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  • Why Punishing Civilians Has Not Yielded Strategic Success

    Why Punishing Civilians Has Not Yielded Strategic Success

    After nearly 700 days of war, the death toll in Gaza has risen to extraordinary levels. Amid heavy bombardment that has turned the territory into a wasteland of rubble and stringent blockades that have led to mass hunger and even starvation, over 61,000 Palestinians have died and over 145,000 have been seriously wounded, according to Gaza’s Hamas-affiliated health authorities, which do not distinguish between civilians and Hamas fighters.

    But the true number of the war’s casualties may far outstrip those figures, which do not include the thousands of bodies that remain under the rubble, the large number of dead that could not arrive at morgues, and the excess deaths from the destruction of infrastructure and the ensuing disease, famine, and lack of medical care. In February, the medical journal The Lancet published an extensive analysis based on a wide variety of sources (including obituaries) and estimated that the official death toll underreported the direct war deaths in Gaza by at least 41 percent and perhaps by as much as 107 percent, while not accounting at all for nontrauma-related deaths resulting from the impact of Israeli military operations on Gaza’s health services, food and water supplies, and sanitation.

    In sum, the authors of the study suggested that Israel’s campaign has caused at least an additional 26,000 Palestinian deaths and perhaps over 120,000 additional deaths, with the true death toll possibly exceeding 186,000. Taking that into account, as of late July 2025, Israel’s war in Gaza has led to the deaths of between five to ten percent of the prewar population of about 2.2 million. This represents an unprecedented slaughter. Israel’s campaign in Gaza is the most lethal case of a Western democracy using the punishment of civilians as a tactic of war.

    Leaders and scholars have long assumed that democracy offered a solution to the worst pathologies of authoritarian states, especially the willingness of a government to subject populations to coercion, cruelty, and violence. Indeed, the United States and other Western democracies, including Israel, have insisted that democracy is crucial for the promotion of fundamental human rights, individual prosperity, and a more peaceful world. For Israel, a country that has long touted its democratic bona fides, to violate core democratic norms in such dramatic fashion cheapens the value of democratic government itself.

    Israel’s defenders may insist that civilian deaths are inevitable in a conflict against a burrowed-in terrorist enemy. But it has been clear from Israeli actions—including the targeting of children by snipers, the relentless bombing of civilian infrastructure and residences, and the blockade and starvation of the civilian population—as well as the rhetoric of numerous Israeli officials that Israel’s war is not simply against Hamas but aimed at all the residents of Gaza. That is also the conclusion of numerous international institutions and human rights groups. Indeed, the notion that Hamas can be eradicated via military means is a “fantasy,” as the former Shin Bet director Yoram Cohen said this week. As civilians continue to suffer in Gaza, Israel has squandered the moral high ground for no good strategic purpose.

    Israel’s critics may demand that, based on its treatment of the Palestinians, the country should not be considered a democracy. That understates the full dimensions of Israel’s behavior in Gaza. Even now, Israel retains the political institutions built on majority rule and the high levels of citizen participation in free elections that are the hallmarks of representative government and that have long characterized Western democracy. Independent experts, such as Freedom House, still recognize Israel as a democracy. What is truly shocking about events in Gaza is both the scale of the devastation and that the government of Israel can genuinely say that its policies reflect the will of most Israelis. The carnage in Gaza is not the work of authoritarians or demagogues but bears the imprimatur of democracy. Israel’s campaign thus has profound implications both for the long-term security of the country and the value of democracy around the world.

    IN THE LIGHT OF HISTORY

    In my 1996 book, Bombing to Win, I studied every campaign in the twentieth century that employed airpower with the intention of inflicting harm on civilians: 40 campaigns in all, including the Spanish Civil War, the Vietnam War, and the 1991 Gulf War. Only five of the 40 involved civilian deaths greater than one percent of the civilian population. These included four campaigns in and around World War II—Japan’s invasion of China from 1937 to 1945, Germany’s invasion of Poland from 1939 to 1945, the Allied bombing and invasion of Germany from 1939 to 1945, and the U.S. bombing and conquest of Japan from 1942 to 1945—and the Soviet invasion of Afghanistan from 1979 to 1988. In proportional terms, Nazi Germany’s attack on Poland ranks as the deadliest of these campaigns, killing more than 20 percent of the prewar population over six years. That figure was enlarged, of course, by the Holocaust and the slaughter in ghettos and concentration camps of millions of Polish Jews.

    Until Gaza, the worst civilian punishment campaign by a Western democracy was the bombing and ground invasion of Germany in World War II, which killed approximately two to four percent of the population, outpacing even the U.S. nuclear attacks and fire-bombing raids on Japan, which killed about one percent of the population. Those estimates from Germany account for deaths caused by both Soviet and Western forces, as well as direct and indirect deaths (as in The Lancet’s study on Gaza).

    Whether it is called a “genocide” or not, no sensible observer could look at Israel’s war in Gaza and miss the stunning levels of devastation that Palestinians have endured. Beyond the mass death and suffering, the level of physical devastation is remarkable: satellite analysis by credible independent media outlets, such as The Economist and the Financial Times, reveals that at least 60 percent of all the buildings and 90 percent of homes in Gaza have either been severely damaged or completely destroyed. All 12 of Gaza’s universities, 80 percent of its schools and mosques, and numerous churches, museums, and libraries have also been demolished. No hospital in Gaza is fully functioning, and only 20 out of 36 hospitals are partially functioning.

    And yet despite this mammoth destructive enterprise, Israel has not come close to fulfilling its stated aim of eliminating Hamas. The group still has significant appeal among Palestinians in Gaza and the West Bank. It may be diminished as a military force, but it can replenish its depleted ranks with new recruits—indeed, by some accounts, it has managed to bring in over 10,000 new fighters since the war began. The extreme brutality Israel has inflicted on the Palestinian people has not produced the strategic gains that Israeli officials promised.

