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A little over twenty-five years ago, the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) approved the chimeric antibody rituximab which fundamentally altered the landscape of anti-cancer drugs. While only a few antibodies were approved in the immediate years that followed the rituximab approval, the last decade saw a wave of antibody-drug approvals in the oncology arena. In the last three years, the EMA and FDA greenlighted eighteen antibodies, the majority of them designed in the formats of antibody-drug conjugates (ADC) and bispecific antibodies (BsAb). While the use of ADC and BsAb formats and the current rapid pace of approvals appear routine and almost inevitable, such progress was thought to be quite improbable in the early days of therapeutic antibody development. To understand how we arrived at the current state of antibody development in oncology, we focus on six monumental events that shaped antibody approvals over the last two and half decades. We examine the circumstances that led to the approval of rituximab and trastuzumab, the first successful antibodies for the treatment of hematologic and solid cancers. We detail the generation of the ADC and BsAb formats that dramatically augmented antibody-mediated precision cytotoxicity. Finally, we explore the development of ipilimumab, the first immune checkpoint-inhibiting antibody that activates the immune system to kill cancer cells, and the discovery that allowed the use of checkpoint inhibitors across all cancer types based on the presence of genetic markers. Revisiting these key events provides critical insights into the process of antibody development in oncology.

With rapid urbanisation and the pressure on urban areas for service delivery, the role of urban local governments is undoubtedly becoming important and, here, their financial capacity can hold the key. At the same time, there are several issues in urban governance that need to be addressed yet. Delegation of decision making powers to urban local bodies (ULBs), which are traditionally considered as a part of the system of State government and acting on behalf of it, is one of them. The constitutional mechanisms like inter-governmental fiscal transfers were an attempt to reduce the gap of ULBs, but they were not effective in implementation at ground. It has become imperative now to understand the financial position of ULBs in order to move forward with the new means of fund flow. This paper presents a cross sectional analysis of the finance of 27 ULBs in North 24 Parganas District of West Bengal, India in terms of their financial base and its adequacy vis-à-vis norms, and their revenue and expenditure performance. Using certain ratios, the relative performance of municipalities on dependency measures was also assessed. The implications of finances of ULBs, in terms of raising resources, improving inter-governmental transfers and charting new mechanisms are also discussed. Lastly, an approach has been made to develop an index, i.e. Urban Governance Index (UGI) to a better understanding of the per-capita expenditure scenario of ULBs.

Evergreen conifers in boreal forests can survive extremely cold (freezing) temperatures during long dark winter and fully recover during summer. A phenomenon called “sustained quenching” putatively provides photoprotection and enables their survival, but its precise molecular and physiological mechanisms are not understood. To unveil them, here we have analyzed seasonal adjustment of the photosynthetic machinery of Scots pine ( Pinus sylvestris ) trees by monitoring multi-year changes in weather, chlorophyll fluorescence, chloroplast ultrastructure, and changes in pigment-protein composition. Analysis of Photosystem II and Photosystem I performance parameters indicate that highly dynamic structural and functional seasonal rearrangements of the photosynthetic apparatus occur. Although several mechanisms might contribute to ‘sustained quenching’ of winter/early spring pine needles, time-resolved fluorescence analysis shows that extreme down-regulation of photosystem II activity along with direct energy transfer from photosystem II to photosystem I play a major role. This mechanism is enabled by extensive thylakoid destacking allowing for the mixing of PSII with PSI complexes. These two linked phenomena play crucial roles in winter acclimation and protection. Evergreen conifers rely on ‘sustained quenching’ to protect their photosynthetic machinery during long, cold winters. Here, Bag et al. show that direct energy transfer (spillover) from photosystem II to photosystem I triggered by loss of grana stacking in chloroplast is the major component of sustained quenching in Scots pine.

