A tale of 2 diseases: ALD and MASLD requirements and monitoring for liver transplantation.

The requirements for eligibility and monitoring before and after liver transplantation for alcohol-associated liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD) are different and not as well defined for MASLD as they are for ALD. Two groups of patients with ALD considered for liver transplant (LT) include those with decompensated cirrhosis from alcohol and those with severe alcohol-associated hepatitis. Both groups are required to commit to lifelong abstinence from alcohol. Pretransplant eligibility criteria for LT in those with ALD varies between transplant centers, but generally, a period of alcohol abstinence with or without counseling is required to be considered for an LT, or the candidate must meet specific requirements. In contrast to ALD, the pre-LT requirements for patients with MASLD, such as weight loss goals or control of metabolic diseases, are not as well defined. Reviews and consensus statements on MASLD and LT discuss risk stratification and management for conditions associated with MASLD, but there are no consensus recommendations regarding obesity and metabolic disease goals before and after transplant. Candidates and recipients of LT may be held to more stringent requirements and monitoring for alcohol use compared to weight loss goals and metabolic parameters advised for patients with MASLD. Because of the disparities in requirements between ALD and MASLD, consensus recommendations should be developed for pre-LT and post-LT monitoring and requirements for candidates and recipients with MASLD.

Trajectories and tipping points of piñon-juniper woodlands after fire and thinning.

Piñon-juniper (PJ) woodlands are a dominant community type across the Intermountain West, comprising over a million acres and experiencing critical effects from increasing wildfire. Large PJ mortality and regeneration failure after catastrophic wildfire have elevated concerns about the long-term viability of PJ woodlands. Thinning is increasingly used to safeguard forests from fire and in an attempt to increase climate resilience. We have only a limited understanding of how fire and thinning will affect the structure and function of PJ ecosystems. Here, we examined vegetation structure, microclimate conditions, and PJ regeneration dynamics following ~20 years post-fire and thinning treatments. We found that burned areas had undergone a state shift that did not show signs of returning to their previous state. This shift was characterized by (1) distinct plant community composition dominated by grasses; (2) a lack of PJ recruitment; (3) a decrease in the sizes of interspaces in between plants; (4) lower abundance of late successional biological soil crusts; (5) lower mean and minimum daily soil moisture values; (6) lower minimum daily vapor pressure deficit; and (7) higher photosynthetically active radiation. Thinning created distinct plant communities and served as an intermediate between intact and burned communities. More intensive thinning decreased PJ recruitment and late successional biocrust cover. Our results indicate that fire has the potential to create drier and more stressful microsite conditions, and that, in the absence of active management following fire, there may be shifts to persistent ecological states dominated by grasses. Additionally, more intensive thinning had a larger impact on community structure and recruitment than less intensive thinning, suggesting that careful consideration of goals could help avoid unintended consequences. While our results indicate the vulnerability of PJ ecosystems to fire, they also highlight management actions that could be adapted to create conditions that promote PJ re-establishment.

Ethical aspects of GMO regulation in the EU: Regulating new plant breeding techniques as GM has negative effects on sustainability, diversity and inclusion: Regulating new plant breeding techniques as GM has negative effects on sustainability, diversity and inclusion.

Plant breeding plays a crucial role for the EU to live up to its values and promises of sustainability, innovation and diversity and inclusion. The current regulations, however, make it de facto impossible to use new breeding technologies.

Determination of electric and thermoelectric properties of molecular junctions by AFM in peak force tapping mode.

Molecular thin films, such as self-assembled monolayers (SAMs), offer the possibility of translating the optimised thermophysical and electrical properties of high-Seebeck-coefficient single molecules to scalable device architectures. However, for many scanning probe-based approaches attempting to characterise such SAMs, there remains a significant challenge in recovering single-molecule equivalent values from large-area films due to the intrinsic uncertainty of the probe-sample contact area coupled with film damage caused by contact forces. Here we report a new reproducible non-destructive method for probing the electrical and thermoelectric (TE) properties of small assemblies (10-103) of thiol-terminated molecules arranged within a SAM on a gold surface, and demonstrate the successful and reproducible measurements of the equivalent single-molecule electrical conductivity and Seebeck values. We have used a modified thermal-electric force microscopy approach, which integrates the conductive-probe atomic force microscope, a sample positioned on a temperature-controlled heater, and a probe-sample peak-force feedback that interactively limits the normal force across the molecular junctions. The experimental results are interpreted by density functional theory calculations allowing quantification the electrical quantum transport properties of both single molecules and small clusters of molecules. Significantly, this approach effectively eliminates lateral forces between probe and sample, minimising disruption to the SAM while enabling simultaneous mapping of the SAMs nanomechanical properties, as well as electrical and/or TE response, thereby allowing correlation of the film properties.