    The moral case for harming civilians is always dubious even when such violence serves a strategic purpose. When that strategic purpose does not exist, however, the moral case evaporates altogether. Israel now finds itself in a morally untenable situation. Rather than incur the world’s growing wrath, increased economic pressure, and the greater likelihood of future violence, Israel must reverse course and pursue alternatives to its campaign of mass death in Gaza.

    THE END OF STRATEGY

    Throughout history, states have repeatedly punished civilian populations harshly to try to compel local communities to turn against governments and terrorist groups. But even intense civilian punishment rarely achieves these goals. Instead, it often leads to what I have termed the “Pearl Harbor effect”: growing support among the assailed civilian community for its government or for the local terrorist group.

    In June 2024, I argued in Foreign Affairs that at least in one way, Hamas was stronger then than it was before October 7, 2023. To be sure, Israeli attacks had devastated the group’s leadership and smashed much of its infrastructure. But according to the most reliable polling information available at that point, Palestinian support for Hamas had remained the same or risen in Gaza and the West Bank. Overall, the taproot of Hamas’s power—its ability to recruit new fighters to replenish losses—had actually increased. In January 2025, U.S. officials revealed that according to their estimates, Hamas had recruited around 15,000 new fighters since the start of Israel’s military operations in 2023, more than making up for the 11,000 to 13,000 losses that U.S. intelligence estimated the group had suffered.

    Israel now finds itself in a morally untenable situation.

    Much has happened since the start of this year: the end of a two-month cease-fire in March, the escalating Israeli siege and the tightened blockade on food and humanitarian goods entering the territory, the humanitarian crisis affecting Gaza’s entire population, and Israel’s announced intention to conquer at least 75 percent of Gaza—along with the overt consideration by some Israeli leaders that they should expel all Palestinians from the territory. For its part, Hamas seems to be stepping up its guerrilla tactics of ambushes and bombings targeting Israeli soldiers in Gaza, but the group has not been able to meaningfully defend the territory and its population from Israeli attacks.

    Media reports in recent months have revealed sporadic demonstrations in Gaza against Hamas, suggesting that some Palestinians are fed up with the group and its actions. But according to recent polling, Hamas remains broadly popular among Palestinians in both Gaza and the West Bank. The unprecedented scale of Israeli action has not yet exploded the assumptions in my original analysis.

    Hamas’s relative power cannot simply be measured the same way one would measure the military balance between Israel and its state rivals. In contests between states, the military balance between opponents is of paramount importance. Their militaries usually engage in direct, large-scale battles to take and hold territory, control the skies over territory, or secure access to contested territory. The success of these operations is determined by key indicators, such as the numbers of fighters, stocks of weapons, and levels of economic support. If such factors determined the nature of combat between Hamas and Israel, the war would have been over long ago, since Israel far outpaces the group on all the usual indicators of military strength. That the war has continued for nearly two years and Hamas retains sufficient governing authority in Gaza to hide the remaining Israeli hostages and inflict casualties on the Israeli security forces strongly suggests that the true power of Hamas cannot be found in the traditional metrics of the military balance.

    THE PERSISTENCE OF HAMAS

    Terrorist groups such as Hamas fight asymmetrically. They rarely seek to seize and hold territory and almost never attempt to win pitched military-to-military battles. Instead, these groups seek to impose losses on their opponents in other ways, mostly through guerrilla operations that pick off enemy military personnel in small numbers and over long stretches of time and through attacks against civilians. Most often, they simply want to maximize harm to vulnerable civilian targets. And since they are always weaker than their state rivals in the usual military indicators, terrorist groups expect to suffer great losses as the conflict persists. As a result, the most telling power of Hamas is its ability to replace the fighters it loses with new ones. Estimates of Hamas’s fighting strength bear out this logic. According to the Israeli military, in early 2025, Hamas had as many as 23,000 fighters, a figure roughly the same as an Israeli estimate of the group’s size before October 7, 2023.

    Hamas can recruit new fighters because it still enjoys support. Surveying public opinion is the best way to measure how much support exists among Palestinians for Hamas. The best available surveys conducted among Palestinian populations in Gaza and the West Bank are by the Palestinian Center for Policy and Survey Research (PSR), an independent, nonprofit survey center established in 1993 following the Oslo accords that collaborates with Israeli scholars and institutions.

    My previous June 2024 analysis relied on the PSR surveys from 2023 and 2024. When recent surveys from May 2025 are added to the mix, a striking finding emerges: Hamas has more support among Palestinians today than it did before October 7. Hamas is now, for instance, substantially more popular than its main political rival, the Fatah faction of the Palestine Liberation Organization, which dominates the Palestinian Authority. In September 2023, Fatah enjoyed a four-point lead over Hamas (26 to 22 percent). In polling from May 2025, Hamas now enjoys an 11-point lead over Fatah (32 to 21 percent).

    The shift toward Hamas is particularly acute in the West Bank, where support for Hamas has more than doubled. There, support for armed attacks on Israeli civilians has risen from 48 percent in June 2023 to 59 percent in May 2025.

    Waiting for food in Khan Younis, southern Gaza Strip, August 2025  Hatem Khaled / Reuters

    In Gaza, support for Hamas has remained flat, despite the enormous suffering brought on the territory in the wake of Hamas’s October 2023 attack. In September 2023, Hamas had a 13-point lead over Fatah in Gaza (38 to 25 percent), and in May 2025, the numbers were almost the same: Hamas held a 12-point edge over Fatah (37 to 25 percent). The one sign that the Israeli campaign may have changed some views in Gaza is the drop in support among Gazans for armed attacks on Israeli civilians, which fell from 67 percent in September 2023 to 37 percent in May 2025.

    But the polling suggests that Israel has not succeeded in severing the connection between Gazans and Hamas. Far from dwindling, support for Hamas has grown or remained the same, and the willingness of Palestinians to attack Israeli civilians remains high enough to satisfy Hamas’s recruiting needs, despite the most brutal punishment campaign by a Western democracy in history. For Israel’s security, the tragic reality is that Hamas likely retains the key asset that could allow it to carry out another major attack down the road: vast numbers of fighters willing to fight and die for the cause.