Efficient acclimation to different growth light intensities is essential for plant fitness. So far, most studies on light acclimation have been conducted with plants grown under different constant light regimes, but more recent work indicated that acclimation to fluctuating light or field conditions may result in different physiological properties of plants. Thale cress ( ) was grown under three different constant light intensities (LL: 25 μmol photons m s ; NL: 100 μmol photons m s ; HL: 500 μmol photons m s ) and under natural fluctuating light (NatL) conditions. We performed a thorough characterization of the morphological, physiological, and biochemical properties focusing on photo-protective mechanisms. Our analyses corroborated the known properties of LL, NL, and HL plants. NatL plants, however, were found to combine characteristics of both LL and HL grown plants, leading to efficient and unique light utilization capacities. Strikingly, the high energy dissipation capacity of NatL plants correlated with increased dynamics of thylakoid membrane reorganization upon short-term acclimation to excess light. We conclude that the thylakoid membrane organization and particularly the light-dependent and reversible unstacking of grana membranes likely represent key factors that provide the basis for the high acclimation capacity of NatL grown plants to rapidly changing light intensities.

Velocity of compressional wave (VP) of coal and non-coal lithology is predicted from five wells from the Bokaro coalfield (CF), India. Shear sonic travel time logs are not recorded for all wells under the study area. Shear wave velocity (Vs) is available only for two wells: one from east and other from west Bokaro CF. The major lithologies of this CF are dominated by coal, shaly coal of Barakar formation. This paper focuses on the (a) relationship between Vp and Vs, (b) prediction of Vp using regression and neural network modeling and (c) estimation of maximum horizontal stress from image log. Coal characterizes with low acoustic impedance (AI) as compared to the overlying and underlying strata. The cross-plot between AI and Vp/Vs is able to identify coal, shaly coal, shale and sandstone from wells in Bokaro CF. The relationship between Vp and Vs is obtained with excellent goodness of fit (R2) ranging from 0.90 to 0.93. Linear multiple regression and multi-layered feed-forward neural network (MLFN) models are developed for prediction Vp from two wells using four input log parameters: gamma ray, resistivity, bulk density and neutron porosity. Regression model predicted Vp shows poor fit (from R2 = 0.28) to good fit (R2 = 0.79) with the observed velocity. MLFN model predicted Vp indicates satisfactory to good R2 values varying from 0.62 to 0.92 with the observed velocity. Maximum horizontal stress orientation from a well at west Bokaro CF is studied from Formation Micro-Imager (FMI) log. Breakouts and drilling-induced fractures (DIFs) are identified from the FMI log. Breakout length of 4.5 m is oriented towards N60°W whereas the orientation of DIFs for a cumulative length of 26.5 m is varying from N15°E to N35°E. The mean maximum horizontal stress in this CF is towards N28°E.

Background The implementation of JSY in India completed nearly 25 years since from its inception. Studies on beneficiary of the scheme based on various nationally provided data set indicates its persistence level over socio-economic inequality. Present study concerns such inequality and utilisation in terms of most recent NFHS-5 data set. Methods The study considers purification of data by deleting large and influential observations and use logistic regressions with robust standard error and inequality measurement technique to observe the condition of ultimate beneficiaries. Results Study observes an improvement in terms favourable distribution towards marginalised section of the society. Illiterate mothers benefitted most probably for the health manager intermediation. Media exposure and distance from health facilities are found significant contribution.

While antibody-based immunotherapeutic strategies have revolutionized the treatment of B-cell lymphomas, progress in T-cell lymphomas has suffered from suboptimal targets, disease heterogeneity, and limited effective treatment options. Nonetheless, recent advances in our understanding of T-cell biology, the identification of novel targets, and the emergence of new therapies provide hope for the future. In this review, we explore four areas of current and evolving antibody-based strategies for the treatment of peripheral T-cell lymphoma (PTCL): monoclonal antibodies (mAbs), bispecific antibodies (BsAs), chimeric antigen receptor T-cell therapy (CAR-T), and antibody–drug conjugates (ADCs). As part of this discussion, we will also include limitations, lessons learned, and potential future directions.