Alpha-arrestins Aly1/Art6 and Aly2/Art3 regulate trafficking of the glycerophosphoinositol transporter Git1 and impact phospholipid homeostasis.

BACKGROUND INFORMATION: Phosphatidylinositol (PI) is an essential phospholipid, critical to membrane bilayers. The complete deacylation of PI by B-type phospholipases produces intracellular and extracellular glycerophosphoinositol (GPI). Extracellular GPI is transported into the cell via Git1, a member of the Major Facilitator Superfamily of transporters at the yeast plasma membrane. Internalized GPI is degraded to produce inositol, phosphate and glycerol, thereby contributing to these pools. GIT1 gene expression is controlled by nutrient balance, with phosphate or inositol starvation increasing GIT1 expression to stimulate GPI uptake. However, less is known about control of Git1 protein levels or localization. RESULTS: We find that the α-arrestins, an important class of protein trafficking adaptor, regulate Git1 localization and this is dependent upon their interaction with the ubiquitin ligase Rsp5. Specifically, α-arrestin Aly2 stimulates Git1 trafficking to the vacuole under basal conditions, but in response to GPI-treatment, either Aly1 or Aly2 promote Git1 vacuole trafficking. Cell surface retention of Git1, as occurs in aly1∆ aly2∆ cells, is linked to impaired growth in the presence of exogenous GPI and results in increased uptake of radiolabeled GPI, suggesting that accumulation of GPI somehow causes cellular toxicity. Regulation of α-arrestin Aly1 by the protein phosphatase calcineurin improves steady-state and substrate-induced trafficking of Git1, however, calcineurin plays a larger role in Git1 trafficking beyond regulation of α-arrestins. Interestingly, loss of Aly1 and Aly2 increased phosphatidylinositol-3-phosphate on the limiting membrane of the vacuole, and this was further exacerbated by GPI addition, suggesting that the effect is partially linked to Git1. Loss of Aly1 and Aly2 leads to increased incorporation of inositol label from [3 H]-inositol-labelled GPI into PI, confirming that internalized GPI influences PI balance and indicating a role for the a-arrestins in this regulation. CONCLUSIONS: The α-arrestins Aly1 and Aly2 are novel regulators of Git1 trafficking with previously unanticipated roles in controlling phospholipid distribution and balance. SIGNIFICANCE: To our knowledge, this is the first example of α-arrestin regulation of phosphatidyliniositol-3-phosphate levels. In future studies it will be exciting to determine if other α-arrestins similarly alter PI and PIPs to change the cellular landscape.

Impaired Filtering and Hyperfocusing: Neural Evidence for Distinct Selective Attention Abnormalities in People with Schizophrenia.

Although schizophrenia is classically thought to involve impaired attentional filtering, people with schizophrenia (PSZ) exhibit a more intense and more exclusive attentional focus than healthy control subjects (HCS) in many tasks. To resolve this contradiction, this functional magnetic resonance imaging study tested the impact of attentional control demands on the modulation of stimulus-induced activation in the fusiform face area and parahippocampal place area when participants (43 PSZ and 43 HCS) were looking for a target face versus house. Stimuli were presented individually, or as face-house overlays that challenged attentional control. Responses were slower for house than face stimuli and when prioritizing houses over faces in overlays, suggesting a difference in salience. Blood-oxygen-level-dependent activity reflected poorer attentional selectivity in PSZ than HCS when attentional control was challenged most, that is, when stimuli were overlaid and the task required detecting the lower-salience house target. By contrast, attentional selectivity was exaggerated in PSZ when control was challenged least, that is, when stimuli were presented sequentially and the task required detecting the higher-salience face target. These findings are consistent with 2 distinct attentional abnormalities in schizophrenia leading to impaired and exaggerated selection under different conditions: attentional control deficits, and hyperfocusing once attention has been directed toward a stimulus.