    Hamas’s abiding popularity could be a factor in wider violence beyond Gaza. With Israeli forces stepping up raids on Palestinian refugee camps and settlers attacking Palestinians in the West Bank, the region is now a powder keg. The West Bank is home to 2.7 million Palestinians and 670,000 Israeli settlers living in proximity. Recent Israeli plans to expand settlements in the West Bank and rhetoric from far-right figures calling for the territory’s annexation will likely add fuel to this potential fire.

    Israel’s announced intention to seize control of at least 75 percent of Gaza and then confine Gazans to a small portion of territory won’t succeed in divorcing the population from Hamas. As Palestinians are driven into a small corner of the enclave, Hamas will just move with them; this plan is no more likely to defeat Hamas than were the previous population transfers that forced people from area to area inside Gaza. Indeed, such Israeli actions will cause more suffering among civilians—and produce more terrorists. Israel could go further still, expelling Gazans into the Sinai Desert, but such a drastic measure would stoke the possibility of future retributive violence targeting Israelis. And most damaging for long-term Israeli security, throwing Gazans out of the territory would leave Israel open to accusations of engaging in ethnic cleansing, undermining any moral case for supporting the country.

    Military operations that, intentionally or not, result in historic levels of civilian deaths are ultimately leading to a more dangerous situation for Israel, making it a less desirable home for Jews and a more likely target for those seeking revenge. Instead, Israel should establish a new security perimeter between Israeli civilian population centers and the Palestinians in Gaza, allowing Gazans enough space to rebuild their lives, letting humanitarian and economic aid to flow into the territory unimpeded, and working with international allies to foster alternative political arrangements to Hamas or Israeli control in Gaza.

    THE STRATEGIC COSTS OF IMMORAL ACTIONS

    Since the founding of the state of Israel in 1948, international support for the country has been based in significant part on the recognition that Jews were the victims of the worst genocide in history. The war in Gaza, however, has seen a swelling tide of condemnation of Israel for committing intentional harm to civilians, mass atrocities, and even genocide. The International Criminal Court has issued arrest warrants that require some 125 countries, including France and the United Kingdom, to detain Israel’s prime minister and other members of Israel’s cabinet. Even within Israel, prominent voices are calling for a course correction: former Israeli Prime Minister Ehud Olmert has declared that Israel’s actions in Gaza are tantamount to a “war crime,” arguing that “what we are doing in Gaza now is a war of devastation: the indiscriminate, limitless, cruel and criminal killing of civilians.” As Israel becomes an international pariah and faces stiffening resistance to its rule in Gaza, the historic scale of its punishment of civilians is only jeopardizing the country’s long-term security.

    Many Western countries have already begun to make moves to chastise Israel, including by joining much of the rest of the world in formally recognizing a Palestinian state, a step that could lead to large-scale humanitarian intervention in Gaza and economic sanctions on Israel. The United States will likely not follow that path, but U.S. President Donald Trump is mercurial. He has already contradicted Israeli Prime Minister Benjamin Netanyahu and insisted that the starvation of Gaza must end. Rifts within Trump’s base are widening over Israel. U.S. Representative Marjorie Taylor Greene, a leading hard-right Republican, declared that Israel is in fact committing genocide in Gaza, borrowing from rhetoric heard more often on the left. A tactical alliance could grow in the United States between elements of the far right and the far left that seek to roll back U.S. support for Israel.

    Israel is the most militarily powerful country in the Middle East and has scored numerous victories over its opponents in recent years. But it is also a tiny country surrounded by rivals. And it needs close relations with major Western democracies to ensure the viability of its economy. Those relations could be tested and strained as Israel continues waging the worst campaign of civilian punishment ever performed by a Western democracy, a campaign that has not come close to eliminating Hamas and has given Israel more adversaries and left it more isolated. Israeli leaders must decide whether their ongoing immoral actions in Gaza are really worth the costs to their country’s future.

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  • Investigative report exposes Microsoft support for Israeli war crimes in Gaza and the West Bank

    Investigative report exposes Microsoft support for Israeli war crimes in Gaza and the West Bank

    The Microsoft logo is pictured outside the headquarters in Paris, Jan. 8, 2021. [AP Photo/Thibault Camus]

    A joint investigation by The Guardian and +972 Magazine has revealed that Microsoft has been providing its Azure cloud computing infrastructure to Israeli military intelligence to store a vast archive of intercepted communications by Palestinians. The data stored and utilized by intelligence agents within Israel Defense Forces (IDF) Unit 8200 has facilitated deadly airstrikes and military operations in both Gaza and the West Bank.

    This unprecedented integration of Microsoft with the war crimes of the Israeli military exposes the increasingly central role played by and correspondence of interests between giant global tech corporations and the strategic aims of US imperialism in the ongoing genocide and ethnic cleansing of the Palestinian people.

    According to the investigative reports, the collaboration between Microsoft and Unit 8200 was brokered at the highest levels. In late 2021, a delegation from Israel’s military intelligence, led by then-commander Brigadier General Yossi Sariel, met at Microsoft’s Seattle headquarters with CEO Satya Nadella and other key executives.

    Nadella personally committed Microsoft’s technological resources to the project, reportedly calling the partnership “critical” for Microsoft’s future, and approved the creation of a customized, segregated area within Azure for exclusive use by Unit 8200.

    This platform, according to anonymous sources and leaked internal Microsoft documents, was not for hosting generic cloud services but was designed to meet “the most ambitious demands for mass data collection and analysis ever proposed to the company.” Within months, Unit 8200 was able to begin storing and analyzing intercepted communications on a scale that the Israeli military had previously regarded as technically impossible.

    The technological infrastructure that Microsoft built and now maintains is significant in its scale and scope. The foundation of the system is Azure data centers located in the Netherlands, with additional clusters in Ireland and within Israel itself. By July 2025, at least 11,500 terabytes of Israeli military data—equivalent to about 200 million hours of audio—were being stored on Microsoft servers.

