from large blastocysts (96%) than from smaller embryos (70-85%). In total, 38% of biopsies were positive for Y chromosome DNA (Y-DNA) and were diagnosed as male. Subsequently, 95% of Y-DNA-positive embryos were confirmed as male and 78% of Y-DNA-negative embryos were confirmed as female. The accuracy of prediction of female (Y-DNA negative) was significantly higher when the biopsy sample was probed for Y-DNA only compared with probing for both gDNA and Y-DNA. We estimate that by transferring only Y-DNA-negative embryos, 3% of potential female pregnancies may have been lost, and production of male pregnancies was reduced by 72%.

Ice growth rate: Temperature dependence and effect of heat dissipation.

The transformation of liquid water into solid ice is arguably the most important phase transition on Earth. A key aspect of such transformation is the speed with which ice grows once it is nucleated. There are contradictory experimental results as to whether the ice growth rate shows a maximum on cooling. Previous simulation results point to the existence of such a maximum. However, simulations were performed at constant temperature with the aid of a thermostat that dissipates the heat released at the ice-water interface unrealistically fast. Here, we perform simulations of ice growth without any thermostat. Large systems are required to perform these simulations at constant overall thermodynamic conditions (pressure and temperature). We obtain the same growth rate as in previous thermostatted simulations. This implies that the dynamics of ice growth is not affected by heat dissipation. Our results strongly support the experiments predicting the existence of a maximum in the ice growth rate. By using the Wilson-Frenkel kinetic theory, we argue that such maximum is due to a competition between an increasing crystallization thermodynamic driving force and a decreasing molecular mobility on cooling.

Cosmological Signature of the Standard Model Higgs Vacuum Instability: Primordial Black Holes as Dark Matter.

For the current central values of the Higgs boson and top quark masses, the standard model Higgs potential develops an instability at a scale of the order of 10^{11} GeV. We show that a cosmological signature of such instability could be dark matter in the form of primordial black holes seeded by Higgs fluctuations during inflation. The existence of dark matter might not require physics beyond the standard model.

Cosmological implications of Higgs near-criticality.

The Standard Model electroweak (EW) vacuum, in the absence of new physics below the Planck scale, lies very close to the boundary between stability and metastability, with the last option being the most probable. Several cosmological implications of this so-called 'near-criticality' are discussed. In the metastable vacuum case, the main challenges that the survival of the EW vacuum faces during the evolution of the Universe are analysed. In the stable vacuum case, the possibility of implementing Higgs inflation is critically examined.This article is part of the Theo Murphy meeting issue 'Higgs cosmology'.

Association of serum testosterone levels and testicular volume in adult patients.

A retrospective observational study was undertaken to gain new insight into the relationship between total testicular volume and levels of serum testosterone, luteinising hormone, follicle-stimulating hormone, prolactin and clinical variables. A total of 312 men with sexual dysfunction or infertility were divided into groups A and B (156 each) on the basis of basal plasma testosterone ≤5 nmol/L of ≥12 nmol/L respectively. Group A was subclassified in A1 (primary hypogonadism) and A2 (secondary hypogonadism). There were significant differences in total testicular volume between group A (15.33 ± 11.94 ml) and group B (36.74 ± 6.9; p < .001) and also between subgroup A1 (11.07 ± 8.49 ml) and subgroup A2 (23.62 ± 13.04 ml; p < .001). Only 13.5% of patients in group B had a total testicular volume <30 ml. Differences in all studied parameters were found between group A and group B. There were no variations when comparing age, body mass index and testosterone in groups A1 and A2 . The use of total testicular volume and body mass index together for predicting testosterone levels yields a sensitivity and specificity of 85.3% and 86.5% respectively. Logistic regression analysis, univariate and multivariate models, using the measurement of total testicular volume resulted in a high capacity to predict testosterone levels.

Straight and tilted implants for supporting screw-retained full-arch dental prostheses in atrophic maxillae: A 2-year prospective study.

BACKGROUND: To evaluate, over a 2-year period, the treatment outcomes for maxillary full-arch fixed dental prostheses (FDPs) supported by a combination of both tilted and axially-placed implants and to compare the marginal bone loss (MBL) and implant survival rates (SR) between tilted and axial implants. MATERIAL AND METHODS: A retrospective study has been carried out. Thirty-two patients (16 males and 16 females) treated with maxillary full-arch FDPs were included in this retrospective study. A total of 187 implants were inserted to rehabilitate the fully edentulous maxillary arches: 36% of them were tilted (T group, n = 68) and the remaining 64% were axially placed (A group, n = 119). From the total, 28% of the implants (n=53) were immediately loaded with screw-retained provisional acrylic restorations, whereas 72% underwent conventional delayed prosthetic loading 6 months post-operatively. Definitive restorations were hybrid implant prostheses (metal framework covered with high-density acrylic resin) and metal-ceramic screw-retained implant prostheses, and were placed 6 months after surgery. Such definitive restorations were checked for proper function and aesthetics every three months for two years. Peri-implant marginal bone levels were assessed by digital radiographs immediately after surgery and MBL was assessed at definitive implant loading (baseline) and 2 years afterwards. RESULTS: The 2-year implant SR were 100% for axially placed implants and 98.5% for tilted implants. No significant differences were found amongst the A and T implant groups. Marginal bone loss measured at 2 years after definitive prosthetic loading was of -0.73 ± 0.72 mm (maximum MBL of 1.43 mm) for axially positioned implants vs. -0.51 ± 0.92 mm for tilted implants (maximum bone 1.45 mm). Differences in MBL were statistically significant when comparing immediately and delayed loaded implants. CONCLUSIONS: Based on the results of this retrospective clinical study, full-arch fixed prostheses supported by a combination of both tilted and axially placed implants may be considered a predictable and viable treatment modality for the prosthetic rehabilitation of the completely edentulous maxilla.