GPER is a mechanoregulator of pancreatic stellate cells and the tumor microenvironment.

The mechanical properties of the tumor microenvironment are emerging as attractive targets for the development of therapies. Tamoxifen, an agonist of the G protein-coupled estrogen receptor (GPER), is widely used to treat estrogen-positive breast cancer. Here, we show that tamoxifen mechanically reprograms the tumor microenvironment through a newly identified GPER-mediated mechanism. Tamoxifen inhibits the myofibroblastic differentiation of pancreatic stellate cells (PSCs) in the tumor microenvironment of pancreatic cancer in an acto-myosin-dependent manner via RhoA-mediated contractility, YAP deactivation, and GPER signaling. This hampers the ability of PSCs to remodel the extracellular matrix and to promote cancer cell invasion. Tamoxifen also reduces the recruitment and polarization to the M2 phenotype of tumor-associated macrophages. Our results highlight GPER as a mechanical regulator of the tumor microenvironment that targets the three hallmarks of pancreatic cancer: desmoplasia, inflammation, and immune suppression. The well-established safety of tamoxifen in clinics may offer the possibility to redirect the singular focus of tamoxifen on the cancer cells to the greater tumor microenvironment and lead a new strategy of drug repurposing.

Tamoxifen mechanically reprograms the tumor microenvironment via HIF-1A and reduces cancer cell survival.

The tumor microenvironment is fundamental to cancer progression, and the influence of its mechanical properties is increasingly being appreciated. Tamoxifen has been used for many years to treat estrogen-positive breast cancer. Here we report that tamoxifen regulates the level and activity of collagen cross-linking and degradative enzymes, and hence the organization of the extracellular matrix, via a mechanism involving both the G protein-coupled estrogen receptor (GPER) and hypoxia-inducible factor-1 alpha (HIF-1A). We show that tamoxifen reduces HIF-1A levels by suppressing myosin-dependent contractility and matrix stiffness mechanosensing. Tamoxifen also downregulates hypoxia-regulated genes and increases vascularization in PDAC tissues. Our findings implicate the GPER/HIF-1A axis as a master regulator of peri-tumoral stromal remodeling and the fibrovascular tumor microenvironment and offer a paradigm shift for tamoxifen from a well-established drug in breast cancer hormonal therapy to an alternative candidate for stromal targeting strategies in PDAC and possibly other cancers.

Co-developing a common glossary with stakeholders for engagement on new genetic approaches for malaria control in a local African setting.

Stakeholder engagement is an essential pillar for the development of innovative public health interventions, including genetic approaches for malaria vector control. Scientific terminologies are mainly lacking in local languages, yet when research activities involve international partnership, the question of technical jargon and its translation is crucial for effective and meaningful communication with stakeholders. Target Malaria, a not-for-profit research consortium developing innovative genetic approaches to malaria vector control, carried out a linguistic exercise in Mali, Burkina Faso and Uganda to establish the appropriate translation of its key terminology to local languages of sites where the teams operate. While reviewing the literature, there was no commonly agreed approach to establish such glossary of technical terms in local languages of the field sites where Target Malaria operates. Because of its commitment to the value of co-development, Target Malaria decided to apply this principle for the linguistic work and to take the opportunity of this process to empower communities to take part in the dialogue on innovative vector control. The project worked with linguists from other institutions (whether public research ones or private language centre) who developed a first potential glossary in the local language after better understanding the project scientific approach. This initial glossary was then tested during focus groups with community members, which significantly improved the proposed translations by making them more appropriate to the local context and cultural understanding. The stepwise process revealed the complexity and importance of elaborating a common language with communities as well as the imbrication of language with cultural aspects. This exercise demonstrated the strength of a co-development approach with communities and language experts as a way to develop knowledge together and to tailor communication to the audience even in the language used.

Teaching the social determinants of health through medical legal partnerships: a systematic review.