    Most of the data, according to Israeli and Microsoft sources cited by the investigation, consist of recordings of phone calls by Palestinians in the West Bank and Gaza. Surveillance officers and internal documents described the ambition to “capture and store up to a million calls an hour.”

    This required “collaboration on security architecture between Microsoft engineers and military staff,” with Unit 8200 alumni among the Azure development teams responsible for implementation. Internal memos reveal “a rhythm of daily, top-down and bottom-up interaction” between the company’s cloud division and its Israeli military client, with project secrecy so tight that non-essential Microsoft personnel were not permitted to refer to the “8200 project” by name.

    The Israeli surveillance of Palestinians is universal. The operations described in the investigation mirror details revealed by former NSA intelligence officer Edward Snowden in 2013 about the scale and scope of US government surveillance, data storage and searching of the electronic communications of everyone in the country, if not throughout the entire world.

    Having long controlled the telecommunications infrastructure in the occupied territories, Israel indiscriminately intercepts all phone calls, radio transmissions and internet traffic, gathering up the communications of millions of ordinary Palestinians.

    Leaked documents show the primary purpose of this data is to generate rapid “targets for kinetic action,” that is, identify cellular phones and voices for tracking and subsequent drone strikes, air raids or ground operations. Several anonymous Israeli intelligence officers, speaking to reporters, described a machinery that “finds incriminating material to be used for anything: blackmail, mass arrests, administrative detention, or retroactive justification for killing.”

    Three sources specifically confirmed the data collected and stored using Microsoft’s cloud has been pivotal in planning lethal airstrikes in Gaza, as well as sweeping military detentions in the West Bank, operations which have left thousands of Palestinians dead or disappeared since October 2023.

    The source of these revelations is derived from a rare trove of leaked documents—internal emails, technical memos, contracts and meeting summaries—supplemented by extensive interviews. At least 11 current and former Microsoft and Israeli intelligence sources, some of whom participated directly in the system’s development, provided corroboration under strict anonymity due to the immense legal and career risks involved.

    One well-placed official warned that a successful legal challenge to this arrangement, especially under international human rights law, would threaten both Israeli and American interests, given the “codependence of government and cloud monopolies in waging cyber and kinetic war.”

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  • Sony Pictures Entertainment Q1 2025 Profit Up 76 Percent

    Sony Pictures Entertainment Q1 2025 Profit Up 76 Percent

    Sony Pictures Entertainment’s operating income for the first quarter ended June 30, 2025 was up 76 percent to $129 million from $73 million in dollar terms for the comparable period a year before, with Q1 sales up 4 percent to $2.263 billion from $2.166 billion.

    SPE comprises the motion pictures division, television productions and media networks.

    The motion pictures unit (which comprises sales from theatrical, home entertainment and streaming sales) saw Q1 revenue fall 13 percent to $742 million from $852 million. SPE released four theatrical movies globally in the period, including Until Dawn, Materialists (outside North America only), Karate Kid: Legends and 28 Years Later (for which only 11 days of release were included in Q1).

    SPE’s TV unit saw Q1 revenue reach $841 million, up a healthy 39 percent from $607 million in the same period a year earlier. SPE’s major streaming television productions from the period included Amazon Prime Video’s Wheel of Time and The Narrow Road to the Deep North, HBO’s The Last of Us, Netflix’s Department Q, The Creature Cases and Yo No Soy Mendoza. Broadcast staples Jeopardy! and Wheel of Fortune, and their various spinoffs, as well as ABC’s Shark Tank and American Idol bolstered the TV unit’s revenues.

    First quarter revenue from media networks (that includes TV channels and digital channels) fell 4 percent to $674 million from $702 million. The company revealed that it ended Q1 2025 with 40 television channels and 675.2 million total subscribers.

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  • Groundbreaking Latin jazz pianist-composer Eddie Palmieri, dead at 88 – Reuters

    1. Groundbreaking Latin jazz pianist-composer Eddie Palmieri, dead at 88  Reuters
    2. Eddie Palmieri, Latin Music’s Dynamic Innovator, Dies at 88  The New York Times
    3. Eddie Palmieri, a trailblazer in Latin music, has died at age 88  Utah Public Radio
    4. Groundbreaking Latin jazz pianist-composer Eddie Palmieri, dead at 88 By Reuters  Investing.com
    5. Eddie Palmieri dies at 88: Cause of death, top songs, wife, children, and other details  Hindustan Times

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  • Degradation kinetics of Andrographolide in aqueous solution, product identification and biological activity evaluation

    Degradation kinetics of Andrographolide in aqueous solution, product identification and biological activity evaluation

    The thermal stability of 1 was assessed kinetically in aqueous solutions at different pH levels relevant to the formulation of commercial products. Andrographolide (1) is the major bioactive metabolite of A. paniculata and is thus a driver for the development of value-added products, either as a single material or as an ingredient in a standardized mixture. The use of standardized preparations of A. paniculata leaves or leaf extracts as functional ingredients for medicinal plant products is also important for commercial development. Knowledge regarding the thermal stability of 1 is therefore of significance for the development of high-quality functional products for the cosmetic and nutraceutical industries. Such standardized extracts and cosmetic products may be exposed to elevated temperatures at different pH levels, depending on the production processes, and may experience a variety of formulation, storage, and manufacturing operations where metabolite integrity could be compromised13,27,28.