PrPC Governs Susceptibility to Prion Strains in Bank Vole, While Other Host Factors Modulate Strain Features.

Bank vole is a rodent species that shows differential susceptibility to the experimental transmission of different prion strains. In this work, the transmission features of a panel of diverse prions with distinct origins were assayed both in bank vole expressing methionine at codon 109 (Bv109M) and in transgenic mice expressing physiological levels of bank vole PrPC (the BvPrP-Tg407 mouse line). This work is the first systematic comparison of the transmission features of a collection of prion isolates, representing a panel of diverse prion strains, in a transgenic-mouse model and in its natural counterpart. The results showed very similar transmission properties in both the natural species and the transgenic-mouse model, demonstrating the key role of the PrP amino acid sequence in prion transmission susceptibility. However, differences in the PrPSc types propagated by Bv109M and BvPrP-Tg407 suggest that host factors other than PrPC modulate prion strain features. IMPORTANCE: The differential susceptibility of bank voles to prion strains can be modeled in transgenic mice, suggesting that this selective susceptibility is controlled by the vole PrP sequence alone rather than by other species-specific factors. Differences in the phenotypes observed after prion transmissions in bank voles and in the transgenic mice suggest that host factors other than the PrPC sequence may affect the selection of the substrain replicating in the animal model.

A potential model for sodium chloride solutions based on the TIP4P/2005 water model.

Despite considerable efforts over more than two decades, our knowledge of the interactions in electrolyte solutions is not yet satisfactory. Not even one of the most simple and important aqueous solutions, NaCl(aq), escapes this assertion. A requisite for the development of a force field for any water solution is the availability of a good model for water. Despite the fact that TIP4P/2005 seems to fulfill the requirement, little work has been devoted to build a force field based on TIP4P/2005. In this work, we try to fill this gap for NaCl(aq). After unsuccessful attempts to produce accurate predictions for a wide range of properties using unity ionic charges, we decided to follow recent suggestions indicating that the charges should be scaled in the ionic solution. In this way, we have been able to develop a satisfactory non-polarizable force field for NaCl(aq). We evaluate a number of thermodynamic properties of the solution (equation of state, maximum in density, enthalpies of solution, activity coefficients, radial distribution functions, solubility, surface tension, diffusion coefficients, and viscosity). Overall the results for the solution are very good. An important achievement of our model is that it also accounts for the dynamical properties of the solution, a test for which the force fields so far proposed failed. The same is true for the solubility and for the maximum in density where the model describes the experimental results almost quantitatively. The price to pay is that the model is not so good at describing NaCl in the solid phase, although the results for several properties (density and melting temperature) are still acceptable. We conclude that the scaling of the charges improves the overall description of NaCl aqueous solutions when the polarization is not included.

CD57(+) CD4 T Cells Underlie Belatacept-Resistant Allograft Rejection.

Belatacept is a B7-specific fusion protein used to prevent allograft rejection by blocking T cell costimulation. Generally efficacious, it fails to prevent acute rejection in a sizable minority of patients. In experimental models, memory T cells mediate costimulation blockade-resistant rejection (CoBRR), but this remains undefined in humans. To explore relationships between individual patients' immune cell phenotypes and CoBRR, we studied patients receiving belatacept or conventional calcineurin inhibitor-based immunosuppression. We identified a population of CD57(+) PD1(-) CD4 T cells present prior to transplantation that correlated with CoBRR. Contrary to data recognizing CD57 as a marker of senescence on CD8 T cells, we discovered a nonsenescent, cytolytic phenotype associated with CD57 on CD4 T cells. Moreover, CD57(+) CD4 T cells expressed high levels of adhesion molecules implicated in experimental CoBRR, were CD28(-) , expressed a transcriptional phenotype broadly defining allograft rejection and were shown to be present in rejecting human kidney allografts. These data implicate CD57(+) CD4 T cells in clinical CoBRR. If prospectively validated, this characteristic could identify patients at higher risk for acute rejection on belatacept-based therapy.