BACKGROUND: Undergraduate and graduate medical education often includes the social determinants of health, but questions remain regarding how best to ensure that trainees become empowered to take action on the social determinants of health in their future practice. The authors conducted a systematic review to better define the impact that educational programs centered on medical legal partnerships have on trainees' knowledge, attitudes and future practice. The authors sourced data from PubMed, Web of Science, Index to Legal Periodicals, LegalTrac, Google Scholar, Academic Search Complete, Business Source Complete, SocINDEX, SSRN, and Proquest Social Sciences. Selected studies included those centered on Medical Legal Partnerships in undergraduate or graduate medical education and that measured outcomes of the participating trainees. Two abstractors independently extracted information about the study population, setting, design, intervention and outcomes. RESULTS: Six out of 483 studies met the inclusion criteria. One study highlighted four different MLPs, thus nine total MLP programs were included. Trainees included medical students as well as interns and residents from pediatrics, family medicine and internal medicine. Interventions ranged from didactic sessions, to advocacy projects, to hands-on community-based learning, to poverty simulation trainings. Benefits to trainees were wide in scope but all programs showed improvements in participants' understanding, comfort, confidence, and/or abilities in identifying and intervening on the social determinants of health in their patients. CONCLUSION: As medical schools and residency programs are increasingly considering how to effectively teach trainees to understand and address the social determinants of health, the findings in this systematic review suggest that inclusion of Medical Legal Partnerships into training programs is an effective approach.

The Impact of COVID-19 on the Provision of Adult Cardiac Surgery at a Dedicated COVID Hospital in Australia.

BACKGROUND: Internationally, the response to the COVID-19 pandemic has resulted in fewer cardiac surgical procedures being performed and an increase in the proportion of non-elective cases. To date there has been no study examining the impact of COVID-19 on the provision of cardiac surgery in Australia. AIM: The aim of this study was to evaluate the impact that the COVID-19 pandemic has had on the provision of cardiac surgery in a single, large major cardiac centre and dedicated COVID-19 hospital. A retrospective cohort study was undertaken utilising prospectively collected data. METHODS: Prospectively collected patient and operative data was examined to assess whether there was a reduction in the number of cases performed and whether there was a difference in patient demographics, surgical procedures or case urgency. Data was examined from the period of COVID-restrictions in 2020 and compared with data from the same time period in 2019. RESULTS: From 3 March 2020 to 30 June 2020, 136 adults underwent cardiac surgery at our institution, representing an overall reduction in operative caseload of 21%. The largest impact was noticed in May and April and coincided with statewide restrictions on elective surgery. Surgical acuity was unchanged with 58% of operations classified as non-elective procedures performed during the index admission. There was a small non-significant increase in the proportion of isolated coronary artery bypass surgery and aortic valve surgeries performed. CONCLUSION: From March to June 2020 our local hospital response to the COVID-19 pandemic resulted in a reduction in cardiac surgery service delivery. No change was seen in the urgency or type of surgeries performed.

Scale-Up of Room-Temperature Constructive Quantum Interference from Single Molecules to Self-Assembled Molecular-Electronic Films.

The realization of self-assembled molecular-electronic films, whose room-temperature transport properties are controlled by quantum interference (QI), is an essential step in the scale-up of QI effects from single molecules to parallel arrays of molecules. Recently, the effect of destructive QI (DQI) on the electrical conductance of self-assembled monolayers (SAMs) has been investigated. Here, through a combined experimental and theoretical investigation, we demonstrate chemical control of different forms of constructive QI (CQI) in cross-plane transport through SAMs and assess its influence on cross-plane thermoelectricity in SAMs. It is known that the electrical conductance of single molecules can be controlled in a deterministic manner, by chemically varying their connectivity to external electrodes. Here, by employing synthetic methodologies to vary the connectivity of terminal anchor groups around aromatic anthracene cores, and by forming SAMs of the resulting molecules, we clearly demonstrate that this signature of CQI can be translated into SAM-on-gold molecular films. We show that the conductance of vertical molecular junctions formed from anthracene-based molecules with two different connectivities differ by a factor of approximately 16, in agreement with theoretical predictions for their conductance ratio based on CQI effects within the core. We also demonstrate that for molecules with thioether anchor groups, the Seebeck coefficient of such films is connectivity dependent and with an appropriate choice of connectivity can be boosted by ∼50%. This demonstration of QI and its influence on thermoelectricity in SAMs represents a critical step toward functional ultra-thin-film devices for future thermoelectric and molecular-scale electronics applications.