    Identification of degradation products

    The HPLC method for the analysis of 1 was adapted from the American Herbal Pharmacopoeia29. The separation of 1 and its major degradation products from the pH-adjusted solutions in methanol (MeOH) was accomplished within a 25 min time frame. The isolates were characterized using nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry and comparison with published spectroscopic data (Supplementary Tables S3 and S4, Figures S1−S10). In the acidic environment (pH 2.0), the degradation products 230,31,32,33,34,35 and 324,36 eluted at retention times (tR) of 4.1 min and 7.6 min, respectively (Fig. 1). Isoandrographolide (2), a white amorphous powder, possessed a molecular formula of C20H30O5 as determined by (+)-LC-MS-QTOF [M + Na]+ at m/z 373.1976 (Supplementary Figure S11). The 1H- and 13C-NMR spectra of 2 were similar to those of 1, except for a methyl group at C-17 (δH 1.19) and an oxymethine proton at C-12 (δH 4.58), instead of an exo-methylene group H-7α (δH 4.67) and H-7β (δH 4.89) and an olefinic proton H-12 (δH 6.85) in 1, respectively (Supplementary Table S3). The 13C NMR data of 2 showed two oxymethine carbons at C-8 (δC 83.2) and C-12 (δC 72.3) instead of the two resonances of olefinic carbons in 1 (Supplementary Table S4). The NMR data of 2 agree with those reported35. 8,9-Didehydroandrographolide (3), white amorphous powder, C20H30O5, showing (–)-LC-MS-QTOF at m/z 395.2069 ([M + HCOO] (Supplementary Figure S12). The 1H- and 13C-NMR data were closely related to those of 1, except for an endo-olefinic group at C-8 (δC 129.2), C-9 (δC 134.9), and C-17 (δC 20.9) in 3, instead of an exo-methylene group in 1 (Supplementary Table S4). The NMR spectral data of 3 agreed with those previously reported24.

    For the pH 8.0 solution, the degradation products 43,24,37,38, 539, and 619,20,24 eluted at tR of 5.5, 10.2, and 19.8 min, respectively. Compound 6 was not detected in strongly basic conditions (pH 10.0–12.0) (Fig. 1). 15-Seco-andrographolide (4) was isolated as a white amorphous powder, C20H32O6, m/z 367.2123 ([M – H]) (Supplementary Figure S13). The structure of 4 was confirmed by comparison of the NMR data with 1, through the presence of an acyclic oxy-methylene group at C-15 (δH 3.75 and δH 3.61; δC 66.3) instead of the cyclic oxy-methylene protons (δH 4.16 and δH 4.46; δC 76.1) in 1 (Supplementary Table S3). The NMR data of 4 agreed with those reported24. 14-Deoxy-15-methoxyandrographolide (5) was obtained as a white solid, C21H32O5, m/z 365.2328 ([M + H]+) (Supplementary Figure S14). The NMR data were similar to those of 1, except for resonances for a methylene at C-14 (δH 3.09, 2.67; δC 33.5) and di-oxymethine at C-15 (δH 5.55; δC 104.4), instead of resonances for an oxymethine and oxymethylene in 1. The structure of 5 was confirmed by comparison of the NMR data with those reported39. The structure of 11,14-dehydro-14-deoxy-andrographolide (6) was confirmed by analysis of the 1H-NMR data with those reported24. A trans-olefinic group was observed at C-11 (δH 6.86; δC 136.54) and C-12 (δH 6.16; δC 122.5). and by the resonances for an olefinic group at C-13 (δC 129.6) and C-14 (δH 7.44; δC 146.7) instead of an oxy methine in 1. The (+)-LC-MS-QTOF at m/z 333.2060 ([M + H]+) confirmed the molecular formula to be C20H28O5 (Supplementary Figure S15).

    The HPLC chromatograms illustrating the degradation products formed at pH 2.0, pH 6.0, and pH 8.0 are presented in Fig. 1 and Supplementary Figures S16–S18. In experiments using DMSO, the degradation product observed under acidic conditions (pH 2.0) produced similar signals as in MeOH, whereas under strongly basic conditions (pH 10.0 and pH 12.0), only 4 was formed from 1 (Supplementary Figure S19). Polarity or nucleophilicity therefore plays an important role in the degradation pathways of 1 since MeOH is a stronger nucleophile than DMSO and thus 5 could be observed in the MeOH conditions.

    Fig. 1

    HPLC chromatograms of pH 2.0, pH 6.0, and pH 8.0 stressed solutions at 70 °C on a Poroshell EC C18 column, flow rate: 1 mL/min, 25 min, 50% MeOH–H2O, detected at UV 224 nm. A; pH 2.0 shows the peaks of 2 (4.1 min), 1 (5.7 min), and 3 (7.6 min). B and C; pH 6.0 and pH 8.0 showing the peaks for 4 (5.5 min), 1 (5.7 min), 5 (10.2 min), and 6 (19.8 min). D and E; pH 10.0 and pH 12.0 at 70 °C showing the peaks for 4 (5.5 min) and 5 (10.2 min).

    The persistence of the degradation products from 1 in pH 2.0 solution was evident with compounds detected for at least 7 days (Supplementary Figure S16), whereas at pH 6.0 and pH 8.0 4 was the major degradation product, and 5 and 6 were observed in small amounts under these conditions (Fig. 1 and Supplementary Figures S17 and S18). The formation of products 4, 5, and 6 was initially detected after 2 days at pH 6.0, and after 1 h at pH 8.0 (Supplementary Figures S17 and S18). These studies support the previous reports on the kinetic degradation of 1 in solution24. Andrographolide (1) therefore undergoes distinctive acid and base-catalyzed degradation pathways which provides a critical insight into the degradation mechanisms of 1 and highlights the importance of pH on the stability and transformation of this bioactive compound when different pharmaceutical or cosmeceutical formulations are being considered.

    Kinetics of the degradation of 1

    HPLC chromatographic analysis revealed a direct relationship between the pH of the solution and the rate of the degradation reaction. Specifically, at pH 2.0 and pH 4.0, the degradation of 1 occurred at a slower rate compared to solutions at higher pH levels (pH 6.0 to pH 12.0) (Figs. 2 and 3). The HPLC chromatogram of 1 at pH 2.0 over a period of 7 days at 70 °C indicated two degradation products, 2 and 3 (Supplementary Figure S16), while no degradation was detected at pH 4.0 in the same time frame and temperature (Supplementary Figure S20). Thus, 1 exhibited greater stability in pH 4.0 buffer solution compared to pH 2.0, consistent with previous findings that noted the optimal stability of 1 within the pH range of 3–540. Although the degradation rates increase below pH 3.0, 1 remains largely present at pH 2.0, a typical human gastric value, and making this low pH relevant in the context of food, cosmetic, and drug processing.

