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Abstract Vitamin B6 is a water-soluble vitamin which possesses antioxidant properties. Its catalytically active form, pyridoxal 5’-phosphate (PLP), is a crucial cofactor for DNA and amino acid metabolism. The inverse correlation between vitamin B6 and cancer risk has been observed in several studies, although dietary vitamin B6 intake sometimes failed to confirm this association. However, the molecular link between vitamin B6 and cancer remains elusive. Previous work has shown that vitamin B6 deficiency causes chromosome aberrations (CABs) in Drosophila and human cells, suggesting that genome instability may correlate the lack of this vitamin to cancer. Here we provide evidence in support of this hypothesis. Firstly, we show that PLP deficiency, induced by the PLP antagonists 4-deoxypyridoxine (4DP) or ginkgotoxin (GT), promoted tumorigenesis in eye larval discs transforming benign Ras V12 tumors into aggressive forms. In contrast, PLP supplementation reduced the development of tumors. We also show that low PLP levels, induced by 4DP or by silencing the sgll PNPO gene involved in PLP biosynthesis, worsened the tumor phenotype in another Drosophila cancer model generated by concomitantly activating RasV12 and downregulating Discs-large (Dlg) gene. Moreover, we found that Ras V12 eye discs from larvae reared on 4DP displayed CABs, reactive oxygen species (ROS) and low catalytic activity of serine hydroxymethyltransferase (SHMT), a PLP-dependent enzyme involved in thymidylate (dTMP) biosynthesis, in turn required for DNA replication and repair. Feeding Ras V12 4DP-fed larvae with PLP or ascorbic acid (AA) plus dTMP, rescued both CABs and tumors. The same effect was produced by overexpressing catalase in Ras V12 Dlg RNAi 4DP-fed larvae, thus allowing to establish a relationship between PLP deficiency, CABs, and cancer. Overall, our data provide the first in vivo demonstration that PLP deficiency can impact on cancer by increasing genome instability, which is in turn mediated by ROS and reduced dTMP levels.

Abstract The increasing availability of experimental and computational protein structures entices their use for function prediction. Here we develop an automated procedure to identify enzymes involved in metabolic reactions by assessing substrate conformations docked to a library of protein structures. By screening AlphaFold-modeled vitamin B6-dependent enzymes, we find that a metric based on catalytically favorable conformations at the enzyme active site performs best (AUROC Score=0.84) in identifying genes associated with known reactions. Applying this procedure, we identify the mammalian gene encoding hydroxytrimethyllysine aldolase (HTMLA), the second enzyme of carnitine biosynthesis. Upon experimental validation, we find that the top-ranked candidates, serine hydroxymethyl transferase (SHMT) 1 and 2, catalyze the HTMLA reaction. However, a mouse protein absent in humans (threonine aldolase; Tha1) catalyzes the reaction more efficiently. Tha1 did not rank highest based on the AlphaFold model, but its rank improved to second place using the experimental crystal structure we determined at 2.26 Å resolution. Our findings suggest that humans have lost a gene involved in carnitine biosynthesis, with HTMLA activity of SHMT partially compensating for its function.

Abstract Moiré excitons (MXs) are electron-hole pairs localised by the periodic (moiré) potential forming in two-dimensional heterostructures (HSs). MXs can be exploited, e.g., for creating nanoscale-ordered quantum emitters and achieving or probing strongly correlated electronic phases at relatively high temperatures. Here, we studied the exciton properties of WSe2/MoSe2 HSs from T = 6 K to room temperature using time-resolved and continuous-wave micro-photoluminescence also under a magnetic field. The exciton dynamics and emission lineshape evolution with temperature show clear signatures that MXs de-trap from the moiré potential and turn into free interlayer excitons (IXs) for temperatures above 100 K. The MX-to-IX transition is also apparent from the exciton magnetic moment reversing its sign when the moiré potential is not capable of localising excitons at elevated temperatures. Concomitantly, the exciton formation and decay times reduce drastically. Thus, our findings establish the conditions for a truly confined nature of the exciton states in a moiré superlattice with increasing temperature and photo-generated carrier density.