Retinoic Acid Receptor-ß Is Downregulated in Hepatocellular Carcinoma and Cirrhosis and Its Expression Inhibits Myosin-Driven Activation and Durotaxis in Hepatic Stellate Cells.

Hepatic stellate cells (HSCs) are essential perisinusoidal cells in both healthy and diseased liver. HSCs modulate extracellular matrix (ECM) homeostasis when quiescent, but in liver fibrosis, HSCs become activated and promote excess deposition of ECM molecules and tissue stiffening via force generation and mechanosensing. In hepatocellular carcinoma (HCC), activated HSCs infiltrate the stroma and migrate to the tumor core to facilitate paracrine signaling with cancer cells. Because the function of HSCs is known to be modulated by retinoids, we investigated the expression profile of retinoic acid receptor beta (RAR-ß) in patients with cirrhosis and HCC, as well as the effects of RAR-ß activation in HSCs. We found that RAR-ß expression is significantly reduced in cirrhotic and HCC tissues. Using a comprehensive set of biophysical methods combined with cellular and molecular biology, we have elucidated the biomechanical mechanism by which all trans-retinoic acid promotes HSC deactivation via RAR-ß-dependent transcriptional downregulation of myosin light chain 2 expression. Furthermore, this also abrogated mechanically driven migration toward stiffer substrates. Conclusion: Targeting mechanotransduction in HSCs at the transcriptional level may offer therapeutic options for a range of liver diseases.

People with schizophrenia show enhanced cognitive costs of maintaining a single item in working memory.

BACKGROUND: Working memory (WM) deficits are seen as a core deficit in schizophrenia, implicated in the broad cognitive impairment seen in the illness. Here we examine the impact of WM storage of a single item on the operation of other cognitive systems. METHODS: We studied 37 healthy controls (HCS) and 43 people with schizophrenia (PSZ). Each trial consisted of a sequence of two potential target stimuli, T1 and T2. T1 was a letter presented for 100 ms. After delays of 100-800 ms, T2 was presented. T2 was a 1 or a 2 and required a speeded response. In one condition, subjects were instructed to ignore T1 but respond to T2. In another condition, they were required to report T1 after making their speeded response to T2 (i.e. to make a speeded T2 response while holding T1 in WM). RESULTS: PSZ were dramatically slowed at responding to T2 when T1 was held in WM. A repeated measures ANOVA yielded main effects of group, delay, and condition with a group by condition interaction (p's < 0.001). Across delays, the slowing of the T2 response when required to hold T1 in memory, relative to ignoring T1, was nearly 3 times higher in PSZ than HCS (633 v. 219 ms). CONCLUSIONS: Whereas previous studies have focused on reduced storage capacity, the present study found that PSZ are impaired at performing tasks while they are successfully maintaining a single item in WM. This may play a role in the broad cognitive impairment seen in PSZ.

Mapping nanoscale dynamic properties of suspended and supported multi-layer graphene membranes via contact resonance and ultrasonic scanning probe microscopies.

Graphene's (GR) remarkable mechanical and electrical properties-such as its Young's modulus, low mass per unit area, natural atomic flatness and electrical conductance-would make it an ideal material for micro and nanoelectromechanical systems (MEMS and NEMS). However, the difficulty of attaching GR to supports, coupled with naturally occurring internal defects in a few layer GR can significantly adversely affect the performance of such devices. Here, we have used a combined contact resonance atomic force microscopy (CR-AFM) and ultrasonic force microscopy (UFM) approach to characterise and map with nanoscale spatial resolution GR membrane properties inaccessible to most conventional scanning probe characterisation techniques. Using a multi-layer GR plate (membrane) suspended over a round hole, we show that this combined approach allows access to the mechanical properties, internal structure and attachment geometry of the membrane providing information about both the supported and suspended regions of the system. We show that UFM allows the precise geometrical position of the supported membrane-substrate contact to be located and provides an indication of the local variation of its quality in the contact areas. At the same time, we show that by mapping the position sensitive frequency and phase response of CR-AFM response, one can reliably quantify the membrane stiffness, and image the defects in the suspended area of the membrane. The phase and amplitude of experimental CR-AFM measurements show excellent agreement with an analytical model accounting for the resonance of the combined CR-AFM probe-membrane system. The combination of UFM and CR-AFM provide a beneficial combination for the investigation of few-layer NEMS systems based on two dimensional materials.