    The metabolite remained stable at the boiling point of MeOH (64.7 °C for 28 days), whereas in DMSO, the degradation rate of 1 depended on the temperature and the composition of the solvent23. The rate constant for the degradation of 1 was investigated at pH 2.0, pH 6.0, and pH 8.0, and at three individualized, elevated temperatures of 70, 77, and 85 °C (Table 1). Chemical kinetic parameters and profiles for the degradation of 1 are shown in Table 2. As expected, in each case the apparent kinetic rate constant (k) increased with increasing temperature. Strong correlation coefficients (0.9800 < r2 < 0.9978) from the plot of ln (C) against reaction time (day) were found (Table 1). The rate constant obtained from Eq. (1) was fitted to an Arrhenius-type equation in each kinetic model studied to determine the effect of temperature on the chemical reaction (Fig. 2). The k values indicated the decreased thermal stability of 1 as the temperature was increased. Under different conditions, the k value of solid-state andrographolide under heat-accelerating conditions was reported to be 3.8 × 10− 6 per day17 and 6.58 × 10− 6 per day18 while in pH-dependent solutions the k value was revealed as 6.5 × 10− 5 per day (at pH 2.0), 2.5 × 10− 3 per day (at pH 6.0), and 9.9 × 10− 2 per day (at pH 8.0). Thus 1 decomposed faster in acid and basic solutions than in the solid state. This is the first report documenting the thermal degradation kinetics of 1 at specific pH conditions. These results align with earlier studies that characterized the degradation of 1 as following a first-order reaction model in solution through intermolecular interactions23. First-order kinetics indicated that the degradation of 1 is concentration dependent, therefore the amount of 1 degrading per unit of time is not constant for the ambient pH conditions. Most drugs tend to degrade with either zero- or first-order kinetics41. On the other hand, solid state 1 decomposed through second-order degradation kinetics under accelerated conditions through intramolecular interactions19,20. Second-order degradation occurs when the rate is influenced by the concentration of two separate or identical reactants. Therefore, the varied matrix or formulation of 1 under study may be the cause of the identified differences in degradation kinetics. The intermolecular interactions of 1 influence the rate of degradation17,18,19,20. However, the intramolecular interactions of 1, particularly through hydrogen bonds and hydrophobic interactions are crucial for stability and function. The calculated activation energies (Ea) derived from the curves showed that the values for 1 at pH 2.0, pH 6.0, and pH 8.0 were 118.9, 82.8, and 79.4 kJ/mol1, respectively (Table 2). A high Ea generally indicates that the reaction is less sensitive to temperature fluctuations15. Hence, the higher Ea value of 1 at pH 2.0 portends a lower sensitivity to temperature-induced degradation than in pH 6.0 and pH 8.0 solutions. The stability of 1 in acidic conditions may be due to the presence of free –OH groups causing clustering, followed by strong intermolecular hydrogen bonding. The shelf-life values for 1 at pH 2.0, pH 6.0, and pH 8.0 at 25 °C were 4.3 years, 41 days, and 1.1 days, respectively (Table 2) which is highly significant for product formulation studies.

    Fig. 2
    figure 2

    First-order plot and Arrhenius plots of the degradation of andrographolide based on pH, (A) pH 2.0, (B) pH 6.0, and (C) pH 8.0.

    Fig. 3
    figure 3

    First-order plot of the degradation of andrographolide (1) in MeOH between pH 2.0 and pH 4.0 at 70 °C for 35 days.

    Table 2 Predicted shelf-life (t90%) of 1 in pH 2.0, pH 6.0, and pH 8.0 solutions at 25 °C using an arrhenius method.

    Formation of degradation products

    The transformation of 1 into 2 can occur through (a) allylic rearrangement of the hydroxyl group on the lactone ring, (b) protonation of the exo-methylene group, and (c) cyclization of the tetrahydrofuran ring30. The formation of 3 was visualized to occur through isomerization of the 8,17-double bond by (a) protonation of the exo-methylene moiety, and (b) abstraction of the proton at C-9[22] (Scheme 1). However, the13C-NMR spectrum indicated a mixture of formation olefinic isomers of 3 for which the precise configuration could not be established. Compound 4 could be produced through fragmentation of the lactone ring of 1, and 6 could arise through E2 elimination by base following abstraction of the δ-proton in 1 leading to 1,4-elimination from an allylic alcohol24 (Scheme 1). The formation of 5 may occur through methoxylation at C-15 involving an enol lactone intermediate (m/z 333.2060)42 which may be derived from 6 (Scheme 1 and Supplementary Figure S21). However, the1H-NMR spectrum indicated either a mixture of C-15-epimers of 5, or only one epimer for which the precise configuration could not be established. This mechanistic possibility was revealed from the HPLC analysis of 5 when 6 was treated at pH 8.0 in MeOH solution (Supplementary Figure S22). This chemical reaction supports the biogenetic pathway for 5 that is proposed to occur in plants39. However, 5 could also be an artifact due to the presence of MeOH in the solution which acts as a nucleophile to react with an enol lactone intermediate (Figure 4 and Scheme 1). This analysis enumerates some of the mechanisms underlying the degradation of 1 and highlights the potential for exploring reaction opportunities towards further analogues for biological assessment while retaining their stability.

    Fig. 4
    figure 4

    Chemical structures of 1 and its degradation products.

    Scheme 1
    scheme 1

    Reaction mechanisms for the degradation of 1 under acidic and basic conditions.