Summary: Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in adults. Depolarizing GABA responses have been well characterized at neuronal-population average level during typical neurodevelopment and partially in brain disorders. However, no investigation has specifically assessed whether a mosaicism of cells with either depolarizing or hyperpolarizing/inhibitory GABAergic responses exists in animals in health/disease at diverse developmental stages, including adulthood. Here, we showed that such mosaicism is present in wild-type (WT) and down syndrome (DS) neuronal networks, as assessed at increasing scales of complexity (cultures, brain slices, behaving mice). Nevertheless, WT mice presented a much lower percentage of cells with depolarizing GABA than DS mice. Restoring the mosaicism of hyperpolarizing and depolarizing GABA-responding neurons to WT levels rescued anxiety behavior in DS mice. Moreover, we found heterogeneous GABAergic responses in developed control and trisomic human induced-pluripotent-stem-cells-derived neurons. Thus, a heterogeneous subpopulation of GABA-responding cells exists in physiological/pathological conditions in mouse and human neurons, possibly contributing to disease-associated behaviors.

Abstract Autonomous vehicles offer greater passenger convenience and improved fuel efficiency. However, they are likely to increase road transport activity and life cycle greenhouse emissions, due to several rebound effects. In this study, we investigate tradeoffs between improved fuel economy and rebound effects from a life-cycle perspective. Our results show that autonomy introduces an average 21.2% decrease in operation phase emissions due to improved fuel economy while manufacturing phase emissions can surge up to 40%. Recycling efforts can offset this increase, cutting emissions by 6.65 tons of Carbon dioxide equivalent per vehicle. However, when examining the entire life cycle, autonomous electric vehicles might emit 8% more greenhouse gas emissions on average compared to nonautonomous electric vehicles. To address this, we suggest; (1) cleaner and more efficient manufacturing technologies, (2) ongoing fuel efficiency improvements in autonomous driving; (3) renewable energy adoption for charging, and (4) circular economy initiatives targeting the complete life cycle.

This study examines the impact of the spacing parameter on the efficacy of an array of hybrid modules functioning as both floating breakwaters and wave energy converters. The dual functionality is ensured by the ability of the device to autoadjust its submergence. The behavior of multiple 1:40 scaled modules was tested in the wave tank of the University of Campania “Luigi Vanvitelli”. The objective was to assess the hydraulic performance of the array by analyzing transmission, reflection, and dissipation coefficients under different wave conditions. Specifically, the transmission coefficient ranges between 0.85 and 0.51, depending on the relative wavelength and wave steepness, while the reflection and dissipation coefficients vary, respectively, between 0.70–0.20 and 0.55–0.3. In any case, the results underscore the critical importance of the spacing parameter.

Hitherto, over 50% of countries with marine waters have established MSPs or launched related legal actions. However, there are still conceptual and practical challenges to be overcome in the development of MSP. In this study, we investigate two main approaches in MSP (hard vs. soft sustainability) through reports, published manuscripts and meeting proceedings in seven pioneering countries (Belgium, Netherlands, Norway, Germany, United Kingdom, Australia, and Canada). We highlight the gaps, challenges, and solutions in each of these approaches. From our findings, there are four common challenges in both soft and hard sustainability approaches as follows: (i) the political framework and inconsistent support of MSP efforts, (ii) insufficient knowledge on social dimensions, (iii) insufficient stakeholder engagement in the diversity of stakeholder’s groups or in their contribution to the planning process from the initial steps, and (iv) finding a balance between environmental conservation and economic growth. We recommend that future studies should investigate how MSP can become more adaptive to long-term environmental and economic targets, how effective involving socioeconomic strata is in MSP, and how decision-making tools could help to cover the gaps in MSP. Furthermore, public forums are suggested to be developed to facilitate the systematic sharing of MSP experiences worldwide.

Here, Prakasam and colleagues show that polyQ-expanded androgen receptor toxicity can be attenuated using artificial miRNAs targeting Lsd1 and Prmt6, two AR-co-activators overexpressed in an androgen-dependent manner specifically in skeletal muscle, thus ameliorating spinal-bulbar muscular atrophy phenotypes in flies and mice.