Non-photochemical quenching (NPQ) in photosynthetic organisms provides the necessary photoprotection that allows them to cope with largely and quickly varying light intensities. It involves deactivation of excited states mainly at the level of the antenna complexes of photosystem II using still largely unknown molecular mechanisms. In higher plants the main contribution to NPQ is the so-called qE-quenching, which can be switched on and off in a few seconds. This quenching mechanism is affected by the low pH-induced activation of the small membrane protein PsbS which interacts with the major light-harvesting complex of photosystem II (LHCII). We are reporting here on a mechanistic study of the PsbS-induced LHCII quenching using ultrafast time-resolved chlorophyll (Chl) fluorescence. It is shown that the PsbS/LHCII interaction in reconstituted proteoliposomes induces highly effective and specific quenching of the LHCII excitation by a factor ≥ 20 via Chl–Chl charge-transfer (CT) state intermediates which are weakly fluorescent. Their characteristics are very broad fluorescence bands pronouncedly red-shifted from the typical unquenched LHCII fluorescence maximum. The observation of PsbS-induced Chl–Chl CT-state emission from LHCII in the reconstituted proteoliposomes is highly reminiscent of the in vivo quenching situation and also of LHCII quenching in vitro in aggregated LHCII, indicating a similar quenching mechanism in all those situations. The PsbS mutant lacking the two proton sensing Glu residues induced significant, but much smaller, quenching than wild type. Added zeaxanthin had only minor effects on the yield of quenching in the proteoliposomes. Overall our study shows that PsbS co-reconstituted with LHCII in liposomes represents an excellent in vitro model system with characteristics that are reflecting closely the in vivo qE-quenching situation.

Tuberculosis (TB) remains among the leading infectious causes of death. Due to the limited number of antimicrobials in the TB drug discovery pipeline, interest has developed in host-directed approaches to improve TB treatment outcomes. C-C motif chemokine-like receptor 2 (CCRL2) is a unique seven-transmembrane domain receptor that is upregulated by inflammatory signals and mediates leucocyte migration. However, little is known about its role in TB infection. Here, we show that Mycobacterium tuberculosis (Mtb) infection increases CCRL2 protein expression in macrophages in vitro and alveolar macrophages (AMs), dendritic cells (DCs) and neutrophils in mouse lungs. To target selectively CCRL2-expressing cells in vivo , we developed a novel mouse anti-CCRL2 antibody-drug conjugate (ADC) linked with the cytotoxic drug SG3249. We tested its adjunctive therapeutic efficacy against TB when combined with the first-line regimen for drug-susceptible TB (isoniazid, rifampin, pyrazinamide, ethambutol; RHZE). The anti-CCRL2 ADC treatment potentiated RHZE efficacy in Mtb-infected mice and decreased gross lung inflammation. CCRL2 expression in lung DCs and AMs was lower in mice receiving anti-CCRL2 ADC treatment+RHZE compared to those receiving RHZE alone or the control group, although the total innate cell populations did not differ across treatment groups. Interestingly, neutrophils were completely absent in the anti-CCRL2 ADC treatment + RHZE group, unlike in the other treatment groups. IFN-γ+-and IL17-α+-T-cell responses, which are associated with optimal TB control, were also elevated in the anti-CCRL2 ADC treatment + RHZE group. Our findings suggest that CCRL2-targeting approaches may improve TB treatment outcomes, possibly through selective killing of Mtb-infected innate immune cells.

A re-configurable, QoS-enhanced intelligent stochastic real-time optimal fair packet scheduler, QUEST, for IP routers is proposed and investigated. The objective is to maximize the system QoS subject to the constraint that the processor utilization is kept at 100%. All past work on router schedulers for multimedia traffic were of earlier generation, in that they focused on maximizing utilization whereas being QoS-aware but without explicitly maximizing the QoS. Keeping utilization fixed at nearly 100%, QoS is dynamically maximized, thus moving to the next generation. QUEST’s other unique advantages are three-fold. First, it solves the challenging problem of starvation for low priority processes; second, it solves the major bottleneck of Earliest Deadline First scheduler’s failure at heavy traffic loads. Finally, QUEST offers the benefit of arbitrarily pre-programming the process utilization ratio. Three classes of multimedia IP traffic, namely, VoIP, IPTV and HTTP have been considered. Two most important QoS metrics, namely, packet loss rate (PLR) and mean waiting time, are addressed. All claims are supported by discrete event and Monte Carlo simulations. The proposed scheduler outperforms benchmark schedulers and offers 37% improvement in packet loss rate and 23% improvement in mean waiting time over the best competing current scheduler Accuracy-aware EDF. The proposed scheduler was validated in a test-bed platform of a NetFPGA® router and results were observed with Paessler® PRTG network monitor.