    Biological activity assessments

    To investigate the changes in the biological profile of the degradation products in comparison with 1, two bioassays were performed. The first assay evaluated the inhibitory effect on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 macrophages. The results of this anti-inflammatory bioassay for 1 and its degradation products are summarized in Table 3. The presence of a newly formed tetrahydrofuran ring and an olefinic bond in 2 did not enhance the anti-inflammatory activity when compared to 1 and the other degradation products. This affirmed that the conjugated Δ12(13)-double bond and the hydroxy group at C-14 are critical structural elements for the inhibition of NO production33. In addition, the anti-inflammatory activity of 5 and 6 was not enhanced relative to 1, 3, and 4 through the introduction of a methoxy group at C-15 in 5, and a conjugated double bond in compound 6. These results align with molecular docking studies on the nitric oxide production inhibition activity of 1 and its derivatives43. The formation of a C-8 vinylic methyl group, as in 3, and 4 where the lactone ring is opened, were less active than 1. These data confirm that, since in the degradation products of 1 the strong anti-inflammatory activity is not retained, the stability of 1 in formulated medicinal products must be monitored over time to avoid diminished efficacy for the patient. In this study it was affirmed that 1 was extensively degraded under strongly basic conditions. Therefore, alkaline products of 1, such as soaps and shampoos, can be explored for other activities, recognizing that the anti-inflammatory activity of 1 will have been lost.

    Table 3 NO production and cytotoxic activity of 1 and its degradation products 26.

    The cytotoxic activities of the degradation products and 1 were assessed against the SW480 human colon cancer cell line, with the resulting IC50 values presented in Table 3. Compounds 2 and 6 exhibited no activity at the tested concentrations, in agreement with earlier studies across a selection of cancer cell lines42,43,44,45,46,47. In this investigation, the parent compound 1 was identified as the most cytotoxic with a modest IC50 value of 4.17 µM, suggesting the important role of the allylic hydroxyl lactone moiety of 1 in imparting cytotoxic effects. Compounds with a C-8 vinylic methyl group, e.g., 3, and with the lactone ring-opened, e.g., 4, demonstrated weaker cytotoxic activity compared to 1. In summary, the structural integrity of 1 is necessary for maintaining both the anti-inflammatory and cytotoxic activities in developed products.

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  • A tree that grows underneath the ground? Discover the trees that grow trunks, fruit and even flowers below the earth

    A tree that grows underneath the ground? Discover the trees that grow trunks, fruit and even flowers below the earth

    Subterranean forests are not a figment of a science-fiction writer’s imagination, but actually exist.

    The Hayward Gallery’s ‘Among the Trees’ exhibition in 2020 included a remarkable photograph by Rachel Sussman of a 13,000-year-old tree, Parinari capensis, growing beneath the red sandy soil of South Africa’s savannah. Or rather, it showed the uppermost crown, the only part of the tree in view.

    The appearance is of a small, ground-hugging shrub, rather than the full-sized tree it really is. Sometimes these strange trees cluster together – a veritable underground forest. Botanists have a theory that their extraordinary growth pattern, seen in several species of savannah tree, is a strategy to avoid wildfires. With the trunk and most branches below the surface, they survive the flames.

    Do underground trees exist?

    As well as the shrub-like Parinari capensis, two new trees species were discovered in 2023 that are nearly entirely underground.

    During a National Geographic Expeditions survey of remote Angola, Kew Gardens’ Dr David Goyder found two new tree species buried in the Kalahari sands; their flowers the only parts visible above ground. Trees known to this region have as much as 90% of their body mass deep under the surface – a smart adaptation to the arid surroundings, allowing them to access the small amount of moisture that ends up underground.

    Baphia arenicola belongs to the bean family and is named literally “growing on sand” and has white flowers. The second tree, Cochlospermum adjanyae, has bright yellow flowers and is named after Adjany Costa, an Angolan biologist and conservationist who won the UN Young Champions of the Earth Africa prize back in 2019.

    In the same year, a new palm was also discovered by Kew’s research team – this time in Borneo. The palm, Pinanga subterranea, is remarkable in its ability to flower and fruit underground. This is a phenomenon only recorded so far in one other plant group (an orchid, Rhizanthella).

    The P.subterranea‘s leaves are above ground, so can photosynthesise like other palms, but with its flowers and fruit below the surface, scientists are grappling with how it disperses its pollen.

    It’s possible that insects are carrying pollen from one palm’s flowers to another, but for now the true workings of its pollination remains a mystery!

    Discover more amazing wildlife stories from around the world

    Top image: a mature Pinanga subterranea tree in Gunung Niut Natural Reserve, West Kalimantan, Indonesia. Credit: Agusti Randi, CC BY 4.0, via Wikimedia Commons

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  • Sugarcoating hides cellular RNA from the immune system

    Sugarcoating hides cellular RNA from the immune system

    To our immune system, naked RNA is a sign of a viral or bacterial invasion and must be attacked. But our own cells also have RNA. To ward off trouble, our cells clothe their RNA in sugars, Vijay Rathinam and colleagues in the UConn School of Medicine and Ryan Flynn at Boston Children’s Hospital report on Aug. 6 in Nature.

    Ribonucleic acid (RNA) is a family of large biological molecules fundamental to all forms of life, including viruses, bacteria, and animals. Viruses as diverse as measles, influenza, SARS-CoV-2, and rabies all have RNA, which is why the immune system starts attacking when it sees RNA in the bloodstream or in other inappropriate locations. But our own cells have RNA as well, sometimes displaying it on their surface, plain for roaming immune cells to see – and yet the immune system ignores it.

    “Recognizing RNA as a sign of infection is problematic, as every single cell in our body has RNA,” says UConn School of Medicine immunologist Vijay Rathinam. The question is, how does our immune system distinguish our own RNA from that of dangerous invaders?

    Previous research led by Boston Children’s Hospital and Stanford University researchers Ryan Flynn and Carolyn Bertozzi had noticed that our bodies add sugars onto RNA. These sugarcoated RNAs (also known as glycosylated RNAs, or glycoRNAs) are displayed on the cell surface and don’t seem to provoke the immune system.

    Rathinam and his colleagues wondered whether the sugar was somehow shielding the glycoRNAs from the immune system. This could be a strategy the body uses to prevent our own RNA from provoking inflammation.