Novel Oral Anticoagulants Compared to Warfarin for Postoperative Atrial Fibrillation After Isolated Coronary Artery Bypass Grafting.

BACKGROUND: Postoperative atrial fibrillation (POAF) is common after cardiac surgery and contributes to short- and long-term morbidity, particularly thromboembolism. Anticoagulation for sustained or recurrent POAF is suggested to reduce thromboembolism. Novel oral anticoagulants may present a safe alternative to warfarin with further benefits including shorter hospital length of stay and better patient convenience. METHODS: A retrospective analysis was performed on all isolated cases of coronary artery surgery (CABG) at our institution between January 2015 and December 2018, totalling 960 patients. Rates of POAF were examined with particular focus on preoperative factors, postoperative outcomes, and anticoagulation practices. RESULTS: The incidence of POAF was 31.8% (305 patients) and was higher in older patients (67.6±9.4 yrs vs 63.0±10.7 yrs, p<0.001), those with a history of cerebrovascular disease (14.6% vs 8.7%, p=0.02), those with higher CHADS-VASc scores (2.5±1.3 vs 2.8±1.3, p<0.001) those who had a postoperative return to theatre (2.6% vs 0.8%, p=0.002), and those with new renal failure (4.9% vs 1.8%, p=0.02). Off-pump surgery was associated with lower incidence of POAF (29.8% vs 37.1%, p=0.03). Patients who developed POAF had significantly longer admissions than those without (12.6±10.6 days vs 9.3±16.3 days, p<0.001). In total, 106 patients (11.0%) went home anticoagulated; 77 (72.6%) on warfarin and 29 (27.4% on a NOAC). Readmission for bleeding was higher in patients on anticoagulation (1.0% vs 0.0%, p=0.02), but did not drive readmission for pericardial effusion (0.3% vs 0.6%, p=0.55). No bleeding complications occurred in patients who were discharged on a NOAC. Overall mortality at median of 2 years was 1.8% (17 patients) and no mortality occurred in any patient discharged on anticoagulation. CONCLUSION: Postoperative atrial fibrillation is a common adverse event and is linked to higher preoperative and postoperative morbidity. Anticoagulation may be safely started in these patients and use of novel anticoagulation does not appear to increase postoperative complications, although overall numbers are low.

Carbazole-Based Tetrapodal Anchor Groups for Gold Surfaces: Synthesis and Conductance Properties.

As the field of molecular-scale electronics matures and the prospect of devices incorporating molecular wires becomes more feasible, it is necessary to progress from the simple anchor groups used in fundamental conductance studies to more elaborate anchors designed with device stability in mind. This study presents a series of oligo(phenylene-ethynylene) wires with one tetrapodal anchor and a phenyl or pyridyl head group. The new anchors are designed to bind strongly to gold surfaces without disrupting the conductance pathway of the wires. Conductive probe atomic force microscopy (cAFM) was used to determine the conductance of self-assembled monolayers (SAMs) of the wires in Au-SAM-Pt and Au-SAM-graphene junctions, from which the conductance per molecule was derived. For tolane-type wires, mean conductances per molecule of up to 10-4.37  G0 (Pt) and 10-3.78  G0 (graphene) were measured, despite limited electronic coupling to the Au electrode, demonstrating the potential of this approach. Computational studies of the surface binding geometry and transport properties rationalise and support the experimental results.

Posterior Parietal Cortex Dysfunction Is Central to Working Memory Storage and Broad Cognitive Deficits in Schizophrenia.