We experimentally demonstrate the use of an integrated optical frequency comb (OFC) for remotely generating low-phase noise millimeter-waves (mm-waves) carriers. The Indium Phosphide (InP) device is composed of phase modulators in tandem and is configurable in OFC center frequency and tone spacing. The device is applied in a centralized radio access network (C-RAN) architecture and the realized OFC is transported over 12.5 km of a conventional single-mode fiber (SMF) link aiming to remotely generate mm-waves. The impairments induced by the chromatic dispersion (CD) on the photodetected electrical carriers are evaluated, i.e., the periodic RF power fluctuations based on the electrical frequency and the SMF length. Experimental results demonstrate that, by properly managing the phase modulator bias and the phase delay supplied to the PIC, the impact of CD on the electrical carriers can be significantly reduced, leading the optical frequency comb to sum up in-phase after the photodetection process. The OFC-based and remotely generated carrier at 28 GHz is used to up-convert a 100 MHz 5G new radio (NR) signal, demonstrating suitable root mean square error vector magnitude (EVMRMS) performance. Indeed, the OFC-based 5G NR signals met the 3GPP requirements with margins up to 7.7%, which enables the 5G wireless link at 28 GHz. Therefore, the proposed system is able to remotely generate mm-waves signal while minimizing the fading impact on the electrical signals, allowing to replace high-frequency up-converters at the remote 5G radio units.

Abstract We experimentally demonstrate the use of optical frequency combs (OFCs), generated by a photonic integrated circuit (PIC), in a flexible optical distribution network based on fiber-optics and free-space optics (FSOs) links, aimed at the fifth generation of mobile network (5G) Xhauls. The Indium Phosphide (InP) monolithically integrated OFC is based on cascaded optical modulators and is broadly tunable in terms of operating wavelength and frequency spacing. Particularly, our approach relies on applying the PIC in a centralized radio access network (C-RAN) architecture, with the purpose of optically generating two low-phase noise mm-waves signals for simultaneously enabling a 12.5-km of single-mode fiber (SMF) fronthaul and a 12.5-km SMF midhaul, followed by a 10-m long FSO fronthaul link. Moreover, the demonstrator contemplates two 10-m reach 5G wireless access networks operating in the 26 GHz band, i.e. over the frequency range 2 (FR2) from the 5G NR standard. The proposed integrated OFC-based 5G system performance is in accordance to the 3rd Generation Partnership Project (3GPP) Release 15 requirements, achieving a total wireless throughput of 900 Mbit/s.

Orthopedic costs associated with gunshot wounds (GSWs) totaled approximately USD 510 million from 2005 to 2014. Previous studies have identified differences in injuries associated with self-inflicted (SI) GSWs; however, there remains a gap in understanding injury patterns. This study aims to expand upon the current literature and shed light on injury patterns and outcomes associated with SI vs. non-self-inflicted (NSI) GSWs. This is a retrospective cohort study of upper extremity GSWs from January 2012 to December 2022. Data were analyzed using the two-sample t-test, Pearson’s chi-squared test, and Fisher’s exact test. SI GSWs tended to be high-velocity GSWs and occurred more often in distal locations compared to NSI GSWs (p = 0.0014 and p < 0.0001, respectively). SI GSWs were associated with higher Gustilo–Anderson (GA) and Tscherne classifications (p < 0.0001 and p = 0.0048, respectively) and with a greater frequency of neurovascular damage (p = 0.0048). There was no difference in fracture rate or need for operative intervention between the groups. GA and Tscherne classifications were associated with the need for and type of surgery (p < 0.0001), with a higher classification being associated with more intricate operative intervention; however, GSW velocity was not associated with operative need (p = 0.42). Our findings demonstrate that velocity, wound grading systems, and other factors are associated with the manner in which GSWs to the upper extremity are inflicted and may thus have potential for use in the prediction of injury patterns and planning of trauma management and surgical intervention.

The main purpose of this paper is the investigation of the feasibility of a novel hybrid module specifically designed for the Mediterranean Sea. This module is intended to work as an offshore floating breakwater in severe sea states, and alternatively as a wave energy converter in the more frequent mild sea states, depending on its level of submergence. An experimental campaign on a 1:10 module has been carried out in the wave tank of the University of Campania. The dynamic response of the device, as well as its hydraulic performances, was investigated under various wave conditions. The experimental results highlight the possibility of realizing and installing hybrid structures combining energy conversion and wave attenuation.