    When Vincent Graziano, a Ph.D. student in Rathinam’s lab and lead author on the paper, took glycoRNA from human cell cultures and blood, cut off the sugars, and reintroduced it into cells, the immune cells attacked it. The immune cells had ignored the same RNA when it was sugarcoated.

    The sugarcoating hides our own RNA from the immune system.”


    Vijay Rathinam, immunologist, UConn School of Medicine

    It is particularly significant to our body because cells are often covered by glycoRNAs. When cells die and are cleaned up by the immune system, the sugarcoating of RNA prevents dead cells from unnecessarily stimulating inflammation.

    The findings could help when thinking about autoimmune diseases. Certain autoimmune diseases, such as lupus, are associated with specific RNA and dead cells setting off the immune system. Now that scientists understand the role of RNA glycosylation in deflecting immune system attention, they can check on whether that strategy is somehow going awry, and, if so, how it might be fixed.

    This study was done in collaboration with the laboratories of Ryan Flynn, Thomas Carell, Franck Barrat, Beiyan Zhou, Sivapriya Kailasan Vanaja, Michael Wilson, and Penghua Wang and was funded by grants from the National Institutes of Health.

    Source:

    University of Connecticut

    Journal reference:

    Graziano, V. R., et al. (2025) RNA N-glycosylation enables immune evasion and homeostatic efferocytosis. Nature. doi.org/10.1038/s41586-025-09310-6.

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  • Detained PTI leaders condemn police action – Newspaper

    Detained PTI leaders condemn police action – Newspaper

    LAHORE: The Pakistan Tehreek-i-Insaf’s senior leaders, incarcerated in Kot Lakhpat Jail, have termed Punjab and Sindh governments’ actions of arrests and baton-charging of peaceful protesters as mockery of democracy.

    A hand-written letter signed by PTI leaders Shah Mahmood Qureshi, Dr Yasmin Rashid, Omar Sarfraz Cheema and Mian Mahmoodur Rasheed titled “Is this Democracy” was delivered here on Wednesday.

    The PTI leaders stated that a peaceful protest call was given by the party for Aug 5 but the “response of the Form-47 government showed its insecurity to the highest level.”

    In the National Assembly, the incarcerated leaders stated, the parliamentarians were locked inside on Aug 5 as they were preparing to leave for Adiala Jail. “Did the Speaker, who is the custodian of the House, ordered this atrocity or was he never taken into confidence – is this democracy,” they questioned.

    They stated that MPAs including deputy opposition leader Moeen Riaz Qureshi were arrested from Lahore, while he was leading a rally in support of Kashmir cause. “Isn’t mockery of democracy,” they asked.

    Mr Qureshi and other leaders stated that some 800 party workers and third-tier leadership were arrested from Punjab. They said PTI Punjab chief organiser Aliya Hamza’s car was destroyed by the police goons, when she took out a rally. They stated Rehana Dar was arrested along with other women workers.

    The incarcerated leaders resolved that all the PTI leaders at Kot Lakhpat Jail were standing firm with Imran Khan’s stance. “We believe in the rule of law and our Constitution,” they stated.

    Published in Dawn, August 7th, 2025

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  • Celtics’ Jayson Tatum seen without boot or brace at Patriots training camp

    Celtics’ Jayson Tatum seen without boot or brace at Patriots training camp

    Jayson Tatum hangs out with Von Miller during the Commanders-Patriots joint training camp practice.

    • Download the NBA App

    FOXBOROUGH, Mass. (AP) — Jayson Tatum was spotted at practice on Wednesday — just not on a basketball court.

    The Celtics star made an appearance at the New England Patriots’ joint training camp practice with the Washington Commanders.

    Tatum, who had surgery in May to repair the ruptured right Achilles tendon injury he suffered in Boston’s Eastern Conference semifinal loss to the New York Knicks, was seen walking without a boot or brace.

    It’s a welcomed sign for Tatum as he continues a rehabilitation that is expected to keep him out most — if not all — of next NBA season. Tatum mostly stood on the sideline during his appearance Wednesday, interacting with Patriots players and Washington quarterback Jayden Daniels.

    Tatum has been seen in multiple social media videos working out in the weight room at the Celtics’ team practice facility.

    Boston president of basketball operations Brad Stevens said in June that the All-Star is progressing well following surgery. But asked about whether the team had put a potential timeline on Tatum’s return, Stevens was definitive that there would be no rushing the star’s recovery process.

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  • Amid buzz of Asim Munir seeking presidency, here’s what Pakistan army says | World News

    Amid buzz of Asim Munir seeking presidency, here’s what Pakistan army says | World News

    Updated on: Aug 07, 2025 09:20 am IST

    The army’s response came after rumours on social media during the previous weeks that Munir plans to replace President Asif Ali Zardari.

    The Pakistan army has denied as “baseless” the rumours that army chief Asim Munir plans to become the next president.

    Army spokesperson Lt Gen Ahmed Sharif Chaudhry, in an interview with The Economist, made it clear that the army chief has no interest in the presidency (AP)

    The army’s response came following rumours and a wave of disinformation on social media during the previous weeks that Munir plans to replace President Asif Ali Zardari.

    Army spokesperson Lt Gen Ahmed Sharif Chaudhry, in an interview with The Economist, made it clear that the army chief has no interest in the presidency and no such proposal is under consideration, the state-run PTV posted on social media on Wednesday.

    “Talks about Field Marshal Asim Munir becoming the president of Pakistan are completely baseless,” he said.

    On July 10, Interior Minister Mohsin Naqvi rejected rumours regarding the possible ouster of President Zardari and termed it a “malicious campaign”.

    Get the latest headlines from US news and global updates from Pakistan, UK, Bangladesh, and Russia get all the latest headlines in one place with including Tsunami Warning Liveon Hindustan Times.

    Get the latest headlines from US news and global updates from Pakistan, UK, Bangladesh, and Russia get all the latest headlines in one place with including Tsunami Warning Liveon Hindustan Times.

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