PFC dysfunction is widely believed to underlie working memory (WM) deficits in people with schizophrenia (PSZ), but few studies have focused on measures of WM storage devoid of manipulation. Research in neurotypical individuals has shown that storage capacity is more closely related to posterior parietal cortex (PPC) than PFC, suggesting that reductions in WM storage capacity in schizophrenia that are associated with broad cognitive deficits may be related to neural activity in PPC. In the present human neuroimaging study, 37 PSZ and 37 matched healthy control subjects of either sex completed a change detection task with varying set sizes while undergoing fMRI. The task was designed to emphasize WM storage with minimal top-down control demands. Whole-brain analysis identified areas in which BOLD activity covaried with the number of items maintained in WM (K), as derived from task performance at a given set size. Across groups, K values independent of set size predicted BOLD activity in PPC, including superior and inferior parietal lobules and intraparietal sulcus, and middle occipital gyrus. Whole-brain interaction analysis found significantly less K-dependent signal modulation in PSZ than healthy control subjects in left PPC, a phenomenon that could not be explained by a narrower K value range. The slope between K and PPC activation statistically accounted for 43.4% of the between-group differences in broad cognitive function. These results indicate that PPC dysfunction is central to WM storage deficits in PSZ and may play a key role in the broad cognitive deficits associated with schizophrenia.SIGNIFICANCE STATEMENT People with schizophrenia exhibit cognitive deficits across a wide range of tasks. Explaining these impairments in terms of a small number of core deficits with clearly defined neural correlates would advance the understanding of the disorder and promote treatment development. We show that a substantial portion of broad cognitive deficits in schizophrenia can be explained by a failure to flexibly modulate posterior parietal cortex activity as a function of the amount of information currently stored in working memory. Working memory deficits have long been considered central to schizophrenia-related cognitive deficits, but the focus has been on paradigms involving some form of top-down control rather than pure storage of information, which may have unduly narrowed the focus on prefrontal dysfunction.

Cell-geometry-dependent changes in plasma membrane order direct stem cell signalling and fate.

Cell size and shape affect cellular processes such as cell survival, growth and differentiation1-4, thus establishing cell geometry as a fundamental regulator of cell physiology. The contributions of the cytoskeleton, specifically actomyosin tension, to these effects have been described, but the exact biophysical mechanisms that translate changes in cell geometry to changes in cell behaviour remain mostly unresolved. Using a variety of innovative materials techniques, we demonstrate that the nanostructure and lipid assembly within the cell plasma membrane are regulated by cell geometry in a ligand-independent manner. These biophysical changes trigger signalling events involving the serine/threonine kinase Akt/protein kinase B (PKB) that direct cell-geometry-dependent mesenchymal stem cell differentiation. Our study defines a central regulatory role by plasma membrane ordered lipid raft microdomains in modulating stem cell differentiation with potential translational applications.

When trust is lost: the impact of interpersonal trauma on social interactions.

BACKGROUND: Trauma due to deliberate harm by others is known to increase the likelihood of developing Post-Traumatic Stress Disorder (PTSD). This is the first study investigating basic and dynamic trust in 'interpersonal' PTSD. METHODS: Thirty-two participants with PTSD and 22 healthy controls played a novel multi-round version of a monetary investment protocol, the so-called 'Trust Game', a task from the behavioural economics literature, which is considered to involve trust and reciprocity. We used two 'Trust Games' including cooperative and unfair partners. RESULTS: Findings showed an effect for lower basic investment in PTSD compared to healthy controls, that trended towards significance (p = 0.09). All participants showed behavioural flexibility and modified their trust based on behavioural cues from their cooperative and unfair game partners. However, participants with PTSD made significantly lower investments towards the cooperative partner than controls. Investments towards the unfair partner did not differ between groups. Higher trauma scores were associated with lower levels of trust-related investments towards the cooperative but not the unfair game partner. CONCLUSION: The association between reduced trust towards cooperative others in individuals who experienced interpersonal trauma could indicate acquired insensitivity to social rewards or inflexible negative beliefs about others as a sequel of the traumatic experience, which increases in a dose response relationship with the severity of the trauma. A specific focus on cooperation and trusting behaviour could provide a treatment target for future cognitive and pharmacological interventions.